These guidelines recommend that:
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection.
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
• All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. Use of HBIg rarely achieves HBsAg negativity, and is not recommended.
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
• HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. HBsAg positive donors should not be used for HBV/HDV co-infected recipients. A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection.
• In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
Guidelines for Hepatitis B & Solid Organ Transplantation: 1-HBV Biology and Disease: Recommendation;
–HBsAg, HBsAb (absolute titres) ,HBcAb in all solid organ transplant recipients and HBeAg, HBeAb and HDV Ab serology, and HBV DNA level (quantitative ) in all HBsAg positive patients (1B).PCR for HDV RNA only to be done in cases where HDV serology is positive or equivocal. (1B).To rule out occult HBV or HDV infection, HBV DNA and HDV serology testing should be done in patients with HBsAg negative but HBcAb positive. (1B) – 2-Indications for Transplantation for HBV-Related Disease: Acute Fulminant Hepatitis B; Recommendation;
Such patients should be managed in a specialist liver centre. (1C).Liver transplantation-option should be given to patients according to UK listing criteria defined by National Health Service Blood and Transplant (NHSBT). (1A) Suggestion;
Treatment with tenofovir or entecavir should be strongly considered. (2B) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma; Recommendation;
Treatment should be carried out in specialist liver units and antiviral treatment with NA(Entecavir and tenofovir) should be given to all decompensated cirrhosis patients with detectable HBV DNA.(1A) Suggestion;
Liver transplantation-hepatitis B cirrhosis and a United Kingdom end stage liver disease (UKELD) score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A) 3-HBV and Other (Non-Liver) Transplantation: Suggestion;
Combined transplantation should be considered . (2C) 4-Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation: Recommendation;
All HBsAg positive individuals-treatment with either tenofovir or entecavir before transplantation, achieving an undetectable HBV DNA level. (1B).However, for non-liver solid organ transplantation with positive HBsAg -liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantationshoud be done. (1B) 5-Use of HBcAb Positive or HBsAg Positive Donors: General Recommendations; Suggestion;
-The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be done. (2C) HBcAb positive donation for liver recipients; Recommendation;
-The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
HBV reactivation prevention strategy should be adopted in cases of HbsAg positive recipient and prophylactic lamivudine for an indefinite period to HBV immune or non-immune recipient. (1A) HBsAg Positive Donation for Liver Recipients; Recommendation;
-HBsAg positive donor livers can be given to following recipients i.e., HBsAg positive recipients(1C) HBsAg negative patient in urgent cases . (1D)Treatment with entecavir or tenofovir (1B) HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients; Recommendation;
-The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient.(1A) Suggestion;
Non-liver solid organs of the HBsAg positive organ donor for any recipient in urgent cases(2C) Lamivudine prophylaxis for six months after transplantation in HBcAb positive donor (2C) Transplantation and Co-Infection (HDV, HCV, HIV)
HBV/NA prophylaxis for HBV/HDV patients in such cases Post-Transplant HBV Prevention –Preventing Recurrence of HBV Post-Transplantation:
Combination therapy with Hepatitis B immunoglobulin and/or a potent NA should be started from the time of transplantation.(1B)
Either prophylactic antiviral treatment for 6-12 months or close monitoring for HBV recurrence can be considered for past HBV infection (HBcAb positive alone) in post-non-liver transplant patients.(2B) Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation:
Lifelong antiviral therapy with Entecavir or Tenofovir is recommended. Resistance testing from specialized laboratory should be considered.(1B) Monitoring for HBV Recurrence or De Novo Infection: Recommendation;
HBsAg positive liver transplant recipients or recipient with HBcAb positive donor-Monitoring every three months for the first year and then every six months.(1C) HBV Vaccination and Solid Organ Transplantation: Recommendation;
Vaccination should be done for all solid organ transplant recipients who are HBV naïve(1C)
Second series or booster should be considered for those whom initial series failed. (2C)
Hepatitis B Virus (HBV) is a hepatotrophic DNA virus that belongs to the Hepadnaviridae family of viruses.
Infect 257 million people worldwide, an estimated 600,000 deaths every year through complications of end stage liver disease and HCC.
The majority of chronic HBV infection result:
Vertical transmission from mother to child.
Or horizontal transmission through unsafe medical practice.
Patient age at the time of initial infection with HBV is a major determinant of whether the infection becomes chronic.
Infection in infants results in chronic infection in up to 90% of cases, whereas approximately 30% of children infected before the age of five develop chronic infection.
Adult-to-adult transmission can also occur through sexual, nosocomial or blood borne transmission, In adult cases only, less than 10% progress to chronic. Virology and Phases of Infection:
HBV has a partly circular double stranded DNA genome.
When partially circular DNA is transported to the nucleus. Here is it converted to covalently closed circular DNA (cccDNA). This forms the template for the production of virions and on-going infection. HBV 4 phases:
1. HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
During the first 20-30 years of life if the infection is acquired in infancy or early childhood,
HBeAg positive and HBeAb negative with HBV DNA viral loads generally >107 log IU/mL.
The ALT level is in the normal range and liver biopsy (if performed) shows no or minimal inflammation or fibrosis.
Treatment is rarely indicated for such patient.
2-HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” or “immune active” or “immune elimination phase”).
HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive chronic infection are.
There is immune-mediated damage to the liver with resultant inflammation and fibrosis that can progress to cirrhosis in those with prolonged, unrecognized inflammation.
This phase is often asymptomatic, although it can lead to hepatic decompensation or acute liver failure (ALF) in those with underlying cirrhosis.
Antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis.
3-HBe Antigen Negative Chronic Infection (previously called “inactive phase”). This phase is characterized by HBeAg negativity, HBeAb positivity with normal ALT levels and HBV DNA levels being.
Individuals who undergo later HBeAg seroconversion have a much higher likelihood HCC AND CIRRHOSIS. Patients do not generally require therapy, FOLLOW UP (25% RISK).
4. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).
Result of mutations in the basal core promoter and/or the pre-core region of the pre C/C gene [These HBV DNA levels >2000 IU/mL and frequently >20,000 IU/mL,
Serum ALT levels are raised and can fluctuate significantly.
Resultant liver damage can progress rapidly towards cirrhosis and HCC.
Antiviral therapy forms the cornerstone. Serological and Virological Testing:
HBsAg and HBV ab, HBC antibody, HBV DNA. Reactivation of HBV:
HBV reactivation is defined as the reappearance of markers of active HBV replication in a patient with previously controlled HBV infection, or an increase in levels of replication compared to previous levels.
Reactivation may be asymptomatic or associated with a flare of hepatitis in previously minimal or inactive disease, manifesting clinically with acute hepatitis, which can progress to acute liver failure and even death if untreated.
Initial profile: Reactivation profile
HBsAg HBc Ab HBV DNA
Positive Positive not detected HBV DNA detectable >100 IU/mL, confirmed on 2 sample
Positive Positive detected ≥2 log increase in HBV DNA levels from baseline levels HBV DNA with level ≥100,000 IU/mL (if no baseline HBV DNA level available).
Negative Positive Not Detected HBsAg positive/HBV DNA detectable.
Negative Positive Detected (Occult) HBsAg positive/increase in HBV viral load (≥2 log).
Hepatitis Delta Co-Infection:
Hepatitis delta (HDV) is a hepatotrophic replication deficient single stranded.
A diagnosis of past or current HDV co-infection is dependent on the finding of serum HDV IgG positivity. Active HDV co-infection is confirmed by HDV RNA positivity.
. In cases of HDV co-infection where HBV DNA levels are above 2000 IU/mL or fluctuate above this level, it is generally recommended that HBV replication is inhibited with nucleoside analogues. Recommendations: Recommend that:
1-HBsAg, HBsAb (absolute titres) and HBc Ab in all SOT recipient.
2-All HBsAg positive patients undergoing transplant tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
3-All recipients found to be HBcAb positive, HBsAg negative must have HBV DNA and HDV serology
• All donors who are positive for HBcAb. HBsAg negative (past HBV, must have HBV DNA testing. Acute Hepatitis B:
95-99% of adults who acquire AHB) will recover spontaneously
One% of cases of AHB progress to fulminant hepatitis, high mortality rate (up to 80%), often require OLT .
Antiviral treatment is indicated in:
• Fulminant hepatitis B
• Severe AHB – based on the presence of at least two of the following criteria:
– Bilirubin >100 µmol/L
– International normalized ratio (INR) ≥1.6
– Hepatic encephalopathy
• Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
• Immunocompromised host. LAM is controversy
The current EASL guidelines on treatment of AHB recommend the use of ETV (0.5 mg/day) or TFV
(245 mg/day). Therapy should be continued for at least three months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss.
Liver transplantation should be considered in all patients with fulminant hepatitis:
Hepatic encephalopathy and:
• Prothrombin time >100 seconds or INR >6.5 or
– Any three from: – age >40 or <10 years – jaundice to encephalopathy time >7 days – serum bilirubin >300 µmol/L – prothrombin time >50 seconds or INR >3.5. Chronic Hepatitis B:
Current treatment guidelines consider NAs or PEGylated-interferon (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis. Decompensated Cirrhosis: Guidelines recommend starting oral NAs for patients with decompensated cirrhosis, irrespective of serum ALT, HBV DNA and e antigen status. TFV and ETV are currently the first-line agents, with greater potency and higher barrier to resistance. ETV dose for patients with decompensated cirrhosis is 1 mg once daily (instead of 0.5 mg for patients with compensated liver disease).
OLT should be considered. List patients with a MELD >15 (or UKELD equivalent approximately 55).
Criteria which must be satisfied for consideration of OLT in the UK include:
1. A projected one year liver disease mortality without transplantation of >9%, predicted by a United Kingdom Model for End-Stage Liver Disease (UKELD) score of ≥ 49 . 2. A variant syndrome (e.g. diuretic resistant ascites or chronic hepatic encephalopathy) in those with a UKELD of 49. HCC:
Common with HBV 50-55%.
Risk is more with high viral load; NS reduce incidence plus regular surveillance 6, months, with abdominal ultrasound.
Surgical resection is the first line treatment for patients with solitary HCC and well-preserved liver function. Resection or radiofrequency ablation may be curative options for smaller lesions.
Liver transplantation for HCC is a well-established treatment option.
Management of SOT Recipient with CHB or Past HBV CHBV and past HBV are not contraindications for solid organ transplantation.
Such patients must be referred to a specialist in viral hepatitis
Recommendations:
We suggest that
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION: Liver Transplantation:
Patients presenting with decompensated cirrhosis from HBV may regain liver function with effective viral suppression, thus avoiding the need for transplantation .The risk of recurrent HBV after OLT is low with effective viral suppression before transplant. Non-Liver Solid Organ Transplantation:
HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
USE OF HBCAB ANTIBODY POSITIVE OR HBSAG POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION:
General Recommendations
We suggest that:
• The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis.
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection.
Donors with HBC Ab high risk of transmission HBV to recipient, even if HBsAg negative. Core Antibody Positive Donation for Liver Recipients:
HIGH risk of DE novo HBV infection HB infection, risk more with naïve recipient.
Prophylaxis from the time of liver transplantation can reduce the risk of de novo infection.
Lamivudine is the most cost-effective approach to prophylaxis, prevents most de novo infection
The ideal recipient of the core antibody positive donation is the HBsAg positive recipient.
Recommendation that:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. • When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted
• When the liver comes from an HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
Suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver:
1. The HBsAg-positive recipient
2. The HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. The HBV non-immune recipient,
HBsAg Positive Donation for Liver Recipients:
May be considered for any recipient, including non-immune HBsAg negative recipients.
HBV/HDV co-infected livers not to be used, also not suitable for HBV/HDV co-infected recipient.
Use of oral antivirals (entecavir or tenofovir) in HBsAg Recipients from the time of transplantation will prevent HBV-related graft damage, and should be continued indefinitely.
The HBV-immune recipient may be the preferred recipient of an HBsAg positive liver donation with use of antiviral.
We recommend that:
• HBsAg positive donor livers can be given to HBsAg positive recipients as long as the recipient is known to be HDV negative.
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
• Use of HBIg rarely achieves HBsAg negativity, and is not recommended.
HBsAg Positive Donation for Non-Liver Recipients,Core Antibody Positive Donation for Non-Liver Solid Organ Recipients
Recommendations
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
We suggest that:
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualized assessment of risk and benefit. (2C)
• When an HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
MANAGEMENT OF CO-INFECTION (HDV, HCV, HIV) IN THE LIVER TRANSPLANT RECIPIENT : Management of HBV/HDV Co-Infection: The only available antiviral therapy for HBV/HDV co-infection is alpha interferon, but response rates are disappointing, and are further reduced in patients with cirrhosis.
HDV/HBV infection is unresponsive to treatment with nucleoside analogues.
HDV-infected liver recipients should receive antiviral prophylaxis that includes the use of HBIg from time of transplantation for a period of 12-24months.
There is no proven effective treatment for recurrent (or acquired) graft HBV/HDV infection, and rapid progression to cirrhosis is likely. Management of HBV/HCV Co-Infection:
HCV-infected potential liver transplant recipients will be successfully treated with DAAs before or following liver transplantation.
HBV antiviral protocols for the management of HBV infection in the recipient, and protocols for the use of core antibody positive or HBsAg positive donations are unaffected by the presence of HCV co-infection. Management of HBV/HIV Co-Infection:
The multidisciplinary team before transplantation should agree a plan for the peri-operative management of each of the HIV and HBV infections.
• HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the perioperative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection.
PREVENTING RECURRENCE OF HBV POSTTRANSPLANTATION: Hepatitis B Surface Antigen Positive Recipients:
Pretransplant: Antiviral treatment .either TEV OR ENT.
Following transplantation, prophylactic treatment of HBV recurrence should be with a combination of HBIG and NA antivirals.
Low risk of HBV recurrence, i.e. Antigen negative and HBV DNA negative at time of transplant, early HBIG withdrawal and maintenance with NA monotherapy can be considered.
HBV/HDV co-infected patients in these patients, HBIG prophylaxis should continue for longer. Hepatitis B Core Antibody Positive Recipients:
Managed same as HB sag patient. In general, there is evidence for prophylactic treatment, with lamivudine being the most studied, Entecavir has also been studied with good efficacy in the setting of rituximab treatment. Hepatitis B Core Antibody Positive Donors:
Risk is more with liver transplant, so and vaccination of recipient is recommended. Prophylaxis is is needed. Either LAM entecavir or TFV could be used.
HBcAb positive organs are also used in other non-liver transplantation such as kidney or heart. The risk reduced with Pre-transplant vaccination against HBV potentially offers enough protection, although some centers use LAM. For 12 months.
Hepatitis B Surface Antigen Positive Donors:
Organs from donors chronically infected with HBV are not routinely used at present.
However, single-center case series exist of HBsAg positive donor livers used either in patients who are HBsAg positive with HBV-related liver disease or in HBcAb positive recipients. Adequate antiviral treatment plus HBIG. TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION:
More common in HBsAg negative and HBC AB NEGATIVE PATEINT.
Risk:
HBcAb donors.
FAILURE OF AVCCINATION.
HCC and HIV.
Detectable HBV DNA levels at the time of transplantation.
Immunosuppression.
Entecavir and/or tenofovir post-transplant, both were demonstrated to be safe and effective in prophylaxis treatment.
Recommendations:
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory.
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
• Entecavir or tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST LIVER TRANSPLANTATION:
Recommendations:
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from an HBcAb positive donor, regardless of treatment or prophylaxis regimen.
• Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION:
Recommendation:
Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice.
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are 100 IU/mL, then vaccination should be considered to boost the protective titer of HBsAb and minimize the risk of reactivation.
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule.
• In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
Guidelines forHepatitis B & Solid Organ Transplantation
Chapter 3: HBV Biology and Disease
We recommend that:
1- All patients must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
2- All HBsAg positive patients must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
3- HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
4- Any potential recipients with HBcAb +ve but HBsAg -ve (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
5- All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
==========================================================
Chapter 4: Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B
We recommend that:
1- Individuals with fulminant liver failure must be managed in a specialist liver centre. (1C)
2- Liver transplantation must be considered in patients with fulminant hepatitis B. (1A)
We suggest that
1- treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
We recommend that:
1- Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units. (1C)
2- in Individuals with decompensated cirrhosis and detectable HBV DNA Entecavir and tenofovir are the first line antiviral agents (1A).
We suggest that
1- Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A).
======================
Chapter 5: HBV and Other (Non-Liver) Transplantation.
We suggest that
1- Patients with advanced HBV-related liver disease requiring another organ transplant
be considered for combined transplantation . (2C)
==============================
Chapter 6: Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
We recommend that:
1- All HBsAg positive individuals being considered for liver transplantation should be
treated with either tenofovir or entecavir . (1B)
2- Individuals undergoing non-liver solid organ transplantation should be treated by either tenofovir or entecavir . (1B)
=================================
Chapter 7: Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
We suggest that:
1- The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
2- All potential recipients should be counselled during the assessment process about the receiving a liver from a HBV infection patient.
========== HBcAb positive donation for liver recipients
We recommend that:
1- The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
2- When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
3- When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be continued indefinitely. (1A)
We suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver
should be allocated in the following order:
1- the HBsAg-positive recipient
2- the HBV-immune recipient .
3- the HBV non-immune recipient. (2C)
=========== HBsAg Positive Donation for Liver Recipients
We recommend that:
1- HBsAg positive donor livers can be given to HBsAg positive recipients. . (1C)
2- If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
3- All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
4- Use of HBIg not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
We recommend that:
1- The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient . (1A)
We suggest that:
1- If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient. (2C)
2- When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation. (2C)
=============================
Chapter 8: Management of Co-Infection (HDV, HCV, HIV) and Transplantation
We recommend that:
1- HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
2- HBsAg positive donors should not be used for HBV/HDV co-infected recipients.(1C)
3- A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
4- HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
We suggest that:
1- For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA
prophylaxis can be considered, but not within 12 months of transplantation. (2C)
========================
Chapter 9: Preventing Recurrence of HBV Post-Transplantation
We recommend that:
1- In HBsAg positive individuals deemed to be at high risk of recurrence,
combination therapy with HBIg and/or a potent NA is recommended . (1B)
We suggest that:
1- Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in low risk patients . (2C)
2- Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence . (2B)
3- Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a prophylactic antiviral treatment . (2B)
=============================================
Chapter 10: Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
We recommend that
1- All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. (1C)
2- Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
3- Entecavir or Tenofovir are recommended as first line treatment . (1B)
====================================
Chapter 11: Monitoring for HBV Recurrence or De Novo Infection
We recommend that
1- HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months . (1C)
2- Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
==================================
Chapter 12: HBV Vaccination and Solid Organ Transplantation
We recommend that
1- All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
We suggest that
1- Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
2- Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
3- All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
4- In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
Summarize the guidelines; Introduction;
According to this guidance every recipient should be screened for HBsAg, for further confirmation DNA PCR should be done to rule out occult infection. Indication of transplantation;
NHSBT criteria should be considered for fulminant HBV associated hepatitis.
Indicated to treat with antiviral medication. Decompensated HBV infection with cirrhosis and HCC;
With compensated liver disease and cirrhosis antiviral with Entecavir/ tenofovir should started as soon as possible.
Should consider to transplant combine with liver and kidney. Pre-transplant management;
The copies are important to proceed for transplantation, and the treatment should be considered with lowest level of viral copies then proceed for transplantation.
The treatment choice are Tenofovie and Entecavir.
If a recipient is considered for HBV positive DONOR, should be counseled before proceeding.
If only HBc-Ab positive should be started with Limuvidine before transplantation to prevent re-activation. HBc-Ab, HBs-Ag positive donation;
The risk of de novo HBV infection is low for non liver organ donation. Prevention of recurrence of HBV post-transplantation;
If a recipient is negative its recommended HBIG and NA in then early withdrawal if low risk patient, if high risk patient its recommended to give lifelong NA plus HBIG therapy. HBV recurrence of de novo;
Recommended to continue life long treatment. HBV vaccination and SOT:
Recommended should be vaccinated and documented Pre-transplant. Indication for transplantation for HBV-infected patient; Acute hepatitis B infection;
Recommended to treat if Bilirubin is >100umol, INR >1.6, as it has better and early recovery, and better survival.
The current guidelines recommend early treatment for acute cases with Entecavir 0.5mg/day, Tenofovir 145mg/D. therapy should be continued for at least 3 months, however, there is no such consensus for duration treatment.
If fulminant hepatitis, liver transplantation should be considered.
Poor prognosis if untreated. Hepatocellular carcinoma;
The literature says there are >500,000 diagnosed new cases annually, and this is the fifth most common cancer worldwide. Incidence; it accounts for around50-60% of HCC.
. Cirrhosis of liver 70-90%.
Impact of transplantation on HBV;
Immunosuppressive drugs increases risk of HBV replication, drugs does suppress immune system and worsened the risk. Impact of HBV infection on transplant outcomes;
In immunocompromised patients the infection is associated with rapid progression and increase risk of HCC in recipient.
British Transplantation Society Guidelines for Hepatitis B & Solid Organ Transplantation-
HBV Biology and Disease
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb.
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
• Any potential transplant recipients/donor found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Decompensated Hepatitis B Cirrhosis
Hepatocellular Carcinoma
HBV and Other (Non-Liver) Transplant
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit.
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection.
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation
Preventing Recurrence of HBV Post-Transplantation
• In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. • Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence.
Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
All patients with HBV recurrence post-liver/kidney transplant should have a careful review of adherence with NA prophylaxis.
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver /kidney transplantation.
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure
Monitoring for HBV Recurrence or De Novo Infection
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver/kidney transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
HBV Vaccination and Solid Organ Transplantation
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation.
We recommend that:
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
We recommend that:
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT.
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
We recommend that:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
We recommend that:
• All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors General
Recommendations
We suggest that:
• The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients
We recommend that:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
• When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
• When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation and should be continued indefinitely. (1A)
HBsAg Positive Donation for Liver Recipients
We recommend that:
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
• Use of HBIg rarely achieves HBsAg negativity and is not recommended. (1C)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
We recommend that.
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
Monitoring for HBV Recurrence or De Novo Infection We recommend that.
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
• Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
HBV Vaccination and Solid Organ Transplantation We recommend that.
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Guidelines for Hepatitis B & Solid Organ Transplantation
This guideline is the first British Transplantation Society (BTS) guideline on the management of hepatitis B in the transplant setting.
Tests for HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. – Any potential transplant recipients and donor found to be HBcAb positive but HBsAg negative must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. -Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre and liver transplantation must be considered . – Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. – Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. We suggest that – Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. -Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. -All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. – Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. -All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. -The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. -When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. -If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order: 1. the HBsAg-positive recipient 2. the HBV-immune recipient . 3. the HBV non-immune recipient. -HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. – If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. -All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. -The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. -When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation . – HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. -HBsAg positive donors should not be used for HBV/HDV co-infected recipients. -A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. -Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected. -Recipients with HBcAb positive alone are at risk of HBV reactivation post-non-liver transplant and could be considered for 6-12 months course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. – Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. -HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. – All prospective solid organ transplant recipients who are HBV naive must be vaccinated and the response documented. -Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. -Renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered . -In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
EXECUTIVE SUMMARY OF RECOMMENDATIONS Recommendation: All patients being prepared for SOT should be sreened for HBsAg, HBsAb (absolute titers) and HBcAb, as well as testing for HBV DNA and HDV RNA to rule out occult HBV or HDV infection.
Indications of Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B Recommendation: Liver transplantation should be considered in patients with fulminant hepatitis B – (NHSBT criteria). Suggestion – Early antiviral treatment with nucleoside analogues to improve AHB survival. Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma Recommendation: Decompensated cirrhosis due to Hepatitis B (DNA positive) à urgent antiviral treatment with Entecavir or Tenofovir.
Suggestion – Listing for liver transplant for patients with UKELD score >49. HBV and Other (Non-Liver) Transplantation Suggestion – Advanced HBV-related liver disease should consider combined transplantation. Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation Recommendation: HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels. Use of HBcAb Positive or HBsAg Positive Donors General Recommendations Suggestion – potential recipients should be counselled about the possibility of receiving a liver from a donor with HBV infection. HBcAb positive donation for liver recipients Recommendation: Prophylactic lamivudine from the time of transplantation to prevent HBV reactivation. Suggestion – Anti-HBc positive donor liver should be allocated in order of priority. HBsAg Positive Donation for Liver Recipients Recommendation: HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir. HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients Recommendation: The risk of de novo HBV infection is low for organ donors.
Suggestion – HBcAb-positive donor organs can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation. Management of Co-Infection (HDV, HCV, HIV) and Transplantation Recommendation: HBV/HDV recipients should receive combination HBIg + NA prophylaxis from the time of transplantation; HBsAg-positive donor should not be used. Suggestion – HBIg withdrawal from combination HBIg-NA prophylaxis can be considered, but not within 12 months of transplantation. Preventing the Recurrence of HBV Post-Transplantation Recommendation: HBIg + NA recommended to prevent HBV reinfection post-liver transplant.
Suggestion – low risk recipients à Early withdrawal of HBIG or HBIG-free prophylaxis High risk recipients à life-long combination therapy with HBIG + NA HBV Recurrence or De Novo Hepatitis B after SOT Recommendation: Treatment – Lifelong antiviral therapy is recommended Monitoring – 3monthly for 1year, then every 6month thereafter at shorterintervals in cases of non-adherence.
HBV Vaccination and Solid Organ Transplantation Recommendation: Prospective SOT recipients must be vaccinated and documented. Suggestion – development of protective serum titres of HBsAb; those who fail to respond should be administered a second series of vaccine.
HBV BIOLOGY AND DISEASE Introduction – HBV is a major human pathogen, infecting about 257 million people worldwide; causing 600,000 deaths every year. – It is transmitted through blood and blood product transfusion, sexual or vertical transmission or through unsafe medical practice. – Patient age at the time of initial infection is a major determinant chronicity of infection. Virology and Phases of Infection HBV is not directly hepatotoxic; complex interaction with the host immune system drives the hepatic inflammation-fibrosis-cancer axis. 1. HBeAg positive Chronic Infection (“non-inflammatory” or “immune tolerant phase”) – Treatment is rarely indicated for HBeAg-positive and HBeAb-negative patients with HBV DNA viral loads >107 IU/mL
2. HBeAg positive Chronic Hepatitis (inflammatory /immune active /immune elimination phase) – characterized by a persistent or intermittent elevation in ALT and fluctuating HBV-DNA levels, leading to inflammation and fibrosis that can progress to cirrhosis.
Antiviral therapy is indicated if prolonged or there is evidence of significant liver fibrosis. 3. HBeAg Negative Chronic Infection (inactive phase) – characterized by negative HBeAg, HBeAb positive, normal ALT levels; – HBe seroconversion determined by age and HBV genotype. Antiviral therapy can also result in HBeAg seroconversion. – Regular follow-up is mandatory as reactivation and development of HBeAg-negative chronic hepatitis occurs in 25%. 4. HBeAg negative Chronic Hepatitis (immune escape phase) – Mutations in the pre-C/C gene can lead to increased HBV-DNA levels, resulting in liver damage and HCC.
– Antiviral therapy is the cornerstone of management. Serological and Virological Testing Testing for HBV surface antigen (HBsAg) and core antibody (HBcAb) is important for diagnosis and veracity of the host immune response. Reactivation of HBV – HBV reactivation varies depending on baseline HBV status, underlying condition, type of immunosuppressive therapy, and host immunity. Hepatitis Delta Co-Infection – HDV is a hepatotropic replication-deficient single-stranded covalently closed circular RNA virus. It uses the HBV replication-machinery for its replication. Recommendation: All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb, and HBcAb; potential transplant recipients must have HBV-DNA and HDV serology (PCR) testing to exclude occult infection.
INDICATIONS FOR TRANSPLANTATION FOR HBV-RELATED DISEASE Acute Hepatitis B Antiviral treatment indicated in Acute hepatitis B (AHB) if Bilirubin >100 µmol/L and INR ≥1.6. Prompt antiviral administration shorten disease duration, promote recovery, improve survival. A case series of 17 patients with severe or fulminant AHB showed that Lamivudine (LAM) administered until HBsAg clearance improved survival compared to historical, untreated controls (82.4 vs. 20%; p<0.001). – However, the evidence for LAM has not been universally positive. – Current EASL guidelines on the treatment of AHB recommend Entecavir (ETV) 0.5 mg/day or Tenofovir (TFV) 245 mg/day. Antiviral treatment should be started early in the course of severe AHB, without waiting for the development of fulminant hepatitis. Delayed initiation of NAs is associated with higher mortality or requirement for transplant There are limited data on duration of antiviral treatment in AHB, but therapy should be continued for at least 3months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss. Liver transplantation should be considered in all patients with liver failure related to hepatitis B – (withhepatic encephalopathy, prothrombin time >100 seconds, INR >6.5). Recommendation: Liver transplantation must be considered in patients with fulminant hepatitis B infection. Suggestion – early antiviral treatment with nucleoside analogues can improve AHB survival. Chronic Hepatitis B (CHB): Aim of treatment in CHB is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death. NAs or PEG-IFN are first-line therapy in patients with higher HBV DNA levels. Decompensated Cirrhosis: · 5-year cumulative incidence of hepatic decompensation for untreated CHB-associated cirrhotic patients is approximately 20%. · Untreated patients with have poor prognosis – 5-year survival 14-35%, compared to 84% in compensated state. · Decompensated HBV cirrhosis is declining as an indication for transplantation, due to success of HBV vaccination and potent oral antiviral agents. · Objectives of Antiviral treatment: improvement of liver function and decreased risk of HBV recurrence after transplantation. · TFV and ETV are currently the first-line agents, with greater potency and higher barriers to resistance. NAs have a good safety profile in patients with advanced liver disease, and a phase 2 double-blind study compared the safety of TFV and ETV in decompensated HBV cirrhosis. – Serious side effects due to mitochondrial toxicity, can manifest as lactic acidosis, myopathy, neuropathy, hepatotoxicity. – Treatment-naive patients with ETV (0.5 mg/day) showed significant improvement in CTP and MELD scores, but not all patients improved with ETV. · Studies are on way to identify prognostic indicators that could help to stratify 2 distinct subgroups – patients who will experience prolonged survival with antiviral therapy and those who require OLT. Hepatocellular Carcinoma HCC is the 5th most common cancer worldwide; >500,000 new cases diagnosed annually. Incidence and Risk Factors – HBV is the leading risk factor for HCC globally, accounts for 50-60% of HCC.
– 70-90% HCC develops in cirrhotic livers, although HBV can cause HCC in the absence of cirrhosis
· Several factors are known to increase the risk of HCC among individuals with HBV infection, including demographic, viral, clinical, environmental, and HBeAg status.
· The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study from Taiwan showed that HCC increased in proportion to viral load.
Surveillance· HCC surveillance is necessary even if HBV DNA is suppressed, with six-monthly abdominal ultrasound scans recommended. Treatment· Treatment of HCC related to HBV is based on size, number of lesions, and serum AFP concentration.
· Salvage transplantation is an option if listing criteria are fulfilled.
· Non-cirrhotic patients with non-resectable HCC should be considered for OLT in the absence of macrovascular invasion and extra-hepatic spread. Recommendation: Individuals with decompensated cirrhosis and detectable HBV DNA need urgent antiviral treatment with NA(s). Suggestion· Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and HCC. HEPATITIS B AND OTHER (NON-LIVER) TRANSPLANTATION Introduction: HBV infection is a major risk factor for hepatic dysfunction in SOT recipients, leading to progressive liver damage, morbidity and mortality. Impact of Transplantation on HBV: Immunosuppressive agents can modify the natural history of HBV infection through disruption of the host immune response and enhanced replication.
– Immunosuppressive drugs (net immunosuppression) promote HBV replication, when used in combination with other drugs. Impact of HBV Infection on Transplant Outcome: HBV infection is associated with more frequent and rapid progression to cirrhosis and hepatocellular carcinoma in SOT recipients, leading to higher mortality.
Prevalence of HBV Infection in SOT: Chronic HBV infection in SOT recipients varies according to geographical regions – CHB prevalence ranging from 2-20%; past HBV prevalence generally higher than CHB. Risk of HBV Infection in the SOT Recipient: Post-transplant anti-HBsAb monitoring is not recommended. Management of SOT Recipient with CHB or Past HBV: HBV infection and CHB are not contraindications for solid organ transplantation. Non-Liver SOT Recipients with Advanced Liver Disease: Patients with an advanced liver disease requiring transplantation of non-liver organs should be assessed by multidisciplinary team to consider combined transplantation Suggestion – advanced HBV-related liver disease should consider combined transplantation. PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION Non-Liver Solid Organ Transplantation – Patients should be screened for hepatitis B carriage and pre-transplant suppression should be given with tenofovir or entecavir to avoid the progression of liver disease. Recommendation: HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels. USE OF HBCAB ANTIBODY-POSITIVE OR HBSAG-POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION Introduction: The use of solid organs from donors with core antibodies can transmit HBV infection to the organ recipient, with the risk of transmission being high for liver transplantation and lower for kidney and thoracic organs. Suggestion – Potential recipients should be counselled about the possibility of receiving a liver from a donor with HBV infection. Core Antibody Positive Donation for Liver Recipients De novo HBV infection is associated with core antibody-positive liver donation and is dependent on the recipient’s HBV immune status. Lamivudine is the most cost-effective approach to prophylaxis, prevents most de novo infections, and should be given indefinitely. Recommendation: Prophylactic lamivudine should be given from the time of transplantation to prevent HBV reactivation. Suggestion – The hepatitis B core antibody-positive donor liver should be allocated in order of priority. HBsAg Positive Donation for Liver Recipients· HBsAg positive liver donation is suitable for non-immune HBsAg negative recipients, but not for HBV/HDV co-infected recipients.
Recommendation: HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir. Core Antibody Positive Donation for Non-Liver Solid Organ Recipients Donation of non-liver solid organs from core antibody-positive donors is rarely associated with de novo infection, making antiviral prophylaxis ineffective. HBsAg Positive Donation for Non-Liver Recipients· Antivirals should be used to suppress HBV after transplantation, and long-term monitoring should be provided to prevent chronic infection. Recommendation: The risk of de novo HBV infection is low. Suggestion: HBcAb-positive organ donors can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation. PREVENTING THE RECURRENCE OF HBV POST-TRANSPLANTATION Introduction: Hepatitis B virus (HBV) recurrence after liver transplantation is defined as the reappearance of circulating hepatitis B surface antigen (HBsAg), with or without detectable HBV DNA. Without appropriate prophylactic treatment, HBV recurrence is almost universal. – Prophylactic treatment with HBIG and NA has reduced graft reinfection rates and HBV-related liver disease is now a well-accepted indication for liver transplantation. Hepatitis B Surface Antigen Positive Recipients – Prevention of post-transplant HBV recurrence in HBsAg-positive patients begins before transplantation with antivirals, such as nucleo(t)side analogues (NA) such as entecavir or tenofovir. – Combination therapy with NA antivirals is recommended. Early HBIG withdrawal and maintenance with NA monotherapy is effective and safe, but not appropriate for high-risk patients. – HBIG-free NA prophylaxis can be considered in low-risk recipients, but more robust evidence is needed. Hepatitis B Core Antibody Positive Recipients – HBcAb positivity, with or without HBsAb, with negative HBsAg and negative HBV DNA is indicative of past HBV infection and should be managed in the same way as HBsAg positive patients. Hepatitis B Core Antibody Positive Donors – Pre-transplant vaccination against HBV can reduce the risk of de novo hepatitis B, with lamivudine being the most widely used. Hepatitis B Surface Antigen Positive Donors – Organs from donors chronically infected with HBV are not routinely used, but single-center case series exist of HBsAg-positive donor livers used in patients with HBV-related liver disease or HBcAb-positive recipients, with no differences in graft or patient survival and no episodes of graft dysfunction. Recommendation: Combination therapy with HBIg and NA is recommended to prevent HBV reinfection post-liver transplant.
Suggestion – Early withdrawal of HBIG or HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence, and life-long combination therapy with HBIG and NA can be given to those at high risk. TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION Introduction· Hepatitis B recurrence after liver transplantation is associated with biochemical or clinical evidence of active disease and can occur in those without prior CHB (HBcAb negative).
· The risk of developing de novo hepatitis B in recipients depends on their hepatitis B serological status and prophylactic measures used. Review of Literature Treatment should be started at diagnosis to control viral replication and stabilize graft function, based on prior treatment and prophylaxis history. E Entecavir and tenofovir are safe and effective in prophylaxis treatment, but not recommended in patients previously treated with lamivudine. Recommendation: Lifelong antiviral therapy is recommended for HBV recurrence or de novo hepatitis B post-liver transplantation. MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST-LIVER TRANSPLANTATION Introduction: Monitoring post-transplant patients to detect HBV infection in a timely manner. Review of Literature – Monitoring of virological, serological, and clinical markers of infection post-transplantation is essential to evaluate prophylaxis efficacy. – Non-adherence increases the risk of recurrence, so monitoring should consist of both HBV DNA quantification and HBsAg testing. Recommendation: Monitoring intervals should be shortened in cases of non-adherence. HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION Rationale: Vaccination is important to protect solid-organ recipients from HBV infection.
Renal Transplantation – HBV infection renal transplant recipients, is associated with high all-cause mortality and graft loss. HBV vaccination is recommended in HBV seronegative patients with ESRD, to increase the use of HBcAb-positive kidneys and reduce the risk of reactivation. Timing of Vaccination HBV vaccination is highly immunogenic in healthy individuals but is less effective in patients with organ failure and immunosuppressed. Vaccination should be considered early in the course of the disease, as the response to the HBV vaccine is suboptimal in pre-transplant and post-transplant periods. Vaccination Method The usual vaccination schedule is three intramuscular doses of the HBV vaccine, but higher-dose formulations are available for end-stage renal disease.
INTRODUCTION: HBV Biology and Disease: Recommendations:
All patients waiting for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb. (1B)
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C) Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B: Recommendations:
Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver center. (1C) Suggestions:
As early antiviral treatment with nucleotide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma: Recommendations:
Decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C) Suggestions:
Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A) HBV and Other (Non-Liver) Transplantation:
Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C) Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation: Recommendations:
All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B) Use of HBcAb Positive or HBsAg Positive Donors: General Recommendations: Suggestions:
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C) HBcAb positive donation for liver recipients: Recommendations:
When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A) Suggestions:
Hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient
3. the HBV non-immune recipient. (2C) HBsAg Positive Donation for Liver Recipients: Recommendations:
HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B) HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients: Recommendations:
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A). Suggestions:
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C) Management of Co-Infection (HDV, HCV, HIV) and Transplantation: Recommendations:
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C) Suggestions:
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation: Recommendations:
HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B) Suggestions:
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2)
INDICATIONS FOR TRANSPLANTATION FOR HBV RELATED DISEASE:
Acute Hepatitis B:
Indications of antiviral therapy:
A. Fulminant hepatitis B
B. Severe AHB – based on the presence of at least two of the following criteria: – bilirubin >100 µmol/L – international normalized ratio (INR) ≥1.6 – hepatic encephalopathy
C. Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
D. Immunocompromised host
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma:
Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units with antiviral therapy and possible liver transplantation. (1C)
Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A) HEPATITIS B AND OTHER (NON-LIVER) TRANSPLANTATION:
Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION:
All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
USE OF HBCAB ANTIBODY POSITIVE OR HBSAG POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION:
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded). HBcAb positive donation for liver recipients:
The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
prevention of HBV reactivation, if liver from a + HBcAb donor and is given to an HBsAg + recipient. (1B)
When the liver comes from a HBcAb + donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A) HBsAg Positive Donation for Liver Recipients
HBsAg (+) donor livers can be given to HBsAg (+) recipients, as long as the recipient is known to be HDV (-). (1C)
If urgency demands, the HBsAg (+) liver can be given to an HBsAg (-) patient. (1D)
All recipients of a liver from an HBsAg (+) donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
Use of HBIg rarely achieves HBsAg (-), and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart and lungs from the HBcAb (+) organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A).
If need demands, the non-liver solid organs of the HBsAg (+) organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C).
When a HBcAb (+) donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C). MANAGEMENT OF CO-INFECTION (HDV, HCV, HIV) IN THE LIVER TRANSPLANT RECIPIENT:
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation. (1C)
HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
A plan for the peri-operative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the perioperative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 24 months of transplantation. (2C) PREVENTING RECURRENCE OF HBV POSTTRANS:
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C).
Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma, or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B). TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION:
All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
Entecavir or tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B) MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST LIVER TRANSPLANTATION:
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C).
Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded). HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION:
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are
<100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C).
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
All potential recipients need HBsAg , anti HBc, anti HBs AB
all HBsAg positive recipient must have HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
both donor and recipinet with past infection ,(based on HBsAG negative , anti HBc AB positive serology ) should have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection
Acute fulminant hepatitis and decompensated cirrhosis sholud be managed in specialist liver centre with use of anti viral drugs tenofovir/ entecavir and listed for liver transplantation.
USE OF HBV related organ —
HBsAg positive patient going for liver or non liver transplant should be treated with antiviral till HBV DNA copies are undetectable.
HBcAb positive but HBsAg negative liver can be used in the HBsAg-positive recipient ,the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity) AND the HBV non-immune recipient.
Liver from HBsAG positive patient acn be used in HBsAG positive recipient along with anti viral drugs
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low
HBIg/NA prophylaxis is used in HBV/HDV positive recipient
Preventing Recurrence of HBV Post-Transplantation
Life-long combination therapy with HBIG and a potent NA for HIGH RISK cases like HBsAG positive , liver transplant for HCC , coinfected with HIV
Limited 6-12 month treatmet with same drugs in LOW RISK ( PAST INFECTION HBcAB POSITIVE )
HBV RECURRENCE
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence
or de novo hepatitis B post-liver transplantation.
HBV DNA and HBsAg should be monitored during teh therapy
HBV Vaccination
All SOT recipeint who are HBV naive should be vacccinated
Booster dose can be given to KT patient to increase the antibody titre more tha 100 IU/ML
Phases of infection
HBeAg positive chronic infection and the HBeAg positive chronic hepatitis followed by
HBeAg negative chronic infection and HBeAg negative chronic hepatitis
Here, in general , DNA copies goes down and enzymes may get elevated
REACTIVATION OF HBV
HBsAG NEGATIVE TO POSITIVE
DNA COPY ZERO TO POSITIVE or 2 LOG INCREASE IN NUMBER OF COPIES
ABSOLUTE NUMBER OF DNA MORE THAN 1LAC IN HBsAG POSITIVE PATINET
HDV ( DELTA )
Not present in isolation
hijacks the HBV replication machinery to replicate
diagnosis – serum HDV IgG positivity
active infection -HDV RNA copies in serum
should be tested in HBsAg postive prospective recipient and also those who has PAST INFECTION with HBV on serology
● All SOT candidates must be tested for HBsAg, HBsAb, and HBcAb.
● All HBsAg positive patients undergoing transplant work up must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
● HDV RNA where HDV is positive or equivocal
● Recipients with HBcAb positive but HBsAg negative must have HBV DNA and HDV serology to exclude occult HBV or HDV infection.
● Donors who are positive for HBcAb but HBsAg negative must have HBV DNA
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
● In patients with fulminant hepatitis B Liver transplantation must be considered and treatment with tenofovir or entecavir should be strongly considered
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
● Decompensated cirrhosis patients due to hepatitis B may be candidates for liver LTx
● positive HBV DNA with decompensated cirrhosis patients require urgent antiviral treatment with NA.
● Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and HCC
HBV and Other (Non-Liver) Transplantation
Patients with advanced HBV-related liver disease requiring another organ transplant
be considered for combined transplantation after careful consideration of the potential risks and benefits.
Pre-Transplant Management of HBV in Transplantation candidates
● All liver transplantation candidates with positive HBsAg should be treated with tenofovir or entecavir before transplantation, aiming for negative HBV DNA level.
Use of HBcAb Positive or HBsAg Positive Donors
● Donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis.
● Potential recipient should be counselled about possibility of receiving a liver from a donor with past or current HBV infection
HBcAb positive donation for liver recipients
● The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient
● When HBcAb positive liver donor to an HBsAg positive recipient we should adopte approach to prevent HBV reactivation
● When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
● Hepatitis B core antibody positive donor liver should be allocated in the following :
1. the HBsAg-positive recipient
2. the HBV-immune recipient(naturally or by vaccin )
3. the HBV non-immune recipient.
HBsAg Positive Donation for Liver Recipients
● HBsAg positive donor livers can be given to HBsAg positive recipients as the recipient is negative HDV and If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
● All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
● Use of HBIg rarely achieves HBsAg negativity, and is not recommended.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
● The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
● If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient
● When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
● HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
● HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
● Perioprative management of HIV and HBV infections should be agreed by MDT before transplantation.
● HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period.
● For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA
prophylaxis can be considered, but not within 12 months of transplantation.
Preventing Recurrence of HBV Post-Transplantation
● In HBsAg positive individuals combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
● Early withdrawal of HBIG or use of HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence.
● High risk patients for HBV recurrence
☆ HBV DNA positive at time of transplant
☆ HBeAg positive patients
☆ Hepatocellular carcinoma recipiant
☆ HIV co-infected
These patients should recieve Life-long combination therapy with HBIG and a potent NA
● Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
● HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis.
● Resistance testing should be undertaken at a specialist laboratory.
● Lifelong antiviral therapy for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
● Entecavir or Tenofovir are the first line treatment. Tenofovir used if the patient has previous lamivudine exposure
Monitoring for HBV Recurrence or De Novo Infection
● HBV DNA and HBsAg every three months in the first year then every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
● Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
HBV Vaccination and Solid Organ Transplantation
● All prospective SOT recipients who are HBV naive must be vaccinated
● Vaccination considered a protective strategy to develop protective serum titres of HBsAb
● In HBcAb positive recipients with HBsAb <100 IU/mL, vaccination boost the protective titre of HBsAb and minimise the risk of reactivation
● All prospective SOT recipients should receive a high-dose, accelerated vaccine
● In case of fail to respond to the initial HBV vaccination schedule, a second series should be administered.
HBV Biology and Disease
• All candidates for solid organ transplantation must be tested for HBsAg, HBsAb, and HBcAb. (1B)
• All HBsAg positive candidates should be investigated for: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be done for candidates with HDV serology is positive or equivocal. (1B)
• Any candidate found to have + HBcAb but – HBsAg (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease
• Fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B according to criteria defined by NHSBT. (1A)
• Early antiviral treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units with antiviral therapy and possible liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
• All HBsAg positive candidates for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and treated with either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors
• The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All candidates should be counselled about the possibility of receiving a liver from a donor with past or current HBV infection.
HBcAb positive donation for liver recipients
· The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
· prevention of HBV reactivation, if liver from a + HBcAb donor and is given to an HBsAg + recipient. (1B)
· When the liver comes from a HBcAb + donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
· If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
· HBsAg (+) donor livers can be given to HBsAg (+) recipients, as long as the recipient is known to be HDV (-). (1C)
· If urgency demands, the HBsAg (+) liver can be given to an HBsAg (-) patient. (1D)
· All recipients of a liver from an HBsAg (+) donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
· Use of HBIg rarely achieves HBsAg (-), and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
· The kidneys, heart and lungs from the HBcAb (+) organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
· If need demands, the non-liver solid organs of the HBsAg (+) organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
· When a HBcAb (+) donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
· HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
· HBsAg (+) donors should not be used for HBV/HDV co-infected recipients. (1C)
· A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
· HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is the same as that used for transplantation of HBV monoinfection. (1C)
· For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
· In HBsAg (+) individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
· Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
· Life-long combination therapy with HBIG and a potent NA can potentially be given to those who are HBV DNA (+) at time of transplant, HBeAg (+) patients, those transplanted for HCC or those who are HIV co-infected. (2B)
· Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
· All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
· Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
· Entecavir or Tenofovir are recommended as first-line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
· HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg (+) liver transplant recipients or individuals receiving a graft from a HBcAb (+) donor, regardless of treatment or prophylaxis regimen. (1C)
· Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
HBV Vaccination and Solid Organ Transplantation
· All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
· Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
· In renal transplant recipients with HBcAb (+), if HBsAb are <100 IU/mL, needs a booster vaccination. (2C)
· All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
· In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
HBV Biology and Disease Recommendation:
• All patients being worked up for SOT must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative
(past infection) must have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure)
must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B Recommendation:
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in
keeping with UK listing criteria defined by NHSBT. (1A)
Suggestion:
• As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery,
shorten disease duration and improve transplant free survival in severe AHB,
treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Recommendation:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these
patients may be candidates for liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent
antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents
and should be continued indefinitely. (1A)
Suggestion:
• Listing for liver transplantation should be considered in patients with hepatitis B
cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK
NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation Suggestion:
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of th potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation Recommendation:
• All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an
undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or
entecavir before transplantation if there is a standard clinical indication.(1B)
Use of HBcAb Positive or HBsAg Positive Donors General Recommendations Suggestion:
• The appropriate matching of an organ recipient with a donor positive for HBsAg or
HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients Recommendation:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver
recipient. (1C)
• When the liver comes from a hepatitis B core antibody positive donor and is given to
an HBsAg positive recipient, the standard approach to prevent HBV reactivation
should be adopted. (1B)
• When the liver comes from a HBcAb positive donor and is given to a HBV immune or
non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
Suggestion:
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver
should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity)
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients Recommendation:
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative
patient. (1D)
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
• Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients Recommendation:
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for
any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion:
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
• When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation Recommendtion:
• HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time
of transplantation. (1C)
• HBsAg positive donors should not be used for HBV/HDV co-infected recipients.(1C)
• A plan for the perioperative management of each of the HIV and HBV infections
should be agreed by the multidisciplinary team before transplantation. (1D)
• HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in
the peri-operative period. After HIV antiviral treatment is re-established, the
approach to HBV prophylaxis is no different from that used for transplantation of
HBV monoinfection. (1C)
Suggestion:
• For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA
prophylaxis can be considered, but not within 12 months of transplantation (2C)
Preventing Recurrence of HBV Post-Transplantation Recommendation:
• In HBsAg positive individuals deemed to be at high risk of recurrence,
combination therapy with HBIg and/or a potent NA is recommended from the time
of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Suggestion:
• Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be
considered in recipients who are at low risk for post-transplant HBV recurrence.
(2C)
• Life-long combination therapy with HBIG and a potent NA can potentially be
given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these
groups come from retrospective studies in the lamivudine era. (2B)
• Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk
of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although
monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid OrganTransplantation Recommendtion
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be
undertaken at a specialist laboratory. (1C)
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
• Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should
be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection Recommendation:
• HBV DNA and HBsAg should be monitored every three months in the first year
and thereafter every six months in HBsAg positive liver transplant recipients or
individuals receiving a graft from a HBcAb positive donor, regardless of treatment
or prophylaxis regimen. (1C)
• Monitoring intervals should be shortened in cases of self-reported or suspected
non-adherence. (Not graded)
HBV Vaccination and Solid Organ Transplantation Recommendation:
• All prospective solid organ transplant recipients who are HBV naive must be
vaccinated (time permitting) and the response documented. (1C)
Suggestion:
• Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot
currently be recommended as routine practice. (2C)
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are
<100 IU/mL, then vaccination should be considered to boost the protective titre of
HBsAb and minimise the risk of reactivation. (2C)
• All prospective solid organ transplant recipients should receive a high-dose,
accelerated vaccine schedule. (2C)
• In those who fail to respond to the initial HBV vaccination schedule, a second series
should be administered. (2C)
General recommendations:
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative
(past infection) must have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure)
must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Acute Hepatitis B recommendation
Antiviral treatment is indicated in certain subgroups of patients:
• Fulminant hepatitis B
• Severe AHB – based on the presence of at least two of the following criteria:
– bilirubin >100 μmol/L
– international normalised ratio (INR) ≥1.6
– hepatic encephalopathy
• Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
• Immunocompromised host
Liver transplantation should be considered in all patients with fulminant hepatitis. The criteria for listing for liver transplantation for acute liver failure related to hepatitis B must include hepatic encephalopathy and:
• Prothrombin time >100 seconds or INR >6.5
or
• Any three from:
– age >40 or <10 years
– jaundice to encephalopathy time >7 days
– serum bilirubin >300 μmol/L
– prothrombin time >50 seconds or INR >3.5
Recommendations:
• Individuals with fulminant liver failure associated with hepatitis B infection must be
managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in
keeping with UK listing criteria defined by NHSBT. (1A)
Suggestion:
• As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery,
shorten disease duration and improve transplant free survival in severe AHB,
treatment with tenofovir or entecavir should be strongly considered. (2B)
Chronic Hepatitis B
The goal of treatment in chronic HBV (CHB) infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death. Current treatment guidelines consider NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis.
Recommendations:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and such
patients may be candidates for liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s).
Entecavir and tenofovir are the first line antiviral agents
and should be continued indefinitely. (1A)
Suggestion:
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
who need testing ? recommended
all potential recipients need HBsAg , anti HBc, anti HBs AB
all HBsAg positive recipient must have HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
both donor and recipinet with past infection ,(based on HBsAG negative , anti HBc AB positive serology ) should have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection
Acute fulminant hepatitis and decompensated cirrhosis sholud be managed in specialist liver centre with use of anti viral drugs tenofovir/ entecavir and listed for liver transplantation.
USE OF HBV related organ —
HBsAg positive patient going for liver or non liver transplant should be treated with antiviral till HBV DNA copies are undetectable.
HBcAb positive but HBsAg negative liver can be used in the HBsAg-positive recipient ,the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity) AND the HBV non-immune recipient.
Liver from HBsAG positive patient acn be used in HBsAG positive recipient along with anti viral drugs
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low
HBIg/NA prophylaxis is used in HBV/HDV positive recipient
Preventing Recurrence of HBV Post-Transplantation
Life-long combination therapy with HBIG and a potent NA for HIGH RISK cases like HBsAG positive , liver transplant for HCC , coinfected with HIV
Limited 6-12 month treatmet with same drugs in LOW RISK ( PAST INFECTION HBcAB POSITIVE )
HBV RECURRENCE
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence
or de novo hepatitis B post-liver transplantation.
HBV DNA and HBsAg should be monitored during teh therapy
HBV Vaccination
All SOT recipeint who are HBV naive should be vacccinated
Booster dose can be given to KT patient to increase the antibody titre more tha 100 IU/ML
Phases of infection
HBeAg positive chronic infection and the HBeAg positive chronic hepatitis followed by
HBeAg negative chronic infection and HBeAg negative chronic hepatitis
Here, in general , DNA copies goes down and enzymes may get elevated
REACTIVATION OF HBV
HBsAG NEGATIVE TO POSITIVE
DNA COPY ZERO TO POSITIVE or 2 LOG INCREASE IN NUMBER OF COPIES
ABSOLUTE NUMBER OF DNA MORE THAN 1LAC IN HBsAG POSITIVE PATINET
HDV ( DELTA )
Not present in isolation
hijacks the HBV replication machinery to replicate
diagnosis – serum HDV IgG positivity
active infection -HDV RNA copies in serum
should be tested in HBsAg postive prospective recipient and also those who has PAST INFECTION with HBV on serology
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A)
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients
We recommend that:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
• When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
• When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
We suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity)
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
We recommend that:
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
• Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
We recommend that:
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
We suggest that:
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
• When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
We recommend that:
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C) HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C) A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D) HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Chapter 9: Preventing Recurrence of HBV Post-Transplantation
We recommend that:
•
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
We suggest that:
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C) Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B) Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Chapter 10: Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
We recommend that
All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C) Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
We recommend that
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C) Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
HBV Vaccination and Solid Organ Transplantation
We recommend that
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
We suggest that
• Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
• All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
• In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
Summary
HBV infection is one of the common viral infections and can cause chronic liver damage and cirrhosis, HBV vaccination should be adopted and applied to all to prevent the disease. This guideline was reviewed and written by experts in the field and shows different level of recommendation, published in 2016 and contain 12 chapters with many recommendations with different levels of evidence.
Introduction
HBV DNA virus belongs to the Hepadnaviridae. According to WHO data, HBV have infected more than 257 million with estimated annual death of around 600,000 due to advanced liver cirrhosis including HCC,
Despite the vaccination programs HBV still is responsible for infection worldwide.
HBV transmission
Vertical transmission from mother to child is common and 90% can progress to chronic infection before 5 years of age.
Horizontal transmission due to sexual transmission, nosocomial and contamination with blood and blood related products, IV drug abuser are also major source but < 10% in adults can progress to chronic stage.
Phases of Infection It is double-stranded DNA virus. It has compound interaction with the host immune system through inflammation, fibrosis, and finally cancer.
chronic carrier status refers to the failure tof the innate and adaptive immune response during the primary infection.
These phases can present as following 1.HBe Ag Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”). categorized by HBeAg positive and Anti HBeAb negative with HBV DNA viral loads generally >10 7logs IU/mL. ALT level is normal, and a liver biopsy (if performed) shows no or minimal inflammation. However, in this phase there’s no true immune tolerance in fact there is ongoing cytotoxic T-cell activity. Treatment is therefore indicated in this phase. 2. HBe Ag Positive Chronic Hepatitis (previously called “inflammatory” “Immune active” or “immune elimination phase”).
Patients in this phase are HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive
chronic infection this phase is asymptomatic, there is immune-mediated damage to the liver with resultant inflammation and fibrosis that can progress to cirrhosis in those with prolonged, unrecognized inflammation.
Antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis.
3. HBe Antigen Negative Chronic Infection (previously called “inactive phase”). This phase is characterized by HBeAg negativity, HBeAb positivity with normal ALT levels, and HBV DNA levels being characteristically <2000 IU/mL. but the rate of seroconversion depends on the genotype. Those with age of > 40 years have a higher chance for seroconversion. 2. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”). Usually associated with fluctuation in the level of ALT and lead to increased risk of cirrhosis and needs treatment with antiviral. Serological and Virological Testing HBV serological profile Interpretation is as follows.
1. HBsAg negative, HBcAb negative, and HBsAb negative indicate no evidence of
current or past HBV infection. But No immunity to HBV.
2.HBsAg negative, HBcAb negative, & HBsAb positive indicate vaccination with immunity.
3.HBsAg positive indicates active infection with HBcAb positive,
4. IgM HBcAb positive, but HBsAb negative. indicates acute HBV infection (window period), or non-specific reactivity (false positive). This is mainly applicable to donors who have received blood products.
4.HBcAb positive with all other markers negative (‘core alone’) may indicate past HBV infection,
5. HBsAg negative, HBcAb positive, and HBsAb positive again indicate past infection with good immunity.
6. HB ‘core alone’ positive profile in the recipient needs further workup including a history of blood products and risk factors for HBV, full HBV serological markers, and HBV DNA (+/- follow-up testing) to explain the patient’s HBV status.
Reactivation of HBV
Reactivation may be asymptomatic or accompanied with flare up of inactive disease, demonstrating clinically with acute hepatitis which can progress to liver failure and even death. Reactivation risk depends on the HBV status and the type of immunosuppression and the underlying condition, lack of immune response, or resistance to the antiviral therapy.
All patients being worked up for solid organ transplantation must be tested for
HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
All HBsAg positive patients undergoing transplant workup must have tests:
HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to eliminate the opportunity of occult HBV infection. (1C)
Hepatitis Delta Co-Infection
Co-infection with HBV in > 5%, can worsen the course of progressive chronic liver disease cirrhosis, and HCC. The diagnosis is done by positive serology test for HDV IgG, and confirmation of co-infection with HDV BY HDV RNA positive test >2000IU/ML
Acute HBV infection
acute HBV infection is self-limiting in the majority up 95-99% even without treatment, but up to 1% can progress to fulminant hepatic failure with a high mortality rate of > 80%.
Acute Fulminant hepatitis B is Severe form – diagnosed based on the presence of at least two of the following criteria:
– bilirubin >100 µmol/L
– international normalized ratio (INR) ≥1.6
– hepatic encephalopathy.
Early initiation of antiviral can hasten the recovery, and shortening the disease course while preventing complications, and improving transplant-free survival. Treatment with tenofovir or entecavir should be strongly considered. Chronic hepatitis B infection
The main goal for treating CHB infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC), and death. NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients
Antiviral treatment has two objectives:
1. Improvement of liver function
2. Decreased risk of HBV recurrence after transplantation
Tenofovir TFV and entecavir ETV are currently the first-line agents, with superior potency and higher barrier to Lamivudine resistance (4).
Both are well tolerated with good safety profiles more effective in the suppression of viral duplication and rapid in the clearance of viral load. Entecavir is not nephrotoxic and have an exceptional resistance profile, can be used at even higher doses in decompensated liver cirrhosis 1 mg instead of 0.5mg daily, can be used indefinitely with 3 months monitoring for the SVR by HBV PCR
Any persistent viremia after 6-12 months of treatment indicates treatment failure and consider alternative therapy.
Hepatocellular carcinoma Hcc For listing OLT for HCC, the following criteria must be satisfied: • A single tumor ≤5 cm in diameter, or
• Up to 5 separate tumors, all ≤3 cm, or
• Single tumor >5 cm and ≤7 cm diameter, where there has been no evidence of tumor progression, no extra-hepatic spread, and no new nodule formation over a six-month period. Regional therapy +/- chemotherapy may be given during that time. Sustained viral response with antiviral therapy is required.
Impact of Transplantation on HBV
immunosuppressive therapy used in SOT can modify the natural history of HBV infection with enhanced replication of HBV facilitated by some drugs.
Rapamycin (mTOR inhibitor) has been shown to enhance HBV production by inducing cellular autophagy. Steroids enhance viral replications by their effect on the viral genome and both prednisolone and azathioprine increased intracellular viral DNA and RNA levels by approximately two-fold and four-fold respectively. Cyclosporin did not alter the levels of viral RNA or DNA. However, a combination of all three immunosuppressive agents increased the level of intracellular viral DNA eightfold, indicating an additive effect.
Impact of HBV Infection on Transplant Outcome HBV infection is associated with more frequent and rapid progression to cirrhosis and
hepatocellular carcinoma in SOT recipients.
HBsAg positivity is a risk factor for death in renal transplant recipients. It also increases the risk of denovo membranous nephropathy. Recent studies in kidney and heart transplant recipients with CHB without cirrhosis have reported excellent outcomes with antiviral therapy alone.
Prevalence of HBV Infection in SOT
The pattern of HBV infection in SOT is similar to the general population and its overall prevalence is decreasing worldwide due to the improvement in vaccination and screening programs. In developing countries prevalence varies between 2-20% in HD populations while it’s even lower 0-10% in developed countries. Risk of HBV Infection in the SOT Recipient
All donors and recipients should be screened for possible active or Cronic HBV infection and risk of reactivation after SOT, and the use of antiviral prophylaxis after transplantation.
Those with high titer anti-HBsAB considered low risk for reactivation however breakthrough reactivation still can occur. Hence post-transplant anti-HBsAb monitoring is not routinely recommended to predict the risk of reactivation.
However, donors with HBsAg positive, anti-HBc positive to recipients with HBsAg positive, anti-HBc positive are considered the highest risk for HBV reactivation/infection without antiviral treatment. All HBsAg-positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels. (1B)
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive
must have liver disease staging and suppression of HBV DNA by either tenofovir or
entecavir before transplantation if there is a standard clinical indication. (1B)
Organs like kidneys, heart, and lungs from the HBcAb-positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
If needed the non-liver solid organs of the HBsAg positive donor can be used for any recipient, after an individualized assessment of risk and benefit. (2C)
When an HBcAb-positive donor is used, lamivudine prophylaxis may be given for six
months after transplantation, although the risk of transmission is very low. (2c)
All SOT pairs must have HBsAg,HBaAb and HBcAb tests done with those found to be HBsAg +VE getting further evaluation with HBeAg,HBeAb,HDVAb and HBV DNA levels. Positive HDV serology is an indication for HDVRNA to R/O an co infection.
Those with past HBV infection must have occult infection R/0 by HBVDNA testing.
Indication for transplantation for HBV related disease;
Acute fulminant Hep B- These pts must be treated by a liver specialist and early antivirals started to shorten dx duration and improve prognosis post transplant,
Decompensated Hep B cirrhosis and HCC – These group should be attended to by a hepatologist with early indefinite antiviral treatment started and thereafter considered for liver transplantation in line with UK NHSBT guidelines.
HBV and other non liver transplantation;
MDT approach with extensive counselling to be done before concurrent transplantation.
Pre transplant mgt of HBV in individuals being considered for transplantation.
Tx should be given with TDF or entecavir until VL gets undetectable.
Use of HBcAb +VE or HBsAg +VE donor;
A virologist opinion should be sort and extensive counselling done pre- transplant.
HBcAb +VE donation for liver recipient;
If the recipient is immune or non immune,3TC prophylaxis is given indefinitely. These donors can also give organs to HBsAg +VE recipients, HBV immune and non immune recipients.
HBsAg +VE donation for liver recipients.
As long as HDV is negative they can donate to recipients of similar serostatus and in urgent cases to those who were seronegative for HBV.Tx with anti virals (entecavir or TDF) is given post transplant with HBIg being discouraged.
HBcAb +VE and HBsAg donation for non liver solid organ recipients.
HBcAb positive has low infection risk and thus can donate to any one with 6/12 prophylaxis post transplant.
Risk stratification should be done in HBsAg +VE donor before organ donation.
MGT of CO- infection(HDV,HCV,HIV) and transplantation.
MDT approach in HBV/HIV co infection pair pre transplant and HBsAg +VE donor not to be considered.
HBV/HDV recipient to get both HBIg/NA prophylaxis pre transplant and tx for a minimum of 1 year.
Consider HBIg as prophylaxis when HAART is suspended peri op then restart HAART and HBV prophylaxis post op.
Preventing recurrence of HBV post transplantation.
High risk individuals should be given combined HBIg +/- NA post transplant to decrease recurrence and given indefinitely.
Low risk individuals can have early HBIg withdrawal or no HBIg post transplant.
Isolated HBcAb +VE recipients should get 6-12/12 of prophylactic anti virals + VL monitoring.
Tx of HBV recurrence or de novo Hep B after SOT.
Drug adherence to be assessed and resistance testing done before lifelong tx is initiated with TDF/Entecavir. TDF used in those with prior 3TC exposure.
Monitoring HBV recurrence or De novo infection.
HBVDNA and HBsAg monitored every 3 monthly in 1st 1 year then every 6 monthly regardless of tx regimen in those (HBsAg +VE) with kidneys from HBcAb +VE donors.
HBV Vaccination and SOT.
All HBV naive potential recipients should be vaccinated.
In renal transplant recipients, those with HBsAb <100iu/ml should be vaccinated with a second vaccine considered in those who fail to respond to initial HBV vaccine.
II. Guidelines for Hepatitis B & Solid Organ Transplantation
Summarise these guidelines
HBV biology and disease
– all potential SOT recipients should be tested for HBsAg, HBsAb (absolute titers) and HBcAb
– all HBsAg positive potential recipients should be tested for HBeAg, HBeAb, HDV Ab, HBV DNA levels
– for potential recipients with a positive or equivocal HDV serology, perform HDV RNA
– for potential recipients with HBcAb positive and a negative HBsAg (past infection), perform HBV DNA and HDV serology test to exclude occult HBV or HDV infection
– for donors with a positive HBcAb and a negative HBsAg (past HBV exposure), perform HBV DNA testing to exclude occult HBV infection
Pre-transplant management of potential HBV transplant recipients
– potential HBsAg positive non-liver SOT recipients should have liver disease staging and HBV DNA suppression using tenofovir or entecavir before transplantation
Use of HBcAb positive or HBsAg positive donors in non-liver SOT recipients
– organs from a HBcAb donor can be used on any recipient, the risk of de novo infection is low, but antiviral prophylaxis may be offered for 6 months post-transplant
– if the demand is high, organs from a HBsAg donor can be used on any recipient after individualized assessment of risk vs benefit
Management of co-infection (HCV, HDV, HIV) and transplantation
– HBV/ HDV recipients should receive HBIG/NA prophylaxis post-transplant
– the HBIG can be withdrawn after 12months post-transplant
– HBV/ HDV co-infected recipients should not receive organs from
HBsAg positive donors
– a MDT should plan the management of each of the HIV and HBV infections before transplantation
– HBIG can be used for HBV prophylaxis when antiviral prophylaxis cannot be used in the perioperative period
– HBV prophylaxis in the HIV/ HBV co-infected recipients is similar to that offered to the HBV mono-infection recipients
Preventing recurrence of HBV post-transplantation
– HBIG ± a potent NA is recommended to prevent HBV reinfection post-transplant in HBsAg positive patients at high risk of recurrence
– for patients with a low risk for post-transplant HBV recurrence, HBIG can be withdrawn early or avoided altogether i.e., HBIG-free prophylaxis
– indications for life-long HBIG + NA therapy: – HBV DNA positive recipients at time of transplant, HBeAg positive patients, HCC transplant patients, HCV co-infected patients
– isolated HBcAb positive recipients at risk of HBV reactivation post-transplant can be offered 6-12months of antiviral prophylactic therapy although monitoring of HBV recurrence is also an acceptable strategy
Treatment of HBV recurrence or de novo hepatitis after SOT
assess adherence to NA prophylaxis
perform resistance testing
offer lifelong antiviral therapy in recipients with HBV recurrence or de novo hepatitis post-transplantation
1st line treatment is entecavir or tenofovir
use tenofovir in patients previously exposed to tenofovir
Monitoring for HBV recurrence of de novo infection
– for recipients who receive a graft from a HBcAb positive, HBV DNA and HBsAg should be monitored every 3months in the 1st year then every 6months thereafter irrespective of treatment or prophylaxis regimen
HBV vaccination and SOT
– if time allows, all potential SOT recipients who are HBV naïve must be vaccinated and the response documented
– consider vaccination to boost the protective HBsAb titers and minimize risk of reactivation among HBcAb positive potential kidney transplant recipients with HBsAb <100IU/ml
– a high-dose accelerated vaccine schedule should be offered to all potential SOT recipients
– repeat vaccination should be offered to patients who fail to respond to the initial HBV vaccination schedule
British Transplantation Society Guidelines. Guidelines for Hepatitis B & Solid Organ Transplantation HBV Biology and Disease They recommend that:
=All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titers) and HBcAb. (1B)
=All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology(if came positive , should send HDV RNA), and HBV DNA levels. (1B)
=HBcAb positive recipients/ Donors and HBsAg negative, occult
HBV or HDV infection should be excluded by HBV DNA and HDV serology testing. Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B They recommend that:
=Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A) They suggest that
=Early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or Entecavir should be strongly considered. (2B) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma They recommend that:
=Antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely in patients with decompensated cirrhosis and detectable HBV DNA (1A) They suggest that
=Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A). HBV and Other (Non-Liver) Transplantation. They suggest that
=Combined transplantation is considered in patients with advanced HBV-related liver disease after careful consideration of potential risks and benefits. (2C) Pre-Transplant Management of HBV in Individuals Being Considered forTransplantation They recommend that:
=All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or Entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
=Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or Entecavir before transplantation if there is a standard clinical indication. (1B). Use of HBcAb Positive or HBsAg Positive Donors HBcAb positive donation for liver recipients They recommend that:
=The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
=Donation from hepatitis B core antibody positive donor to an HBsAg positive recipient, we should follow the standard approach to prevent HBV reactivation. (1B)
=Liver donation from a HBcAb positive to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A) They suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver
should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity)
3. the HBV non-immune recipient. (2C) HBsAg Positive Donation for Liver Recipients They recommend that:
=HBsAg positive donor livers can be given to HBsAg positive recipients and if urgent can be given to HBsAg negative (1C).
=Treatment by Entecavir or tenofovir should be started from the time of transplantation for recipients of a liver from an HBsAg positive donor (1B). HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients They recommend that:
=The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A) They suggest that:
=When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C) Management of Co-Infection (HDV, HCV, HIV) and Transplantation They recommend that:
=HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation and not allowed to receive from HBsAg. (1C) They suggest that:
=For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C) Preventing Recurrence of HBV Post-Transplantation They recommend that:
=A combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B) They suggest that:
=Patients who were considered at high risk for HBV recurrence; such as those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; should receive life-long combination therapy with HBIG and a potent NA (2B)
• Recipients with HBcAb positive alone are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment or monitoring for HBV recurrence . (2B) Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation They recommend that
= Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation and should look for drug resistance and drug adherence (1C)
= Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B) Monitoring for HBV Recurrence or De Novo Infection They recommend that
=Monitoring HBV DNA and HBsAg every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C) HBV Vaccination and Solid Organ Transplantation They recommend that
=All HBV naïve, prospective solid organ transplant recipients must be vaccinated (time permitting) and the response documented. (1C) They suggest that
=Vaccination for renal transplant recipients who are HBcAb positive, if HBsAb are
<100 IU/mL, then vaccination should be considered to boost the protective titer of HBsAb and minimize the risk of reactivation. (2C)
= Accelerated vaccination for all prospective solid organ transplant recipients should be given and those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
This is the British Transplantation Society Guidelines for Hepatitis B & Solid Organ Transplantation 2018
HBV Biology and Disease
-All patients worked up for SOT must be tested for HBsAg, HBsAb and HBcAb. (1B)
-All HBsAg positive patients undergoing transplant work up must have: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
-HDV RNA testing must be performed where HDV serology is positive or equivocal. (1B)
-Any potential transplant recipients or donor found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B Recommendations: – Must be managed in a specialist liver center. (1C) – Liver transplantation must be considered in patients with fulminant hepatitis B (1A)
Suggestion; – As early antiviral treatment with tenofovir or entecavir should be strongly considered. (2B) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma Recommendations: – Should be treated in specialist liver units and patients may be need liver Tx (1C) – If HBV DNA is detectable. Entecavir and tenofovir are the first line antiviral agents and should be started urgently and continued indefinitely. (1A)
Suggestions: – Listing for liver Tx; in HBV cirrhosis and UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A) HBV and Other (Non-Liver) Transplantation Suggestion: • Advanced HBV-related liver disease requiring another Organ Transplant to be considered for combined transplantation (2C) Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation Recommendation: – All HBsAg +ve individuals should be treated before transplantation with tenofovir or entecavir, aiming for an undetectable HBV DNA level. (1B) – HBsAg +ve individuals undergoing non-liver OT must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation (1B)
Use of HBcAb Positive or HBsAg Positive Donors General Recommendations Suggestion: – Matching a recipient with donor +ve for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C) HBcAb positive donation for liver recipients Recommendation: – If liver comes from HBcAb donor. It can be used for any potential liver recipient. (1C) – If HBsAg positive recipient, approach to prevent HBV reactivation should be adopted. (1B) – Prophylactic lamivudine should be given at the time of transplantation, and should be continued indefinitely, if recipient HBV immune or non-immune (1A)
Suggestion: – If other waiting list priorities permit, the HBcAb positive donor liver should be allocated in the following order: 1. the HBsAg-positive recipient 2. the HBV-immune recipient (natural and vaccine immune) 3. the HBV non-immune recipient. (2C) HBsAg Positive Donation for Liver Recipients Recommendation: – Can be given to HBsAg positive recipients if HDV negative. (1C) – If urgent demands, can be given to an HBsAg negative patient. (1D) – All recipients must be treated with entecavir or tenofovir from the time of transplantation. (1B) – Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C) HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients Recommendation: – The kidneys, heart and lungs of HbcAb+ve can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion: -If need demands, HBsAg positive organs can be used for any recipient risk against benefit assessment (2C) -When a HBcAb positive donor is used, lamivudine prophylaxis may be given for 6 months after transplantation, although the risk of transmission is very low. (2C) Management of Co-Infection (HDV, HCV, HIV) and Transplantation Recommendations: – HBV/HDV recipients; should receive combination HBIg/NA prophylaxis from time of transplantation. (1C) – HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
– Perioperative management plan of the HIV and HBV infections should be agreed by the MDT (1D)
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
Suggestion: – For HBV/HDV recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C) Preventing Recurrence of HBV Post-Transplantation Recommendation: – In HBsAg positive individuals; the use of HBIg and/or a potent NA at the time of transplantation is recommended for prevention. (1B)
Suggestion: – Early withdrawal of HBIG or HBIG-free prophylaxis in low risk recipients (2C) – Life-long combination HBIG and NA for individual at high risk for HBV recurrence (2B) – Post-non-liver transplant with past HBV infection (HBcAb positive alone) are considered for (6-12 months) course of prophylactic antiviral treatment; with monitoring for recurrence (2B) Treatment of HBV Recurrence or De Novo Hepatitis B after SOT Recommendation: – Review of adherence with NA prophylaxis and test for resistance (1C) – Lifelong antiviral therapy for all individuals with HBV recurrence or de novo HBV (1C) – Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B) Monitoring for HBV Recurrence or De Novo Infection Recommendation: – HBV DNA and HBsAg every 3 months in the first year and then every 6 months (1C) HBV Vaccination and Solid Organ Transplantation Recommendation: -All HBV naïve recipients must be vaccinated and the response documented. (1C)
Suggestion: – Liver recipients transplanted for HBV, vaccination cannot recommended as routine. (2C) – Renal recipients if HBsAb are <100 IU/mL, vaccination is recommended. (2C) – All recipients should receive a high-dose, accelerated vaccine schedule. (2C) – Second vaccination series is considered if failed response (2C)
British Transplantation Society (BTS) Guidelines for hepatitis B and solid organ transplantation (2018)
This guideline aims to provide consensus expert opinion regarding the management of hepatitis B infection and solid organ transplantation. The GRADE system is used to highlight for the reader the quality of evidence available for a particular area and the subsequent certainty of the expert recommendation made based upon this evidence and clinical experience.
Why is a guideline needed?
· Hepatitis B (HBV) affects 257 million people worldwide (WHO estimate)
· Patients with chronic HBV may end up requiring a liver transplant due to end-stage liver disease
· There is potential for transmission of HBV through solid organ transplantation (SOT) from donors with prior or current HBV (de novo HBV)
· SOT recipients require significant immunosuppression and this may put them at risk of reactivation of prior HBV
· Given the availability of a hepatitis B vaccine, a proactive approach should be taken to protecting potential SOT recipients prior to transplantation, especially as vaccine efficacy will decrease with advancing chronic renal disease and even more so following transplantation when the patient is immunosuppressed
· HBV infection can have a negative impact on post-transplantation care if it limits the immunosuppression options that are suitable for the patient, and HBV infection itself is associated with worse patient outcomes post-transplantation
· We now have effective antiviral prophylaxis which can be used efficiently to reduce the rates of HBV reactivation post-transplantation (previously 50-94% post renal transplantation, now <6.4% in one study)
· HBV infection can be associated with the development of membranous glomerulonephritis which may lead to worsening allograft function in the renal transplant recipient
What should happen prior to SOT?
1. Screening for HBV should be a mandatory part of work-up for transplantation. Test for HBsAg, HBsAb and HBcAb. If HBsAg is positive then further screening should be done for HBeAg, HBeAb, HDV and HBV DNA levels
2. Any patient with evidence of past HBV infection (HBcAb positive and HBsAg negative) should have HBV DNA levels measured and should also be tested for hepatitis D (HDV)
3. If the patient is HBsAg positive and is being considered for renal transplantation they must be screened for cirrhosis and should be given tenofovir or entecavir to suppress HBV DNA prior to transplantation
4. Wherever possible, patients should be vaccinated against HBV prior to transplantation
What is the role of hepatitis B vaccination in renal transplantation?
· Patients should be offered a high-dose accelerated vaccination course: vaccination is more effective in the pre-transplantation stage than post-transplantation when immunosuppression may interfere with the effectiveness of the vaccine
· If, after 3 doses, the patient does not demonstrate a sufficient immune response then a further course should be offered
· In patients who have evidence of prior HBV infection (HBcAb positive), if their HBsAb titres are <100 IU/ml they should also receive vaccination in order to boost their antibody levels and reduce the risk of HBV reactivation post-transplantation
What happens if the kidney being offered is from a patient with current or past HBV infection?
· If the kidney is coming from a patient with previous HBV infection (HBcAb positive) this kidney could be given to any potential recipient and it is acknowledged that the risk of HBV in this context is very low the recipient should be given a 6 month course of lamivudine as a precaution
· If the kidney is being offered from a patient who with current HBV infection (HBsAg positive) then this decision should be made based upon how urgent/necessary the transplant is, the availability of donor organs and a risk/benefit assessment for the individual potential recipient
What happens if the potential renal transplant recipient is HBV positive and also has either hepatitis D (HDV), hepatitis C or HIV?
· Potential transplant recipients who have HBV and HDV co-infection should receive hepatitis B immunoglobulin (HBIg) and nucleotide analogues following transplantation and both of these should continue for the first year after transplantation, after which withdrawal of HBIg may be considered. They are not suitable to receive an organ from a donor who is HBsAg positive
· Patients on HIV antivirals often have these medications temporarily suspended around the time of transplantation to prevent the development of drug resistance- during this time there may be a different approach to HBV prophylaxis in these patients (ie use of hepatitis B immunoglobulin)
What about post-transplantation management?
· Renal transplant recipients who had evidence of past HBV infection (only HBcAb positivity) can be managed via 2 approaches: either 6-12 month course of prophylactic antiviral treatment, or regular monitoring for HBV recurrence
HBV Biology and Disease Recommendation· HBsAg, HBsAb (absolute titers), and HBcAb tests are required for all patients undergoing preparation for solid organ transplantation, as well as HDV RNA testing and HBV DNA testing to rule out occult HBV or HDV infection. Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B Recommendation· Liver transplantation must be considered in patients with fulminant hepatitis B in accordance with NHSBT criteria.Suggestion· Early antiviral treatment with nucleot(s)ide analogues can improve AHB survival. Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma Recommendation:· Individuals with decompensated cirrhosis and detectable HBV DNA need urgent antiviral treatment with Entecavir and tenofovir. Suggestion· Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and UKELD score >49. HBV and Other (Non-Liver) Transplantation Suggestion· Patients with advanced HBV-related liver disease should consider combined transplantation.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation Recommendation:· HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels.
Use of HBcAb Positive or HBsAg Positive DonorsGeneral Recommendations
Suggestion:· Potential recipients should be counseled about the possibility of receiving a liver from a donor with HBV infection.
HBcAb positive donation for liver recipients Recommendation:· Prophylactic lamivudine should be given from the time of transplantation to prevent HBV reactivation.
Suggestion· The hepatitis B core antibody-positive donor liver should be allocated in order of priority.
HBsAg Positive Donation for Liver Recipients Recommendation:· HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients Recommendation:· The risk of de novo HBV infection is low for organ donors.
Suggestion:· HBcAb-positive organ donors can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation Recommendation:· HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation, and HBsAg-positive donors should not be used.
Suggestion:· HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation.
Preventing the Recurrence of HBV Post-Transplantation Recommendation:· Combination therapy with HBIg and NA is recommended to prevent HBV reinfection post-liver transplant.
Suggestion:· Early withdrawal of HBIG or HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence, and life-long combination therapy with HBIG and NA can be given to those at high risk.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation Recommendation· Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
Monitoring for HBV Recurrence or De Novo Infection Recommendation · Monitoring intervals should be shortened in cases of non-adherence. HBV Vaccination and Solid Organ Transplantation
Recommendation · Prospective solid organ transplant recipients must be vaccinated and documented.
Suggestion· Vaccination should be considered to develop protective serum titers of HBsAb in liver, renal, and solid organ transplant recipients, and in those who fail to respond, a second series should be administered. HBV BIOLOGY AND DISEASE Introduction· Hepatitis B Virus (HBV) is a major human
pathogen, estimated to infect 257 million people worldwide
and cause 600,000 deaths every year. · It is transmitted through either vertical transmission from mother to child or horizontal transmission through unsafe medical practice. · Patient age at the time of initial infection is a major determinant of whether the infection becomes chronic. Virology and Phases of Infection · HBV is not directly hepatotoxic, but a complex interaction with the host immune system drives the hepatic inflammation-fibrosis-cancer axis.
1. HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).· Treatment is rarely indicated for HBeAg-positive and HBeAb-negative patients with HBV DNA viral loads >107 IU/mL.
2. HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” “immune active” or “immune elimination phase”).· This phase is characterized by a persistent or intermittent elevation in ALT and fluctuating HBV DNA levels, leading to inflammation and fibrosis that can progress to cirrhosis. · Antiviral therapy is indicated if prolonged or there is evidence of significant liver fibrosis.
3. HBe Antigen Negative Chronic Infection (previously called “inactive phase”).
· This phase is characterized by HBeAg negativity, HBeAb positivity, and normal ALT levels, with HBe antigen seroconversion rates determined by age and HBV genotype. Antiviral therapy can also result in HBeAg seroconversion.
· Regular follow-up is mandatory as reactivation and the development of HBeAg-negative chronic hepatitis occurs in 25%.
4. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).· Mutations in the basal core promoter and pre-core region of the pre-C/C gene can lead to increased HBV DNA levels, resulting in liver damage and HCC.
· Antiviral therapy is the cornerstone of management.
Serological and Virological Testing
· Testing for HBV surface antigen (HBsAg) and core antibody (HBcAb) is important for diagnosis and veracity of the host immune response.
Reactivation of HBV
· HBV reactivation varies depending on baseline HBV status, underlying condition, type of immunosuppressive therapy, and host immunity.
Hepatitis Delta Co-Infection
· HDV is a hepatotropic replication-deficient single-stranded covalently closed circular RNA virus that hijacks the HBV replication machinery to facilitate its viral replication.
Recommendation:· All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb, and HBcAb, and any potential transplant recipients must have HBV DNA and HDV serology testing to exclude occult infection.
INDICATIONS FOR TRANSPLANTATION FOR HBV-RELATED DISEASE Acute Hepatitis B
· Antiviral treatment is indicated in certain subgroups of acute hepatitis B (AHB) due to the presence of at least two of the following criteria: bilirubin >100 µmol/L and international normalized ratio (INR) ≥1.6.
· Prompt antiviral administration is warranted to shorten disease duration, promote recovery, and improve survival.
· A case series of 17 patients with severe or fulminant AHB showed that LAM administered until HBsAg clearance improved survival compared to historical, untreated controls (82.4 vs. 20% survival, p<0.001).
· However, the evidence for LAM has not been universally positive.
· The current EASL guidelines on the treatment of AHB recommend the use of ETV (0.5 mg/day) or TFV (245 mg/day).
· Antiviral treatment should be started early in the course of severe AHB, without waiting for the development of fulminant hepatitis.
· Delayed initiation of NAs is associated with higher mortality or requirement for OLT.
· There are limited data regarding the required duration of antiviral treatment in AHB, but therapy should be continued for at least three months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss.
· Liver transplantation should be considered in all patients with liver failure related to hepatitis B, with hepatic encephalopathy and prothrombin time >100 seconds or INR >6.5.
Recommendation:· Liver transplantation must be considered in patients with fulminant hepatitis B infection.
Suggestion· Early antiviral treatment with nucleot(s)ide analogues can improve AHB survival.
Chronic Hepatitis B· Treatment in chronic HBV infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death, with NAs or PEG-IFN as first-line treatment in patients with higher HBV DNA levels.
Decompensated Cirrhosis· The 5-year cumulative incidence of hepatic decompensation for untreated CHB-associated cirrhotic patients is approximately 20%.
· Untreated patients with decompensated cirrhosis have a poor prognosis, with a 14-35% 5-year survival, compared with 84% in the compensated state.
· However, decompensated HBV cirrhosis is declining as an indication for transplantation due to the success of HBV vaccination and the advent of potent oral antiviral agents.
· Antiviral treatment has two objectives: improvement of liver function and decreased risk of HBV recurrence after transplantation.
· TFV and ETV are currently the first-line agents, with greater potency and higher barriers to resistance. NAs have a good safety profile in patients with advanced liver disease, and a phase 2 double-blind study compared the safety of TFV and ETV in decompensated HBV cirrhosis.
· One serious potential side effect is mitochondrial toxicity, which can manifest as lactic acidosis, myopathy, neuropathy, or even hepatotoxicity.
· Treatment-naive patients with ETV (0.5 mg/day) showed significant improvement in Child-Turgotte-Pugh (CTP) and MELD scores, but not all patients improved with ETV.
· Two distinct subgroups of patients exist – those who will experience prolonged survival with antiviral therapy and those who require OLT.
· Studies have attempted to identify prognostic indicators that could help to stratify these patient groups.
Hepatocellular Carcinoma
· HCC is the fifth most common cancer worldwide, with over 500,000 new cases diagnosed annually.
Incidence and Risk Factors
· HBV is the leading risk factor for HCC globally, accounting for 50-60% of HCC.
· It can cause HCC in the absence of cirrhosis, but the majority of HCC (70-90%) develops in cirrhotic livers.
· Several factors are known to increase the risk of HCC among individuals with HBV infection, including demographic, viral, clinical, environmental, and HBeAg status.
· The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study from Taiwan showed that HCC increased in proportion to viral load.
Surveillance· HCC surveillance is necessary even if HBV DNA is suppressed, with six-monthly abdominal ultrasound scans recommended. Treatment· Treatment of HCC related to HBV is based on size, number of lesions, and serum AFP concentration.
· Salvage transplantation is an option if listing criteria are fulfilled.
· Non-cirrhotic patients with non-resectable HCC should be considered for OLT in the absence of macrovascular invasion and extra-hepatic spread.
Recommendation:· Individuals with decompensated cirrhosis and detectable HBV DNA need urgent antiviral treatment with NA(s).
Suggestion· Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and HCC.
HEPATITIS B AND OTHER (NON-LIVER) TRANSPLANTATION Introduction· Hepatitis B virus (HBV) infection is a major risk factor for hepatic dysfunction in SOT recipients, leading to progressive liver damage and morbidity, and mortality.
Impact of Transplantation on HBV· Immunosuppressive agents can modify the natural history of HBV infection through disruption of the host immune response and enhanced replication.
· Immunosuppressive drugs have a net immunosuppressive effect, promoting HBV replication when used in combination with other drugs.
Impact of HBV Infection on Transplant Outcome
· HBV infection is associated with more frequent and rapid progression to cirrhosis and hepatocellular carcinoma in SOT recipients, leading to higher mortality.
Prevalence of HBV Infection in SOT· Chronic HBV infection in SOT recipients varies according to geographical regions, with CHB prevalence ranging from 2% to 20%, and past HBV prevalence generally higher than CHB.
Risk of HBV Infection in the SOT Recipient· Post-transplant anti-HBsAb monitoring is not recommended to predict the risk of reactivation. Management of SOT Recipient with CHB or Past HBV· CHBV and HBV are not contraindications for solid organ transplantation.
Non-Liver SOT Recipients with Advanced Liver Disease· Patients with an advanced liver disease requiring transplantation of non-liver organs should be assessed by a multidisciplinary team to consider combined transplantation
Suggestion
· Patients with advanced HBV-related liver disease should consider combined transplantation.
PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION Non-Liver Solid Organ Transplantation· Patients should be screened for hepatitis B carriage and pre-transplant suppression should be given with tenofovir or entecavir to avoid the progression of liver disease.
Recommendation:· HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels.
USE OF HBCAB ANTIBODY-POSITIVE OR HBSAG-POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION Introduction· The use of solid organs from donors with core antibodies can transmit HBV infection to the organ recipient, with the risk of transmission being high for liver transplantation and lower for kidney and thoracic organs.
Suggestion:· Potential recipients should be counseled about the possibility of receiving a liver from a donor with HBV infection.
Core Antibody Positive Donation for Liver Recipients
· De novo HBV infection is associated with core antibody-positive liver donation and is dependent on the recipient’s HBV immune status.
· Lamivudine is the most cost-effective approach to prophylaxis, prevents most de novo infections, and should be given indefinitely.
Recommendation:· Prophylactic lamivudine should be given from the time of transplantation to prevent HBV reactivation.
Suggestion· The hepatitis B core antibody-positive donor liver should be allocated in order of priority.
HBsAg Positive Donation for Liver Recipients· HBsAg positive liver donation is suitable for non-immune HBsAg negative recipients, but not for HBV/HDV co-infected recipients.
Recommendation:· HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir.
Core Antibody Positive Donation for Non-Liver Solid Organ Recipients
· Donation of non-liver solid organs from core antibody-positive donors is rarely associated with de novo infection, making antiviral prophylaxis ineffective.
HBsAg Positive Donation for Non-Liver Recipients· Antivirals should be used to suppress HBV after transplantation, and long-term monitoring should be provided to prevent chronic infection.
Recommendation:· The risk of de novo HBV infection is low.
Suggestion:· HBcAb-positive organ donors can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation.
PREVENTING THE RECURRENCE OF HBV POST-TRANSPLANTATION Introduction
· Hepatitis B virus (HBV) recurrence after liver transplantation is defined as the reappearance of circulating hepatitis B surface antigen (HBsAg), with or without detectable HBV DNA. Without appropriate prophylactic treatment, HBV recurrence is almost universal.
· Prophylactic treatment with HBIG and NA has reduced graft reinfection rates and HBV-related liver disease is now a well-accepted indication for liver transplantation.
Hepatitis B Surface Antigen Positive Recipients
· Prevention of post-transplant HBV recurrence in HBsAg-positive patients begins before transplantation with antivirals, such as nucleo(t)side analogues (NA) such as entecavir or tenofovir.
· Combination therapy with NA antivirals is recommended. Early HBIG withdrawal and maintenance with NA monotherapy is effective and safe, but not appropriate for high-risk patients.
· HBIG-free NA prophylaxis can be considered in low-risk recipients, but more robust evidence is needed.
Hepatitis B Core Antibody Positive Recipients
· HBcAb positivity, with or without HBsAb, with negative HBsAg and negative HBV DNA is indicative of past HBV infection and should be managed in the same way as HBsAg positive patients.
Hepatitis B Core Antibody Positive Donors
· Pre-transplant vaccination against HBV can reduce the risk of de novo hepatitis B, with lamivudine being the most widely used.
Hepatitis B Surface Antigen Positive Donors
· Organs from donors chronically infected with HBV are not routinely used, but single-center case series exist of HBsAg-positive donor livers used in patients with HBV-related liver disease or HBcAb-positive recipients, with no differences in graft or patient survival and no episodes of graft dysfunction.
Recommendation:· Combination therapy with HBIg and NA is recommended to prevent HBV reinfection post-liver transplant.
Suggestion:· Early withdrawal of HBIG or HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence, and life-long combination therapy with HBIG and NA can be given to those at high risk.
TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION
Introduction· Hepatitis B recurrence after liver transplantation is associated with biochemical or clinical evidence of active disease and can occur in those without prior CHB (HBcAb negative).
· The risk of developing de novo hepatitis B in recipients depends on their hepatitis B serological status and prophylactic measures used.
Review of Literature
· Treatment should be started at diagnosis to control viral replication and stabilize graft function, based on prior treatment and prophylaxis history. E
· entecavir and tenofovir are safe and effective in prophylaxis treatment, but not recommended in patients previously treated with lamivudine.
Recommendation· Lifelong antiviral therapy is recommended for HBV recurrence or de novo hepatitis B post-liver transplantation.
MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST-LIVER TRANSPLANTATION
Introduction· Monitoring post-transplant patients to detect HBV infection in a timely manner.
Review of Literature · Monitoring of virological, serological, and clinical markers of infection post-transplantation is essential to evaluate prophylaxis efficacy. · Non-adherence increases the risk of recurrence, so monitoring should consist of both HBV DNA quantification and HBsAg testing.
Recommendation· Monitoring intervals should be shortened in cases of non-adherence.
HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION
Rationale for Vaccination
· HBV vaccination is important to protect solid-organ recipients from HBV infection.
Renal Transplantation
· HBV infection is an important consideration in potential renal transplant recipients, with a higher risk of all-cause mortality and graft loss.
· HBV vaccination is recommended in HBV seronegative patients with end-stage renal disease to increase the use of HBcAb-positive kidneys and reduce the risk of reactivation.
Timing of Vaccination
· HBV vaccination is highly immunogenic in healthy individuals but is less effective in patients with organ failure and immunosuppressed.
· Vaccination should be considered early in the course of the disease, as the response to the HBV vaccine is suboptimal in pre-transplant and post-transplant periods.
Vaccination Method
· The usual vaccination schedule is three intramuscular doses of the HBV vaccine, but higher-dose formulations are available for end-stage renal disease.
Summarise these guidelines
-All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb.All HBsAg positive patients should
Tests for HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
– Any potential transplant recipients and donor found to be HBcAb positive but HBsAg negative must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
-Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre and liver transplantation must be considered .
– Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation.
– Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
We suggest that
– Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines.
-Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
-All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level.
– Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
-All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection.
-The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient.
-When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
-If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient .
3. the HBV non-immune recipient.
-HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative.
– If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
-All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
-The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation .
– HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
-HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
-A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation.
-Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected.
-Recipients with HBcAb positive alone are at risk of HBV reactivation post-non-liver transplant and could be considered for 6-12 months course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy.
– Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
-HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
– All prospective solid organ transplant recipients who are HBV naive must be vaccinated and the response documented.
-Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice.
-Renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered .
-In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
Guidelines for Hepatitis B & Solid Organ Transplantation
This guideline is the first British Transplantation Society (BTS) guideline on the management of hepatitis B in the transplant setting.
HBV Biology and Disease:
• All HBsAg positive patients undergoing transplant work up should be assessed regarding hepatitis B status serology (HBeAg, HBeAb and HDV Ab) – and HBV DNA levels plus HDV RNA because it can only infect people who are also infected by the hepatitis B virus (HBV) .
In the past infection ( presence of HBcAb and absence of HBsAg ) in potential transplant recipient they must have HBV DNA and HDV serology testing to exclude any occult HBV or HDV infection.
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B:
Itis recommended that Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver center , and liver transplantation must be considered .
It is suggested that early antiviral treatment with nucleot(s)ide analogues (tenofovir or entecavir ) may promote recovery,shorten disease duration and improve transplant free survival in severe AHB.
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma:
-Decompensated Hepatitis B cirrhosis and Hepatocellular Carcinoma should be treated in specialist liver units, with urgent antiviral treatment with NA(s). -Listing for liver transplantation should be considered in patients with liver transplantation and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines.
All HBsAg positive individuals should be treated before transplantation, aiming for an undetectable HBV DNA level.
Severe HBV-related liver disease requiring another organ transplant should be considered for combined transplantation after careful consideration of the potential risks and benefits.
Use of HBcAb Positive or HBsAg Positive Donors General Recommendations
The use of HBcAb Positive or HBsAg Positive Donors for liver recipients should be discussed with a specialist in viral hepatitis, and all potential recipients should be counselled about this .
When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient they should receive prophylactic lamivudine .
The liver should be allocated in the following order:
1. The HBsAg-positive recipient. 2. The HBV-immune recipient . 3.The HBv-non-immune recipient.
All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir..
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation :
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation, and HBsAg positive donors should not be used for co-infected recipients.
Perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation.
Preventing Recurrence of HBV Post-Transplantation:
Combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
Life-long combination therapy can be given to patients following high risk patients :
1. HBV DNA positive at time of transplant, 2. HBeAg positive patients 3.Those transplanted for hepatocellular carcinoma 4.Those who are HIV co-infected.
A limited (6-12 months) course of prophylactic antiviral treatment is used in recipients with evidence of past HBV infection (HBcAb positive alone)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
If HBV recurrence occurs post-liver transplant patients adherence with NA prophylaxis should be reviewed and resistance testing at a specialist laboratory should be done with the start of life long antiviral therapy (Entecavir or Tenofovir ) .
Monitoring for HBV Recurrence or De Novo Infection:
Monitoring of HBV DNA and HBsAg should be done every three months in the first year then every 6 month for HBsAg positive liver transplant recipients, regardless of treatment or prophylaxis regimen.
HBV Vaccination and Solid Organ Transplantation
Vaccination should be recommended for all prospective solid organ transplant recipients who are HBV naive and have a response documented.
It can be used to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice.
If HBsAb are <100 IU/mL, vaccination should be considered to boost the protective titre and minimize the risk of reactivation. In those who fail to respond, a second series should be administered.
HBV Biology and disease Introduction Hepatitis B virus (HBV) is a hepatotrophic DNA virus, it belongs to the hepadnaviridae family. It is estimated to infect 257 million people worldwide and results in approximately 600,000 deaths every year due to complications of end-stage liver disease and hepatocellular carcinoma (HCC). Most of chronic HBV infection results from vertical transmission from mother to child or horizontal transmission through unsafe medical practice. Adult-to-adult transmission can also occur through sexual, nosocomial or blood borne routes. In adults, less than 10% progressed to chronic infection. Virology and phases of infection HBV has a party circular double stranded DNA genome. It is converted to covalently closed circular DNA (cccDNA), which forms the template for the production of virions and ongoing infection. There are phases of the illness and they influence patient management:
HBe antigen positive chronic infection
HBe antigen positive chronic hepatitis
HBe antigen negative chronic infection
HBe antigen negative chronic hepatitis
Serological and virological testingThe cornerstone for the diagnosis of HBV infection is the testing for HBV surface antigen (HBsAg). Any individuals who are HBsAg positive should be considered to have active infection and will require post-transplant treatment to control viral replication. They should also have HBV DNA levels measured to determine the status of the infection and help classify their current disease phase.
Testing for HBV core antibody (HBcAb) indicates whether or not an individual has been exposed to HBV in the past. Those who have spontaneously cleared the virus from the blood will be HBsAg negative but HBcAb positive. Testing for HBV surface antibody (HBsAb) is helpful to assess the veracity of the host immune response against HBV. Patients who have been vaccinated against HBV are HBcAb negative but HBsAb positive. Those who have spontaneously cleared HBV are HBsAg negative but HBcAb positive and generally HBsAb positive.
It is important to note that cccDNA remains permanently present in the hepatocytes of individuals who have cleared HBsAg from blood. Immunosuppression of these individuals with past infection can therefore result in the reactivation of HBV and the re-emergence of HBsAg. Reactivation of HBV HBV reactivation is defined as the reappearance of markers of active HBV replication in a patient with previously controlled HBV infection, or an increase in levels of replication compared to previous levels. Reactivation may result from loss of immune control of HBV or lack of antiviral efficacy due to the emergence of antiviral resistant variants. Hepatitis Delta co-infectionHepatitis delta (HDV) is a hepatotropic replication deficient single stranded covalently closed circular RNA virus that hijacks the HBV replication machinery within hepatocytes to facilitate its viral replication. It cannot exist in isolation. Virions are coated in HBsAg. It is estimated that around 5% of HBV infected patients worldwide are co-infected with HDV. A diagnosis of past or current HDV co-infection is dependent on the finding of serum HDV IgG positivity. Active HDV co-infection is confirmed by HDV RNA positivity. Indeed, HDV RNA should be performed in all cases of suspected HDV co-infection rather than relying on serology alone. HDV is either acquired at the time of infection with HBV or can occur as a super-infection. HDV co-infection results in more rapid progression of liver disease to cirrhosis and HCC, especially as it is difficult to treat. Recommendations
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb.
All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection.
Indications for transplantation for HBV related diseaseAcute Hepatitis BMore than 95-99% of adults who acquire acute HBV (AHB) will recover spontaneously and seroconvert to HBsAb without antiviral therapy. Approximately 1% of cases of AHB progress to fulminant hepatitis, which is characterized by a very high mortality rate (up to 80%), often requiring liver transplantation (OLT).
Antiviral treatment is indicated in certain subgroups of patients:
Fulminant hepatitis B
Severe AHB – based on the presence of at least two of the following criteria:
bilirubin >100 µmol/L
international normalised ratio (INR) ≥1.6
hepatic encephalopathy
Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
Immunocompromised host
Recommendations
Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver center
Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT.
As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered.
Chronic hepatitis B The goal of treatment in chronic HBV (CHB) infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death. Current treatment guidelines consider NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis. Decompensated cirrhosis Studies have shown that patients with untreated CHB have a 8 to 20% incidence of developing cirrhosis, and patients with untreated decompensated cirrhosis have poor prognosis. Prolonged and adequate suppression of HBV DNA with antiviral agents can prevent progression to decompensation and may even enable regression of fibrosis and the reversal of cirrhosis. Hepatocellular carcinoma HCC represents more than 90% of primary liver cancers. A large proportion of HCC related mortality is due to chronic viral hepatitis.
Several factors are known to increase the risk of HCC among individuals with HBV infection:
Demographic – male gender, older age, Asian or African ancestry, family history of HCC
Viral – higher HBV DNA levels, genotype (C>B), pre-core mutations, longer duration of infection, co-infection with HCV, HIV and HDV
Surveillance should be offered to patients with CHB who remain at risk of HCC development due to baseline factors. Treatment of HCC is similar to that in other causes of HCC. Liver transplantation is an established treatment option. For listing for OLT for HCC, the following criteria must be satisfied:
A single tumor ≤5 cm diameter, or
Up to 5 separate tumors, all ≤3 cm, or
Single tumor >5 cm and ≤7 cm diameter, where there has been no evidence of tumor progression, no extra-hepatic spread and no new nodule formation over a six month period. Loco-regional therapy +/- chemotherapy may be given during that time.
Recommendations
Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and such patients may be candidates for liver transplantation.
Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines.
Hepatitis B and other (non-liver) transplantationIntroductionHepatitis B virus (HBV) infection is a major risk factor for hepatic dysfunction in solid organ transplant (SOT) recipients. Immunosuppressive therapy used in the SOT setting can modify the natural history of HBV infection leading to progressive liver damage, including fulminant hepatitis, and resulting in significant morbidity and mortality. Impact of transplantation on HBV Both the adaptive and innate immune responses are important for the control of HBV infection. Reactivation of HBV is well described in association with the use of immunosuppressive agents such as B-cell depleting agents (e.g. rituximab), anthracycline derivatives, TNF-alpha inhibitors, cytokine inhibitors and tyrosine kinase inhibitors. Impact of HBV infection on transplant outcomes HBV infection is associated with more frequent and rapid progression to cirrhosis and hepatocellular carcinoma in SOT recipients, thus contributing to higher mortality. Hepatitis associated with HBV reactivation can lead to liver failure, especially in patients with cirrhosis. HBV may also cause de novo membranous glomerulonephritis, potentially impacting on renal function after transplantation. With the introduction of effective antiviral therapy, post-transplant patient and graft survival rates have improved significantly. Prevalence of HBV infection in SOT The prevalence of chronic HBV infection (HBsAg positive, HBcAb positive) or past HBV infection (HBsAg negative, HBcAb positive) amongst SOT recipients varies according to geographical regions of the world, following a similar pattern to HBV prevalence in the general population. The prevalence of past HBV infection in the SOT setting is not well reported, but will be generally higher than that of CHB. All patients likely to require SOT must be screened for HBV infection at the earliest opportunity, ideally before the administration of blood products or immunosuppression. Risk of HBV infection in the SOT recipient The overall risk of HBV reactivation/de novo infection in a SOT recipient without antiviral treatment/prophylaxis is dependent upon the donor and recipient HBV status. Management of SOT recipient with CHB or past HBV CHBV and past HBV are not contraindications for solid organ transplantation. With the introduction of effective HBV vaccinations and antiviral therapy, SOT can be carried out safely in patients with CHB or past HBV infection. Non-liver SOT recipients with advanced liver disease Patients with advanced liver disease requiring transplantation of non-liver organs can experience hepatic decompensation following transplantation and need careful assessment by a multidisciplinary team including a liver specialist. Combined transplantation may be considered where appropriate. Recommendations
Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
Pre-transplant management of HBV in individuals being considered for transplantationLiver TransplantationSince the implementation of oral antiviral agents and effective vaccination programmes, liver transplantation for decompensated hepatitis B (HBV) cirrhosis has become less common. HCC complicating HBV remains a prevalent indication for liver transplantation (OLT). The first line antiviral therapy for patients with decompensated cirrhosis is tenofovir or entecavir monotherapy, which are preferred due to their potency and high barrier to resistance. Non-liver solid organ transplantation As part of the work up for non-liver solid organ transplantation, patients should be screened for hepatitis B carriage. Pre-transplant suppression for patients with HBsAg positive disease should be given with tenofovir or entecavir to avoid progression of liver disease with immune suppression after transplantation. Recommendations
All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level.
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
Use of HBcAb antibody positive or HBsAg positive donors in solid organ transplantationIntroductionIt is recognised that the use of solid organs from donors with core antibodies (in the absence of HBsAg and regardless of the presence or absence of HBsAb) can transmit HBV infection to the organ recipient. The risk of transmission is very high for liver transplantation and much lower for transplantation of kidneys and thoracic organs. Transmission of infection is associated with the development of recipient HBsAg positivity, with an almost inevitable progression to chronic infection, and with high levels of HBV viral replication (typically serum HBeAg positivity with high titres of HBV DNA). This transmission has been called de novo HBV infection. Recommendations
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis.
All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection.
Core Antibody Positive Donation for Liver RecipientsDe novo HBV infection denotes the development in the recipient of serum HBsAg positivity, and is associated with the use of core antibody positive liver donation, regardless of the HBsAb donor status. The ideal recipient of the core antibody positive donation is the HBsAg positive recipient. Such a recipient will receive prophylaxis to prevent graft reinfection by HBV, and the same prophylaxis will prevent de novo infection. Published series demonstrate the potential for antiviral prophylaxis to reduce the risk of de novo infection. Most series have examined the use of lamivudine, HBIg or the combination to reduce the risk of de novo infection. The preferred treatment of de novo infection is with tenofovir and the stopping of lamivudine. Recommendations
The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient.
When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted.
When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
The HBsAg-positive recipient
The HBV-immune recipient (including both naturally immune and vaccine-induced immunity)
The HBV non-immune recipient.
HBsAg Positive Donation for Liver RecipientsHBsAg positive liver donation may be considered for any recipient, including non-immune HBsAg negative recipients. This is possible because antiviral treatment with entecavir or tenofovir can reliably suppress HBV replication to prevent HBV-related liver disease in the recipient after liver transplantation. When considering the use of the liver from an HBsAg positive donor, the transplant surgeon should be confident that the liver does not have significant HBV-related fibrotic damage. Recommendations
HBsAg positive donor livers can be given to HBsAg positive recipients as long as the recipient is known to be HDV negative.
If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
Use of HBIg rarely achieves HBsAg negativity, and is not recommended.
Core Antibody Positive Donation for Non-Liver Solid Organ RecipientsDonation of non-liver solid organs from the core antibody positive donor is rarely associated with de novo infection of the recipient. With such a low risk for de novo infection, it is hard to demonstrate a benefit of antiviral prophylaxis. Pre-transplant recipient HBV immunity appears to protect against de novo infection. HBsAg Positive Donation for Non-Liver RecipientsThe donation of non-liver solid organs from an HBsAg positive donor to an HBsAg positive recipient can be undertaken as long as antivirals are used to suppress HBV after transplantation. Transplantation of a non-liver solid organ from an HBsAg positive donor to a non-immune recipient will result in chronic infection of the recipient. Recommendations
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit.
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
Management of co-infection (HDV, HCV, HIV) in the liver transplant recipientManagement of HBV/HDV Co-InfectionHBV/HDV infection is typically associated with an aggressive chronic hepatitis with progression to cirrhosis and liver failure. HBV replication is relatively suppressed, so the majority of co-infected patients will be HBeAg negative with relatively low levels of serum HBV DNA. The only available antiviral therapy for HBV/HDV co-infection is alpha interferon, but response rates are disappointing, and are further reduced in patients with cirrhosis. HDV/HBV infection is unresponsive to treatment with nucleoside analogues. There is no proven effective treatment for recurrent (or acquired) graft HBV/HDV infection, and rapid progression to cirrhosis is likely. Management of HBV/HIV Co-InfectionThe management of HBV/HIV co-infection has been aided by the availability of tenofovir which provides potent monotherapy against HBV infection, and is also a frequent component of combination antiretroviral therapy. Recommendations
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation.
HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
A plan for the peri-operative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation.
HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the perioperative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection.
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 24 months of transplantation.
Preventing recurrence of HBV post-transplantationIntroductionHepatitis B virus (HBV) recurrence after liver transplantation is defined as the reappearance of circulating hepatitis B surface antigen (HBsAg), with or without detectable HBV DNA. Without appropriate prophylactic treatment, HBV recurrence is almost universal. Hepatitis B Surface Antigen Positive RecipientsThe prevention of post-transplant HBV recurrence in HBsAg positive patients begins before transplantation. The HBV DNA viral load at the time of transplantation is a key determinant in the risk of HBV recurrence. All patients on the transplant waiting list should therefore be treated with antivirals with the aim of achieving an undetectable HBV DNA level. Following transplantation, prophylactic treatment of HBV recurrence should be with a combination of HBIG and NA antivirals. Although HBV/HDV co-infected patients have been shown to have reduced rates of HBV recurrence, there are very limited treatment options for delta hepatitis and thus HBV/HDV co-infected patients are often managed as high risk. Hepatitis B Core Antibody Positive RecipientsHepatitis B core antibody (HBcAb) positivity, with or without HBsAb, with negative HBsAg and negative HBV DNA is indicative of past HBV infection. When the immune system is therapeutically suppressed in the context of non-liver solid organ transplantation, there is potential for HBV reactivation.
Following liver transplantation, patients with occult HBV infection should be managed in the same way as HBsAg positive patients. Hepatitis B Core Antibody Positive DonorsOrgans from donors chronically infected with HBV are not routinely used at present. However, single-centre case series exist of HBsAg positive donor livers used either in patients who are HBsAg positive with HBV-related liver disease or in HBcAb positive recipients. In these cases, HBV recurrence is 100% and there is persistence of HBsAg. In carefully selected patients with appropriate consent, the use of HBsAg positive donor organs may be a useful strategy to further expand the donor pool. Recommendations
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence.
Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma, or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era.
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy.
Treatment of HBV recurrence or de novo hepatitis b post solid organ transplantationIntroductionHepatitis B recurrence after liver transplantation (OLT) is defined as detectable hepatitis B surface antigen (HbsAg) and/or detectable viral load (HBV DNA) after transplantation for complications of chronic hepatitis B. In chronic hepatitis B (CHB) infection, spontaneous eradication of hepatitis B virus (HBV) from the host is rare. Even after hepatitis B surface antigen (HBsAg) seroconversion, it is likely that HBV persists within the host due to a stable pool of covalently-closed circular HBV DNA. Despite the removal of the liver, HBV may persist in extrahepatic sites and the circulation in sufficient quantities to re-infect the donor graft. Recurrence of hepatitis B represents a failure of preventative strategies to mitigate this risk.
De novo hepatitis B infection after OLT is defined as newly detectable HbsAg, and/or detectable HBV DNA, in those without prior CHB (HBcAb negative). The main risk of de novo hepatitis B after OLT is in those who receive allografts from donors who are hepatitis B core antibody (HBcAb) positive. Review of literature HBV recurrence after OLT represents a failure of prophylaxis. Some of the reasons of recurrence include viral resistance and patient adherence. Other significant risk factors include detectable HBV DNA levels at the time of transplantation, hepatocellular carcinoma, or HIV. Immunosuppression taken by all post-transplant patients increases levels of HBV replication and progression of liver disease with HBV recurrence. The therapeutic goal once recurrent or de novo hepatitis is diagnosed is control of viral replication (suppression of HBV DNA) and stabilisation of graft function. In deciding on the type of treatment, it is important to establish the individual’s prior treatment and prophylaxis history. Due to increasing evidence of lamivudine resistance in patients post-transplantation, lamivudine is not recommended for treatment of hepatitis B recurrence or de novo hepatitis B. For patients who have previously been exposed to lamivudine and not responded, tenofovir should be offered as first line therapy. Recommendations
All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory.
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
Entecavir or tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
Monitoring for HBV recurrence or de novo infection post liver transplantationIntroductionTo prevent graft dysfunction secondary to recurrent hepatitis B infection, monitoring of virological, serological, and clinical markers of infection post-transplantation is essential to evaluate prophylaxis efficacy. There are no randomised trials comparing different intervals of monitoring for recurrence of HBV infection post-liver transplant. Non-transplant patients receiving immunoprophylaxis against HBV recurrence during high-risk immunosuppression are typically monitored for reactivation, but guidelines do not indicate an ideal monitoring interval. Three-monthly monitoring is recommended for those at low risk of HBV recurrence taking immunosuppressive therapy without HBV prophylaxis. It is recommended to monitor for recurrence more frequently in the first year post-OLT, where failure of prophylaxis is more likely to manifest. Although both recurrent and de novo infection are conventionally defined by the reappearance of HBsAg, it is recommended that monitoring should consist of both HBV DNA quantification and HBsAg testing. Recommendations
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
Hepatitis B vaccination and solid organ transplantationRationale for VaccinationImmunosuppressed solid-organ recipients develop a more severe and rapidly progressive HBV infection upon acquisition of HBV. It is especially important to prevent this in areas where there is a high prevalence of HBV infection amongst the organ donor pool, as donors may transmit HBV infection to recipients. HBV vaccination may provide protection against donor-derived HBV infection. Liver transplantation Donor-derived infection Liver donors with serological evidence of past resolved HBV infection (i.e. HBsAg negative, HBcAb positive) may transmit HBV infection to recipients. Successful pre-transplant HBV vaccination can substantially reduce the risk of de novo HBV infection to around 10% and, with additional HBV prophylaxis, this risk can almost be entirely eliminated. This may allow recipients to access the full donor pool. Recurrent HBV HBV vaccination cannot currently be recommended as a routine alternative strategy for the prevention of HBV recurrence after liver transplantation. Further work is required to define the optimal patient and vaccine characteristics. Renal transplantation HBV infection is also an important consideration in potential renal transplant recipients. HBV vaccination is recommended in HBV seronegative patients with end-stage renal disease. In part, this is in order to increase the use of HBcAb positive kidneys amongst those who mount a protective HBsAb response. Also, in patients with resolved past resolved infection (HBcAb positive), vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. Timing of vaccination In healthy individuals, HBV vaccine is highly immunogenic. Upon administration of a series of three doses of HBV vaccine (either plasma-derived or recombinant), healthy subjects will develop HBsAb in the vast majority of cases. In the pre-transplant period, the immunogenicity of the HBV vaccine has been shown to be less potent. In patients who are not yet at the stage of requiring liver transplantation, higher HBV vaccination efficacy of around 90% has been reported in patients with chronic hepatitis C. An association between the severity of renal impairment and lack of response to the HBV vaccine has been shown, therefore, vaccination should be considered early in the course of disease. While the response to HBV vaccine may be suboptimal in the pre-transplant period, it is even more disappointing in the post-transplant period. Vaccination method In healthy individuals, the usual vaccination schedule is a series of three intramuscular doses of HBV vaccine which are administered at baseline, one and six months. In patients with end-stage liver disease, the response to standard-dose HBV vaccinations is lower. These patients may benefit from a high-dose HBV vaccine. Similarly, patients with end-stage renal disease, particularly those on dialysis, demonstrate a poorer response to the standard-dose regimen. If HBV vaccination has to be given after solid-organ transplantation, the standard vaccine schedule with standard-dose vaccines at 0, 1 and 6 months is recommended. Recommendations
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice.
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation.
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule.
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
Summary
HBV infection is one of the common chronic progressive viral infections and can cause chronic liver damage and cirrhosis, HBV vaccination should be adopted and applied to all to prevent the disease
This guideline was reviewed and written by experts in the field and contain different level of recommendation to help and guide decision-making in regard to kidney transplantation workup in those specific group of patients, published in 2016 contain 12 chapters with many recommendations varies in the level of evidence from strong evidence of 1 A level to moderate of B level, and weak or limited evidence at C and D levels. Introduction
HBV DNA virus belongs to the Hepadnaviridae virus group, its major human antigen was first discovered in 1966 and according to WHO data, HBV infected more than 257 million with estimated annual death of around 600,000 due to advanced liver cirrhosis and complicated HCC, despite the vaccination programs against HBV still there is growing infections worldwide. HBV transmission
Vertical transmission from mother to child and 90% can progress to chronic infection before 5 years old.Horizontal transmission due to unsafe medical work, adult to adult transmission, through sexual transmission, nosocomial and contaminated blood and blood products, IV drug abuse, < 10% in adults can progress to chronic infection.
Virology and Phases of Infection HBV is a double-stranded DNA virus with no straight hepatoxicity effect, but rather compound interaction with the host immune system through inflammation, fibrosis, and cancer axis that defined the effect of chronic HBV infection. chronic carrier status refers to the failure to stand an innate and adaptive immune response during the primary infection. This complex interaction resulted in different and overlapping different phases of viral effects on the patient’s illness and management. These phases refer to patients’ hepatitis B e antigen (HBeAg) and hepatitis B e antibody (HBeAb)
status, alanine aminotransferase (ALT) levels, and HBV DNA quantification.
1.HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
categorized by HBeAg positive and HBeAb negative with HBV DNA viral loads generally >10 7logs IU/mL.The ALT level is in the normal range and a liver biopsy (if performed) shows no or minimal inflammation or fibrosis. However, in this phase there’s no true immune tolerance in fact there is ongoing cytotoxic T-cell activity
Treatment is really indicated in this phase.
2.HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” “Immune active” or “immune elimination phase”).
Patients in this phase are HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive
chronic infection this phase is asymptomatic, there is immune-mediated damage to the liver with resultant inflammation and fibrosis that can progress to cirrhosis in those with prolonged, unrecognized inflammation. Antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis.
1. HBe Antigen Negative Chronic Infection (previously called “inactive phase”).
This phase is characterized by HBeAg negativity, HBeAb positivity with normal ALT levels, and HBV DNA levels being characteristically <2000 IU/mL. but the rate of seroconversion depends on the age, genotype
Those > 40 years with genotype have a higher chance for seroconversion. 2. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).
Usually associated with fluctuation in the level of ALT and lead to increased risk of cirrhosis and needs treatment with antiviral. Serological and Virological Testing
1.HBV serological profile Interpretation
HBsAg negative, HBcAb negative, and HBsAb negative indicate no evidence of current or past, controlled HBV infection.
No immunity to HBV.
2.HBsAg negative, HBcAb negative, & HBsAb positive indicate vaccination with immunity
3.HBsAg positive indicates active infection HBsAg positive, HBcAb positive, IgM HBcAb positive, HBsAb negative
acute HBV infection (window period), or non-specific reactivity (false positive). This is mainly applicable to donors who may have received blood products
4.HBcAb positive with all other markers negative (‘core alone’) may indicate past HBV infection, HBsAg negative, HBcAb positive, and HBsAb positive again indicate past infection with good immunity.
HB ‘core alone’ positive profile in the recipient needs further workup including a history of blood products and risk factors for HBV, full HBV
serological markers, and HBV DNA (+/- follow-up testing) to explain the patient’s HBV status.
Reactivation of HBV
Reactivation may be asymptomatic or accompanied by a flare of hepatitis in previously minimal or inactive disease, demonstrating clinically with
acute hepatitis which can progress to acute liver failure and even death if untreated
reactivation risk depends on the HBV status and the type of immunosuppression and the underlying patient condition, lack of immune response, or resistance to the antiviral therapy.
All patients being worked up for solid organ transplantation must be tested for
HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant workup must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B) Any potential transplant recipients found to be HBcAb positive but HBsAg negative
(past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B) All donors who are positive for HBcAb but HBsAg negative (past HBV exposure)
must have HBV DNA testing to eliminate the opportunity of occult HBV infection. (1C)
Hepatitis Delta Co-Infection
Co-infection with HBV in > 5%, can worsen the course of progressive chronic liver disease cirrhosis, HCC, diagnosis by positive serology test for HDV IgG, and confirmation of co-infection with HDV BY HDV RNA positive test >2000IU/ML
Acute HBV infection
acute HBV infection is self-limiting in the majority up 95-99% even without treatment, only 1% can progress to fulminant hepatic failure with a high mortality rate of> 80% and the need for OLT.
Acute Fulminant hepatitis B
• Severe AHB – based on the presence of at least two of the following criteria:
– bilirubin >100 µmol/L
– international normalized ratio (INR) ≥1.6
– hepatic encephalopathy.
Early initiation of antiviral will hasten the recovery, shortening the disease course, preventing complications, and improving transplant-free survival in severe AHB,
treatment with tenofovir or entecavir should be strongly considered. Chronic hepatitis B infection
The main goal for treating CHB infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC), and death
NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients
with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine
aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis
Antiviral treatment has two objectives:
1. Improvement of liver function
2. Decreased risk of HBV recurrence after transplantation
Tenofovir TFV and entecavir ETV are currently the first-line agents, with superior potency and higher barrier to Lamivudine resistance (4). Both are well tolerated with good safety profiles more effective in the suppression of viral duplication and rapid in the clearance of viral load, not nephrotoxic and have an exceptional resistance profile, can be used at even higher doses in decompensated liver cirrhosis 1 mg instead of 0.5mg daily, can be used indefinitely with 3 months monitoring for the SVR BY HBV PCR
Any persistent viremia after 6-12 months of treatment consider treatment failure and consider alternative therapy
HBV-related decompensated liver cirrhosis with A MELD score of >20 was the most important predictor of mortality and should be listed for OLT. If
HBV DNA is detectable at any level, and ETV or TFV should be started as soon as possible [4]. Rendering HBV DNA undetectable before OLT decreases the risk of recurrence of HBV in
the graft
Hepatocellular carcinoma Hcc For listing OLT for HCC, the following criteria must be satisfied [57]: • A single tumor ≤5 cm in diameter, or
• Up to 5 separate tumors, all ≤3 cm, or
• Single tumor >5 cm and ≤7 cm diameter, where there has been no evidence of tumor progression, no extra-hepatic spread, and no new nodule formation over a six month
period. Loco-regional therapy +/- chemotherapy may be given during that time. Sustained viral response with antiviral therapy
Impact of Transplantation on HBV
immunosuppressive therapy used in SOT can modify the natural history of HBV infection its believed this is due to disruption of the host immune response and perhaps with enhanced replication of HBV facilitated by some drugs.Rapamycin (mTOR inhibitor) has been shown to enhance HBV production by inducing cellular autophagy.
Steroids enhance viral replications by their effect on the viral genome and both prednisolone and azathioprine increased intracellular viral DNA and RNA levels by approximately two-fold and four-fold respectively.
ciclosporin did not alter the levels of viral RNA or DNA. However, a combination of all three immunosuppressive agents increased the level of intracellular viral DNA eightfold, indicating an additive effect
Impact of HBV Infection on Transplant Outcome
HBV infection is associated with more frequent and rapid progression to cirrhosis and
hepatocellular carcinoma in SOT recipients, thus contributing to higher mortality and inferior survival before the era of antiviral prophylaxis
HBsAg positivity to be a risk factor for death in renal transplant recipients up to 94 % in some reports.
Also increased the risk of denovo membranous nephropathy.
Recent studies in kidney and heart transplant recipients with CHB without cirrhosis have reported excellent outcomes with antiviral therapy alone. In another recent study from Canada, HBV reactivation occurred in 4.1% of non-liver SOT patients with evidence of past HBV infection, with a median time to HBV reactivation of 4.7 years and even < than 2.5% in those with HBsABs with improved 5-year survival up to 82%. Prevalence of HBV Infection in SOT
The pattern of HBV infection is similar to the general population and it’s overall reduced worldwide due to the improvement in vaccination and screening programs in addition to the development of infection control policies the prevalence of CBV infection depends on geographical areas Like is more in developing countries and the prevalence varies between 2-20% in HD populations while it’s even lower 0-10% in developed countries. Risk of HBV Infection in the SOT Recipient
All donors and recipients should be screened for possible active or Chronic HBV infection and risk of reactivation after SOT, and the risk of reactivation or denovo infection depends on the donor and recipient HBV status and the use of antiviral prophylaxis after transplantation, as shown in table 4 from the guideline .those with high titer antiHBsAB considered low risk for reactivation however breakthrough reactivation still can occur Hence post-transplant anti-HBsAb monitoring is not routinely recommended to predict the risk of reactivation. However, donors with HBsAg positive, anti-HBc positive to recipients with HBsAg positive, anti-HBc positive are considered the highest risk for HBV reactivation/infection without antiviral treatment
All HBsAg-positive individuals being considered for liver transplantation should be
treated with either tenofovir or entecavir before transplantation, aiming for an
undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive
must have liver disease staging and suppression of HBV DNA by either tenofovir or
entecavir before transplantation if there is a standard clinical indication. (1B)
The kidneys, heart, and lungs from the HBcAb-positive organ donor can be used for
any recipient, and the risk of de novo HBV infection is low. (1A)
If need demands, the non-liver solid organs of the HBsAg positive organ donor can
be used for any recipient, after an individualized assessment of risk and benefit. (2C)
• When an HBcAb-positive donor is used, lamivudine prophylaxis may be given for six
months after transplantation, although the risk of transmission is very low. (2c)
Summary
Patients undergoing pre-transplantation workup should have HBsAg, HBsAb and HBcAb.
HBsAg is the corner stone for diagnosis for HBV infection.
HBsAb positive alone indicates vaccination.
HBsAb and HBcAb positive indicates past infection.
Patients with positive HBsAg should have HBeAg, and DNA levels for HDV and HBV.
Recipients and donors with positive HBcAb positive and negative HBsAg should have HBV and HDV DNA to exclude occult infection.
HBcAb positive alone may indicate past infection, acute infection window period and occult infection transmitted passively.
HDV infection can occur either at the time of infection with HBV or superinfection.
It accelerates progression to liver cirrhosis and HCC.
Patients with fulminant hepatitis B liver failure should be referred for liver transplantation.
Early antivirals will promote their recovery and shorten disease duration.
Antivirals are associated with better virological and clinical outcomes.
Tenofovir and entecarvir are superior to lamivudine.
Treatment should be continued for at least 3 months after seroconversion to HBsAb, or 12 months after HBeAb seroconversion without loss of HBsAg.
Patients with decompensated cirrhosis should be initiated on antivirals regardless of ALT, DNA levels and e antigen status.
Interferon contraindicated due to associated life threatening complications.
Entecavir and tenofovir are first line due to their greater potency and barrier to resistance.
ETV suppresses HBV replication more rapid and effectively than LAM and it’s not nephrotoxic.
Treatment should be continued indefinitely and viral response monitored every 3 months with HBV DNA.
High HBV DNA in chronic hepatitis B untreated are associated with progression to liver cirrhosis and hepatocellular carcinoma.
Recommended treatment for CHB is antivirals and pegylated interferon.
HBV is the major risk factor for HCC.
HCC mainly occurs in cirrhotic livers, though can occur in the absence of cirrhosis.
Antivirals don’t eliminate the risk of HCC.
HCC with HBV should be treated as other HCC with surgical resection being first line.
HBV and non-liver SOT transplantation is associated with increased risk of hepatic dysfunction and rapid progression to cirrhosis and HCC.
The risk of reactivation/de-novo HBV infection in SOT is dependent on D/R HBV status.
Recipients with high HBsAb have lower rates of reactivation in comparison to those who don’t.
CHBV and past HBV infection are not contraindication to transplantation.
Patients with HBsAg positive should be treated with entecarvir/tenofovir prior to transplantation.
Donors with HBcAb positive non-liver SOT may be accepted due to low risk of reactivation, lamivudine prophylaxis may be given for 6 months.
Donors with HBsAg positive may also donate to recipients who are HBsAg positive as long as antiviral prophylaxis is given.
HBV/HDV co-infection is associated with aggressive hepatitis and progression to cirrhosis and liver failure.
Nucleoside analogues have no role in treatment of HBV/HDV confection.
Available antiviral is alpha interferon associated with reduced response rates mainly in cirrhotic patients.
HBIg has shown excellent results as a prophylaxis given indefinitely against HBV/HDV recurrence.
HBIG can also be given in HBV/HIV co-infection during the peri-transplant period when antivirals are withdrawn.
HBV recurrence is defined as reappearance of HBsAg with or without detectable HBV DNA.
Recurrence is associated with poor graft and patient survival.
HBV DNA viral load at time of transplantation linearly correlates with risk of recurrence.
Recipients with HBsAg positive should be on antivirals (Tenofovir/entecavir) targeting undetectable viral loads prior to transplantation.
Post transplant should receive prophylaxis with HBIG and nucleoside analogues.
Monotherapy nucleoside analogues may be used in those with low risk of recurrence.
HBcAb positive alone may indicates past infection.
HBV DNA is undetectable but the HBV still persists in the liver
Risk of reactivation post-transplantation due to IS therapy hence recipient should receive lamivudine prophylaxis.
HBcAB donor to a naive recipient there is high risk of de-novo infection, this risk may be reduced by vaccination prior to transplantation.
Lamivudine prophylaxis for 1 year post-transplant may be considered.
HBcAb positive alone may also indicate occult infection.
HBsAg negative but HBV DNA detectable, thus recipient should be on antivirals prior to transplantation.
Donors with HBsAg positive may be accepted with prophylaxis give to recipients at high risk of recurrence.
HBV vaccination should be offered to all SOT recipients.
Recipients with immunity from past infection with HBcAb titers <100iu/ml should be considered for boaster vaccination.
Patients with end organ disease (liver/kidney) have poor response to standard HBV vaccine.
This patients should thus receive high dose HBV vaccine with an accelerated regimen given at 0,1,2 and 6 months.
HBsAB titers should be done 1-3 months after completion of vaccination and those who fail to mount an immune response should have a further vaccine schedule.
. For all D& R ….. HBsAg , HBsAb & HBcAb should be done
. HBsAg positive + HBsAb positive + HBcAb positive……. Acute infection
. HBcAb positive …….past infection
. HBsAb posive …….vaccination
. If HBsAg + HBsAb positive …….require HBeAg, HBeAb, HBV DNA & HBD Ab testing
. if HDV Ab positive or suspicious ……require HDV RNA
. HDV co infection with HBV
. All patents with viral positive ….require a multidisciplinary team discussion
This guideline outlines the transplantation of solid organs in the context of HBV infection.
It advocates the assessment for HBV and HDV infection whenever HBcAb is detected in the work up before transplantation. As HBcAb is indicative of previous infection that might have progressed to Chronic HBV infection or had resolved previously. Other markers of infection must be explored similarly including HBsAg, anti HBsAb, HBeAg, anti HBeAb, in addition to HBV DNA and HDV.
In the setting of active infection with HBV, it is suggested to treat the patient properly with Tenofovir and Entecavir. Treatment of HBV infection depends on detecting markers of replication and activity.
Markers involved in assessment includes HBeAg, HBeAb, ALT, HBV PCR copies, and liver fibrosis. Accordingly categorizing the result into HBV infection vs HBV Hepatitis.
In the presence of HBeAg, HBV DNA copies of more than 200000 and normal ALT is corresponding to minimal hepatic inflammation and categorized as HBV infection. In this situation its not warranted to commence treatment.
On the other hand, when HBeAg is positive with or without HBeAb , HBV copies of more than 2000 and elevated ALT is congruent with hepatitis and hepatic fibrosis. It’s indicative to start treatment with Tenofovir and Entecavir.
Transplanting a kidney from HBcAb positive is indicative to undertake prophylactic treatment with Lamivudine. When donor is HBsAg positive, the SOT can be performed to HBV infected , but not HDV /HBV infected patient.
Next is immunized recipient.
Last is HBsAg negative patient.
Occult HBV infection : when HBsAg is negative and HBV DNA is positive. Life long treatment is indicated for those at high risk of recurrence including
HBeAg positive.
HBV DNA positive
Transplant for HCC.
Transplant for Acute haptic failure
I make note of your interpretation of serological testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your summary.
II. Guidelines for Hepatitis B & Solid Organ Transplantation Summarise these guidelines. HBV Biology & Disease Recommendations:
• Pre-TX All SOT patients tested for HBsAg, HBsAb & HBcAb. (1B)
• HBsAg +ve patients must have: HBeAg, HBeAb & HDV Ab serology, & HBV DNA levels. (1B)
• HDV RNA done if HDV serology is +ve or equivocal. (1B)
• If HBcAb +ve but HBsAg -ve (past infection), HBV DNA & HDV serology done to exclude occult HBV or HDV infection. (1B)
• Donors HBcAb +ve but HBsAg -ve (past HBV exposure) must have HBV DNA test to exclude occult HBV infection. (1C)
============================ Indications for TX for HBV-Related Disease Acute Fulminant Hepatitis B Recommendations:
• Management in a specialist liver centre. (1C)
• Liver TX according to UK listing criteria defined by NHSBT. (1A) Suggestions:
• Early antiviral treatment with NA promote recovery, shorten disease duration & improve TX free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B) Decompensated Hepatitis B Cirrhosis & HCC Recommendations:
• Decompensated cirrhosis treated in specialist liver units as the use of antiviral is complex & patients may need liver TX. (1C)
• Urgent antiviral may be required in decompensated cirrhosis & detectable HBV DNA. Entecavir & tenofovir are the 1stline agents & used indefinitely. (1A) Suggestions:
• Listing for liver TX if hepatitis B cirrhosis & a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
============================ HBV & Non-Liver TX Suggestions:
• Careful consideration of the potential risks and benefits. (2C)
============================ Pre-TX Management of HBV Recommendations:
• Treatment with either tenofovir or entecavir before TX, aiming for an undetectable HBV DNA level. (1B)
• Non-liver SOT who are HBsAg +ve must have liver disease staging & suppression of HBV DNA by tenofovir or
entecavir before TX. (1B)
============================ Use of HBcAb +ve or HBsAg +ve Donors General Recommendations Suggestions:
• Appropriate matching of recipient with a donor +ve for HBsAg or HBcAb discussed with a specialist in viral hepatitis. (2C)
• Recipients counselled about the possibility of receiving a liver from a donor with past or current HBV infection.
(Not graded) HBcAb +ve donation for liver recipients Recommendations
• The HBcAb +ve (HBsAg +ve) donor liver used for any recipient. (1C)
• If liver from a HBcAb +ve donor is given to HBsAg+ve recipient, the standards to prevent HBV reactivation are adopted. (1B)
• If liver from a HBcAb +ve donor is given to a HBV immune or non-immune recipient, lamivudine is given & continued indefinitely. (1A) Suggestions:
• HBcAb +ve donor liver allocated in the following order:
1. HBsAg-+ve recipient
2. HBV-immune recipient (naturally immune & vaccine-induced)
3.HBV non-immune recipient. (2C) HBsAg Positive Donation for Liver Recipients Recommendations
• HBsAg +ve donor livers can be given to HBsAg +ve recipients, as long as the recipient is known to be HDV -ve. (1C)
• HBsAg +ve liver can be given to HBsAg –ve patient on urgent demand. (1D)
• Recipients of a liver from HBsAg +ve donor treated with entecavir or tenofovir. (1B)
• Use of HBIg is not recommended. (1C) HBcAb +ve & HBsAg +ve Donation for Non-Liver SOT Recipients Recommendations
• Kidneys, heart & lungs from HBcAb +ve organ donor can be used for any recipient (risk of de novo HBV infection is low). (1A) Suggestions:
• Non-liver organs of HBsAg +ve donor can be used for any recipient, after assessin risk & benefit. (2C)
• If HBcAb +ve donor used, lamivudine is given for 6 months after TX. (2C)
============================ Management of Co-Infection (HDV, HCV, HIV) & TX Recommendations
• HBV/HDV recipients given HBIg/NA prophylaxis. (1C)
• HBsAg +ve donors not to be used for HBV/HDV co-infected recipients. (1C)
• MDT plan of management of each of the HIV & HBV infections before TX. (1D)
• HBIg used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. (1C) Suggestions:
• HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of TX. (2C)
============================ Preventing Recurrence of HBV Post-Transplantation Recommendations
• For HBsAg +ve individuals at high risk of recurrence, HBIg &/or a potent NA is recommended from the time of TX to prevent HBV reinfection post-liver TX. (1B) Suggestions:
• Early withdrawal of HBIG or use of HBIG-free prophylaxis in recipients at low risk for post-TX HBV recurrence. (2C)
• Life-long HBIG & a potent NA for patients at high risk for HBV recurrence:
HBV DNA +ve at time of TX
HBeAg +ve patients
Those transplanted for HCC
Those who are HIV co-infected
• Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver TX & could be given a limited (6-12 months) course of prophylactic antiviral treatment. (2B)
============================ Treatment of HBV Recurrence or De Novo Hepatitis B after SOT Recommendations
• Review of adherence with NA prophylaxis.Resistance testing at a specialist laboratory. (1C)
• Lifelong antiviral for all with HBV recurrence or de novo hepatitis B post-liver TX. (1C)
Entecavir or Tenofovir are first line treatment. Tenofovir if there is previous lamivudine exposure. (1B)
============================ Monitoring for HBV Recurrence or De Novo Infection Recommendations
• HBV DNA & HBsAg monitored every 3 months 1styear & then every 6 months in HBsAg +ve liver TX recipients or patients receiving a graft from a HBcAb +ve donor. (1C)
• Monitoring intervals shortened in cases of non-adherence. (Not graded)
============================ HBV Vaccination & SOT Recommendations
• All prospective HBV naive SOT recipients must be vaccinated & the response documented. (1C) Suggestions:
• Amongst liver recipients transplanted for HBV, vaccination cannot currently be recommended as routine. (2C)
• Amongst KTX recipients who are HBcAb +ve, if HBsAb are <100 IU/mL, then vaccination considered to boost the protective titre & minimise the risk of reactivation. (2C)
• All prospective SOT recipients should receive a high dose, accelerated vaccine schedule. (2C)
• If initial HBV vaccination schedule failed, a second series given. (2C)
BTS recommendations for hepatitis B and solid organ transplantation 2018:
All patients being worked up for SOT must be tested for HBsAg, HBsAb (absolute titres) and HBcAb.
All HBsAg positive patients must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
HDV RNA testing must be performed in patient with positive HDV serology positive or equivocal.
Patient and donors with HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
Patients with advanced HBV-related liver disease requiring another organ transplant should be considered for combined transplantation after careful consideration of the potential risks and benefits.
Pre-transplant management of HBV:
Individuals undergoing non-liver SOT who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
Use of HBcAb Positive or HBsAg Positive Donors:
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis.
If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1- The HBsAg-positive recipient
2- The HBV-immune recipient (including both naturally immune and vaccine-
induced immunity)
3- The HBV non-immune recipient.
Prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative.
Recipient must be treated with entecavir or tenofovir from the time of transplantation
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
Preventing Recurrence of HBV Post-Transplantation
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent nucleotides analogue (NA) is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory.
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
Monitoring for HBV Recurrence or De Novo Infection:
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
HBV Vaccination and Solid Organ Transplantation
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation.
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule.
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
I make note of your interpretation of serological and genotyping testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your well-structured reply that is a very clinically oriented summary.
HBV is a Hepadnaviridae hepatotrophic DNA virus.
The World Health Organization estimates that 257 million people worldwide are infected with it, causing 600,000 deaths annually from end-stage liver disease and hepatocellular cancer (HCC).
Despite the immunization protocol, HBV infection from vertical transfer from mother to child or horizontal transmission from unsafe medical practice is rising.
Up to 90% of infants infected develop chronic infection, while 30% of pre-five-year-olds do.
Sexual, nosocomial, and blood-borne adult-to-adult transmission can occur (the latter often in intravenous drug users). Less than 10% persistent infection.
HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
HBV DNA viral loads are typically >107 log IU/mL, and HBeAg positivity is associated with an absence of HBeAb. Manifest between the ages of 20 and 30. Liver biopsy showing modest inflammation and fibrosis but normal ALT levels. There’s no need for medical treatment.
HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” or “immune active” or “immune elimination phase”).
HBeAg positive with persistent or intermittent increase in ALT and fluctuating HBV DNA levels that are typically lower than HBeAg positive chronic infection. Asymptomatic inflammation and fibrosis caused by the immune system leading to liver cirrhosis. May result in decompensated cirrhosis of the liver or abrupt liver failure. Antiviral therapy for patients with prolonged phase and severe liver fibrosis as determined by liver biopsy.
HBe Antigen Negative Chronic Infection (previously called “inactive phase”)
HBV DNA levels are typically <2000 IU/mL with negative HBeAg, positive HBeAb, and normal ALT values. Age at HBV acquisition affects the rate of HBe antigen seroconversion, which results in the establishment of chronic HBeAg-negative infection. HBV genotype also has a major influence: for example, people with genotype B seroconvert more than those with genotype C. In children under the age of three, the annual seroconversion rate is above 2%, whereas in early adulthood, the rate is 12%. Up to 8% of patients may have reversion to e antigen positive, however the underlying mechanism is unclear. The risk of developing cirrhosis and/or HCC is significantly increased in people who have later HBeAg seroconversion . This is particularly true for individuals over the age of 40 and could be due to a lifetime of exposure to subclinical hepatic inflammation.
HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”)
HBV DNA levels lower than HBeAg +ve hepatitis, often >2000 IU/mL and commonly >20,000 IU/Ml.There is an increase in serum ALT levels, which is highly variable. Damage to the liver can quickly lead to cirrhosis and HCC. Serum HBV DNA levels have been demonstrated to directly correlate with the risk of HCC in such patients through long-term follow-up studies. Antiviral treatment is the mainstay of treatment.
Indications for Transplantation for HBV-Related Disease
Acute fulminant hepatitis B patients should be treated in a liver center. (1C)
Fulminant hepatitis B patients should consider liver transplantation.
Consider tenofovir or entecavir for early nucleoside analogue (NA) antiviral treatment. (2B) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma guidelines
Specialist liver units should treat hepatitis B-related decompensated cirrhosis (1C)
Decompensated cirrhosis patients with HBV DNA need prompt NA antiviral treatment (s). First-line antivirals entecavir and tenofovir should be taken forever. (1A) Patients with hepatitis B cirrhosis and a UKELD score >49 or HCC within UK NHSBT guidelines should be listed for liver transplantation. (2A)
Selection of donor and recipient Guidelines
Before being considered for liver transplantation, potential patients must be treated with entecavir or tenofovir and reach undetectable HBV DNA levels.
Recipients should be counseled if a donor has a history of or is currently infected with HBV.
Donor livers with negative HBsAg and positive HBcAb can be used for liver transplantation, but lamivudine should be administered prophylactically beginning at the time of transplantation and continuing permanently.
HBsAg-positive donor livers may be transplanted into HBsAg-positive recipients who are HDV-negative.
In emergency instances, HBsAg-positive livers can be transplanted to HBsAg-negative recipients, providing they begin treatment with entecavir or tenofovir immediately after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
From the moment of transplantation, HBV/HDV recipients must undergo HBIg/NA prophylaxis. HBV/HDV co-infected patients cannot receive organs from HBsAg-positive donors – HBV infection treatment must involve a hepatologist. Hepatitis B immunoglobulins as HBV prophylaxis if HIV antivirals are discontinued prior to surgery. After HIV antiviral medication is reinstated, HBV prophylaxis will be identical to HBV prophylaxis.
Preventing Recurrence of HBV Post-Transplantation
Using HBIg and/or a NA beginning at the time of transplantation. In instances with low risk for post-transplant HBV recurrence, HBIg-free regimens can be utilized. -In cases with high risk, HBIg and NA can be used for life.
For people with a history of HBV infection who are at risk of HBV reactivation following a non-liver transplant, a limited (6-12 month) course of preventive antiviral therapy may be recommended.
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Lifelong antiviral therapy in the form of Entecavir or Tenofovir is recommended as first-line therapy. HBV DNA and HBsAg should be tested every three months for the first year, and then every six months thereafter (1C)
Solid Organ Transplantation and HBV Vaccination
HBV-naive solid organ transplant candidates must be vaccinated (time allowed) and their reaction monitored. (1C) If HBsAb are <100 IU/mL in HBcAb-positive renal transplant recipients, immunization may reduce reactivation risk. (2C) Solid organ transplant candidates should receive high-dose, expedited vaccines. (2C) Provide a second HBV immunization series to nonresponders. (2C)
I like your well structured detailed summary. I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding treatment.
Hepatitis B Virus (HBV) is a hepatotrophic DNA virus that belongs to the Hepadnaviridae family of viruses.
It is a major human pathogen and is estimated by the World Health Organisation to infect 257 million people worldwide, and results in an estimated 600,000 deaths every year through complications of end stage liver disease and hepatocellular carcinoma (HCC).
The number of individuals who are chronically infected with HBV is increasing, despite the vaccination protocol, chronic HBV infection result from either vertical transmission from mother to child or horizontal transmission through unsafe medical practice.
Infection in infants results in chronic infection in up to 90% of cases, whereas approximately 30% of children infected before the age of five develop chronic infection.
Adult-to-adult transmission can also occur through sexual, nosocomial or blood borne transmission (the latter often in intravenous drug users). Results in less than 10% chronic infection.
HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
HBeAg positive and HBeAb negative with HBV DNA viral loads generally >107 log IU/mL.
Occur during the first 20-30 years of life.
Normal ALT level, and no or mild inflammation and fibrosis by liver biopsy.
No treatment needed.
HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” or “immune active” or “immune elimination phase”).
HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive chronic infection.
Asymptomatic, but immune mediated inflammation and fibrosis leading to liver cirrhosis.
May lead to decompensated liver cirrhosis or acute liver failure.
Anti viral therapy for prolonged phase and those with advanced liver fibrosis by biopsy.
HBe Antigen Negative Chronic Infection (previously called “inactive phase”).
HBeAg negativity, HBeAb positivity with normal ALT levels and HBV DNA levels being characteristically <2000 IU/mL. HBe antigen seroconversion rates, leading to the development of HBeAg negative chronic infection, are determined by the age at the time of acquisition of HBV. HBV genotype also has a significant influence: for example, those with genotype B seroconvert more than those with genotype C [16]. The annual seroconversion rate is ><2% in children younger than three years of age, whereas the equivalent rate is 12% in early adulthood [2]. Reversion to e antigen positivity can occur in up to 8% of patients but the mechanism behind this is poorly understood [17]. Individuals who undergo later HBeAg seroconversion have a much higher likelihood of developing cirrhosis and/or HCC [18]. This is especially true aged >40 years old and may reflect the lifetime exposure to subclinical hepatic inflammation. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).
HBV DNA levels >2000 IU/mL and frequently >20,000 IU/Ml, usually lower than HBeAg +ve hepatitis.
Serum ALT levels are raised and can fluctuate significantly.
Liver damage can progress rapidly towards cirrhosis and HCC.
Long term follow-up studies have shown that the risk of HCC is directly correlated to serum HBV DNA levels in such patients.
Antiviral therapy forms the cornerstone of management
Recommendations:
– All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B).
– All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B).
– HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B).
– Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B).
– All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C).
Indications for Transplantation for HBV-Related Disease:
Acute Fulminant Hepatitis B
– Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C).
– Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A).
– Early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B).
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
– Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C).
– Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A).
– Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
– Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
– All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B).
– Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B).
Use of HBcAb Positive or HBsAg Positive Donors General Recommendations
– The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C).
– All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded).
HBcAb positive donation for liver recipients
– The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C).
– When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B).
– When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A).
– If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient.
2. the HBV-immune recipient.
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
– HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C).
– If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D).
– All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B).
– Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C).
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
– The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A).
– If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C).
– When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C).
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
– HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C).
– HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C).
– A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D).
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period.
– After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C).
– For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C).
Preventing Recurrence of HBV Post-Transplantation
– HBsAg positive individuals are at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B).
– Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C).
– Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; (HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected) although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B).
– Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B).
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
– All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C).
– Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C).
– Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B).
Monitoring for HBV Recurrence or De Novo Infection
– HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C).
– Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded).
HBV Vaccination and Solid Organ Transplantation
– All prospective solid organ transplant recipients who are HBV naive must be vaccinated and the response documented. (1C).
– Liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C).
– Renal transplant recipients who are HBcAb positive, if HBsAb are < 100 IU/ml, vaccination should be done to boost the titer and minimize the risk of reactivation.(2C).
– All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C).
– Those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C).
I like your well structured detailed summary. I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding treatment.
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb
HBsAg positive– They should unergo HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
HDV positive or equivocal– Perform HDV RNA testing
HBcAb positive but HBsAg negative- HBV DNA and HDV serology testing to exclude occult HBV or HDV infection
HBcAb but HBsAg negative– Perform HBV DNA testing to exclude the possibility of occult HBV infection
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 (The United Kingdom Model for End-Stage Liver Disease)or with HCC within criteria.
HBV and Other (Non-Liver) Transplantation
Consider for combined transplantation after careful consideration of the potential risks and benefits
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
HBcAb Positive or HBsAg Positive Donors
All recipients should be counselled
HBcAb positive donation for liver recipients
Can be allocated to –
HBsAg-positive recipient
HBV-immune recipient
HBV non-immune recipient
HBsAg Positive Donation for Liver Recipients
Can be donated to HBsAg positive recipients only.
Preventing Recurrence of HBV Post-Transplantation
Those at high risk of recurrence should have combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT-
Check adherence with NA prophylaxis
Lifelong antiviral therapy with Entecavir or Tenofovir
HBV Vaccination and SOT
All prospective HBV naive must be vaccinated
Renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/ml.
I make note of your interpretation of serological testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your summary.I note that you have explained how a donor with evidence of past infection of HBV in relation to the decision -making necessary for transplantation.
· During work up for recipient with SOT: must be tested for HBsAg, HBsAb and HBcAb (1B)
ü If HBsAg +ve: we must do: HBeAg, HBeAb, HBV PCR (markers of active disease)and HDV Ab serology.
ü If HDV serology is positive or equivocal: we must do HDV RNA (PCR).
ü If HBcAb positive and HBsAg negative (past infection): must do HBV PCR and HDV serology to exclude occult HBV or HDV infection.
· Donors (positive for HBcAb but HBsAg negative) (indicating past HBV exposure) must have HBV PCR testing to exclude occult HBV infection.
· Liver transplantation in HBV infection is either:
o Fulminant hepatic failure (Early treatment with nucleot(s)ide analogues (NA) as tenofovir or entecavir may promote recovery, shorten disease duration and improve transplant free survival).
o Chronic decompensated liver disease (with life-long antiviral as (tenofovir or entecavir).
· For SOT as kidney in HBV positive recipients:
o Treatment with 1st line antiviral therapy as (tenofovir or entecavir) must be completed before transplantation, till undetectable HBV DNA level.
· Use of HBcAb Positive or HBsAg Positive Donors(? past infection) for kidney transplantation:
o can be used for any recipient, after counseling of the recipient.
o If HBcAb positive donor is used, prophylaxis for 6 months post- transplantation with lamivudine may be given, but the risk of transmission is very low.
· While In liver transplantation:
o Positive for positive as (HBsAg positive is used only for HBsAg positive recipients and in emergency situations for those with HBsAg negative).
o The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient.
· HBV Recurrence or De Novo Hepatitis B after liver transplantation:
o Monitoring is indicated in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor.
o Monitor by HBV DNA and HBsAg every 3 months in the first year and thereafter every 6 months regardless prophylaxis regimen.
o HBV recurrence: check adherence to NA prophylaxis.
o Resistance testing in special lab.
o Lifelong antiviral therapy is recommended for -liver transplantation.
o Entecavir or Tenofovir are recommended as first line treatment. Tenofovir is used in case of previous lamivudine exposure
· HBV vaccination in renal transplantation:
o All HBV naive potential SOT recipients must be vaccinated (time permitting) and the response documented.
o Renal transplant recipients who are HBcAb positive, if HBsAb are < 100 IU/ml should receive booster dose to prevent reactivation post transplantation.
o If patient fails to respond to the initial HBV vaccine, a second series should be given.
I like your well structured detailed summary. I note that you have explained how a donor with evidence of past infection of HBV in relation to the decision -making necessary for transplantation.
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Phases of Chronic Hepatitis B Infection ———————————————-
HBeAg positive chronic infection
HBeAg status Positive
HBeAb status Negative
ALT levels Normal
HBV DNA Levels Very high
Histological liver damage None
HBeAg positive chronic hepatitis
HBeAg status Positive
HBeAb status Neg or pos
ALT levels high
HBV DNA Levels Usually high
Histological liver damage Yes
HBeAg negative chronic infection
HBeAg status Negative
HBeAb status positive
ALT levels Normal
HBV DNA Levels <2000 IU/mL
Histological liver damage None
HBeAg negative chronic hepatitis
HBeAg status Negative
HBeAb status positive
ALT levels high
HBV DNA Levels >2000 – >20000 IU/mL
Histological liver damage Yes
HBV serological profiles and interpretation
——————————————————————– No evidence of current or past, controlled HBV infection. No immunity to HBV.
HBsAg negative
HBcAb negative
HBsAb negative
Evidence of past HBV infection and immunity.
HBsAg negative
HBcAb positive
HBsAb positive
Evidence of vaccine-induced immunity.
HBsAg negative
HBcAb negative
HBsAb positive
Consistent with acute HBV infection.
(Note: IgM HBcAb may be positive in HBV reactivation)
HBsAg positive
HBcAb positive
IgM HBcAb positive
HBsAb negative
Evidence of chronic HBV, if confirmed on two samples six months apart
HBsAg positive
HBcAb positive
IgM HBcAb negative
HBsAb negative
HBeAg positive/negative
HBeAb negative/positive
Antiviral treatment is indicated in —————————————-
A- • Fulminant hepatitis B
B- • Severe AHB – based on the presence of at least two of the following criteria: – bilirubin >100 µmol/L – international normalised ratio (INR) ≥1.6 – hepatic encephalopathy
C- • Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
D- • Immunocompromised host
The criteria for listing for liver transplantation
———————————————————————–for acute liver failure related to hepatitis B must include
A- hepatic encephalopathy and:
B- Prothrombin time >100 seconds
or INR >6.5
or
C- • Any three from:
– age >40 or <10 years
– jaundice to encephalopathy time >7 days
– serum bilirubin >300 µmol/L
– prothrombin time >50 seconds or INR >3.5
Antiviral Treatment
——————————
•1- As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
. 2- Current treatment guidelines consider NAs or (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis
3- Decompensated Hepatitis B Cirrhosis and —————————————————-Hepatocellular Carcinoma ——————————-
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
———————————————————————
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive ———————————————–Donors
————-
: • The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity)
3. the HBV non-immune recipient. (2C)
HBcAb Positive and HBsAg Positive Donation —————————————————-for Non-Liver Solid Organ Recipients
———————————————————-
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
• When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Preventing Recurrence of HBV Post- —————————————- -Transplantation:
—————————
• In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B):
• Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
• Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
• Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo ————————————————–Hepatitis B after Solid Orgast Transplantation —————————————————-
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
• Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo —————————————————Infection ————
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
HBV Vaccination and Solid Organ —————————————Transplantation ——————
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
• All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
• In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I note that you have explained how a donor with evidence of past infection of HBV in relation to the decision -making necessary for transplantation. I like your well structured detailed summary. I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding treatment.
Summary HBV Biology and Disease For recipient of solid organ transplant
• all receipient of solid organ transplant must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• if recipient found to be HBsAg positive the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
•if HDV serology is positive or equivoca HDV RNA testing must be performed. (1B)
• if recipient found to be HBcAb positive but HBsAg negative (past infection) do HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B) For donor
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) do HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B guidelines they recommend that:
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver center. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B
• As early antiviral treatment with nucleot(s)ide analogues (NA), treatment with tenofovir or entecavir should be strongly considered. (2B) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
guidelines recommend that:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
they suggest that
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A) Selection of donor and recipient Guidelines recommend that
Potential recipients of liver transplantation should be treated with entecavir or tenofovir and achieve undetectable HBV DNA level before being considered for liver transplantation.
Recipients should be counseled about a donor who had a past or current HBV infection.
HBsAg negative, HBcAb positive donor liver can be used for liver transplant, but prophylactic lamivudine should be given from the time of transplant and continued indefinitely.
HBsAg positive donor livers can donate to HBsAg positive recipients if the recipients are HDV negative.
In case of urgent situations, HBsAg positive liver can be given to HBsAg negative recipient, provided they are treated with entecavir or tenofovir from the time of transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation -HBV/HDV recipients need to receive a combination of HBIg/NA prophylaxis from time of transplantation.
– HBV/HDV co-infected recipients cannot receive organs from HBsAg positive donors
-hepatologist need to be involved in HBV infection treatment.
-HBIg as HBV prophylaxis if HIV antivirals are stopped in the peri-operative period. After HIV antiviral treatment is reintroduced the HBV prophylaxis will be the same as that used for HBV . Preventing Recurrence of HBV Post-Transplantation By using HBIg and/or a NA from the time of transplantation.
-For low risk cases for post-transplant HBV recurrence, HBIg free regimen can be used
-For high risk cases HBIg and NA can be used lifelong
– For those with past HBV infection are at risk of HBV reactivation post-non-liver transplant can be considered for a limited (6-12 months) course of prophylactic antiviral treatment. Treatment of HBV Recurrence or De Novo Hepatitis B after SOT -lifelong antiviral therapy in the forum of Entecavir or Tenofovir are advised as first line treatment Monitoring for HBV Recurrence or de novo infection
HBV DNA and HBsAg should be tested every 3 months in the first year then every 6 months(1C)
HBV Vaccination and Solid Organ Transplantation All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C) Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C) All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C) In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
1-All transplant candidates must be tested for HBsAg, HBsAb (absolute titres) and HBcAb . (1B)
2- All HBsAg positive transplant candidates must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
3-Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
4-All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
5-HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
HBV and other (NONE-LIVER) TRANSPLANTATION;
————————————————————————–
The guidelines suggest that;
Candidates with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
PER-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUAL BEING CONSIDERED OR TRANSPLANTATION ;
——————————————————————————————————-
The guidelines recommend that:
1-All HBsAg positive candidates being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
2-Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
USE OF HBcAb POSITIVE or HBsAg POSITIVE DONORS;
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The guidelines suggested that:
1-The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
2-All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb POSITIVE and HBsAg POSITIVE DONATION FOR NON-LIVER SOLID ORGAN RECIPIENTS ;
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The guidelines recommend that:
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
The guidelines suggest that:
1- If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
2-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
MANAGEMENT of CO-INFECTION (HDV, HCV, HIV) and TRANSPLANTATION ;
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The guidelines recommend that:
1- HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
2- HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
3-A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
4-HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
The guidelines suggest that:
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
PREVENTING RECURRENCE of HBV POST TRANSPLANTATION;
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The guidelines recommend that:
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
The guidelines suggest that:
1-Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
2- Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are;
a- HBV DNA positive at time of transplant.
b- HBeAg positive patients.
c- Those transplanted for hepatocellular carcinoma
d- Those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
3- Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
TREATMENT of HBV RECURRENCE or De Novo Hepatitis B after SOLID ORGAN TRANSPLANTATION ;
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The guidelines recommend that;
1-All candidates with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
2-Lifelong antiviral therapy is recommended for all candidates with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
3-Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
MONITORING for HBV RECCURRENCE or De Novo INFECTION;
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The guidelines recommend that;
1-HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
2-Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
HBV VACCINATION and SOLID ORGAN TRANSPLANTATION ;
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The guidelines recommend that;
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
The guidelines suggest that;
1-Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
2- Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
3-All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
4- In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I like your well structured detailed summary. I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
Guidelines for Hepatitis B & Solid Organ Transplantation
HBV Biology and Disease:
Any SOT candidates should be tested for HBsAg, HBs Ab & HBc Ab (1B).
All SOT candidates with HBsAg +ve should be tested for HBe Ag, HBe Ab, HDV Ab & HBV DNA level, (1B).
Positive or equivocal HDV serology patients must undergo HDV RNA, (1B).
All potential donor or recipients with HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
Indications for Transplantation for HBV-Related Disease:
Acute Fulminant Hepatitis B:
Recommendations:
Must be managed in a specialist liver Center (1C)
Liver transplantation must be considered in patients with fulminant hepatitis B (1A)
Suggestion:
As early antiviral treatment with NA may promote recovery, shorten disease duration, and improve transplant free survival in severe Acute HBV, treatment with Tenofovir or Entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma Recommendations:
Should be treated in specialist liver units as antiviral therapy is complex and patients may be needing liver Tx (1C)
If HBV DNA is detectable; urgent antiviral treatment with NA(s). Entecavir and Tenofovir are the first line antiviral agents and should be continued indefinitely (1A)
Suggestions:
Listing for liver Tx; in HBV cirrhosis and UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A) HBV and Other (Non-Liver) Transplantation Suggestion:
Advanced HBV-related liver disease requiring another SOT to be considered for combined transplantation (2C) Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Recommendation:
All HBsAg +ve individuals should be treated before transplantation (with Tenofovir or Entecavir), aiming for an undetectable HBV DNA level (1B)
HBsAg +ve individuals undergoing non-liver SOT must have liver disease staging and suppression of HBV DNA by either Tenofovir or Entecavir before transplantation (1B) Use of HBcAb Positive or HBsAg Positive Donors General Recommendations:
Matching a recipient with donor +ve for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
All recipients should be counselled about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded) HBcAb positive donation for liver recipients:
Recommendation:
If liver comes from HBcAb donor
– It can be used for any potential liver recipient. (1C)
– if recipient HBsAg +ve , measures to prevent HBV reactivation should be adopted (1B)
– Prophylactic Lamivudine should be given at the time of transplantation, and should be continued indefinitely, if recipient HBV immune or non-immune (1A)
Suggestion:
If other waiting list priorities permit, the HBcAb positive donor liver should be allocated in the following order:
-The HBsAg-positive recipient
-The HBV-immune recipient
-The HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
Recommendation:
Can be given to HBsAg positive recipients, with HDV negative. (1C)
If urgency demands, can be given to an HBsAg negative patient. (1D)
All recipients must be treated with Entecavir or Tenofovir from the time of transplantation. (1B)
Use of HBIg rarely achieves HBsAg negativity and is not recommended. (1C) HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
Recommendation:
The kidneys, heart and lungs can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion:
-If need demands, HBsAg positive organs can be used for any recipient (individualized risk assessment) (2C)
-When a HBcAb positive donor is used, Lamivudine prophylaxis may be given for 6 months after transplantation, although the risk of transmission is very low. (2C) Management of Co-Infection (HDV, HCV, HIV) and Transplantation Recommendations:
– HBV/HDV recipients; should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
– HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
– Peri-operative management plan of the HIV and HBV infections should be agreed by the MDT (1D)
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
Suggestion:
– For HBV/HDV recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C) Preventing Recurrence of HBV Post-Transplantation Recommendation:
– In HBsAg positive individuals; the use of HBIg and/or a potent NA at the time of transplantation. (1B)
Suggestion:
– Early withdrawal of HBIG or HBIG-free prophylaxis in low risk recipients (2C)
– Life-long combination HBIG and NA for individual at high risk for HBV recurrence (2B)
– Post-non-liver transplant with past HBV infection (HBcAb positive alone) are considered for (6-12 months) course of prophylactic antiviral treatment; with monitoring for recurrence (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT Recommendation:
– Review of adherence with NA prophylaxis and test for resistance (1C)
– Lifelong antiviral therapy for all individuals with HBV recurrence or de novo HBV (1C)
– Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B) Monitoring for HBV Recurrence or De Novo Infection Recommendation:
– HBV DNA and HBsAg every 3 months in the first year and then every 6 months (1C)
– Shorter interval if non-adherence is suspected. (Not graded) HBV Vaccination and Solid Organ Transplantation Recommendation:
• All HBV naïve recipients must be vaccinated, and the response documented. (1C)
Suggestion:
Liver recipients transplanted for HBV; vaccination cannot recommend as routine. (2C)
Renal recipients if HBsAb are <100 IU/mL, vaccination is recommended. (2C)
All recipients should receive a high dose, accelerated vaccine schedule. (2C) Second vaccination series considered if fail non -response documented (2C)
I like your well structured detailed summary. I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
All transplant recipients should be screened for HBV using HBs Ag, HBsAb (titer) and anti-HBc, and if HBsAg positive the patient should do HBeAg, HBeAb HBV PCR
Isolated anti-HBc positivity (HBsAg negative) may be seen in case of early infection (window period), occult infection or previous infection, in this case HBV PCR should be done to exclude occult HBV infection.
HDV Ab should be done for all transplant recipients especially those with isolated anti-HBc positivity (HBsAg negative) and if positive or equivocal, HBV PCR should be done.
Patients with HBV related liver disease should be considered for liver transplantation in case of fulminant liver failure or decompensated liver cirrhosis and HCC after the use of antiviral therapy (tenofovir or entecavir) started before transplantation (if there is detectable PCR) aiming at negative PCR before proceeding to transplantation
HBsAg positive patients who are candidate for non-liver transplant should proceed to transplantation after the use of antiviral therapy (tenofovir or entecavir) started before transplantation (if there is detectable PCR) aiming at negative PCR before proceeding to transplantation
Patients with HBV related advanced liver disease that are candidate for non-liver transplant, should be considered for dual transplantation
Donors with HBsAg (-) anti-HBc (+) are routinely accepted whatever the immunization state of the recipient due to negligible risk associated with this seropositivity, although 6 months of lamuvidine can be prescribed
Donor with HBsAg (+) can be accepted as case by case after evaluation of the risks and benefits
HBV/HDV recipients should not receive HBsAg positive donor organs, and a combination of HBIg and antiviral should be given at the time of transplantation. (1C), after 1 year HBIg can be withdrawn
HBV/HIV recipients should recive HBIg only if HIV antivirals are suspended in the peri-operative period.
HBsAg positive recipients with high risk of recurrence should receive HBIg in combination with antiviral therapy, after 1 year HBIg can be withdrawn. Previous data suggest lifelong combinaltion therapy in patietns who have positive HBV PCR at the time of transplant, HBeAg positive patients, those transplanted for HCC or patietns with HIV co-infection although most of the data supporting use in these
Recipients with isolated HBcAb positive may be considered for antiviral prophylaxis for 6-12 months to prevent viral replication after non liver transplantation or monitoring
Regular check of serum ALT, HBV DNA, and HBsAg every 3 months in the first year post transplantation then every 6 months in HBsAg positive liver transplant recipients or patients receiving a graft from a HBcAb positive donor.
Monitoring of antiHBs Ab yearly and if < 10 a booster dose should be given
Reactivation is diagnosed once there is detectable HBV DNA or positive HBsAg
Hepatitis is diagnosed once there is elevation of serum ALT more than 3 times the ULN
Any patient develop either reactivation or denovo HBV infection are candidate for lifelong antiviral therapy
Antiviral therapy includes Entecavir or Tenofovir with preference of Tenofovir in case of previous lamivudine exposure.
Vaccination is indicated in all transplant recipients who are HBV negative, and in renal transplant recipients if HBcAb is positive and HBsAb are <100 IU/mL, to decrease the risk of reactivation. And if the first series is not effective a n second series should be recived
I make note of your interpretation of virology reports in relation to timings of test and viral load pertaining to HBV infections I like your detailed well-structured summary.
Guidelines for Hepatitis B & Solid Organ Transplantation
1. HBV Biology and Disease
i. All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
ii. All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
iii. HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
iv. Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
v. All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C) 2. Indications for Transplantation for HBV-Related Disease
a) Acute Fulminant Hepatitis B.
The criteria for listing for liver transplantation for acute liver failure related to hepatitis B must include hepatic encephalopathy and:
i. Prothrombin time >100 seconds or INR >6.5 or
ii. Any three from:
· age >40 or <10 years
· jaundice to encephalopathy time >7 days
· serum bilirubin >300 μmol/L
· prothrombin time >50 seconds or INR >3.5
b) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma. 3. HBV and Other (Non-Liver) Transplantation: it is suggested that;
· Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C) 4. Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
a) All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
b) Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B) 5. Use of HBcAb Positive or HBsAg Positive Donors General Recommendations; We suggest that:
a) The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
b) All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded) 6. HBcAb positive donation for liver recipients We recommend that:
a) The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
b) When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
c) When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A) We suggest that
If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
a) the HBsAg-positive recipient
b) the HBV-immune recipient (including both naturally immune and vaccine-induced immunity)
c) the HBV non-immune recipient. (2C) 7. HBsAg Positive Donation for Liver Recipients We recommend that:
a) HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
b) If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
c) All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
d) Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C) 8. HBsAg Positive Donation for Liver Recipients We recommend that:
a) HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
b) If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
c) All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
d) Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C) 9. HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients We recommend that:
· The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A) We suggest that:
· If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
· When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C) 10.Management of Co-Infection (HDV, HCV, HIV) and Transplantation We recommend that:
a. HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
b. HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
c. A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
d. HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C) We suggest that:
· For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C) 11.Chapter 9: Preventing Recurrence of HBV Post-Transplantation We recommend that:
· In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B) We suggest that:
a) Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
b) Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
c) Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B) 12.Chapter 10: Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation We recommend that
a) All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
b) Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
c) Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B) 13.Monitoring for HBV Recurrence or De Novo Infection We recommend that
a) HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
b) Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded) 14.HBV Vaccination and Solid Organ Transplantation We recommend that
· All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C) We suggest that
a) Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
b) Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
c) All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
d) In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C) 15.Antiviral treatment is indicated in certain subgroups of patients with AHB:
a) Fulminant hepatitis B
b) Severe AHB – based on the presence of at least two of the following criteria:
· bilirubin >100 μmol/L
· international normalised ratio (INR) ≥1.6
· hepatic encephalopathy
c) Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
d) Immunocompromised host
Therapy should be continued for at least three months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss.
Guidelines for Hepatitis B and solid organ transplantation were published in March 2018 by the British Transplantation Society. Its chapters included the following:
Hepatitis B virus (HBV) biology and disease: HBV is a hepatotrophic DNA virus with majority of infections occurring due to unsafe medical practices and vertical transmission. Chronic infection rate in infants, children, and adults is approximately 90%, 30%, and 10% respectively. Four different phases of HBV infection (depending on HBe antigen, HBe antibody, alanine aminotransferase levels, and HBV DNA levels) include HBe antigen positive chronic infection, HBe antigen chronic hepatitis, HBe antigen negative chronic infection, and HBe antigen negative chronic hepatitis. HBsAg testing is cornerstone for HBV infection diagnosis. It is recommended that:
· Test for HBsAg, Anti HBs antibody titres, and anti HBc antibody for all patients being worked up for solid organ transplantation.
· For all potential transplant recipients:
o If HBsAg positive, then test for HBe antigen, Anti HBe antibody, HBV DNA levels, and anti HDV antibody serology.
o If HDV serology is positive or equivocal, get HDV RNA testing
o If HBc antibody positive, get HBV DNA and HDV serology testing done (to rule out occult HBV and HDV infection).
· For all potential organ donors:
o If HBsAg negative and HBc antibody positive, get HBV DNA testing (to rule out occult HBV infection).
Indications for transplantation for HBV related disease: 95-99% of acute HBV infection will recover spontaneously. 1% will progress to fulminant hepatitis with up to 80% mortality.
Acute Hepatitis B:Antiviral treatment is required in fulminant hepatitis B, severe acute HBV infection, immunocompromised patients, and in protracted disease course. Liver transplant should be considered in all patients with fulminant hepatitis. Criteria for listing include hepatic encephalopathy with either prothrombin time, PT >100 seconds (or INR>6.5), or 3 out of 4 criteria including age (>40 or <10 years), serum bilirubin (>300 micromol/L), PT (>50 seconds, or INR >3.5), or jaundice to encephalopathy time >7 days.
Fulminant hepatic failure with HBV infection must be managed in a specialist liver centre and early antiviral treatmentwith nucleot(side analogues (NA), tenofovir or entecavir should be considered.
Chronic Hepatitis B: In patients with chronic HBV infection with increased ALT and HBV DNA >2000 U/ml, NAs or pegylated IFN should be used for treatment.
Decompensated cirrhosis: Patients should be treated in specialist liver unit, and may require antiviral treatment with listing for liver transplant in patients with UKELD score > 49 (predicted 1-year liver disease mortality without transplantation >9%) or UKELD score < 49 with a variant syndrome (diuretic resistant ascites or chronic hepatic encephalopathy).
Hepatocellular carcinoma (HCC): HCC is associated with males, older, Asian or African, positive family history, higher HBV DNA levels, longer duration of infection, cirrhosis, alcohol and tobacco exposure. HCC treatment involves resection if small, single lesion with well-preserved levier function, but is associated with high recurrence rates of 50% and 70% at 3 and 5 years. Liver transplant is indicated if single HCC < 5 cm, or upto 5 tumors with size < 3 cm, or 5-7 cm size without any progression in 6 months. Tumor rupture, AFP >1000, extra-hepatic spread, and macroscopic vascular invasion are contra-indications for transplant.
HBV and other (non-liver) transplantation: Reactivation of HBV is seen with immunosuppression, with 50-94% rates of reactivation after renal transplant. Patients with chronic HBV infection or past HBV infection can undergo solid organ transplantation, and if have HBV-related liver disease, should be considered for combined transplantation after multidisciplinary assessment.
Pre-transplant management of HBV in individuals being considered for transplantation: For liver transplantation, all prospective recipients, who are HBsAg positive, should be treated with antivirals. Tenofovir (in cases of lamuvidine resistance) or entecavir (in cases of adefovir resitance) should be given in doses modified as per creatinine clearance to achieve undetectable HBV DNA levels pre-transplant. For non-liver transplantation in HBsAg positive patient, liver disease should be staged and tenofovir or entecavir should be given (avoid interferon). Monitor HBV DNA levels in HBsAg negative patients with positive HBcAb.
Use of HBcAb positive or HBsAg positive donors in SOT: Appropriate matching of a transplant recipient with a donor positive for HBsAg or HBcAb should be discussed with viral hepatitis specialist, and the recipient should be counselled accordingly.
HBcAb positive liver donor: It should be allocated in order of HBsAg positive patient, then HBV-immune recipient, and last to HBV non-immune recipient. For HBsAg negative liver transplant recipients, if donor is HBV core antibody (HBcAb) positive, then it can be used under cover of prophylactic lamivudine to be given indefinitely (due to increased rates of HBsAg seroconversion, ranging upto 80%). In case of HBsAg positive recipient, standard treatment protocol with HBIg prophylaxis (to prevent HBV reactivation) will suffice.
HBsAg positive liver donor: Such a donor can donate to any recipient (HBsAg negative or HBsAg positive with HDV negative status) who must be treated with entecavir and tenofovir (due to reliable HBV suppression). HBIg use is not recommended as it rarely achieves HBsAg negativity.
HBcAb positive and HBsAg positive non-liver donor: HBcAb positive non-liver organ can be given to any recipient (with lamivudine prophylaxis for 6 months), while HBsAg positive non-liver donor can donate to any recipient. HBsAg positive recipient will be on antivirals, while HBV immune recipients may or may not be given prophylactic antivirals (long-term monitoring for HBsAg appearance would be required). HBV non-immune recipients should be given antivirals.
Management of co-infection (HDV, HCV, HIV) and transplantation: Upto 10% HBV infections have HDV co-infection. HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation. HBsAg positive donors should not be used for HBV/HDV co-infected recipients. There is no effective treatment for recurrent (or acquired) graft HBV/HDV infection, and it rapidly leads to cirrhosis. HCV co-infection will warrant HCV treatment using DAAs, while there is no effect on HBV treatment due to HCV co-infection. HIV con-infection management becomes easy due to tenofovir, which is part of anti-HIV treatment protocols. A multidisciplinary plan for the peri-operative management of each of the HIV and HBV infections should be created and adhered to. HBIg could be used as HBV prophylaxis in the perioperative period.
After post-operative re-introduction of HIV antiviral treatment, HBV prophylaxis approach remains same. For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but only after 24 months of transplant.
Preventing HBV recurrence post-transplantation: Risk factors for recurrence in HBsAg positive recipients include positive HBV DNA, HIV positivity, HDV co-infection, HBeAg positivity, and associated HCC. Such patients should receive HBIg (intravenous 5000 unit/day on alternate days for 1 week) and/or NAs (tenofovir or entecavir) from time of liver-transplant which could be given life-long. Low-risk patienrs (HBeAg negative and HBV DNA negative) can be considered for early HBIg withdrawal, or HBIg –free regimen. HBcAb positive recipient could be considered for 6-12 months of prophylactic antiviral (lamivudine) treatment (or can be monitored for HBV recurrence).
Treatment of HBV recurrence or De novo HBV after SOT: Recurrence implies detectable HBsAg or HBV DNA after transplant in chronic HBV infection. De novo infection implies newly detectable HBsAg or HBV DNA after transplant in those without chronic hepatitis B infection. Patients with HBV recurrence should be assessed for adherence with NA prophylaxis and should be treated with antivirals (entecavir or tenofovir – especially in case of prior lamivudine exposure) lifelong. Resistance testing should be undertaken at a specialist laboratory.
Monitoring of HBV recurrence or de novo infection: HBV DNA and HBsAg should be checked every 3 months for 1 year, and then 6 monthly in HBsAg positive recipient or HBcAb positive donor. The frequency can be increased in case of non-adherence.
Hepatitis B vaccination and SOT: All prospective SSOT recipients should be vaccinated with a high-dose accelerated vaccination schedule and response should be documented (with second series administration, if no response), as successful vaccination decreases risk of de novo infection to 10%. Vaccination for liver transplant recipients (for HBv) is not currently recommended routinely. In HBcAb positive kidney transplant recipients, If HBsAb is <100 IU/ml, then vaccination should be done to increase the antibody levels.
I like your detailed well-structured summary. I note that you have explained how to choose a donor with evidence of past infection in relation to the decision -making necessary for transplantation.
Guidelines for Hepatitis B and Solid Organ Transplantation Summary of the Guidelines HBV Biology and Disease
All potential candidates for SOT should be tested for HBsAg, HBsAb, and HBcAb (1B).
For all positive results, patients should have to do HBeAg, HBeAb, and HDV Ab serology, and HBV DNA levels. (1B).
In HDV-positive serology, potential recipients should have tested for HDV RNA (1B).
Any potential recipient with positive HBcAb with negative HBsAg should be tested for HBV DNA and HDV serology to exclude occult infection (HBV, or HDV). (1B).
All donors with positive HBcAb but negative HBsAg must have HBV DNA to exclude the occult HBV infection. (1C).
Indication for transplantation for HBV-related disease Acute fulminant HB We recommend
Individuals with fulminant HBV infection must be treated in a specialized liver center. (1C).
Liver Tx must be considered in acute fulminant HBV infection in keeping with UK listing criteria defined by NHSBT. (1A).
We suggest
Treatment with tenofovir or entecavir should be strongly considered. (2B).
Decompensated Hepatitis B cirrhosis and HCC We recommend
Decompensated liver cirrhosis should be treated at specialized liver centers, and as treatment is complex, those patients should offer liver transplantation. (1C).
Decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment (entecavir and tenofovir are the first-line antiviral agents. (1A).
We suggest
HB cirrhosis should be listed for liver transplantation and a UKLED score >49 oe with criteria defined in the UK NHSBT guidelines. (2A ).
HBV and other non-liver transplantation We suggest
Combined liver and other organ failure requiring transplantation should be considered with careful consideration of potential benefits/risks. (2C).
Pre-transplantation management of HBV in individuals being considered for transplantation We recommend
All HBsaG-positive potential recipients for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B).
Individuals with potential organ recipients other than the liver, who have HBsAg positive, should have their liver disease staging and should receive either tenofovir or entecavir before transplantation aiming for undetectable DNA level. (1B).
Use of HBcAb-positive or HBsAg-positive donors We suggest that
the appropriate matching of a recipient with a donor positive for HBcAb o HBsAg positive should be discussed with a specialist in viral hepatitis. (2C).
All potential recipients should be counseled about whether they may receive a liver from a donor with past o current HBV infection. (not graded).
HBcAb positive donation for liver recipients We recommend that
HBcAb (HBsAg negative) donor liver can be used for any potential liver recipient. (1C).
When a liver comes from HBcAb positive donor and HBsAg positive recipient, the plan is to reduce the incidence rate of hepatitis reactivation. (1B).
When the liver comes from HBcAb positive but is donated to an HBV immune or non-immune recipient, prophylactic lamivudine should be given from transplantation to b continued indefinitely.
We suggest that
If the other waiting list permit, the hepatitis B core Ab +ve liver should be allocated in the following order;
The HBsAg +ve recipient.
The HBV- immune recipient.
The HBV non-immune recipient.
HBsAg +ve donation for liver recipients We recommend that
HBsAg +ve donor liver can donate to HBsAg +ve recipient, as long as he is known HDV -ve. (1C).
If urgent demands, HBsAg+ve donors can donate to HBsAg -ve recipients. (1D).
All recipients with HBsAg +ve should be treated with tenofovir or entecavir from the time of transplantation. (1B).
Use of HBIg rarely achieves HBsAg negativity and is not recommended. (1C).
HBcAb +ve and HBsAg +ve donation for non-liver SOT We recommend that
The kidneys, heart, and lungs from the HBcAb +ve organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A).
We suggest that
If need demands, the non-liver SOT of the HBsAg +ve organ donor can be used for any recipient, after an individualization of the assessment of risk/benift. (2C).
When HBsAg +ve is used, lamivudine prophylaxis may be given for six months after Tx, although the risk of transmission is very low.
Management of Co-infection (HDV, HCV, HIV) and transplantation We recommend that
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation. (1C).
HBsAg +ve should not use for HBV/HDV co-infection recipients. (1C).
A plan for perioperative management for HIV/HBV infection should be agreed upon by the multidisciplinary team before Tx. (1D).
HBIg could be used for HBV prophylaxis if/when antivirals for HIV are suspended in the perioperative period. after HIV treatment re-started, the approach to HBV prophylaxis is not different from that used for the Tx of HBV mono-infection. (1C).
We suggest
For HBV/HDV infected recipients HBIg withdrawal from the combination, HBIg/NA prophylaxis can be considered, but not within 12 months of Tx. (2C).
preventing recurrence of HBV post-Tx We recommend
In HBsAg +ve individuals (at high risk of recurrence) combination therapy of HBIG and /or a potent NA is recommended from the time of Tx to prevent HBV re-infection post-liver Tx. (1B).
We suggest
Early withdrawal of HGIg or even the use of an HBIg-free regimen is considered in a low risk of pst-Tx recurrence. (2C).
Life-long combination HBIg/NA can be considered in high-risk recipients of HBV recurrence (HBV DNA +ve at Tx, or HBsAg +ve, HCC, HIV co-infection. (2B).
A recipient with evidence of past HBV infection is at risk of HBV reactivation post-non-liver Tx and could be considered for a limited 6-12 months of coarse prophylaxis. (2B).
Treatment of HBV recurrence or De Novo HBV infection after SOT We recommend
All patients with HBV recurrence should be considered for adherence NA prophylaxis, with resistance testing should be undertaken at a specialist laboratory. (1C).
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo HB post-liver Tx.
Entecavir or Tenofovir are recommended as first-line treatment. Tenofovir is used for previous lamivudine exposure. (1B).
Monitor HBV recurrence or de novo infection We recommend
HBV DNA and HBsAg should be monitored every 3 months in the first years and thereafter every 6 months in HBsAg +ve liver Tx recipients or individuals receiving a graft from an HBcAb +ve donor, regardless of treatment or prophylaxis regiment. (1C).
Monitor intervention should be shortened in cases of self-reported or suspected non-adherence. (not graded).
HBV vaccination and SOT We recommend
All prospective SOT recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C).
We suggest
Among liver Tx for HBV, vaccination can be considered as a strategy to develop protective serum titers of HBsAb in some recipients, but not recommended as routine practice. (2C).
Among renal Tx recipients who are HBcAb +ve, if HBsAb is <100 IU/mL, then the vaccination should be considered to boost the protective titer of HBsAb and minimize the risk of reactivation. (2C).
All prospective SOT recipients should receive a high-dose accelerated vaccine schedule, (2C).
In those who fail to respond to the initial HBV vaccination, a second series should be administered. (2C).
Summarise these guidelines
This is the first British Transplantation Society (BTS) guideline of hepatitis B in the transplant setting [Guidelines for Hepatitis B & Solid Organ Transplantation (SOT)], March 2018
HBV Biology and Disease
o All patients being worked up for SOT must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
o All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
o HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
o Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
o All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Phases of Chronic Hepatitis B Infection: (rely on the patient’s HBeAg and HBeAb status, ALT levels, and HBV DNA quantification)
1. HBeAg positive chronic infection: HBeAg positive, HBeAb negative, ALT levels normal, HBV DNA levels very high – classically in the millions, and no histological liver damage (treatment is rarely indicated) 2. HBeAg positive chronic hepatitis: HBeAg positive, HBeAb can be positive or negative, ALT levels is high, HBV DNA Levels usually high, and with histological liver damage with progression to cirrhosis possible (antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis) 3. HBeAg negative chronic infection: HBeAg negative, HBeAb positive, ALT levels normal, HBV DNA Levels <2000 IU/mL, and no histological liver damage (generally not require therapy, regular follow-up is mandatory as reactivation and the development of HBeAg negative chronic hepatitis occurs in 25%) 4. HBeAg negative chronic hepatitis: HBeAg negative, HBeAb usually positive, ALT levels high, HBV DNA Levels >2000 IU/mL and frequently >20000 IU/mL, and with histological liver damage and progression to cirrhosis possible (needs antiviral therapy)
The titre of HBsAb can be variable and levels above 10 miu/mL are protective
HB core alone (HBcAb positive with all other markers negative):
*May indicate
1. past HBV infection
2. passively acquired antibodies (blood transfusion)
3. acute HBV infection (window period)
4. or non-specific reactivity (false positive)
*This is particularly relevant in donors who may have received blood products (HBsAb and HBeAb antibodies may also be passively transferred from blood products)
*HB core alone in the recipient must be further investigated before transplantation (any history of blood products and risk factors for HBV, full HBV serological markers, and HBV DNA (+/- follow-up testing) to clarify the patient’s HBV status)
*Immunosuppression in individuals with past infection can result in the reactivation of HBV and the re-emergence of HBsAg
Reactivation of HBV:
Reappearance of markers of active HBV replication in a patient with previously controlled HBV infection, or an increase in levels of replication compared to previous levels
Depends on:
1. Baseline HBV status
2. Underlying condition
3. Type of immunosuppressive therapy
4. and host immunity
May result from:
1. Loss of immune control of HBV
2. or lack of antiviral efficacy due to the emergence of antiviral resistant variants
May be asymptomatic or associated with a flare of hepatitis in previously minimal or inactive disease, manifesting clinically with acute hepatitis which can progress to acute liver failure and even death if untreated
Serological and virological profile of reactivation may vary depending on the pre-existing profile in the patient
HBV reactivation can occur in:
1. Chronic hepatitis B virus ((exacerbation of chronic hepatitis B virus). The risk of is higher
2. Past HBV (reactivation of past HBV). Reactivation is more likely to occur in those with low or undetectable HBsAb levels and may be preceded by a fall in HBsAb levels over time
3. Patients who were HBeAg negative or had undetectable serum HBV DNA prior to transplant
Hepatitis Delta Co-Infection:
Cannot exist in isolation (Virions are coated in HBsAg)
o Around 5% of HBV infected patients worldwide are co-infected with HDV
o Is more prevalent in South America, Turkey, Eastern Europe and Sub-Saharan Africa (low prevelance in Asia despite the large numbers of HBV-infected people in this continent)
o Either acquired at the time of infection with HBV or can occur as a super-infection
o HDV co-infection results in more rapid progression of liver disease to cirrhosis and HCC, especially as it is difficult to treat
o In cases of HDV co-infection where HBV DNA levels are above 2000 IU/mL or fluctuate above this level, it is generally recommended that HBV replication is inhibited with nucleoside analogues
o A diagnosis of past or current HDV co-infection is dependent on the finding of serum HDV IgG positivity
o Active HDV co-infection is confirmed by HDV RNA positivity
o HDV RNA should be performed in all cases of suspected HDV co-infection rather than relying on serology alone
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B
o Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
o Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A)
o As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe acute hepatitis B, treatment with tenofovir or entecavir should be strongly considered. (2B)
*> 95-99% of adults who acquire acute HBV (AHB) will recover spontaneously and seroconvert to HBsAb without antiviral therapy (1% of cases of AHB progress to fulminant hepatitis, which is characterised by a very high mortality rate (up to 80%), often requiring liver transplantation (OLT))
Indications of antiviral treatment include:
1. Fulminant hepatitis B
2. Severe AHB – two of the following criteria: bilirubin >100 µmol/L, INR ≥1.6, hepatic encephalopathy
3. Protracted disease course – persistent symptoms or marked jaundice for more than 4 weeks after presentation
4. Immunocompromised host
Prompt antiviral administration in patients with severe or fulminant AHB:
1. Shorten disease duration
2. Promote recovery
3. Improve survival
*Antiviral treatment should be started early
*Treatment should be continued for at least 3 months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss
Fulminant hepatitis B:
Liver transplantation should be considered in all patients
The criteria for listing for liver transplantation: hepatic encephalopathy and
prothrombin time >100 seconds or INR >6.5 or any three from: age >40 or <10 years/ jaundice to encephalopathy time >7 days/serum bilirubin >300 µmol/L/ PT >50 seconds or INR >3.5
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
o Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C)
o Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
o Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
Chronic Hepatitis B (CHB):
o The goal of treatment is to prevent disease progression to cirrhosis, HCC and death
o First-line treatment is NAs or pegylated-interferon (PEG-IFN) with serum HBV DNA levels >2000 IU/mL in combination with elevated ALT levels and/or with moderate/severe liver inflammation and/or fibrosis
Decompensated Cirrhosis:
o Poor prognosis in untreated patients (14-35% 5-year survival, compared with 84% in the compensated state)
o Should be treated in specialised liver units
o Start oral NAs, irrespective of serum ALT, HBV DNA and e antigen status (Interferon is contraindicated in cirrhosis because of the risk of potentially life-threatening complications)
Objectives of antiviral treatment:
1. Improvement of liver function
2. Decreased risk of HBV recurrence after transplantation
Criteria for consideration of OLT in the UK include:
1. A projected one year liver disease mortality without transplantation of >9%, predicted by a United Kingdom Model for End-Stage Liver Disease (UKELD) score of ≥ 49 2
2. A variant syndrome (e.g. diuretic resistant ascites or chronic hepatic encephalopathy) in those with a UKELD of <49
Hepatocellular Carcinoma (HCC):
50-60% due to HBV (can occur without cirrhosis, but the majority (70-90%) develops in cirrhotic livers)
Risk factors of HCC in patients with HBV infection:
1. Demographic – male gender, older age, Asian or African ancestry, family history of HCC
2. Viral – higher HBV DNA levels, genotype (C>B), pre-core mutations, longer duration of infection, co-infection with HCV, HIV and HDV
3. Clinical – cirrhosis
4. Environmental – alcohol, tobacco, aflatoxin exposure
HCC surveillance:
1. Six-monthly abdominal ultrasound scans even if HBV DNA is adequately suppressed
2. Serum alpha-fetoprotein (AFP): controversial, six-monthly
Treatment:
Similar to that in other causes of HCC In non-cirrhotic: resection is the treatment of choice for a single lesion In a cirrhotic liver: treatment depends on the size of the lesions, the number of lesions, and the serum AFP concentration. Surgical resection is the first line treatment for patients with solitary HCC and well-preserved liver function
Recurrence is 50% at three years and 70% at five years reported
Liver transplantation: listing
1. A single tumor ≤5 cm diameter
2. Up to 5 separate tumors, all ≤3 cm
3. Single tumor >5 cm and ≤7 cm diameter, with no evidence of tumor progression, no extra-hepatic spread and no new nodule formation over a six month period. Loco-regional therapy +/- chemotherapy may be given during that time
HBV and Other (Non-Liver) Transplantation
o Patients with advanced HBV-related liver disease requiring another organ transplant are considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
Impact of Transplantation on HBV:
o Although some immunosuppressive drugs exhibit anti-HBV properties in vitro, when used in combination with other drugs in the SOT setting, they usually have a net immunosuppressive effect, thus promoting HBV replication
Impact of HBV Infection on Transplant Outcome:
HBsAg positivity is a risk factor for death in renal transplant recipients
HBV may cause de novo membranous glomerulonephritis, potentially impacting on renal function after transplantation
CHB without cirrhosis have excellent outcomes with antiviral therapy alone
HBV reactivation occurred in 4.1% of non-liver SOT patients with evidence of past HBV infection, with a median time to HBV reactivation of 4.7 years () study from Canada. The overall five-year survival was 82%
Risk of HBV Infection in the SOT Recipient:
o The overall risk of HBV reactivation/de novo infection in a SOT recipient without antiviral treatment/prophylaxis is dependent upon the donor and recipient HBV status
Management of SOT Recipient with CHB or Past HBV:
o CHBV and past HBV are not contraindications for SOT
o Should be be referred to a specialist in viral hepatitis for full evaluation
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
o All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
o Individuals undergoing non-liver SOT who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors
o The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
o All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients:
o The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
o When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
o When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
o If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order: 1. the HBsAg-positive recipient 2. The HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. The HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients:
o HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
o If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
o All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
o Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
o The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
o If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit.
o When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
*Use of solid organs from donors with core antibodies (in the absence of HBsAg and regardless of the presence or absence of HBsAb) can transmit HBV infection to the organ recipient (the risk of transmission is very high for liver transplantation and much lower for transplantation of kidneys and thoracic organs)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
o HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
o HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
o A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
o HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
o For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
o In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
o Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
o Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
o Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
o All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
o Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
o Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Definition of hepatitis B recurrence after liver transplantation: detectable HbsAg and/or detectable viral load (HBV DNA) after transplantation for complications of chronic hepatitis B
Definition of de novo hepatitis B infection after OLT: newly detectable HbsAg, and/or detectable HBV DNA, in those without prior CHB (HBcAb negative)
Risk factors of recurrence:
1. Viral resistance (and previous treatment regimens)
2. Patient non-adherence
3. Detectable HBV DNA levels at the time of transplantation
4. Hepatocellular carcinoma
5. HIV 6. Immunosuppression
Monitoring for HBV Recurrence or De Novo Infection
o HBV DNA and HBsAg should be monitored every 3 months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
o Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
Increase the risk of recurrence after liver transplant (OLT):
1. Transplantation for HCC
2. HBeAg positivity pre-OLT
3. HBV viral load >100,000 IU/mL at the time of transplantation
4. Non-adherence (Male gender, lack of social support and mental illness)
HBV Vaccination and Solid Organ Transplantation
o All potential SOT recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
o Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
o Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
o All prospective SOT recipients should receive a high-dose, accelerated vaccine schedule. (2C)
o In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
Timing of Vaccination:
o A series of three doses of HBV vaccine (either plasma-derived or recombinant)
o Healthy subjects will develop HBsAb (with protective serum titres of >10 U/L) in 95-99%
o Poor response in patients with ESRD (60-90%)
o There is an association between the severity of renal impairment and lack of response to the HBV vaccine, therefore, vaccination should be considered early in the course of disease)
o The response to HBV vaccine may be suboptimal in the pre-transplant period and disappointing in the post-transplant period (may be related to immune suppression)
o The loss of protective immunity was significantly more frequent in patients with lower HBsAb titres at the time of transplantation (<100 U/L) compared with those patients with higher titres
Vaccination Method:
o Available recombinant vaccines are HBvaxPro (standard dose 10 µg), Engerix-B (standard dose 20 µg) and Fendrix (standard dose 20 µg)
o Higher-dose vaccine formulations are available for use in patients with ESRD [HBvaxPro® (40 µg/mL standard dose 40 µg) and Fendrix® (40 µg/mL, standard dose 20 µg)]
o An accelerated regimen with 4 doses of the vaccine (HBvaxPro and Engerix-B 40 µg or Fendrix 20µg) given at 0, 1, 2 and 6 months is recommended in ESRD
o If HBV vaccination given after SOT, the standard vaccine schedule with standard-dose vaccines at 0, 1 and 6 months is recommended
o HBsAb titres should be measured 1-3 months after the completion of the vaccination schedule
o In those who fail to respond to the initial vaccination schedule ( antibody titres ⩽10 IU/L), a further vaccine schedule should be administered
Renal Transplantation:
o Significantly higher all-cause mortality (relative risk 2.21, 95% CI 1.56-3.14) and all-cause graft loss (relative risk 1.44, 95% CI 1.26-1.63) in renal transplant recipients with HBV
o Reactivation in patients with past resolved HBV infection (i.e. HBsAg negative/HBcAb positive is around 6.5% (particularly amongst recipients without HBsAb at the time of renal transplantation)
o Transmission of HBV is universal after use of renal grafts from HBsAg positive donors (may also occur from donors who are only HBcAb positive)
o HBV vaccination is recommended in HBV seronegative patients with ESRD
o In patients with past resolved infection (HBcAb positive), vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation
I make note of your interpretation of virology reports in relation to timings of test and viral load pertaining to HBV infections. Your write-up is in a lot of details as if you are writing a chapter.
Guidelines for Hepatitis B & Solid Organ Transplantation (BTS)
HBV Biology and Disease
· All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb.
· All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
· HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
· Any potential transplant recipients or donor found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA testing to exclude occult HBV.
HBV and Other (Non-Liver) Transplantation
· It is suggested that all patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation. Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
· It is recommended that individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation. HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
· It is recommended that the kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
· It is suggested that when a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
· It is recommended that HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
· It is recommended that, a plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation.
Preventing Recurrence of HBV Post-Transplantation
· It is suggested that if HBsAg positive individuals are at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation.
· It is suggested that recipients with evidence of past HBV are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment. Or just monitoring for HBV recurrence without prophylaxis.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
· It is recommended that lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
· Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
Monitoring for HBV Recurrence or De Novo Infection
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor. HBV Vaccination and Solid Organ Transplantation
· It is recommended that all prospective solid organ transplant recipients who are HBV naive must be vaccinated using a high-dose, accelerated vaccine schedule and the response documented.
· It is suggested that liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but not all.
· Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation.
· In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
I like your detailed well-structured summary. I note that you have explained how to choose a donor with evidence of past infection in relation to the decision -making necessary for transplantation.
Hepatitis B is an infectious disease that can lead to progressive liver damage and ultimately liver failure, requiring transplantation. The following are guideline recommendations for Hepatitis B in the setting of solid organ transplantation.
Guidelines and recommendations
All potential SOT recipients must be tested for Hepatitis B markers in serum such as HBsAg, HBsAb and HBcAb.
HDV RNA testing is to be done if HDV serology is positive.
If patient is HBcAb positive but HBsAg negative then HBV DNA and HDV serology is to be done to exclude occult HBV or HDV infection.
If patient has fulminant liver failure associated with hepatitis B then patient should be considered for liver transplantation.
Treatment of fulminant hepatitis B in the early phase with nucleotide or side analogue can promote good recovery, shorten duration of disease and improve survival. Tenofovir and entecavir can be useful in such cases.
Patients with decompensated cirrhosis and detectable HBV DNA should be treated immediately with antivirals such as entecavir and tenofovir and continued indefinitely. It is recommended that the patient is admitted in a specialist liver unit to maintain proper antiviral drug administration.
Potential recipients of liver transplantation should be treated with entecavir or tenofovir and achieve undetectable HBV DNA level before being considered for liver transplantation.
Recipients should be counseled beforehand about a donor who had a past or current HBV infection.
HBsAg negative, HBcAb positive donor liver can be used for liver transplant, but prophylactic lamivudine should be given from the time of transplant and continued indefinitely.
HBsAg positive donor livers can be given to HBsAg positive recipients if the recipients are HDV negative.
In case of urgent situations, HBsAg positive liver can be given to HBsAg negative recipient, provided they are treated with entecavir or tenofovir from the time of transplantation.
HBIg does not achieve HBsAg negativity and is not recommended.
HBV/HDV recipients are to be administered with HBIg/NA prophylaxis from the time of transplant.
HBsAg positive donors are not to be used for HBV/HDV co-infected recipients.
If recipient has HBV recurrence post liver transplant, then two things are to be considered. First is a careful review of whether the patient has adhered to the NA prophylactic regimen. Second would be resistance testing at a specialist lab.
If recipient has HBV recurrence or de novo hepatitis B post liver transplant, then lifelong antiviral therapy is recommended.
Tenofovir is to be used if the patient has previous exposure to lamivudine.
Recipients being treated for HBV should be monitored every three months in the first year post transplant, and every 6 months thereafter, regardless of treatment or prophylactic regimen.
Monitoring intervals are to be drastically shortened in cases of self reported or suspected non adherence to medication.
HBV naive potential recipients must be administered with vaccine.
I make note of your interpretation of virology reports in relation to timings of test and viral load pertaining to HBV infections I like your detailed well-structured summary.
HBV Biology and Disease
– All patients being worked up for SOT must be tested for HBsAg, HBsAb and HBcAb. (1B)
– All HBsAg +ve patients must have: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
– HDV RNA done if recipient HDV serology is positive or equivocal. (1B)
– All potential donor or recipients with HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B Recommendations:
• Must be managed in a specialist liver center. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B (1A) Suggestion;
• As early antiviral treatment with NA may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma Recommendations:
• Should be treated in specialist liver units as antiviral therapy is complex and patients may be need liver Tx (1C)
• If HBV DNA is detectable; urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A) Suggestions:
• Listing for liver Tx; in HBV cirrhosis and UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation Suggestion:
• Advanced HBV-related liver disease requiring another SOT to be considered for combined transplantation (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation Recommendation:
• All HBsAg +ve individuals should be treated before transplantation (with tenofovir or entecavir), aiming for an undetectable HBV DNA level. (1B)
• HBsAg +ve individuals undergoing non-liver SOT must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation (1B)
Use of HBcAb Positive or HBsAg Positive Donors General Recommendations Suggestion:
– Matching a recipient with donor +ve for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
– All recipients should be counselled about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients Recommendation: Ife liver comes from HBcAb donor
– It can be used for any potential liver recipient. (1C)
– if recipient HBsAg +ve , meaures to prevent HBV reactivation should be adopted. (1B)
– Prophylactic lamivudine should be given at the time of transplantation, and should be continued indefinitely, if recipient HBV immune or non-immune (1A)
Suggestion:
– If other waiting list priorities permit, the HBcAb positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients Recommendation:
– Can be given to HBsAg positive recipients, with HDV negative. (1C)
– If urgency demands, can be given to an HBsAg negative patient. (1D)
– All recipients must be treated with entecavir or tenofovir from the time of transplantation. (1B)
– Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients Recommendation:
– The kidneys, heart and lungs can be used for any recipient, and the risk of de novo HBV infection is low. (1A) Suggestion:
-If need demands, HBsAg positive organs can be used for any recipient (individualized risk assessment )(2C)
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for 6 months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation Recommendations:
– HBV/HDV recipients; should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
– HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
– Perioperative management plan of the HIV and HBV infections should be agreed by the MDT (1D)
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
Suggestion:
– For HBV/HDV recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation Recommendation:
– In HBsAg positive individuals; the use of HBIg and/or a potent NA at the time of transplantation. (1B)
Suggestion:
– Early withdrawal of HBIG or HBIG-free prophylaxis in low risk recipients (2C)
– Life-long combination HBIG and NA for individual at high risk for HBV recurrence (2B)
– Post-non-liver transplant with past HBV infection (HBcAb positive alone) are considered for (6-12 months) course of prophylactic antiviral treatment; with monitoring for recurrence (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT Recommendation:
– Review of adherence with NA prophylaxis and test for resistance (1C)
– Lifelong antiviral therapy for all individuals with HBV recurrence or de novo HBV (1C)
– Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection Recommendation:
– HBV DNA and HBsAg every 3 months in the first year and then every 6 months (1C)
– Shorter interval if non-adherence is suspected. (Not graded)
HBV Vaccination and Solid Organ Transplantation Recommendation:
• All HBV naïve recipients must be vaccinated and the response documented. (1C) Suggestion:
• Liver recipients transplanted for HBV, vaccination cannot recommended as routine. (2C)
• Renal recipients if HBsAb are <100 IU/mL, vaccination is recommended. (2C)
• All recipients should receive a high-dose, accelerated vaccine schedule. (2C)
• Second vaccination series considered if fail non response documented (2C)
I like your well structured detailed summary. I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
All SOT candidates should be tested for HBsAg, HBsAb, &HBcAb.
All SOT candidates with HBsAg+ve should be tested for HBeAg, HBeAb, HDVAb & HBV DNA level.
Positive or equivocal HDV serology patients must should undergo HDV RNA.
Any SOT candidates or donor with HBcAb+ve & HBsAg-ve should have HBV DNA & HDV serology to exclude occult infection.
Indications of transplantation for HBV-relaed disease:
Any patient with fulminant hepatic failure due to HBV infection should be treated in specialist liver center å considered for liver transplantation according UK listing criteria.
Antiviral(tenofovir & entacavir) should be stated in severe ABH to enhance recovery, shorten disease duration & improve transplant free survival.
Decompensated liver cirrhosis due to HBV infection treated in specialist center & liver transplantation in addition to starting antiviral urgently which should be used indefinitely if HBV DNA detected.
Patients with liver cirrhosis & UKELD score>49 or have HCC must be enrolled in waiting list for liver transplantation according criteria of NHSBT guidelines.
Patients with advanced HBV-related liver disease & need other organ transplantation are considered for combined transplantation.
Pre-transplant management of HBV infection in transplant candidates:
All patients with HBsAg+ve & listed for liver transplant should be treated with tenofovir or entacavir.
Non liver transplant candidates with HBsAg+ve should undergo liver disease staging & suppression of HBV DNA by antiviral before transplantation.
Use of HBcAb+ve or HBsAg+ve donors:
Matching organ between recipient & donor with HBcAb+ve or HBsAg+ve should be discussed with specialist in viral hepatitis.
All potential candidates should informed during assessment about possibility of receiving a liver from donor with history of past HBV infection.
liver donor with GBsAb+ve(HBsAg-ve) can be offered for ay liver recipient.
In HBcAb+ve donor & HBsAg+ve recipients, prevention of reactivation should be adopted.
Lamuvidin prophylaxis used for HBcA+ve liver donor & immune or non immune recipient from time of transplantation & continued indefinitely.
Order of HBcAb+ve liver donor as follow:
HBsAg+ve recipient.
HBV immune recipient
HBV non immune recipient
HBsAg+ve liver donor can be offered to HBsAg+ve recipient if HDV is negative.
If HBsAg-ve recipient need urgent transplant, a HBsAg+ve liver donor can be used.
All liver transplant recipients with HBsAg+ve donor should be treated with tenofovir or entacavir from time of transplantation.
HBcA+ve & HBsAg+ve donors for non liver SOT recipients:
Kidney, heart & lung from HbcAb+ve donor can be used for any recipient & risk of de novo HBV infection very low.
Post transplant lamuvidin prophylaxis for 6 months used in HBcAb+ve donors.
Non liver SOT donor with HBsAg+ve can be offered to urgently needed transplantation.
Management of co-infection(HDV, HCV,HIV) & transplantation:
HBIg/NA as prophylaxis started from time of transplantation used for any patients with HBV/HDV infection.
HBsAg+ve donors should not offered for any recipients with co-infection HBV/HDV.
Preoperative management of HIV & HBV infection should be done by multidisciplinary team.
HBIg used preoperatively when HIV antiviral stopped ,& HBV prophylaxis as in mono infection of HBV.
HBIg can be withdrawn from HBV/HDV recipients after 1 year post transplantation.
Prevention recurrence of HBV infection post transplantation:
Post transplant recurrence risk is high in HBsAg+ve recipients, so HBIg with or without NA is recommended from time of transplantation.
Low risk recurrence recipient can use early withdrawal or HBIg free prophylaxis.
Life long prophylaxis with HBIg+NA considered for:
HBV DNA +ve at time of transplantation.
HBsAg+ve patients.
Transplant for HCC or HIV infection.
In liver SOT, patients with HBcAb+ve alone can be use antiviral prophylaxis for 6-12 months with monitoring of HBV recurrence.
Treatment of HBV recurrence or de novo HBV after SOT:
All liver transplant recipient with HBV recurrence should be followed carefully for drug adherence & drug resistant tested at specialized center.
All liver transplant recipients with HBV recurrence or de novo infection should be treated for life.
Entacavi & tenofovir are the first line treatment of HBV infection.
Monitoring of HBV recurrence or de novo HBV infection:
HBsAg+ve liver transplant recipients or HBcAb+ve donors should be monitored by HBV DNA & HBsAg every 3 months in first post transplant years & every 6 months after that regardless treatment or prophylaxis use.
Monitoring interval can be reduced in case of self reporting or suspected non adherence.
HBV vaccination & SOT:
All SOT recipients who are HBV naive should be vaccinated before transplantation & their response must be documented.
Liver transplant recipients due to HBV infection can be considered for vaccination to increase serum level of HBsAb, but not recommended as a routine.
Renal transplant recipients with HBsAb<100IU/ml HBV vaccine can be considered.
All potential SOT recipients should receive high dose accelerated vaccine schedule.
Patients failed to achieve response to initial vaccine, a second vaccine series can be given.
I make note of your interpretation of serological and molecular testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections
Summarise these guidelines HBV Biology and Disease
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1BAll HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and hepatitis delta virus ( HDV ) Ab serology, and HBV DNA levels. (1B)
Hepatis delta virus (HDV) RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C) Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation.
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B) Use of HBcAb Positive or HBsAg Positive Donors
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C) • All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C) •
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C) Management of Co-Infection (HDV, HCV, HIV) and Transplantation
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C) HBsAg positive donors should not be used for HBV/Hepatitis Delta Virus (HDV) co-infected recipients. (1C)
A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
HBIg (immunoglobulin )could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV mono infection. (1C). Preventing Recurrence of HBV Post-Transplantation
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent nucleoside analogue (NA ) is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
Life-long combination therapy with HBIG and a potent nucleoside analogue( NA) can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B) Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation.
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B) HBV Vaccination and Solid Organ Transplantation
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I like your well structured detailed summary. I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
Recommendations and suggestions:(Recommendations =1 , suggestions =2)
HBV Biology and Disease
All patients should be tested for HBsAg, HBsAb titres, & HBcAb(1B)
Those who are HBsAg +ve must be tested for: HBeAg, HBeAb, HDV Ab serology, and HBV DNA levels(1B)
Recipients with +ve HDV serology should be checked for HDV RNA(1B)
Recipients with negative HBsAg and +ve HBcAb should be tested for HBV DNA and HDV serology to rule out occult HBV or HDV infection(1B)
Donors who are negative for HBsAg and +vw HBcAb should be tesetd for HBV DNA to rule out occlut HBV(1C)
Acute Fulminant HBV
Manage in a specialist liver center(1C)
Enlist for liver transplantation according to UK NHSBT(1A)
Consider early treatment with tenofovir or entecavir to promote recovery and improve transplant free survival(2B)
Decompensated Hepatitis B cirrhosis and Hepatocelluar Carcinoma
Refer to specialist liver unit(1C)
Tenofovir or entecavir should be given for life(1A)
Consider Liver transplantation according to UK NHSBT citeria
HBV and other Transplantation (non- Liver)
Plan for combined transplantation, weigh the benefits versus the risks(2C)
Pretransplant Management of HBV in Individuals Being Considered for Transplantation
Treat before transplantation with entecavir or tenofovir until undetectable BVV DNA(1B)
Liver disease staging and HBV DNA suppression for non-liver transplantation are mandatory(1B)
Use of HBcAb Positive or HBsAg Positive donors
Refer to liver specialist clinic(2C)
Counseling of recipients is important(not graded)
HBcAb Positive donation for liver recipients
Prophylactic lamivudine should be given to all recipients for life(1A)
If time allows it can be allocated as follows : first priority to HBsAg positive recipient, second priority to HBV-immune recipient and lastly to HBV non-immune recipient(2C)
HBsAg Positive donation for Liver recipients
Provided that the recipient is HDV negative & HBsAg positive(1C)
HBsAg positive donor to HBsAg negative recipients in urgency(1D)
Entecavir is mandatory for all recipients of HBsAg donors
HBcAb Positive and HBsAg positive donation to Non-liver Solid Organ Recipients
HBcAb positive organs can be used for transplantation and the risk of de novo HBV infection is low(1A)
HBsAg positive organs can be use for transplantation in an urgency after assessment of risk and benefits(2C)
In case of HBsAg positive organs, lamivudine should be use for a period of 6 months after transplantation although the risk of transmission is very low(2C)
Management of Co-infection (HDV,HCV, HIV) and Transplantation
HBIg / NA combination are indicated for all HBV/HDV recipients as prophylaxis(1C).
HBIg can be withdrawn from the combination after 12 months posttransplantation (2C)
HBsAg donors are not allowed to donate for HBV/HDV recipients(1C)
Plan for HBV & HIV positive recipients should be discuss with MDT before transplantation(1D)
HBIg should be given when HIV treatment are held in the preoperative period(1C)
Preventing recurrence of HBV posttransplant
Combination of HBIg / NA is indicated for HBsAg positive recipients to prevent re-infection after liver transplantation(1B)
Consider HBIg early withdrawal or HBIg free regimen in low risk recipients(2C)
Long -life combination of HBIg / NA are indicated for high risk group e.g., HBV DNA +ve, HBsAg +ve, History of HCC, & HBV/HIV co-infection(2B)
Consider prophylactic antiviral for 6 to 12 months for a non-liver recipients with evidence of past HBV infection (HBcAb alone) due to risk of HBV reactivation(2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Check adherence to NA prophylaxis & organize resistance testing at specialist laboratory(1C)
Anti-viral therap for life is indicated in this situation(1C)
The firsl line therapy is Entecavir or Tenofovir. Consider Tenofovir in with history of lamivudine treatment(1B)
Monitoring for HBV Recurrence or de novo infection
HBV DNA and HBsAg should be tested every 3 months in the first year then every 6 months(1C)
HBV Vaccination & SOT
All HBV naive recipients should be vaccinated with response captured(1C)
For selected recipients transplanted for HBV to develop protective titres of HBsAb(2C)
Renal recipients who are HBcAb positive and HBsAb < 100 IU/ml to boost the protective titres of HBsAb and reduces the risk of reactivation(2C)
In patients who failed to response to the initial vaccination regimen, another round of vaccination must be considered(2C)
I make note of your interpretation of serological and molecular testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your summary.
HBV Biology and disease
It is recommended that –HBsAg, HBsAb and HBcAb need to be tested for cases prepared for SOT.
– HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels need to be tested for HBsAg positive patients prepared for transplantation
– Potential recipients with positive or equivocal HDV serology need to have HDV RNA testing .
– HBV DNA and HDV serology testing is recommended for potential recipients having HBcAb positive and HBsAg negative to exclude occult HBV or HDV infection.
– HBV DNA test is needed for donors with positive HBcAb and negative HBsAg to exclude occult HBV infection Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B
It is recommended for this group of patients to be manged at specialised centers , Giving antiviral therapy with nucleot(s)ide analogues (NA) can enhance recovery and transplant free survival in severe Acute hepatitis B, treatment with tenofovir or entecavir is highly recommended. Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Those patients need to be treated in specialised liver units and start antiviral treatment with NA(s).
Cases having hepatitis B cirrhosis and a United Kingdom end stage liver disease score (UKELD ) score >49 or with HCC within criteria defined in the UK NHSBT guidelines can be considered for liver transplantation. HBV and Other (Non-Liver) Transplantation
Combined transplantation can be considered for those with advanced HBV-related liver disease requiring another organ transplant Pre-Transplant management of HBV for potential candidates for Transplantation
-HBsAg positive cases prepared for liver transplantation need to be
treated with tenofovir or entecavir before transplantation, to reach undetectable HBV DNA level.
– HBsAg positive candidates undergoing non-liver SOT need liver disease staging and HBV DNA suppression by tenofovir or
entecavir before transplantation . HBcAb Positive or HBsAg Positive Donors
-There inclusion has to be evaluated with viral hepatitis specialist along with conselling.
-The HBcAb positive (HBsAg negative) donor liver can be offered for any possible liver recipient.
– HB c Ab positive donor can donate to HBsAg positive recipient, the standard preventive strategy for HBV reactivation has to be applied.
– Prophylactic lamivudine need to be started at transplantation and continued indefinitely, when a HBc Ab positive donor donates to a HBV immune or non-immune recipient.
-HBsAg positive liver donor can be given to HBsAg positive recipients if HDV is negative.
– HBsAg positive liver can be given to HBsAg negative patient in urgent cases.
– Hepatic recipients from HBsAg positive donor need to be treated with entecavir or tenofovir from the time of transplantation
– HBIg is rarely recommended.
– Kidneys, heart and lungs from the HBcAb positive donors can be donated to any recipient, as de novo HBV infection is low meanwhile lamivudine prophylaxis may be given for 6 months after transplantation. Management of Co-Infection (HDV, HCV, HIV) and Transplantation
-HBV/HDV recipients need to receive a combination of HBIg/NA prophylaxis from time of transplantation.
– HBV/HDV co-infected recipients cannot receive organs from HBsAg positive donors
-MDT need to be involved in HIV and HBV infection treatment.
-HBIg as HBV prophylaxis if HIV antivirals are stopped in the peri-operative period. After HIV antiviral treatment is reintroduced the HBV prophylaxis will be the same as that used for HBV monoinfection. Preventing Recurrence of HBV Post-Transplantation
By using HBIg and/or a NA from the time of transplantation.
-For low risk cases for post-transplant HBV recurrence, HBIg free regimen can be used
-For high risk cases HBIg and NA can be used lifelong
– For those with past HBV infection are at risk of HBV reactivation post-non-liver transplant can be considered for a limited (6-12 months) course of prophylactic antiviral treatment. Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
-Adherence to prophylaxis has to be assessed and resistance has to be tested
-lifelong antiviral therapy in the forum of Entecavir or Tenofovir are adviced as first line treatment Monitoring for HBV Recurrence or De Novo Infection
-HBV DNA and HBsAg need monitoring every 3 months in the first year and then every 6 months in HBsAg positive liver transplant recipients or recipients from a HBcAb positive donor.
-For cases with possible non adherence and self reporting cases monitoring intervals can be shortened. HBV Vaccination and SOT
-All naïve candidates must be vaccinated.
-HBcAb positive cases if HBsAb are <100 IU/mL need vaccination.
All patients being planned for SOT must do the following tests; HBsAg, HBcAb, and HBsAb (absolute titre)
All patients with HBsAg positive and about to undergo KTP must do HBeAg, HBeAb, HDV Ab serology, and HBV DNA
The presence of occult infection must be excluded in patients with HBsAg negative but positive HBcAb and must have an HBV DNA test done.
HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
Indications for Transplantation for HBV-Related Disease
Acute fulminant HBV
Decompensated HBV cirrhosis and HCCC
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Tenofovir or entecavir be used for all potential liver transplant patients with HBsAg positive until the HBV DNA level is undetectable
The staging of the liver disease must be done in non-liver transplantation with HBsAg coupled with the use of tenofovir or entecavir until HBV DNA is undetectable
Use of HBcAb Positive or HBsAg Positive Donors
The appropriate matching method must be discussed with a specialist in viral hepatitis
Proper counseling must be done for the potential recipient to know that they are receiving organs from someone with the current or past infection
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart, and lungs from the HBcAb-positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low
When an HBcAb-positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
The HBsAg donor should not be used in HBV/HDV co-infected recipients
Preventing the Recurrence of HBV Post-Transplantation
HBsAg patients with a high risk of recurrence should be on HBIg/nucleotides analogs from the time of transplantation and this can be given for life
The recipient with evidence of past infection can receive the same treatment for 6-12 months
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation.
All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory.
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
Entecavir or Tenofovir are recommended as first-line treatment. Tenofovir should be used if the patient has previous lamivudine exposure
Monitoring for HBV Recurrence or De Novo Infection
The monitoring of HBsAg and HBV DNA be done every 3 months in the first year post-transplantation, then every 6- months, and also the same in those who received a graft from HBcAb positive donor
HBV Vaccination and Solid Organ Transplantation
All potential SOT recipients who are HBV naive must be vaccinated and the response documented
In KTP who are HBcAb positive, if HBsAb is <100 IU/mL, then the vaccination should be considered to boost the protective titre of HBsAb
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C) •
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
I like your well structured detailed summary. I appreciate your interpretation in relation to the type of disease and corresponding mode of treatment indicated.
These guidelines represent consensus opinion from experts in the field of transplantation in the United Kingdom
For each recommendation the quality of evidence has been graded as:
A (high) -B (moderate) -C (low) -D (very low)
For each recommendation, the strength of recommendation has been indicated as one of: Level 1 (we recommend)
recommendation is a strong recommendation to do (or not do) something where the benefits clearly outweigh the risks (or vice versa) for most, if not all patients
-Level 2 (we suggest)
recommendation is a weaker recommendation, where the risks and benefits are more closely balanced or are more uncertain
– Not graded (where there is not enough evidence to allow formal grading
Hepatitis B virus (HBV) infection is a major risk factor for hepatic dysfunction in solid organ transplant (SOT) recipients
Reactivation of HBV is well described in association with the use of immunosuppressive agents such as B-cell depleting agents (e.g. rituximab), anthracycline derivatives, TNF- inhibitors, cytokine inhibitors and tyrosine kinase inhibitors
Ciclosporin has been shown to inhibit HBV replication
In a hydrodynamic injection mouse model, dexamethasone, ciclosporin and cyclophosphamide were shown to enhance HBV replication, whilst replication was terminated in mice treated with mycophenolate
Rapamycin (an mTOR inhibitor) has been shown to enhance HBV production by inducing cellular autophagy
The use of steroids can induce reactivation of HBV secondary to the stimulatory effect on the glucocorticoid-responsive enhancer region of the HBV genome
. Hepatitis associated with HBV reactivation can lead to liver failure, especially in patients with cirrhosis. Before the introduction of antiviral prophylaxis, the rates of HBV reactivation after renal transplantation ranged from 50 to 94%
post-transplant anti-HBsAb monitoring is not routinely recommended to predict the risk of reactivation.
We suggest that • Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
We recommend that: • The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
We recommend that: In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
We recommend that HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
We recommend that • All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
II. Guidelines for Hepatitis B & Solid Organ Transplantation
==================================================================== Summarise these guidelines
HBV Biology and Disease
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb.
HDV RNA testing must be performed in potential transplant recipients, and any potential transplant recipients found to be HBcAb positive but HBsAg negative must have HBV DNA and HDV serology testing.
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B
Early antiviral treatment with nucleot(s)ide analogues may promote recovery, shorten disease duration and improve transplant free survival in severe AHB.
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Listing for liver transplantation should be considered in patients with decompensated cirrhosis and detectable HBV DNA with urgent antiviral treatment with NA(s).
HBV and Other (Non-Liver) Transplantation
Patients with advanced HBV-related liver disease should consider combined transplantation after careful consideration of potential risks and benefits.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Pre-transplant management of HBV in HBsAg positive individuals should be treated with tenofovir or entecavir before transplantation, aiming for undetectable HBV DNA level.
Use of HBcAb Positive or HBsAg Positive Donors General Recommendations
Potential recipients should be counselled about the possibility of receiving a liver from a donor with HBV infection.
HBcAb positive donation for liver recipients
HBcAb positive donor liver can be used for any potential liver recipient, and prophylactic lamivudine should be given from the time of transplantation to prevent HBV reactivation.
The hepatitis B core antibody positive donor liver should be allocated to three recipients: HBsAg-positive, HBV-immune, and non-immune.
HBsAg Positive Donation for Liver Recipients
HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is HDV negative.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients can be used for any recipient, with low risk of infection and lamivudine prophylaxis for six months after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
HBIg/NA prophylaxis should be used for HBV/HDV co-infected recipients, and a plan for perioperative management should be agreed before transplantation.
HBIg withdrawal from combination HBIg/NAprophylaxis can be considered, but not within 12 months of transplantation.
Preventing Recurrence of HBV Post-Transplantation
Combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
Early withdrawal of HBIG or HBIG-free prophylaxis can be considered in low risk recipients.
Life-long combination therapy can be given to those at high risk.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
Life long antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
Entecavir or Tenofovir is recommended as first line treatment for HBV recurrence after transplantation.
Monitoring for HBV Recurrence or De Novo Infection
Monitoring of HBV DNA and HBsAg should be done every three months in liver transplant recipients, regardless of treatment or prophylaxis regimen.
HBV Vaccination and Solid Organ Transplantation
Vaccination and solid organ transplantation should be recommended for all prospective solid organ transplant recipients who are HBV naive, with vaccination as a strategy to develop protective serum titres of HBsAb and minimise the risk of reactivation.
Vaccination is recommended for renal transplant recipients with HBcAb <100IU/mL to boost protective titre and reduce risk of reactivation.
I like your detailed well-structured summary. I note that you have explained how to choose a donor with evidence of past infection in relation to the decision -making necessary for transplantation.
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors
All potential recipients should be counselled during the assessment process about
the possibility of receiving a liver from a donor with past or current HBV infection.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period.
After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence.
Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
HBV Vaccination and Solid Organ Transplantation
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
Typing whole sentence in bold or typing in capitals amounts to shouting.
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
We urge that: • All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titers), and HBcAb. (1B)
• All HBsAg-positive patients having transplant workups must have the following tests: HBeAg, HBeAb, HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be undertaken in possible transplant patients if HDV serology is positive or ambiguous. (1B)
• All prospective transplant patients found to be HBcAb positive but HBsAg negative (past infection) must undergo HBV DNA and HDV serology testing to eliminate occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (prior HBV exposure) must undergo HBV DNA testing to eliminate the potential of hidden HBV infection. (1C)
HBV Transplantation Indications: Hepatitis B Fulminant
• Hepatitis B-related fulminant liver failure should be treated in a liver center. (1C) NHSBT listing requirements require liver transplantation for fulminant hepatitis B patients. (1A)
Early antiviral therapy with nucleotide analogs (NA) may increase recovery, minimize illness duration, and improve transplant-free survival in severe AHB. Tenofovir or entecavir should be seriously explored. (2B)
Decompensated HBV Cirrhosis and Hepatocellular Carcinoma:
• Hepatitis B patients with decompensated cirrhosis should be treated in liver units since antiviral treatment is complicated and they may be candidates for liver transplantation. (1C)
• Decompensated cirrhosis patients with HBV DNA need prompt NA antiviral therapy (s). First-line antivirals entecavir and tenofovir should be taken forever. (1A)
We recommend listing individuals with hepatitis B cirrhosis and a UKELD score >49 or HCC under UK NHSBT guidelines for liver transplantation. (2A)
HBV and Non-Liver Transplantation:
• Patients with advanced HBV-related liver disease needing another organ transplant may consider combination transplantation after weighing the risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation :
We recommend that: • All HBsAg-positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
HBcAb/HBsAg Positive Donors: General Guidelines:
• A viral hepatitis expert should explore matching an organ recipient with an HBsAg or HBcAb donor. (2C)
• Potential recipients should be informed throughout the screening process that they may get a liver from a donor with HBV infection.
HBcAb-positive liver donation:
• Anybody may receive the HBcAb positive (HBsAg negative) donor’s liver. (1C)
When an HBsAg-positive receiver receives liver from a hepatitis B core antibody-positive donor, the conventional HBV reactivation prevention method should be used. (1B
) When a liver from an HBcAb-positive donor is transplanted to an HBV-immune or non-immune recipient, prophylactic lamivudine should be administered from transplantation and maintained permanently. (1A)
If other waiting list priorities allow, the hepatitis B core antibody-positive donor liver should be distributed as follows:
• HDV-negative HBsAg-positive patients may receive donor’s livers. (1C)
• HBsAg-negative patients may get HBsAg-positive livers in an emergency. (1D)
• HBsAg-positive liver transplant patients must start entecavir or tenofovir treatment. (1B)
• HBIg seldom reduces HBsAg. (1C)
HBcAb/HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
• The kidneys, heart, and lungs from the HBcAb-positive organ donor may be utilized by anybody without danger of de novo HBV infection. (1A)
• After an individual risk-benefit evaluation, the HBsAg-positive donor’s non-liver solid organs may be utilized for any recipient. (2C)
Lamivudine prophylaxis may be administered for six months following transplantation if the donor is HBcAb positive, even if the transmission is unlikely. (2C)
Transplantation and Co-Infection (HDV, HCV, HIV):
HBV/HDV patients should get combined HBV/NA prophylaxis from transplantation. (1C)
HBV/HDV co-infected recipients should not receive HBsAg-positive donors.
(1C)
• Before transplantation, the multidisciplinary team should agree on perioperative HIV and HBV care plans. (1D)
• HBIg may prevent HBV if HIV antivirals are halted during surgery. HBV prophylaxis after HIV antiviral therapy is the same as for HBV mono-infection transplantation. (1C)
• HBV/HDV-infected patients may contemplate HBIg withdrawal from combined HBIg/NA prophylaxis, but not within 12 months of transplantation. (2C)\sC
Post-Transplant HBV Prevention:
• HBIg and/or a powerful NA should be used after transplantation to prevent HBV reinfection in HBsAg-positive patients at high risk of recurrence. (1B)
• Low-risk post-transplant HBV recurrence patients may benefit from early HBIG withdrawal or HBIG-free prophylaxis.
(2C)
• Lifelong combination therapy with HBIG and a potent NA may be given to patients at high risk for HBV recurrence, such as those who are HBV DNA positive at transplant, HBeAg positive, transplanted for hepatocellular carcinoma, or HIV co-infected. Most of the data supporting this use come from retrospective studies in the lamivudine era. (2B)
• Patients with evidence of prior HBV infection (HBcAb positive alone) are at increased risk of HBV reactivation post-non-liver transplant and may benefit from a short (6–12 months) course of preventive antiviral medication. Monitoring for HBV recurrence is also appropriate. (2B)
Recurrence or De Novo Hepatitis B Therapy Following Solid Organ Transplantation:
• All post-liver transplant HBV recurrence patients should carefully assess NA prophylaxis adherence. Specialist labs should test for resistance. (1C)
• All post-liver transplantation HBV recurrence or de novo hepatitis B patients should get lifelong antiviral medication. (1C)
16 • Entecavir or Tenofovir should be used initially. Lamivudine-exposed patients should take tenofovir. (1B)
HBV recurrence/de novo infection monitoring:
HBsAg-positive liver transplant recipients or those getting grafts from HBcAb-positive donors should be examined for HBV DNA and HBsAg every three months in the first year and every six months afterward, regardless of therapy or prophylaxis. (1C)
HBV Vaccination and Solid Organ Transplantation:
• All HBV-naive prospective solid organ transplant patients should be vaccinated (time allows) and the reaction noted. (1C)
• Vaccination may help certain liver transplant patients generate protective serum titers of HBsAb, but it is not advised as a normal practice. (2C)
• If HBsAb is <100 IU/mL in HBcAb-positive kidney transplant patients, immunization may reduce the risk of reactivation. (2C)
• Solid organ transplant candidates should get high-dose, expedited vaccines. (2C)
• A second HBV vaccine series should be given to non-responders. (2C)
Guidelines for Hepatitis B & Solid Organ Transplantation: 1-HBV Biology and Disease: Recommendation; –All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B) –All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B) –HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B) –Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B) –All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C) 2-Indications for Transplantation for HBV-Related Disease: Acute Fulminant Hepatitis B; Recommendation;
-Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
-Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by National Health Service Blood and Transplant (NHSBT). (1A) Suggestion;
-As early antiviral treatment with nucleotide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma; Recommendation;
-Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C)
-Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A) Suggestion;
-Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a United Kingdom end stage liver disease (UKELD) score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A) 3-HBV and Other (Non-Liver) Transplantation: Suggestion;
-Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C) 4-Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation: Recommendation;
-All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
-Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B) 5-Use of HBcAb Positive or HBsAg Positive Donors: General Recommendations; Suggestion;
-The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
-All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded) HBcAb positive donation for liver recipients; Recommendation;
-The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
-When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
-When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A) Suggestion;
-If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. the HBV non-immune recipient. (2C) HBsAg Positive Donation for Liver Recipients; Recommendation;
-HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
-If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
-All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
-Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C) HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients; Recommendation;
-The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A) Suggestion;
-If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C) 6-Management of Co-Infection (HDV, HCV, HIV) and Transplantation: Recommendation;
-HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
-HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
-A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
-HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C) Suggestion;
-For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/nucleo(t)side analogues(NA) prophylaxis can be considered, but not within 12 months of transplantation. (2C) 7-Preventing Recurrence of HBV Post-Transplantation: Recommendation;
-In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B) Suggestion;
-Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
-Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
-Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B) 8-Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation: Recommendation;
-All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
-Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
-Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B) 9-Monitoring for HBV Recurrence or De Novo Infection: Recommendation;
-HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
-Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded) 10-HBV Vaccination and Solid Organ Transplantation: Recommendation;
-All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C) Suggestion;
-Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
-Amongst renal transplant recipients who are HBcAb positive, if HBsAb are < 100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
-All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
-In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
These guidelines recommend that:
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection.
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
• All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. Use of HBIg rarely achieves HBsAg negativity, and is not recommended.
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
• HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. HBsAg positive donors should not be used for HBV/HDV co-infected recipients. A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection.
• In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
Guidelines for Hepatitis B & Solid Organ Transplantation:
1-HBV Biology and Disease:
Recommendation;
–HBsAg, HBsAb (absolute titres) ,HBcAb in all solid organ transplant recipients and HBeAg, HBeAb and HDV Ab serology, and HBV DNA level (quantitative ) in all HBsAg positive patients (1B).PCR for HDV RNA only to be done in cases where HDV serology is positive or equivocal. (1B).To rule out occult HBV or HDV infection, HBV DNA and HDV serology testing should be done in patients with HBsAg negative but HBcAb positive. (1B)
–
2-Indications for Transplantation for HBV-Related Disease:
Acute Fulminant Hepatitis B;
Recommendation;
Such patients should be managed in a specialist liver centre. (1C).Liver transplantation-option should be given to patients according to UK listing criteria defined by National Health Service Blood and Transplant (NHSBT). (1A)
Suggestion;
Treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma;
Recommendation;
Treatment should be carried out in specialist liver units and antiviral treatment with NA(Entecavir and tenofovir) should be given to all decompensated cirrhosis patients with detectable HBV DNA.(1A)
Suggestion;
Liver transplantation-hepatitis B cirrhosis and a United Kingdom end stage liver disease (UKELD) score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
3-HBV and Other (Non-Liver) Transplantation:
Suggestion;
Combined transplantation should be considered . (2C)
4-Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation:
Recommendation;
All HBsAg positive individuals-treatment with either tenofovir or entecavir before transplantation, achieving an undetectable HBV DNA level. (1B).However, for non-liver solid organ transplantation with positive HBsAg -liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantationshoud be done. (1B)
5-Use of HBcAb Positive or HBsAg Positive Donors:
General Recommendations;
Suggestion;
-The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be done. (2C)
HBcAb positive donation for liver recipients;
Recommendation;
-The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
HBV reactivation prevention strategy should be adopted in cases of HbsAg positive recipient and prophylactic lamivudine for an indefinite period to HBV immune or non-immune recipient. (1A)
HBsAg Positive Donation for Liver Recipients;
Recommendation;
-HBsAg positive donor livers can be given to following recipients i.e., HBsAg positive recipients(1C) HBsAg negative patient in urgent cases . (1D)Treatment with entecavir or tenofovir (1B)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients;
Recommendation;
-The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient.(1A)
Suggestion;
Non-liver solid organs of the HBsAg positive organ donor for any recipient in urgent cases(2C) Lamivudine prophylaxis for six months after transplantation in HBcAb positive donor (2C)
Transplantation and Co-Infection (HDV, HCV, HIV)
HBV/NA prophylaxis for HBV/HDV patients in such cases
Post-Transplant HBV Prevention
–Preventing Recurrence of HBV Post-Transplantation:
Combination therapy with Hepatitis B immunoglobulin and/or a potent NA should be started from the time of transplantation.(1B)
Either prophylactic antiviral treatment for 6-12 months or close monitoring for HBV recurrence can be considered for past HBV infection (HBcAb positive alone) in post-non-liver transplant patients.(2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation:
Lifelong antiviral therapy with Entecavir or Tenofovir is recommended. Resistance testing from specialized laboratory should be considered.(1B)
Monitoring for HBV Recurrence or De Novo Infection:
Recommendation;
HBsAg positive liver transplant recipients or recipient with HBcAb positive donor-Monitoring every three months for the first year and then every six months.(1C)
HBV Vaccination and Solid Organ Transplantation:
Recommendation;
Vaccination should be done for all solid organ transplant recipients who are HBV naïve(1C)
Second series or booster should be considered for those whom initial series failed. (2C)
Hepatitis B Virus (HBV) is a hepatotrophic DNA virus that belongs to the Hepadnaviridae family of viruses.
Infect 257 million people worldwide, an estimated 600,000 deaths every year through complications of end stage liver disease and HCC.
The majority of chronic HBV infection result:
Vertical transmission from mother to child.
Or horizontal transmission through unsafe medical practice.
Patient age at the time of initial infection with HBV is a major determinant of whether the infection becomes chronic.
Infection in infants results in chronic infection in up to 90% of cases, whereas approximately 30% of children infected before the age of five develop chronic infection.
Adult-to-adult transmission can also occur through sexual, nosocomial or blood borne transmission, In adult cases only, less than 10% progress to chronic.
Virology and Phases of Infection:
HBV has a partly circular double stranded DNA genome.
When partially circular DNA is transported to the nucleus. Here is it converted to covalently closed circular DNA (cccDNA). This forms the template for the production of virions and on-going infection.
HBV 4 phases:
1. HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
During the first 20-30 years of life if the infection is acquired in infancy or early childhood,
HBeAg positive and HBeAb negative with HBV DNA viral loads generally >107 log IU/mL.
The ALT level is in the normal range and liver biopsy (if performed) shows no or minimal inflammation or fibrosis.
Treatment is rarely indicated for such patient.
2-HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” or “immune active” or “immune elimination phase”).
HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive chronic infection are.
There is immune-mediated damage to the liver with resultant inflammation and fibrosis that can progress to cirrhosis in those with prolonged, unrecognized inflammation.
This phase is often asymptomatic, although it can lead to hepatic decompensation or acute liver failure (ALF) in those with underlying cirrhosis.
Antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis.
3-HBe Antigen Negative Chronic Infection (previously called “inactive phase”). This phase is characterized by HBeAg negativity, HBeAb positivity with normal ALT levels and HBV DNA levels being.
Individuals who undergo later HBeAg seroconversion have a much higher likelihood HCC AND CIRRHOSIS. Patients do not generally require therapy, FOLLOW UP (25% RISK).
4. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).
Result of mutations in the basal core promoter and/or the pre-core region of the pre C/C gene [These HBV DNA levels >2000 IU/mL and frequently >20,000 IU/mL,
Serum ALT levels are raised and can fluctuate significantly.
Resultant liver damage can progress rapidly towards cirrhosis and HCC.
Antiviral therapy forms the cornerstone.
Serological and Virological Testing:
HBsAg and HBV ab, HBC antibody, HBV DNA.
Reactivation of HBV:
HBV reactivation is defined as the reappearance of markers of active HBV replication in a patient with previously controlled HBV infection, or an increase in levels of replication compared to previous levels.
Reactivation may be asymptomatic or associated with a flare of hepatitis in previously minimal or inactive disease, manifesting clinically with acute hepatitis, which can progress to acute liver failure and even death if untreated.
Initial profile: Reactivation profile
HBsAg HBc Ab HBV DNA
Positive Positive not detected HBV DNA detectable >100 IU/mL, confirmed on 2 sample
Positive Positive detected ≥2 log increase in HBV DNA levels from baseline levels HBV DNA with level ≥100,000 IU/mL (if no baseline HBV DNA level available).
Negative Positive Not Detected HBsAg positive/HBV DNA detectable.
Negative Positive Detected (Occult) HBsAg positive/increase in HBV viral load (≥2 log).
Hepatitis Delta Co-Infection:
Hepatitis delta (HDV) is a hepatotrophic replication deficient single stranded.
A diagnosis of past or current HDV co-infection is dependent on the finding of serum HDV IgG positivity. Active HDV co-infection is confirmed by HDV RNA positivity.
. In cases of HDV co-infection where HBV DNA levels are above 2000 IU/mL or fluctuate above this level, it is generally recommended that HBV replication is inhibited with nucleoside analogues.
Recommendations:
Recommend that:
1-HBsAg, HBsAb (absolute titres) and HBc Ab in all SOT recipient.
2-All HBsAg positive patients undergoing transplant tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
3-All recipients found to be HBcAb positive, HBsAg negative must have HBV DNA and HDV serology
• All donors who are positive for HBcAb. HBsAg negative (past HBV, must have HBV DNA testing.
Acute Hepatitis B:
95-99% of adults who acquire AHB) will recover spontaneously
One% of cases of AHB progress to fulminant hepatitis, high mortality rate (up to 80%), often require OLT .
Antiviral treatment is indicated in:
• Fulminant hepatitis B
• Severe AHB – based on the presence of at least two of the following criteria:
– Bilirubin >100 µmol/L
– International normalized ratio (INR) ≥1.6
– Hepatic encephalopathy
• Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
• Immunocompromised host. LAM is controversy
The current EASL guidelines on treatment of AHB recommend the use of ETV (0.5 mg/day) or TFV
(245 mg/day). Therapy should be continued for at least three months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss.
Liver transplantation should be considered in all patients with fulminant hepatitis:
Hepatic encephalopathy and:
• Prothrombin time >100 seconds or INR >6.5 or
– Any three from: – age >40 or <10 years – jaundice to encephalopathy time >7 days – serum bilirubin >300 µmol/L – prothrombin time >50 seconds or INR >3.5.
Chronic Hepatitis B:
Current treatment guidelines consider NAs or PEGylated-interferon (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis.
Decompensated Cirrhosis:
Guidelines recommend starting oral NAs for patients with decompensated cirrhosis, irrespective of serum ALT, HBV DNA and e antigen status. TFV and ETV are currently the first-line agents, with greater potency and higher barrier to resistance. ETV dose for patients with decompensated cirrhosis is 1 mg once daily (instead of 0.5 mg for patients with compensated liver disease).
OLT should be considered. List patients with a MELD >15 (or UKELD equivalent approximately 55).
Criteria which must be satisfied for consideration of OLT in the UK include:
1. A projected one year liver disease mortality without transplantation of >9%, predicted by a United Kingdom Model for End-Stage Liver Disease (UKELD) score of ≥ 49 .
2. A variant syndrome (e.g. diuretic resistant ascites or chronic hepatic encephalopathy) in those with a UKELD of 49.
HCC:
Common with HBV 50-55%.
Risk is more with high viral load; NS reduce incidence plus regular surveillance 6, months, with abdominal ultrasound.
Surgical resection is the first line treatment for patients with solitary HCC and well-preserved liver function. Resection or radiofrequency ablation may be curative options for smaller lesions.
Liver transplantation for HCC is a well-established treatment option.
Management of SOT Recipient with CHB or Past HBV CHBV and past HBV are not contraindications for solid organ transplantation.
Such patients must be referred to a specialist in viral hepatitis
Recommendations:
We suggest that
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION:
Liver Transplantation:
Patients presenting with decompensated cirrhosis from HBV may regain liver function with effective viral suppression, thus avoiding the need for transplantation .The risk of recurrent HBV after OLT is low with effective viral suppression before transplant.
Non-Liver Solid Organ Transplantation:
HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
USE OF HBCAB ANTIBODY POSITIVE OR HBSAG POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION:
General Recommendations
We suggest that:
• The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis.
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection.
Donors with HBC Ab high risk of transmission HBV to recipient, even if HBsAg negative.
Core Antibody Positive Donation for Liver Recipients:
HIGH risk of DE novo HBV infection HB infection, risk more with naïve recipient.
Prophylaxis from the time of liver transplantation can reduce the risk of de novo infection.
Lamivudine is the most cost-effective approach to prophylaxis, prevents most de novo infection
The ideal recipient of the core antibody positive donation is the HBsAg positive recipient.
Recommendation that:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. • When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted
• When the liver comes from an HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
Suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver:
1. The HBsAg-positive recipient
2. The HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. The HBV non-immune recipient,
HBsAg Positive Donation for Liver Recipients:
May be considered for any recipient, including non-immune HBsAg negative recipients.
HBV/HDV co-infected livers not to be used, also not suitable for HBV/HDV co-infected recipient.
Use of oral antivirals (entecavir or tenofovir) in HBsAg Recipients from the time of transplantation will prevent HBV-related graft damage, and should be continued indefinitely.
The HBV-immune recipient may be the preferred recipient of an HBsAg positive liver donation with use of antiviral.
We recommend that:
• HBsAg positive donor livers can be given to HBsAg positive recipients as long as the recipient is known to be HDV negative.
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
• Use of HBIg rarely achieves HBsAg negativity, and is not recommended.
HBsAg Positive Donation for Non-Liver Recipients, Core Antibody Positive Donation for Non-Liver Solid Organ Recipients
Recommendations
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
We suggest that:
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualized assessment of risk and benefit. (2C)
• When an HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
MANAGEMENT OF CO-INFECTION (HDV, HCV, HIV) IN THE LIVER TRANSPLANT RECIPIENT :
Management of HBV/HDV Co-Infection:
The only available antiviral therapy for HBV/HDV co-infection is alpha interferon, but response rates are disappointing, and are further reduced in patients with cirrhosis.
HDV/HBV infection is unresponsive to treatment with nucleoside analogues.
HDV-infected liver recipients should receive antiviral prophylaxis that includes the use of HBIg from time of transplantation for a period of 12-24months.
There is no proven effective treatment for recurrent (or acquired) graft HBV/HDV infection, and rapid progression to cirrhosis is likely.
Management of HBV/HCV Co-Infection:
HCV-infected potential liver transplant recipients will be successfully treated with DAAs before or following liver transplantation.
HBV antiviral protocols for the management of HBV infection in the recipient, and protocols for the use of core antibody positive or HBsAg positive donations are unaffected by the presence of HCV co-infection.
Management of HBV/HIV Co-Infection:
The multidisciplinary team before transplantation should agree a plan for the peri-operative management of each of the HIV and HBV infections.
• HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the perioperative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection.
PREVENTING RECURRENCE OF HBV POSTTRANSPLANTATION:
Hepatitis B Surface Antigen Positive Recipients:
Pretransplant: Antiviral treatment .either TEV OR ENT.
Following transplantation, prophylactic treatment of HBV recurrence should be with a combination of HBIG and NA antivirals.
Low risk of HBV recurrence, i.e. Antigen negative and HBV DNA negative at time of transplant, early HBIG withdrawal and maintenance with NA monotherapy can be considered.
HBV/HDV co-infected patients in these patients, HBIG prophylaxis should continue for longer.
Hepatitis B Core Antibody Positive Recipients:
Managed same as HB sag patient. In general, there is evidence for prophylactic treatment, with lamivudine being the most studied, Entecavir has also been studied with good efficacy in the setting of rituximab treatment.
Hepatitis B Core Antibody Positive Donors:
Risk is more with liver transplant, so and vaccination of recipient is recommended. Prophylaxis is is needed. Either LAM entecavir or TFV could be used.
HBcAb positive organs are also used in other non-liver transplantation such as kidney or heart. The risk reduced with Pre-transplant vaccination against HBV potentially offers enough protection, although some centers use LAM. For 12 months.
Hepatitis B Surface Antigen Positive Donors:
Organs from donors chronically infected with HBV are not routinely used at present.
However, single-center case series exist of HBsAg positive donor livers used either in patients who are HBsAg positive with HBV-related liver disease or in HBcAb positive recipients. Adequate antiviral treatment plus HBIG.
TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION:
More common in HBsAg negative and HBC AB NEGATIVE PATEINT.
Risk:
HBcAb donors.
FAILURE OF AVCCINATION.
HCC and HIV.
Detectable HBV DNA levels at the time of transplantation.
Immunosuppression.
Entecavir and/or tenofovir post-transplant, both were demonstrated to be safe and effective in prophylaxis treatment.
Recommendations:
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory.
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
• Entecavir or tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST LIVER TRANSPLANTATION:
Recommendations:
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from an HBcAb positive donor, regardless of treatment or prophylaxis regimen.
• Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION:
Recommendation:
Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice.
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are 100 IU/mL, then vaccination should be considered to boost the protective titer of HBsAb and minimize the risk of reactivation.
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule.
• In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
Guidelines forHepatitis B & Solid Organ Transplantation
Chapter 3: HBV Biology and Disease
We recommend that:
1- All patients must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
2- All HBsAg positive patients must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
3- HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
4- Any potential recipients with HBcAb +ve but HBsAg -ve (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
5- All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
==========================================================
Chapter 4: Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
We recommend that:
1- Individuals with fulminant liver failure must be managed in a specialist liver centre. (1C)
2- Liver transplantation must be considered in patients with fulminant hepatitis B. (1A)
We suggest that
1- treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
We recommend that:
1- Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units. (1C)
2- in Individuals with decompensated cirrhosis and detectable HBV DNA Entecavir and tenofovir are the first line antiviral agents (1A).
We suggest that
1- Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A).
======================
Chapter 5: HBV and Other (Non-Liver) Transplantation.
We suggest that
1- Patients with advanced HBV-related liver disease requiring another organ transplant
be considered for combined transplantation . (2C)
==============================
Chapter 6: Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
We recommend that:
1- All HBsAg positive individuals being considered for liver transplantation should be
treated with either tenofovir or entecavir . (1B)
2- Individuals undergoing non-liver solid organ transplantation should be treated by either tenofovir or entecavir . (1B)
=================================
Chapter 7: Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
We suggest that:
1- The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
2- All potential recipients should be counselled during the assessment process about the receiving a liver from a HBV infection patient.
==========
HBcAb positive donation for liver recipients
We recommend that:
1- The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
2- When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
3- When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be continued indefinitely. (1A)
We suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver
should be allocated in the following order:
1- the HBsAg-positive recipient
2- the HBV-immune recipient .
3- the HBV non-immune recipient. (2C)
===========
HBsAg Positive Donation for Liver Recipients
We recommend that:
1- HBsAg positive donor livers can be given to HBsAg positive recipients. . (1C)
2- If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
3- All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
4- Use of HBIg not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
We recommend that:
1- The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient . (1A)
We suggest that:
1- If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient. (2C)
2- When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation. (2C)
=============================
Chapter 8: Management of Co-Infection (HDV, HCV, HIV) and Transplantation
We recommend that:
1- HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
2- HBsAg positive donors should not be used for HBV/HDV co-infected recipients.(1C)
3- A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
4- HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
We suggest that:
1- For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA
prophylaxis can be considered, but not within 12 months of transplantation. (2C)
========================
Chapter 9: Preventing Recurrence of HBV Post-Transplantation
We recommend that:
1- In HBsAg positive individuals deemed to be at high risk of recurrence,
combination therapy with HBIg and/or a potent NA is recommended . (1B)
We suggest that:
1- Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in low risk patients . (2C)
2- Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence . (2B)
3- Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a prophylactic antiviral treatment . (2B)
=============================================
Chapter 10: Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ
Transplantation
We recommend that
1- All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. (1C)
2- Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
3- Entecavir or Tenofovir are recommended as first line treatment . (1B)
====================================
Chapter 11: Monitoring for HBV Recurrence or De Novo Infection
We recommend that
1- HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months . (1C)
2- Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
==================================
Chapter 12: HBV Vaccination and Solid Organ Transplantation
We recommend that
1- All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
We suggest that
1- Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
2- Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
3- All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
4- In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
Summarize the guidelines;
Introduction;
According to this guidance every recipient should be screened for HBsAg, for further confirmation DNA PCR should be done to rule out occult infection.
Indication of transplantation;
NHSBT criteria should be considered for fulminant HBV associated hepatitis.
Indicated to treat with antiviral medication.
Decompensated HBV infection with cirrhosis and HCC;
With compensated liver disease and cirrhosis antiviral with Entecavir/ tenofovir should started as soon as possible.
Should consider to transplant combine with liver and kidney.
Pre-transplant management;
The copies are important to proceed for transplantation, and the treatment should be considered with lowest level of viral copies then proceed for transplantation.
The treatment choice are Tenofovie and Entecavir.
If a recipient is considered for HBV positive DONOR, should be counseled before proceeding.
If only HBc-Ab positive should be started with Limuvidine before transplantation to prevent re-activation.
HBc-Ab, HBs-Ag positive donation;
The risk of de novo HBV infection is low for non liver organ donation.
Prevention of recurrence of HBV post-transplantation;
If a recipient is negative its recommended HBIG and NA in then early withdrawal if low risk patient, if high risk patient its recommended to give lifelong NA plus HBIG therapy.
HBV recurrence of de novo;
Recommended to continue life long treatment.
HBV vaccination and SOT:
Recommended should be vaccinated and documented Pre-transplant.
Indication for transplantation for HBV-infected patient;
Acute hepatitis B infection;
Recommended to treat if Bilirubin is >100umol, INR >1.6, as it has better and early recovery, and better survival.
The current guidelines recommend early treatment for acute cases with Entecavir 0.5mg/day, Tenofovir 145mg/D. therapy should be continued for at least 3 months, however, there is no such consensus for duration treatment.
If fulminant hepatitis, liver transplantation should be considered.
Poor prognosis if untreated.
Hepatocellular carcinoma;
The literature says there are >500,000 diagnosed new cases annually, and this is the fifth most common cancer worldwide.
Incidence; it accounts for around50-60% of HCC.
. Cirrhosis of liver 70-90%.
Impact of transplantation on HBV;
Immunosuppressive drugs increases risk of HBV replication, drugs does suppress immune system and worsened the risk.
Impact of HBV infection on transplant outcomes;
In immunocompromised patients the infection is associated with rapid progression and increase risk of HCC in recipient.
British Transplantation Society Guidelines for Hepatitis B & Solid Organ Transplantation-
HBV Biology and Disease
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb.
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
• Any potential transplant recipients/donor found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Decompensated Hepatitis B Cirrhosis
Hepatocellular Carcinoma
HBV and Other (Non-Liver) Transplant
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit.
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection.
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation
Preventing Recurrence of HBV Post-Transplantation
• In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. • Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence.
Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
All patients with HBV recurrence post-liver/kidney transplant should have a careful review of adherence with NA prophylaxis.
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver /kidney transplantation.
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure
Monitoring for HBV Recurrence or De Novo Infection
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver/kidney transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
HBV Vaccination and Solid Organ Transplantation
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation.
HBV Biology and Disease
We recommend that:
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
We recommend that:
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT.
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
We recommend that:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
We recommend that:
• All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors General
Recommendations
We suggest that:
• The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients
We recommend that:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
• When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
• When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation and should be continued indefinitely. (1A)
HBsAg Positive Donation for Liver Recipients
We recommend that:
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
• Use of HBIg rarely achieves HBsAg negativity and is not recommended. (1C)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
We recommend that.
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
Monitoring for HBV Recurrence or De Novo Infection We recommend that.
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
• Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
HBV Vaccination and Solid Organ Transplantation We recommend that.
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Guidelines for Hepatitis B & Solid Organ Transplantation
This guideline is the first British Transplantation Society (BTS) guideline on the management of hepatitis B in the transplant setting.
Tests for HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
– Any potential transplant recipients and donor found to be HBcAb positive but HBsAg negative must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
-Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre and liver transplantation must be considered .
– Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation.
– Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
We suggest that
– Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines.
-Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
-All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level.
– Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
-All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection.
-The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient.
-When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
-If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient .
3. the HBV non-immune recipient.
-HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative.
– If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
-All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
-The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation .
– HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
-HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
-A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation.
-Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected.
-Recipients with HBcAb positive alone are at risk of HBV reactivation post-non-liver transplant and could be considered for 6-12 months course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy.
– Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
-HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
– All prospective solid organ transplant recipients who are HBV naive must be vaccinated and the response documented.
-Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice.
-Renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered .
-In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
SUMMARISE THE GUIDELINES:
EXECUTIVE SUMMARY OF RECOMMENDATIONS
Recommendation: All patients being prepared for SOT should be sreened for HBsAg, HBsAb (absolute titers) and HBcAb, as well as testing for HBV DNA and HDV RNA to rule out occult HBV or HDV infection.
Indications of Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Recommendation: Liver transplantation should be considered in patients with fulminant hepatitis B – (NHSBT criteria).
Suggestion – Early antiviral treatment with nucleoside analogues to improve AHB survival.
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Recommendation: Decompensated cirrhosis due to Hepatitis B (DNA positive) à urgent antiviral treatment with Entecavir or Tenofovir.
Suggestion – Listing for liver transplant for patients with UKELD score >49.
HBV and Other (Non-Liver) Transplantation
Suggestion – Advanced HBV-related liver disease should consider combined transplantation.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Recommendation: HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels.
Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
Suggestion – potential recipients should be counselled about the possibility of receiving a liver from a donor with HBV infection.
HBcAb positive donation for liver recipients
Recommendation: Prophylactic lamivudine from the time of transplantation to prevent HBV reactivation.
Suggestion – Anti-HBc positive donor liver should be allocated in order of priority.
HBsAg Positive Donation for Liver Recipients
Recommendation: HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
Recommendation: The risk of de novo HBV infection is low for organ donors.
Suggestion – HBcAb-positive donor organs can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Recommendation: HBV/HDV recipients should receive combination HBIg + NA prophylaxis from the time of transplantation; HBsAg-positive donor should not be used.
Suggestion – HBIg withdrawal from combination HBIg-NA prophylaxis can be considered, but not within 12 months of transplantation.
Preventing the Recurrence of HBV Post-Transplantation
Recommendation: HBIg + NA recommended to prevent HBV reinfection post-liver transplant.
Suggestion – low risk recipients à Early withdrawal of HBIG or HBIG-free prophylaxis
High risk recipients à life-long combination therapy with HBIG + NA
HBV Recurrence or De Novo Hepatitis B after SOT
Recommendation:
Treatment – Lifelong antiviral therapy is recommended
Monitoring – 3monthly for 1year, then every 6month thereafter
at shorter intervals in cases of non-adherence.
HBV Vaccination and Solid Organ Transplantation
Recommendation: Prospective SOT recipients must be vaccinated and documented.
Suggestion – development of protective serum titres of HBsAb; those who fail to respond should be administered a second series of vaccine.
HBV BIOLOGY AND DISEASE
Introduction – HBV is a major human pathogen, infecting about 257 million people worldwide; causing 600,000 deaths every year.
– It is transmitted through blood and blood product transfusion, sexual or vertical transmission or through unsafe medical practice.
– Patient age at the time of initial infection is a major determinant chronicity of infection.
Virology and Phases of Infection
HBV is not directly hepatotoxic; complex interaction with the host immune system drives the hepatic inflammation-fibrosis-cancer axis.
1. HBeAg positive Chronic Infection (“non-inflammatory” or “immune tolerant phase”) – Treatment is rarely indicated for HBeAg-positive and HBeAb-negative patients with HBV DNA viral loads >107 IU/mL
2. HBeAg positive Chronic Hepatitis (inflammatory /immune active /immune elimination phase) – characterized by a persistent or intermittent elevation in ALT and fluctuating HBV-DNA levels, leading to inflammation and fibrosis that can progress to cirrhosis.
Antiviral therapy is indicated if prolonged or there is evidence of significant liver fibrosis.
3. HBeAg Negative Chronic Infection (inactive phase) – characterized by negative HBeAg, HBeAb positive, normal ALT levels;
– HBe seroconversion determined by age and HBV genotype. Antiviral therapy can also result in HBeAg seroconversion.
– Regular follow-up is mandatory as reactivation and development of HBeAg-negative chronic hepatitis occurs in 25%.
4. HBeAg negative Chronic Hepatitis (immune escape phase) – Mutations in the pre-C/C gene can lead to increased HBV-DNA levels, resulting in liver damage and HCC.
– Antiviral therapy is the cornerstone of management.
Serological and Virological Testing
Testing for HBV surface antigen (HBsAg) and core antibody (HBcAb) is important for diagnosis and veracity of the host immune response.
Reactivation of HBV – HBV reactivation varies depending on baseline HBV status, underlying condition, type of immunosuppressive therapy, and host immunity.
Hepatitis Delta Co-Infection – HDV is a hepatotropic replication-deficient single-stranded covalently closed circular RNA virus. It uses the HBV replication-machinery for its replication.
Recommendation: All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb, and HBcAb; potential transplant recipients must have HBV-DNA and HDV serology (PCR) testing to exclude occult infection.
INDICATIONS FOR TRANSPLANTATION FOR HBV-RELATED DISEASE
Acute Hepatitis B
Antiviral treatment indicated in Acute hepatitis B (AHB) if Bilirubin >100 µmol/L and INR ≥1.6. Prompt antiviral administration shorten disease duration, promote recovery, improve survival.
A case series of 17 patients with severe or fulminant AHB showed that Lamivudine (LAM) administered until HBsAg clearance improved survival compared to historical, untreated controls (82.4 vs. 20%; p<0.001).
– However, the evidence for LAM has not been universally positive.
– Current EASL guidelines on the treatment of AHB recommend Entecavir (ETV) 0.5 mg/day or Tenofovir (TFV) 245 mg/day.
Antiviral treatment should be started early in the course of severe AHB, without waiting for the development of fulminant hepatitis.
Delayed initiation of NAs is associated with higher mortality or requirement for transplant
There are limited data on duration of antiviral treatment in AHB, but therapy should be continued for at least 3months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss.
Liver transplantation should be considered in all patients with liver failure related to hepatitis B – (with hepatic encephalopathy, prothrombin time >100 seconds, INR >6.5).
Recommendation: Liver transplantation must be considered in patients with fulminant hepatitis B infection.
Suggestion – early antiviral treatment with nucleoside analogues can improve AHB survival.
Chronic Hepatitis B (CHB): Aim of treatment in CHB is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death. NAs or PEG-IFN are first-line therapy in patients with higher HBV DNA levels.
Decompensated Cirrhosis:
· 5-year cumulative incidence of hepatic decompensation for untreated CHB-associated cirrhotic patients is approximately 20%.
· Untreated patients with have poor prognosis – 5-year survival 14-35%, compared to 84% in compensated state.
· Decompensated HBV cirrhosis is declining as an indication for transplantation, due to success of HBV vaccination and potent oral antiviral agents.
· Objectives of Antiviral treatment: improvement of liver function and decreased risk of HBV recurrence after transplantation.
· TFV and ETV are currently the first-line agents, with greater potency and higher barriers to resistance. NAs have a good safety profile in patients with advanced liver disease, and a phase 2 double-blind study compared the safety of TFV and ETV in decompensated HBV cirrhosis.
– Serious side effects due to mitochondrial toxicity, can manifest as lactic acidosis, myopathy, neuropathy, hepatotoxicity.
– Treatment-naive patients with ETV (0.5 mg/day) showed significant improvement in CTP and MELD scores, but not all patients improved with ETV.
· Studies are on way to identify prognostic indicators that could help to stratify 2 distinct subgroups – patients who will experience prolonged survival with antiviral therapy and those who require OLT.
Hepatocellular Carcinoma
HCC is the 5th most common cancer worldwide; >500,000 new cases diagnosed annually.
Incidence and Risk Factors
– HBV is the leading risk factor for HCC globally, accounts for 50-60% of HCC.
– 70-90% HCC develops in cirrhotic livers, although HBV can cause HCC in the absence of cirrhosis
· Several factors are known to increase the risk of HCC among individuals with HBV infection, including demographic, viral, clinical, environmental, and HBeAg status.
· The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study from Taiwan showed that HCC increased in proportion to viral load.
Surveillance· HCC surveillance is necessary even if HBV DNA is suppressed, with six-monthly abdominal ultrasound scans recommended.
Treatment· Treatment of HCC related to HBV is based on size, number of lesions, and serum AFP concentration.
· Salvage transplantation is an option if listing criteria are fulfilled.
· Non-cirrhotic patients with non-resectable HCC should be considered for OLT in the absence of macrovascular invasion and extra-hepatic spread.
Recommendation: Individuals with decompensated cirrhosis and detectable HBV DNA need urgent antiviral treatment with NA(s).
Suggestion· Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and HCC.
HEPATITIS B AND OTHER (NON-LIVER) TRANSPLANTATION
Introduction: HBV infection is a major risk factor for hepatic dysfunction in SOT recipients, leading to progressive liver damage, morbidity and mortality.
Impact of Transplantation on HBV: Immunosuppressive agents can modify the natural history of HBV infection through disruption of the host immune response and enhanced replication.
– Immunosuppressive drugs (net immunosuppression) promote HBV replication, when used in combination with other drugs.
Impact of HBV Infection on Transplant Outcome: HBV infection is associated with more frequent and rapid progression to cirrhosis and hepatocellular carcinoma in SOT recipients, leading to higher mortality.
Prevalence of HBV Infection in SOT: Chronic HBV infection in SOT recipients varies according to geographical regions – CHB prevalence ranging from 2-20%; past HBV prevalence generally higher than CHB.
Risk of HBV Infection in the SOT Recipient: Post-transplant anti-HBsAb monitoring is not recommended.
Management of SOT Recipient with CHB or Past HBV: HBV infection and CHB are not contraindications for solid organ transplantation.
Non-Liver SOT Recipients with Advanced Liver Disease: Patients with an advanced liver disease requiring transplantation of non-liver organs should be assessed by multidisciplinary team to consider combined transplantation
Suggestion – advanced HBV-related liver disease should consider combined transplantation.
PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION
Non-Liver Solid Organ Transplantation – Patients should be screened for hepatitis B carriage and pre-transplant suppression should be given with tenofovir or entecavir to avoid the progression of liver disease.
Recommendation: HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels.
USE OF HBCAB ANTIBODY-POSITIVE OR HBSAG-POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION
Introduction: The use of solid organs from donors with core antibodies can transmit HBV infection to the organ recipient, with the risk of transmission being high for liver transplantation and lower for kidney and thoracic organs.
Suggestion – Potential recipients should be counselled about the possibility of receiving a liver from a donor with HBV infection.
Core Antibody Positive Donation for Liver Recipients
De novo HBV infection is associated with core antibody-positive liver donation and is dependent on the recipient’s HBV immune status.
Lamivudine is the most cost-effective approach to prophylaxis, prevents most de novo infections, and should be given indefinitely.
Recommendation: Prophylactic lamivudine should be given from the time of transplantation to prevent HBV reactivation.
Suggestion – The hepatitis B core antibody-positive donor liver should be allocated in order of priority.
HBsAg Positive Donation for Liver Recipients· HBsAg positive liver donation is suitable for non-immune HBsAg negative recipients, but not for HBV/HDV co-infected recipients.
Recommendation: HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir.
Core Antibody Positive Donation for Non-Liver Solid Organ Recipients
Donation of non-liver solid organs from core antibody-positive donors is rarely associated with de novo infection, making antiviral prophylaxis ineffective.
HBsAg Positive Donation for Non-Liver Recipients· Antivirals should be used to suppress HBV after transplantation, and long-term monitoring should be provided to prevent chronic infection.
Recommendation: The risk of de novo HBV infection is low.
Suggestion: HBcAb-positive organ donors can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation.
PREVENTING THE RECURRENCE OF HBV POST-TRANSPLANTATION
Introduction: Hepatitis B virus (HBV) recurrence after liver transplantation is defined as the reappearance of circulating hepatitis B surface antigen (HBsAg), with or without detectable HBV DNA. Without appropriate prophylactic treatment, HBV recurrence is almost universal.
– Prophylactic treatment with HBIG and NA has reduced graft reinfection rates and HBV-related liver disease is now a well-accepted indication for liver transplantation.
Hepatitis B Surface Antigen Positive Recipients
– Prevention of post-transplant HBV recurrence in HBsAg-positive patients begins before transplantation with antivirals, such as nucleo(t)side analogues (NA) such as entecavir or tenofovir.
– Combination therapy with NA antivirals is recommended. Early HBIG withdrawal and maintenance with NA monotherapy is effective and safe, but not appropriate for high-risk patients.
– HBIG-free NA prophylaxis can be considered in low-risk recipients, but more robust evidence is needed.
Hepatitis B Core Antibody Positive Recipients
– HBcAb positivity, with or without HBsAb, with negative HBsAg and negative HBV DNA is indicative of past HBV infection and should be managed in the same way as HBsAg positive patients.
Hepatitis B Core Antibody Positive Donors
– Pre-transplant vaccination against HBV can reduce the risk of de novo hepatitis B, with lamivudine being the most widely used.
Hepatitis B Surface Antigen Positive Donors
– Organs from donors chronically infected with HBV are not routinely used, but single-center case series exist of HBsAg-positive donor livers used in patients with HBV-related liver disease or HBcAb-positive recipients, with no differences in graft or patient survival and no episodes of graft dysfunction.
Recommendation: Combination therapy with HBIg and NA is recommended to prevent HBV reinfection post-liver transplant.
Suggestion – Early withdrawal of HBIG or HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence, and life-long combination therapy with HBIG and NA can be given to those at high risk.
TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION
Introduction· Hepatitis B recurrence after liver transplantation is associated with biochemical or clinical evidence of active disease and can occur in those without prior CHB (HBcAb negative).
· The risk of developing de novo hepatitis B in recipients depends on their hepatitis B serological status and prophylactic measures used.
Review of Literature
Treatment should be started at diagnosis to control viral replication and stabilize graft function, based on prior treatment and prophylaxis history. E
Entecavir and tenofovir are safe and effective in prophylaxis treatment, but not recommended in patients previously treated with lamivudine.
Recommendation: Lifelong antiviral therapy is recommended for HBV recurrence or de novo hepatitis B post-liver transplantation.
MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST-LIVER TRANSPLANTATION
Introduction: Monitoring post-transplant patients to detect HBV infection in a timely manner.
Review of Literature
– Monitoring of virological, serological, and clinical markers of infection post-transplantation is essential to evaluate prophylaxis efficacy.
– Non-adherence increases the risk of recurrence, so monitoring should consist of both HBV DNA quantification and HBsAg testing.
Recommendation: Monitoring intervals should be shortened in cases of non-adherence.
HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION
Rationale: Vaccination is important to protect solid-organ recipients from HBV infection.
Renal Transplantation –
HBV infection renal transplant recipients, is associated with high all-cause mortality and graft loss.
HBV vaccination is recommended in HBV seronegative patients with ESRD, to increase the use of HBcAb-positive kidneys and reduce the risk of reactivation.
Timing of Vaccination
HBV vaccination is highly immunogenic in healthy individuals but is less effective in patients with organ failure and immunosuppressed.
Vaccination should be considered early in the course of the disease, as the response to the HBV vaccine is suboptimal in pre-transplant and post-transplant periods.
Vaccination Method
The usual vaccination schedule is three intramuscular doses of the HBV vaccine, but higher-dose formulations are available for end-stage renal disease.
INTRODUCTION:
HBV Biology and Disease:
Recommendations:
All patients waiting for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb. (1B)
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B:
Recommendations:
Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver center. (1C)
Suggestions:
As early antiviral treatment with nucleotide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma:
Recommendations:
Decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C)
Suggestions:
Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation:
Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation:
Recommendations:
All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
Use of HBcAb Positive or HBsAg Positive Donors:
General Recommendations:
Suggestions:
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
HBcAb positive donation for liver recipients:
Recommendations:
When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
Suggestions:
Hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients:
Recommendations:
HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
Recommendations:
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A).
Suggestions:
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation:
Recommendations:
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
Suggestions:
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation:
Recommendations:
HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Suggestions:
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2)
INDICATIONS FOR TRANSPLANTATION FOR HBV RELATED DISEASE:
Acute Hepatitis B:
Indications of antiviral therapy:
A. Fulminant hepatitis B
B. Severe AHB – based on the presence of at least two of the following criteria: – bilirubin >100 µmol/L – international normalized ratio (INR) ≥1.6 – hepatic encephalopathy
C. Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
D. Immunocompromised host
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma:
Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units with antiviral therapy and possible liver transplantation. (1C)
Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HEPATITIS B AND OTHER (NON-LIVER) TRANSPLANTATION:
Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION:
All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
USE OF HBCAB ANTIBODY POSITIVE OR HBSAG POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION:
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded).
HBcAb positive donation for liver recipients:
The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
prevention of HBV reactivation, if liver from a + HBcAb donor and is given to an HBsAg + recipient. (1B)
When the liver comes from a HBcAb + donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
HBsAg Positive Donation for Liver Recipients
HBsAg (+) donor livers can be given to HBsAg (+) recipients, as long as the recipient is known to be HDV (-). (1C)
If urgency demands, the HBsAg (+) liver can be given to an HBsAg (-) patient. (1D)
All recipients of a liver from an HBsAg (+) donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
Use of HBIg rarely achieves HBsAg (-), and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart and lungs from the HBcAb (+) organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A).
If need demands, the non-liver solid organs of the HBsAg (+) organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C).
When a HBcAb (+) donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C).
MANAGEMENT OF CO-INFECTION (HDV, HCV, HIV) IN THE LIVER TRANSPLANT RECIPIENT:
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation. (1C)
HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
A plan for the peri-operative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the perioperative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 24 months of transplantation. (2C)
PREVENTING RECURRENCE OF HBV POSTTRANS:
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C).
Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma, or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B).
TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION:
All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
Entecavir or tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST LIVER TRANSPLANTATION:
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C).
Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded).
HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION:
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are
<100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C).
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
BTS guidlines
Who need testing ? recommended :
All potential recipients need HBsAg , anti HBc, anti HBs AB
all HBsAg positive recipient must have HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
both donor and recipinet with past infection ,(based on HBsAG negative , anti HBc AB positive serology ) should have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection
Acute fulminant hepatitis and decompensated cirrhosis sholud be managed in specialist liver centre with use of anti viral drugs tenofovir/ entecavir and listed for liver transplantation.
USE OF HBV related organ —
HBsAg positive patient going for liver or non liver transplant should be treated with antiviral till HBV DNA copies are undetectable.
HBcAb positive but HBsAg negative liver can be used in the HBsAg-positive recipient ,the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity) AND the HBV non-immune recipient.
Liver from HBsAG positive patient acn be used in HBsAG positive recipient along with anti viral drugs
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low
HBIg/NA prophylaxis is used in HBV/HDV positive recipient
Preventing Recurrence of HBV Post-Transplantation
Life-long combination therapy with HBIG and a potent NA for HIGH RISK cases like HBsAG positive , liver transplant for HCC , coinfected with HIV
Limited 6-12 month treatmet with same drugs in LOW RISK ( PAST INFECTION HBcAB POSITIVE )
HBV RECURRENCE
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence
or de novo hepatitis B post-liver transplantation.
HBV DNA and HBsAg should be monitored during teh therapy
HBV Vaccination
All SOT recipeint who are HBV naive should be vacccinated
Booster dose can be given to KT patient to increase the antibody titre more tha 100 IU/ML
Phases of infection
HBeAg positive chronic infection and the HBeAg positive chronic hepatitis followed by
HBeAg negative chronic infection and HBeAg negative chronic hepatitis
Here, in general , DNA copies goes down and enzymes may get elevated
REACTIVATION OF HBV
HBsAG NEGATIVE TO POSITIVE
DNA COPY ZERO TO POSITIVE or 2 LOG INCREASE IN NUMBER OF COPIES
ABSOLUTE NUMBER OF DNA MORE THAN 1LAC IN HBsAG POSITIVE PATINET
HDV ( DELTA )
Not present in isolation
hijacks the HBV replication machinery to replicate
diagnosis – serum HDV IgG positivity
active infection -HDV RNA copies in serum
should be tested in HBsAg postive prospective recipient and also those who has PAST INFECTION with HBV on serology
HBV Biology and Disease
● All SOT candidates must be tested for HBsAg, HBsAb, and HBcAb.
● All HBsAg positive patients undergoing transplant work up must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
● HDV RNA where HDV is positive or equivocal
● Recipients with HBcAb positive but HBsAg negative must have HBV DNA and HDV serology to exclude occult HBV or HDV infection.
● Donors who are positive for HBcAb but HBsAg negative must have HBV DNA
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
● In patients with fulminant hepatitis B Liver transplantation must be considered and treatment with tenofovir or entecavir should be strongly considered
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
● Decompensated cirrhosis patients due to hepatitis B may be candidates for liver LTx
● positive HBV DNA with decompensated cirrhosis patients require urgent antiviral treatment with NA.
● Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and HCC
HBV and Other (Non-Liver) Transplantation
Patients with advanced HBV-related liver disease requiring another organ transplant
be considered for combined transplantation after careful consideration of the potential risks and benefits.
Pre-Transplant Management of HBV in Transplantation candidates
● All liver transplantation candidates with positive HBsAg should be treated with tenofovir or entecavir before transplantation, aiming for negative HBV DNA level.
Use of HBcAb Positive or HBsAg Positive Donors
● Donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis.
● Potential recipient should be counselled about possibility of receiving a liver from a donor with past or current HBV infection
HBcAb positive donation for liver recipients
● The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient
● When HBcAb positive liver donor to an HBsAg positive recipient we should adopte approach to prevent HBV reactivation
● When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
● Hepatitis B core antibody positive donor liver should be allocated in the following :
1. the HBsAg-positive recipient
2. the HBV-immune recipient(naturally or by vaccin )
3. the HBV non-immune recipient.
HBsAg Positive Donation for Liver Recipients
● HBsAg positive donor livers can be given to HBsAg positive recipients as the recipient is negative HDV and If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
● All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
● Use of HBIg rarely achieves HBsAg negativity, and is not recommended.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
● The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
● If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient
● When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
● HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
● HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
● Perioprative management of HIV and HBV infections should be agreed by MDT before transplantation.
● HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period.
● For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA
prophylaxis can be considered, but not within 12 months of transplantation.
Preventing Recurrence of HBV Post-Transplantation
● In HBsAg positive individuals combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant.
● Early withdrawal of HBIG or use of HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence.
● High risk patients for HBV recurrence
☆ HBV DNA positive at time of transplant
☆ HBeAg positive patients
☆ Hepatocellular carcinoma recipiant
☆ HIV co-infected
These patients should recieve Life-long combination therapy with HBIG and a potent NA
● Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
● HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis.
● Resistance testing should be undertaken at a specialist laboratory.
● Lifelong antiviral therapy for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
● Entecavir or Tenofovir are the first line treatment. Tenofovir used if the patient has previous lamivudine exposure
Monitoring for HBV Recurrence or De Novo Infection
● HBV DNA and HBsAg every three months in the first year then every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
● Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
HBV Vaccination and Solid Organ Transplantation
● All prospective SOT recipients who are HBV naive must be vaccinated
● Vaccination considered a protective strategy to develop protective serum titres of HBsAb
● In HBcAb positive recipients with HBsAb <100 IU/mL, vaccination boost the protective titre of HBsAb and minimise the risk of reactivation
● All prospective SOT recipients should receive a high-dose, accelerated vaccine
● In case of fail to respond to the initial HBV vaccination schedule, a second series should be administered.
HBV Biology and Disease
• All candidates for solid organ transplantation must be tested for HBsAg, HBsAb, and HBcAb. (1B)
• All HBsAg positive candidates should be investigated for: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be done for candidates with HDV serology is positive or equivocal. (1B)
• Any candidate found to have + HBcAb but – HBsAg (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease
• Fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B according to criteria defined by NHSBT. (1A)
• Early antiviral treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units with antiviral therapy and possible liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
• All HBsAg positive candidates for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and treated with either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors
• The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All candidates should be counselled about the possibility of receiving a liver from a donor with past or current HBV infection.
HBcAb positive donation for liver recipients
· The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
· prevention of HBV reactivation, if liver from a + HBcAb donor and is given to an HBsAg + recipient. (1B)
· When the liver comes from a HBcAb + donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
· If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
· HBsAg (+) donor livers can be given to HBsAg (+) recipients, as long as the recipient is known to be HDV (-). (1C)
· If urgency demands, the HBsAg (+) liver can be given to an HBsAg (-) patient. (1D)
· All recipients of a liver from an HBsAg (+) donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
· Use of HBIg rarely achieves HBsAg (-), and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
· The kidneys, heart and lungs from the HBcAb (+) organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
· If need demands, the non-liver solid organs of the HBsAg (+) organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
· When a HBcAb (+) donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
· HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
· HBsAg (+) donors should not be used for HBV/HDV co-infected recipients. (1C)
· A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
· HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is the same as that used for transplantation of HBV monoinfection. (1C)
· For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
· In HBsAg (+) individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
· Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
· Life-long combination therapy with HBIG and a potent NA can potentially be given to those who are HBV DNA (+) at time of transplant, HBeAg (+) patients, those transplanted for HCC or those who are HIV co-infected. (2B)
· Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
· All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
· Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
· Entecavir or Tenofovir are recommended as first-line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
· HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg (+) liver transplant recipients or individuals receiving a graft from a HBcAb (+) donor, regardless of treatment or prophylaxis regimen. (1C)
· Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence.
HBV Vaccination and Solid Organ Transplantation
· All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented.
· Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
· In renal transplant recipients with HBcAb (+), if HBsAb are <100 IU/mL, needs a booster vaccination. (2C)
· All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
· In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
HBV Biology and Disease
Recommendation:
• All patients being worked up for SOT must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative
(past infection) must have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure)
must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Recommendation:
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in
keeping with UK listing criteria defined by NHSBT. (1A)
Suggestion:
• As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery,
shorten disease duration and improve transplant free survival in severe AHB,
treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Recommendation:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these
patients may be candidates for liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent
antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents
and should be continued indefinitely. (1A)
Suggestion:
• Listing for liver transplantation should be considered in patients with hepatitis B
cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK
NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
Suggestion:
• Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of th potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Recommendation:
• All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an
undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or
entecavir before transplantation if there is a standard clinical indication.(1B)
Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
Suggestion:
• The appropriate matching of an organ recipient with a donor positive for HBsAg or
HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients
Recommendation:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver
recipient. (1C)
• When the liver comes from a hepatitis B core antibody positive donor and is given to
an HBsAg positive recipient, the standard approach to prevent HBV reactivation
should be adopted. (1B)
• When the liver comes from a HBcAb positive donor and is given to a HBV immune or
non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
Suggestion:
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver
should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity)
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
Recommendation:
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative
patient. (1D)
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
• Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
Recommendation:
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for
any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion:
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
• When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Recommendtion:
• HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time
of transplantation. (1C)
• HBsAg positive donors should not be used for HBV/HDV co-infected recipients.(1C)
• A plan for the perioperative management of each of the HIV and HBV infections
should be agreed by the multidisciplinary team before transplantation. (1D)
• HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in
the peri-operative period. After HIV antiviral treatment is re-established, the
approach to HBV prophylaxis is no different from that used for transplantation of
HBV monoinfection. (1C)
Suggestion:
• For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA
prophylaxis can be considered, but not within 12 months of transplantation (2C)
Preventing Recurrence of HBV Post-Transplantation
Recommendation:
• In HBsAg positive individuals deemed to be at high risk of recurrence,
combination therapy with HBIg and/or a potent NA is recommended from the time
of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Suggestion:
• Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be
considered in recipients who are at low risk for post-transplant HBV recurrence.
(2C)
• Life-long combination therapy with HBIG and a potent NA can potentially be
given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these
groups come from retrospective studies in the lamivudine era. (2B)
• Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk
of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although
monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid OrganTransplantation
Recommendtion
• All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be
undertaken at a specialist laboratory. (1C)
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
• Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should
be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
Recommendation:
• HBV DNA and HBsAg should be monitored every three months in the first year
and thereafter every six months in HBsAg positive liver transplant recipients or
individuals receiving a graft from a HBcAb positive donor, regardless of treatment
or prophylaxis regimen. (1C)
• Monitoring intervals should be shortened in cases of self-reported or suspected
non-adherence. (Not graded)
HBV Vaccination and Solid Organ Transplantation
Recommendation:
• All prospective solid organ transplant recipients who are HBV naive must be
vaccinated (time permitting) and the response documented. (1C)
Suggestion:
• Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot
currently be recommended as routine practice. (2C)
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are
<100 IU/mL, then vaccination should be considered to boost the protective titre of
HBsAb and minimise the risk of reactivation. (2C)
• All prospective solid organ transplant recipients should receive a high-dose,
accelerated vaccine schedule. (2C)
• In those who fail to respond to the initial HBV vaccination schedule, a second series
should be administered. (2C)
General recommendations:
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative
(past infection) must have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure)
must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Acute Hepatitis B recommendation
Antiviral treatment is indicated in certain subgroups of patients:
• Fulminant hepatitis B
• Severe AHB – based on the presence of at least two of the following criteria:
– bilirubin >100 μmol/L
– international normalised ratio (INR) ≥1.6
– hepatic encephalopathy
• Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
• Immunocompromised host
Liver transplantation should be considered in all patients with fulminant hepatitis. The criteria for listing for liver transplantation for acute liver failure related to hepatitis B must include hepatic encephalopathy and:
• Prothrombin time >100 seconds or INR >6.5
or
• Any three from:
– age >40 or <10 years
– jaundice to encephalopathy time >7 days
– serum bilirubin >300 μmol/L
– prothrombin time >50 seconds or INR >3.5
Recommendations:
• Individuals with fulminant liver failure associated with hepatitis B infection must be
managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in
keeping with UK listing criteria defined by NHSBT. (1A)
Suggestion:
• As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery,
shorten disease duration and improve transplant free survival in severe AHB,
treatment with tenofovir or entecavir should be strongly considered. (2B)
Chronic Hepatitis B
The goal of treatment in chronic HBV (CHB) infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death. Current treatment guidelines consider NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis.
Recommendations:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and such
patients may be candidates for liver transplantation. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s).
Entecavir and tenofovir are the first line antiviral agents
and should be continued indefinitely. (1A)
Suggestion:
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
BTS guidlines
who need testing ? recommended
all potential recipients need HBsAg , anti HBc, anti HBs AB
all HBsAg positive recipient must have HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
both donor and recipinet with past infection ,(based on HBsAG negative , anti HBc AB positive serology ) should have HBV DNA and HDV serology testing to exclude occult
HBV or HDV infection
Acute fulminant hepatitis and decompensated cirrhosis sholud be managed in specialist liver centre with use of anti viral drugs tenofovir/ entecavir and listed for liver transplantation.
USE OF HBV related organ —
HBsAg positive patient going for liver or non liver transplant should be treated with antiviral till HBV DNA copies are undetectable.
HBcAb positive but HBsAg negative liver can be used in the HBsAg-positive recipient ,the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity) AND the HBV non-immune recipient.
Liver from HBsAG positive patient acn be used in HBsAG positive recipient along with anti viral drugs
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low
HBIg/NA prophylaxis is used in HBV/HDV positive recipient
Preventing Recurrence of HBV Post-Transplantation
Life-long combination therapy with HBIG and a potent NA for HIGH RISK cases like HBsAG positive , liver transplant for HCC , coinfected with HIV
Limited 6-12 month treatmet with same drugs in LOW RISK ( PAST INFECTION HBcAB POSITIVE )
HBV RECURRENCE
Lifelong antiviral therapy is recommended for all individuals with HBV recurrence
or de novo hepatitis B post-liver transplantation.
HBV DNA and HBsAg should be monitored during teh therapy
HBV Vaccination
All SOT recipeint who are HBV naive should be vacccinated
Booster dose can be given to KT patient to increase the antibody titre more tha 100 IU/ML
Phases of infection
HBeAg positive chronic infection and the HBeAg positive chronic hepatitis followed by
HBeAg negative chronic infection and HBeAg negative chronic hepatitis
Here, in general , DNA copies goes down and enzymes may get elevated
REACTIVATION OF HBV
HBsAG NEGATIVE TO POSITIVE
DNA COPY ZERO TO POSITIVE or 2 LOG INCREASE IN NUMBER OF COPIES
ABSOLUTE NUMBER OF DNA MORE THAN 1LAC IN HBsAG POSITIVE PATINET
HDV ( DELTA )
Not present in isolation
hijacks the HBV replication machinery to replicate
diagnosis – serum HDV IgG positivity
active infection -HDV RNA copies in serum
should be tested in HBsAg postive prospective recipient and also those who has PAST INFECTION with HBV on serology
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A)
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients
We recommend that:
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
• When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
• When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
We suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity)
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
We recommend that:
• HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
• If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
• All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
• Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
We recommend that:
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
We suggest that:
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
• When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
We recommend that:
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C) HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C) A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D) HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Chapter 9: Preventing Recurrence of HBV Post-Transplantation
We recommend that:
•
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
We suggest that:
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C) Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B) Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Chapter 10: Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
We recommend that
All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C) Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
We recommend that
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C) Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
HBV Vaccination and Solid Organ Transplantation
We recommend that
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
We suggest that
• Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
• All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
• In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
Guidelines for Hepatitis B & Solid Organ Transplantation
Screening for transplantation
Pre-Transplant Management of HBV (HBsAg +ve) recipient
Preventing Recurrence of HBV Post-Transplantation
Treatment of HBV recurrence or De Novo Hepatitis B after SOT
Monitoring for HBV recurrence or De Novo Infection
HBV Vaccination and Solid Organ Transplantation
Summary
HBV infection is one of the common viral infections and can cause chronic liver damage and cirrhosis, HBV vaccination should be adopted and applied to all to prevent the disease. This guideline was reviewed and written by experts in the field and shows different level of recommendation, published in 2016 and contain 12 chapters with many recommendations with different levels of evidence.
Introduction
HBV DNA virus belongs to the Hepadnaviridae. According to WHO data, HBV have infected more than 257 million with estimated annual death of around 600,000 due to advanced liver cirrhosis including HCC,
Despite the vaccination programs HBV still is responsible for infection worldwide.
HBV transmission
Vertical transmission from mother to child is common and 90% can progress to chronic infection before 5 years of age.
Horizontal transmission due to sexual transmission, nosocomial and contamination with blood and blood related products, IV drug abuser are also major source but < 10% in adults can progress to chronic stage.
Phases of Infection
It is double-stranded DNA virus. It has compound interaction with the host immune system through inflammation, fibrosis, and finally cancer.
chronic carrier status refers to the failure tof the innate and adaptive immune response during the primary infection.
These phases can present as following
1.HBe Ag Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”). categorized by HBeAg positive and Anti HBeAb negative with HBV DNA viral loads generally >10 7logs IU/mL. ALT level is normal, and a liver biopsy (if performed) shows no or minimal inflammation. However, in this phase there’s no true immune tolerance in fact there is ongoing cytotoxic T-cell activity. Treatment is therefore indicated in this phase.
2. HBe Ag Positive Chronic Hepatitis (previously called “inflammatory” “Immune active” or “immune elimination phase”).
Patients in this phase are HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive
chronic infection this phase is asymptomatic, there is immune-mediated damage to the liver with resultant inflammation and fibrosis that can progress to cirrhosis in those with prolonged, unrecognized inflammation.
Antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis.
3. HBe Antigen Negative Chronic Infection (previously called “inactive phase”). This phase is characterized by HBeAg negativity, HBeAb positivity with normal ALT levels, and HBV DNA levels being characteristically <2000 IU/mL. but the rate of seroconversion depends on the genotype. Those with age of > 40 years have a higher chance for seroconversion.
2. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”). Usually associated with fluctuation in the level of ALT and lead to increased risk of cirrhosis and needs treatment with antiviral.
Serological and Virological Testing
HBV serological profile Interpretation is as follows.
1. HBsAg negative, HBcAb negative, and HBsAb negative indicate no evidence of
current or past HBV infection. But No immunity to HBV.
2.HBsAg negative, HBcAb negative, & HBsAb positive indicate vaccination with immunity.
3.HBsAg positive indicates active infection with HBcAb positive,
4. IgM HBcAb positive, but HBsAb negative. indicates acute HBV infection (window period), or non-specific reactivity (false positive). This is mainly applicable to donors who have received blood products.
4.HBcAb positive with all other markers negative (‘core alone’) may indicate past HBV infection,
5. HBsAg negative, HBcAb positive, and HBsAb positive again indicate past infection with good immunity.
6. HB ‘core alone’ positive profile in the recipient needs further workup including a history of blood products and risk factors for HBV, full HBV serological markers, and HBV DNA (+/- follow-up testing) to explain the patient’s HBV status.
Reactivation of HBV
Reactivation may be asymptomatic or accompanied with flare up of inactive disease, demonstrating clinically with acute hepatitis which can progress to liver failure and even death. Reactivation risk depends on the HBV status and the type of immunosuppression and the underlying condition, lack of immune response, or resistance to the antiviral therapy.
HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
Hepatitis Delta Co-Infection
Co-infection with HBV in > 5%, can worsen the course of progressive chronic liver disease cirrhosis, and HCC. The diagnosis is done by positive serology test for HDV IgG, and confirmation of co-infection with HDV BY HDV RNA positive test >2000IU/ML
Acute HBV infection
acute HBV infection is self-limiting in the majority up 95-99% even without treatment, but up to 1% can progress to fulminant hepatic failure with a high mortality rate of > 80%.
Acute Fulminant hepatitis B is Severe form – diagnosed based on the presence of at least two of the following criteria:
– bilirubin >100 µmol/L
– international normalized ratio (INR) ≥1.6
– hepatic encephalopathy.
Early initiation of antiviral can hasten the recovery, and shortening the disease course while preventing complications, and improving transplant-free survival. Treatment with tenofovir or entecavir should be strongly considered.
Chronic hepatitis B infection
The main goal for treating CHB infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC), and death. NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients
Antiviral treatment has two objectives:
1. Improvement of liver function
2. Decreased risk of HBV recurrence after transplantation
Tenofovir TFV and entecavir ETV are currently the first-line agents, with superior potency and higher barrier to Lamivudine resistance (4).
Both are well tolerated with good safety profiles more effective in the suppression of viral duplication and rapid in the clearance of viral load. Entecavir is not nephrotoxic and have an exceptional resistance profile, can be used at even higher doses in decompensated liver cirrhosis 1 mg instead of 0.5mg daily, can be used indefinitely with 3 months monitoring for the SVR by HBV PCR
Any persistent viremia after 6-12 months of treatment indicates treatment failure and consider alternative therapy.
Hepatocellular carcinoma Hcc
For listing OLT for HCC, the following criteria must be satisfied:
• A single tumor ≤5 cm in diameter, or
• Up to 5 separate tumors, all ≤3 cm, or
• Single tumor >5 cm and ≤7 cm diameter, where there has been no evidence of tumor progression, no extra-hepatic spread, and no new nodule formation over a six-month period. Regional therapy +/- chemotherapy may be given during that time. Sustained viral response with antiviral therapy is required.
Impact of Transplantation on HBV
immunosuppressive therapy used in SOT can modify the natural history of HBV infection with enhanced replication of HBV facilitated by some drugs.
Rapamycin (mTOR inhibitor) has been shown to enhance HBV production by inducing cellular autophagy. Steroids enhance viral replications by their effect on the viral genome and both prednisolone and azathioprine increased intracellular viral DNA and RNA levels by approximately two-fold and four-fold respectively. Cyclosporin did not alter the levels of viral RNA or DNA. However, a combination of all three immunosuppressive agents increased the level of intracellular viral DNA eightfold, indicating an additive effect.
Impact of HBV Infection on Transplant Outcome
HBV infection is associated with more frequent and rapid progression to cirrhosis and
hepatocellular carcinoma in SOT recipients.
HBsAg positivity is a risk factor for death in renal transplant recipients. It also increases the risk of denovo membranous nephropathy. Recent studies in kidney and heart transplant recipients with CHB without cirrhosis have reported excellent outcomes with antiviral therapy alone.
Prevalence of HBV Infection in SOT
The pattern of HBV infection in SOT is similar to the general population and its overall prevalence is decreasing worldwide due to the improvement in vaccination and screening programs. In developing countries prevalence varies between 2-20% in HD populations while it’s even lower 0-10% in developed countries.
Risk of HBV Infection in the SOT Recipient
All donors and recipients should be screened for possible active or Cronic HBV infection and risk of reactivation after SOT, and the use of antiviral prophylaxis after transplantation.
Those with high titer anti-HBsAB considered low risk for reactivation however breakthrough reactivation still can occur. Hence post-transplant anti-HBsAb monitoring is not routinely recommended to predict the risk of reactivation.
However, donors with HBsAg positive, anti-HBc positive to recipients with HBsAg positive, anti-HBc positive are considered the highest risk for HBV reactivation/infection without antiviral treatment. All HBsAg-positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels. (1B)
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive
must have liver disease staging and suppression of HBV DNA by either tenofovir or
entecavir before transplantation if there is a standard clinical indication. (1B)
Organs like kidneys, heart, and lungs from the HBcAb-positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
If needed the non-liver solid organs of the HBsAg positive donor can be used for any recipient, after an individualized assessment of risk and benefit. (2C)
When an HBcAb-positive donor is used, lamivudine prophylaxis may be given for six
months after transplantation, although the risk of transmission is very low. (2c)
SUMMARY – BTS GUIDELINES FOR HEP B AND SOT.
HBV biology and disease;
Indication for transplantation for HBV related disease;
HBV and other non liver transplantation;
Pre transplant mgt of HBV in individuals being considered for transplantation.
Use of HBcAb +VE or HBsAg +VE donor;
HBcAb +VE donation for liver recipient;
HBsAg +VE donation for liver recipients.
HBcAb +VE and HBsAg donation for non liver solid organ recipients.
MGT of CO- infection(HDV,HCV,HIV) and transplantation.
Preventing recurrence of HBV post transplantation.
Tx of HBV recurrence or de novo Hep B after SOT.
Monitoring HBV recurrence or De novo infection.
HBV Vaccination and SOT.
II. Guidelines for Hepatitis B & Solid Organ Transplantation
Summarise these guidelines
HBV biology and disease
– all potential SOT recipients should be tested for HBsAg, HBsAb (absolute titers) and HBcAb
– all HBsAg positive potential recipients should be tested for HBeAg, HBeAb, HDV Ab, HBV DNA levels
– for potential recipients with a positive or equivocal HDV serology, perform HDV RNA
– for potential recipients with HBcAb positive and a negative HBsAg (past infection), perform HBV DNA and HDV serology test to exclude occult HBV or HDV infection
– for donors with a positive HBcAb and a negative HBsAg (past HBV exposure), perform HBV DNA testing to exclude occult HBV infection
Pre-transplant management of potential HBV transplant recipients
– potential HBsAg positive non-liver SOT recipients should have liver disease staging and HBV DNA suppression using tenofovir or entecavir before transplantation
Use of HBcAb positive or HBsAg positive donors in non-liver SOT recipients
– organs from a HBcAb donor can be used on any recipient, the risk of de novo infection is low, but antiviral prophylaxis may be offered for 6 months post-transplant
– if the demand is high, organs from a HBsAg donor can be used on any recipient after individualized assessment of risk vs benefit
Management of co-infection (HCV, HDV, HIV) and transplantation
– HBV/ HDV recipients should receive HBIG/NA prophylaxis post-transplant
– the HBIG can be withdrawn after 12months post-transplant
– HBV/ HDV co-infected recipients should not receive organs from
HBsAg positive donors
– a MDT should plan the management of each of the HIV and HBV infections before transplantation
– HBIG can be used for HBV prophylaxis when antiviral prophylaxis cannot be used in the perioperative period
– HBV prophylaxis in the HIV/ HBV co-infected recipients is similar to that offered to the HBV mono-infection recipients
Preventing recurrence of HBV post-transplantation
– HBIG ± a potent NA is recommended to prevent HBV reinfection post-transplant in HBsAg positive patients at high risk of recurrence
– for patients with a low risk for post-transplant HBV recurrence, HBIG can be withdrawn early or avoided altogether i.e., HBIG-free prophylaxis
– indications for life-long HBIG + NA therapy: – HBV DNA positive recipients at time of transplant, HBeAg positive patients, HCC transplant patients, HCV co-infected patients
– isolated HBcAb positive recipients at risk of HBV reactivation post-transplant can be offered 6-12months of antiviral prophylactic therapy although monitoring of HBV recurrence is also an acceptable strategy
Treatment of HBV recurrence or de novo hepatitis after SOT
Monitoring for HBV recurrence of de novo infection
– for recipients who receive a graft from a HBcAb positive, HBV DNA and HBsAg should be monitored every 3months in the 1st year then every 6months thereafter irrespective of treatment or prophylaxis regimen
HBV vaccination and SOT
– if time allows, all potential SOT recipients who are HBV naïve must be vaccinated and the response documented
– consider vaccination to boost the protective HBsAb titers and minimize risk of reactivation among HBcAb positive potential kidney transplant recipients with HBsAb <100IU/ml
– a high-dose accelerated vaccine schedule should be offered to all potential SOT recipients
– repeat vaccination should be offered to patients who fail to respond to the initial HBV vaccination schedule
British Transplantation Society Guidelines.
Guidelines for Hepatitis B & Solid Organ Transplantation
HBV Biology and Disease
They recommend that:
=All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titers) and HBcAb. (1B)
=All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology(if came positive , should send HDV RNA), and HBV DNA levels. (1B)
=HBcAb positive recipients/ Donors and HBsAg negative, occult
HBV or HDV infection should be excluded by HBV DNA and HDV serology testing.
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
They recommend that:
=Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A)
They suggest that
=Early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or Entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
They recommend that:
=Antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely in patients with decompensated cirrhosis and detectable HBV DNA (1A)
They suggest that
=Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A).
HBV and Other (Non-Liver) Transplantation.
They suggest that
=Combined transplantation is considered in patients with advanced HBV-related liver disease after careful consideration of potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
They recommend that:
=All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or Entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
=Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or Entecavir before transplantation if there is a standard clinical indication. (1B).
Use of HBcAb Positive or HBsAg Positive Donors
HBcAb positive donation for liver recipients
They recommend that:
=The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
=Donation from hepatitis B core antibody positive donor to an HBsAg positive recipient, we should follow the standard approach to prevent HBV reactivation. (1B)
=Liver donation from a HBcAb positive to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
They suggest that
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver
should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced
immunity)
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
They recommend that:
=HBsAg positive donor livers can be given to HBsAg positive recipients and if urgent can be given to HBsAg negative (1C).
=Treatment by Entecavir or tenofovir should be started from the time of transplantation for recipients of a liver from an HBsAg positive donor (1B).
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
They recommend that:
=The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
They suggest that:
=When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
They recommend that:
=HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation and not allowed to receive from HBsAg. (1C)
They suggest that:
=For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
They recommend that:
=A combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
They suggest that:
=Patients who were considered at high risk for HBV recurrence; such as those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; should receive life-long combination therapy with HBIG and a potent NA (2B)
• Recipients with HBcAb positive alone are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment or monitoring for HBV recurrence . (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
They recommend that
= Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation and should look for drug resistance and drug adherence (1C)
= Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
They recommend that
=Monitoring HBV DNA and HBsAg every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
HBV Vaccination and Solid Organ Transplantation
They recommend that
=All HBV naïve, prospective solid organ transplant recipients must be vaccinated (time permitting) and the response documented. (1C)
They suggest that
=Vaccination for renal transplant recipients who are HBcAb positive, if HBsAb are
<100 IU/mL, then vaccination should be considered to boost the protective titer of HBsAb and minimize the risk of reactivation. (2C)
= Accelerated vaccination for all prospective solid organ transplant recipients should be given and those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
This is the British Transplantation Society Guidelines for Hepatitis B & Solid Organ Transplantation 2018
HBV Biology and Disease
-All patients worked up for SOT must be tested for HBsAg, HBsAb and HBcAb. (1B)
-All HBsAg positive patients undergoing transplant work up must have: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
-HDV RNA testing must be performed where HDV serology is positive or equivocal. (1B)
-Any potential transplant recipients or donor found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Recommendations:
– Must be managed in a specialist liver center. (1C)
– Liver transplantation must be considered in patients with fulminant hepatitis B (1A)
Suggestion;
– As early antiviral treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Recommendations:
– Should be treated in specialist liver units and patients may be need liver Tx (1C)
– If HBV DNA is detectable. Entecavir and tenofovir are the first line antiviral agents and should be started urgently and continued indefinitely. (1A)
Suggestions:
– Listing for liver Tx; in HBV cirrhosis and UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
Suggestion:
• Advanced HBV-related liver disease requiring another Organ Transplant to be considered for combined transplantation (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Recommendation:
– All HBsAg +ve individuals should be treated before transplantation with tenofovir or entecavir, aiming for an undetectable HBV DNA level. (1B)
– HBsAg +ve individuals undergoing non-liver OT must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation (1B)
Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
Suggestion:
– Matching a recipient with donor +ve for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
HBcAb positive donation for liver recipients
Recommendation:
– If liver comes from HBcAb donor. It can be used for any potential liver recipient. (1C)
– If HBsAg positive recipient, approach to prevent HBV reactivation should be adopted. (1B)
– Prophylactic lamivudine should be given at the time of transplantation, and should be continued indefinitely, if recipient HBV immune or non-immune (1A)
Suggestion:
– If other waiting list priorities permit, the HBcAb positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (natural and vaccine immune)
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
Recommendation:
– Can be given to HBsAg positive recipients if HDV negative. (1C)
– If urgent demands, can be given to an HBsAg negative patient. (1D)
– All recipients must be treated with entecavir or tenofovir from the time of transplantation. (1B)
– Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
Recommendation:
– The kidneys, heart and lungs of HbcAb+ve can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion:
-If need demands, HBsAg positive organs can be used for any recipient risk against benefit assessment (2C)
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for 6 months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Recommendations:
– HBV/HDV recipients; should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
– HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
– Perioperative management plan of the HIV and HBV infections should be agreed by the MDT (1D)
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
Suggestion:
– For HBV/HDV recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
Recommendation:
– In HBsAg positive individuals; the use of HBIg and/or a potent NA at the time of transplantation is recommended for prevention. (1B)
Suggestion:
– Early withdrawal of HBIG or HBIG-free prophylaxis in low risk recipients (2C)
– Life-long combination HBIG and NA for individual at high risk for HBV recurrence (2B)
– Post-non-liver transplant with past HBV infection (HBcAb positive alone) are considered for (6-12 months) course of prophylactic antiviral treatment; with monitoring for recurrence (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Recommendation:
– Review of adherence with NA prophylaxis and test for resistance (1C)
– Lifelong antiviral therapy for all individuals with HBV recurrence or de novo HBV (1C)
– Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
Recommendation:
– HBV DNA and HBsAg every 3 months in the first year and then every 6 months (1C)
HBV Vaccination and Solid Organ Transplantation
Recommendation:
-All HBV naïve recipients must be vaccinated and the response documented. (1C)
Suggestion:
– Liver recipients transplanted for HBV, vaccination cannot recommended as routine. (2C)
– Renal recipients if HBsAb are <100 IU/mL, vaccination is recommended. (2C)
– All recipients should receive a high-dose, accelerated vaccine schedule. (2C)
– Second vaccination series is considered if failed response (2C)
British Transplantation Society (BTS) Guidelines for hepatitis B and solid organ transplantation (2018)
This guideline aims to provide consensus expert opinion regarding the management of hepatitis B infection and solid organ transplantation. The GRADE system is used to highlight for the reader the quality of evidence available for a particular area and the subsequent certainty of the expert recommendation made based upon this evidence and clinical experience.
Why is a guideline needed?
· Hepatitis B (HBV) affects 257 million people worldwide (WHO estimate)
· Patients with chronic HBV may end up requiring a liver transplant due to end-stage liver disease
· There is potential for transmission of HBV through solid organ transplantation (SOT) from donors with prior or current HBV (de novo HBV)
· SOT recipients require significant immunosuppression and this may put them at risk of reactivation of prior HBV
· Given the availability of a hepatitis B vaccine, a proactive approach should be taken to protecting potential SOT recipients prior to transplantation, especially as vaccine efficacy will decrease with advancing chronic renal disease and even more so following transplantation when the patient is immunosuppressed
· HBV infection can have a negative impact on post-transplantation care if it limits the immunosuppression options that are suitable for the patient, and HBV infection itself is associated with worse patient outcomes post-transplantation
· We now have effective antiviral prophylaxis which can be used efficiently to reduce the rates of HBV reactivation post-transplantation (previously 50-94% post renal transplantation, now <6.4% in one study)
· HBV infection can be associated with the development of membranous glomerulonephritis which may lead to worsening allograft function in the renal transplant recipient
What should happen prior to SOT?
1. Screening for HBV should be a mandatory part of work-up for transplantation. Test for HBsAg, HBsAb and HBcAb. If HBsAg is positive then further screening should be done for HBeAg, HBeAb, HDV and HBV DNA levels
2. Any patient with evidence of past HBV infection (HBcAb positive and HBsAg negative) should have HBV DNA levels measured and should also be tested for hepatitis D (HDV)
3. If the patient is HBsAg positive and is being considered for renal transplantation they must be screened for cirrhosis and should be given tenofovir or entecavir to suppress HBV DNA prior to transplantation
4. Wherever possible, patients should be vaccinated against HBV prior to transplantation
What is the role of hepatitis B vaccination in renal transplantation?
· Patients should be offered a high-dose accelerated vaccination course: vaccination is more effective in the pre-transplantation stage than post-transplantation when immunosuppression may interfere with the effectiveness of the vaccine
· If, after 3 doses, the patient does not demonstrate a sufficient immune response then a further course should be offered
· In patients who have evidence of prior HBV infection (HBcAb positive), if their HBsAb titres are <100 IU/ml they should also receive vaccination in order to boost their antibody levels and reduce the risk of HBV reactivation post-transplantation
What happens if the kidney being offered is from a patient with current or past HBV infection?
· If the kidney is coming from a patient with previous HBV infection (HBcAb positive) this kidney could be given to any potential recipient and it is acknowledged that the risk of HBV in this context is very low the recipient should be given a 6 month course of lamivudine as a precaution
· If the kidney is being offered from a patient who with current HBV infection (HBsAg positive) then this decision should be made based upon how urgent/necessary the transplant is, the availability of donor organs and a risk/benefit assessment for the individual potential recipient
What happens if the potential renal transplant recipient is HBV positive and also has either hepatitis D (HDV), hepatitis C or HIV?
· Potential transplant recipients who have HBV and HDV co-infection should receive hepatitis B immunoglobulin (HBIg) and nucleotide analogues following transplantation and both of these should continue for the first year after transplantation, after which withdrawal of HBIg may be considered. They are not suitable to receive an organ from a donor who is HBsAg positive
· Patients on HIV antivirals often have these medications temporarily suspended around the time of transplantation to prevent the development of drug resistance- during this time there may be a different approach to HBV prophylaxis in these patients (ie use of hepatitis B immunoglobulin)
What about post-transplantation management?
· Renal transplant recipients who had evidence of past HBV infection (only HBcAb positivity) can be managed via 2 approaches: either 6-12 month course of prophylactic antiviral treatment, or regular monitoring for HBV recurrence
1. EXECUTIVE SUMMARY OF RECOMMENDATIONS
HBV Biology and Disease
Recommendation· HBsAg, HBsAb (absolute titers), and HBcAb tests are required for all patients undergoing preparation for solid organ transplantation, as well as HDV RNA testing and HBV DNA testing to rule out occult HBV or HDV infection.
Indications for Transplantation for HBV-Related Disease Acute Fulminant Hepatitis B
Recommendation· Liver transplantation must be considered in patients with fulminant hepatitis B in accordance with NHSBT criteria.Suggestion· Early antiviral treatment with nucleot(s)ide analogues can improve AHB survival. Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Recommendation:· Individuals with decompensated cirrhosis and detectable HBV DNA need urgent antiviral treatment with Entecavir and tenofovir.
Suggestion· Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and UKELD score >49.
HBV and Other (Non-Liver) Transplantation
Suggestion· Patients with advanced HBV-related liver disease should consider combined transplantation.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Recommendation:· HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels.
Use of HBcAb Positive or HBsAg Positive DonorsGeneral Recommendations
Suggestion:· Potential recipients should be counseled about the possibility of receiving a liver from a donor with HBV infection.
HBcAb positive donation for liver recipients
Recommendation:· Prophylactic lamivudine should be given from the time of transplantation to prevent HBV reactivation.
Suggestion· The hepatitis B core antibody-positive donor liver should be allocated in order of priority.
HBsAg Positive Donation for Liver Recipients
Recommendation:· HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
Recommendation:· The risk of de novo HBV infection is low for organ donors.
Suggestion:· HBcAb-positive organ donors can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Recommendation:· HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation, and HBsAg-positive donors should not be used.
Suggestion:· HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation.
Preventing the Recurrence of HBV Post-Transplantation
Recommendation:· Combination therapy with HBIg and NA is recommended to prevent HBV reinfection post-liver transplant.
Suggestion:· Early withdrawal of HBIG or HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence, and life-long combination therapy with HBIG and NA can be given to those at high risk.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
Recommendation· Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
Monitoring for HBV Recurrence or De Novo Infection
Recommendation
· Monitoring intervals should be shortened in cases of non-adherence.
HBV Vaccination and Solid Organ Transplantation
Recommendation
· Prospective solid organ transplant recipients must be vaccinated and documented.
Suggestion· Vaccination should be considered to develop protective serum titers of HBsAb in liver, renal, and solid organ transplant recipients, and in those who fail to respond, a second series should be administered.
HBV BIOLOGY AND DISEASE
Introduction· Hepatitis B Virus (HBV) is a major human
pathogen, estimated to infect 257 million people worldwide
and cause 600,000 deaths every year.
· It is transmitted through either vertical transmission from mother to child or horizontal transmission through unsafe medical practice.
· Patient age at the time of initial infection is a major determinant of whether the infection becomes chronic.
Virology and Phases of Infection
· HBV is not directly hepatotoxic, but a complex interaction with the host immune system drives the hepatic inflammation-fibrosis-cancer axis.
1. HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).· Treatment is rarely indicated for HBeAg-positive and HBeAb-negative patients with HBV DNA viral loads >107 IU/mL.
2. HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” “immune active” or “immune elimination phase”).· This phase is characterized by a persistent or intermittent elevation in ALT and fluctuating HBV DNA levels, leading to inflammation and fibrosis that can progress to cirrhosis.
· Antiviral therapy is indicated if prolonged or there is evidence of significant liver fibrosis.
3. HBe Antigen Negative Chronic Infection (previously called “inactive phase”).
· This phase is characterized by HBeAg negativity, HBeAb positivity, and normal ALT levels, with HBe antigen seroconversion rates determined by age and HBV genotype. Antiviral therapy can also result in HBeAg seroconversion.
· Regular follow-up is mandatory as reactivation and the development of HBeAg-negative chronic hepatitis occurs in 25%.
4. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).· Mutations in the basal core promoter and pre-core region of the pre-C/C gene can lead to increased HBV DNA levels, resulting in liver damage and HCC.
· Antiviral therapy is the cornerstone of management.
Serological and Virological Testing
· Testing for HBV surface antigen (HBsAg) and core antibody (HBcAb) is important for diagnosis and veracity of the host immune response.
Reactivation of HBV
· HBV reactivation varies depending on baseline HBV status, underlying condition, type of immunosuppressive therapy, and host immunity.
Hepatitis Delta Co-Infection
· HDV is a hepatotropic replication-deficient single-stranded covalently closed circular RNA virus that hijacks the HBV replication machinery to facilitate its viral replication.
Recommendation:· All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb, and HBcAb, and any potential transplant recipients must have HBV DNA and HDV serology testing to exclude occult infection.
INDICATIONS FOR TRANSPLANTATION FOR HBV-RELATED DISEASE
Acute Hepatitis B
· Antiviral treatment is indicated in certain subgroups of acute hepatitis B (AHB) due to the presence of at least two of the following criteria: bilirubin >100 µmol/L and international normalized ratio (INR) ≥1.6.
· Prompt antiviral administration is warranted to shorten disease duration, promote recovery, and improve survival.
· A case series of 17 patients with severe or fulminant AHB showed that LAM administered until HBsAg clearance improved survival compared to historical, untreated controls (82.4 vs. 20% survival, p<0.001).
· However, the evidence for LAM has not been universally positive.
· The current EASL guidelines on the treatment of AHB recommend the use of ETV (0.5 mg/day) or TFV (245 mg/day).
· Antiviral treatment should be started early in the course of severe AHB, without waiting for the development of fulminant hepatitis.
· Delayed initiation of NAs is associated with higher mortality or requirement for OLT.
· There are limited data regarding the required duration of antiviral treatment in AHB, but therapy should be continued for at least three months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss.
· Liver transplantation should be considered in all patients with liver failure related to hepatitis B, with hepatic encephalopathy and prothrombin time >100 seconds or INR >6.5.
Recommendation:· Liver transplantation must be considered in patients with fulminant hepatitis B infection.
Suggestion· Early antiviral treatment with nucleot(s)ide analogues can improve AHB survival.
Chronic Hepatitis B· Treatment in chronic HBV infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death, with NAs or PEG-IFN as first-line treatment in patients with higher HBV DNA levels.
Decompensated Cirrhosis· The 5-year cumulative incidence of hepatic decompensation for untreated CHB-associated cirrhotic patients is approximately 20%.
· Untreated patients with decompensated cirrhosis have a poor prognosis, with a 14-35% 5-year survival, compared with 84% in the compensated state.
· However, decompensated HBV cirrhosis is declining as an indication for transplantation due to the success of HBV vaccination and the advent of potent oral antiviral agents.
· Antiviral treatment has two objectives: improvement of liver function and decreased risk of HBV recurrence after transplantation.
· TFV and ETV are currently the first-line agents, with greater potency and higher barriers to resistance. NAs have a good safety profile in patients with advanced liver disease, and a phase 2 double-blind study compared the safety of TFV and ETV in decompensated HBV cirrhosis.
· One serious potential side effect is mitochondrial toxicity, which can manifest as lactic acidosis, myopathy, neuropathy, or even hepatotoxicity.
· Treatment-naive patients with ETV (0.5 mg/day) showed significant improvement in Child-Turgotte-Pugh (CTP) and MELD scores, but not all patients improved with ETV.
· Two distinct subgroups of patients exist – those who will experience prolonged survival with antiviral therapy and those who require OLT.
· Studies have attempted to identify prognostic indicators that could help to stratify these patient groups.
Hepatocellular Carcinoma
· HCC is the fifth most common cancer worldwide, with over 500,000 new cases diagnosed annually.
Incidence and Risk Factors
· HBV is the leading risk factor for HCC globally, accounting for 50-60% of HCC.
· It can cause HCC in the absence of cirrhosis, but the majority of HCC (70-90%) develops in cirrhotic livers.
· Several factors are known to increase the risk of HCC among individuals with HBV infection, including demographic, viral, clinical, environmental, and HBeAg status.
· The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study from Taiwan showed that HCC increased in proportion to viral load.
Surveillance· HCC surveillance is necessary even if HBV DNA is suppressed, with six-monthly abdominal ultrasound scans recommended.
Treatment· Treatment of HCC related to HBV is based on size, number of lesions, and serum AFP concentration.
· Salvage transplantation is an option if listing criteria are fulfilled.
· Non-cirrhotic patients with non-resectable HCC should be considered for OLT in the absence of macrovascular invasion and extra-hepatic spread.
Recommendation:· Individuals with decompensated cirrhosis and detectable HBV DNA need urgent antiviral treatment with NA(s).
Suggestion· Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and HCC.
HEPATITIS B AND OTHER (NON-LIVER) TRANSPLANTATION
Introduction· Hepatitis B virus (HBV) infection is a major risk factor for hepatic dysfunction in SOT recipients, leading to progressive liver damage and morbidity, and mortality.
Impact of Transplantation on HBV· Immunosuppressive agents can modify the natural history of HBV infection through disruption of the host immune response and enhanced replication.
· Immunosuppressive drugs have a net immunosuppressive effect, promoting HBV replication when used in combination with other drugs.
Impact of HBV Infection on Transplant Outcome
· HBV infection is associated with more frequent and rapid progression to cirrhosis and hepatocellular carcinoma in SOT recipients, leading to higher mortality.
Prevalence of HBV Infection in SOT· Chronic HBV infection in SOT recipients varies according to geographical regions, with CHB prevalence ranging from 2% to 20%, and past HBV prevalence generally higher than CHB.
Risk of HBV Infection in the SOT Recipient· Post-transplant anti-HBsAb monitoring is not recommended to predict the risk of reactivation.
Management of SOT Recipient with CHB or Past HBV· CHBV and HBV are not contraindications for solid organ transplantation.
Non-Liver SOT Recipients with Advanced Liver Disease· Patients with an advanced liver disease requiring transplantation of non-liver organs should be assessed by a multidisciplinary team to consider combined transplantation
Suggestion
· Patients with advanced HBV-related liver disease should consider combined transplantation.
PRE-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUALS BEING CONSIDERED FOR TRANSPLANTATION
Non-Liver Solid Organ Transplantation· Patients should be screened for hepatitis B carriage and pre-transplant suppression should be given with tenofovir or entecavir to avoid the progression of liver disease.
Recommendation:· HBsAg-positive individuals should be treated with tenofovir or entecavir before transplantation to achieve undetectable HBV DNA levels.
USE OF HBCAB ANTIBODY-POSITIVE OR HBSAG-POSITIVE DONORS IN SOLID ORGAN TRANSPLANTATION
Introduction· The use of solid organs from donors with core antibodies can transmit HBV infection to the organ recipient, with the risk of transmission being high for liver transplantation and lower for kidney and thoracic organs.
Suggestion:· Potential recipients should be counseled about the possibility of receiving a liver from a donor with HBV infection.
Core Antibody Positive Donation for Liver Recipients
· De novo HBV infection is associated with core antibody-positive liver donation and is dependent on the recipient’s HBV immune status.
· Lamivudine is the most cost-effective approach to prophylaxis, prevents most de novo infections, and should be given indefinitely.
Recommendation:· Prophylactic lamivudine should be given from the time of transplantation to prevent HBV reactivation.
Suggestion· The hepatitis B core antibody-positive donor liver should be allocated in order of priority.
HBsAg Positive Donation for Liver Recipients· HBsAg positive liver donation is suitable for non-immune HBsAg negative recipients, but not for HBV/HDV co-infected recipients.
Recommendation:· HBsAg-positive donor livers can be given to HBsAg-positive recipients but must be treated with entecavir or tenofovir.
Core Antibody Positive Donation for Non-Liver Solid Organ Recipients
· Donation of non-liver solid organs from core antibody-positive donors is rarely associated with de novo infection, making antiviral prophylaxis ineffective.
HBsAg Positive Donation for Non-Liver Recipients· Antivirals should be used to suppress HBV after transplantation, and long-term monitoring should be provided to prevent chronic infection.
Recommendation:· The risk of de novo HBV infection is low.
Suggestion:· HBcAb-positive organ donors can be used for any recipient, with lamivudine prophylaxis given for 6 months after transplantation.
PREVENTING THE RECURRENCE OF HBV POST-TRANSPLANTATION
Introduction
· Hepatitis B virus (HBV) recurrence after liver transplantation is defined as the reappearance of circulating hepatitis B surface antigen (HBsAg), with or without detectable HBV DNA. Without appropriate prophylactic treatment, HBV recurrence is almost universal.
· Prophylactic treatment with HBIG and NA has reduced graft reinfection rates and HBV-related liver disease is now a well-accepted indication for liver transplantation.
Hepatitis B Surface Antigen Positive Recipients
· Prevention of post-transplant HBV recurrence in HBsAg-positive patients begins before transplantation with antivirals, such as nucleo(t)side analogues (NA) such as entecavir or tenofovir.
· Combination therapy with NA antivirals is recommended. Early HBIG withdrawal and maintenance with NA monotherapy is effective and safe, but not appropriate for high-risk patients.
· HBIG-free NA prophylaxis can be considered in low-risk recipients, but more robust evidence is needed.
Hepatitis B Core Antibody Positive Recipients
· HBcAb positivity, with or without HBsAb, with negative HBsAg and negative HBV DNA is indicative of past HBV infection and should be managed in the same way as HBsAg positive patients.
Hepatitis B Core Antibody Positive Donors
· Pre-transplant vaccination against HBV can reduce the risk of de novo hepatitis B, with lamivudine being the most widely used.
Hepatitis B Surface Antigen Positive Donors
· Organs from donors chronically infected with HBV are not routinely used, but single-center case series exist of HBsAg-positive donor livers used in patients with HBV-related liver disease or HBcAb-positive recipients, with no differences in graft or patient survival and no episodes of graft dysfunction.
Recommendation:· Combination therapy with HBIg and NA is recommended to prevent HBV reinfection post-liver transplant.
Suggestion:· Early withdrawal of HBIG or HBIG-free prophylaxis can be considered in recipients at low risk for post-transplant HBV recurrence, and life-long combination therapy with HBIG and NA can be given to those at high risk.
TREATMENT OF HBV RECURRENCE OR DE NOVO HEPATITIS B POST SOLID ORGAN TRANSPLANTATION
Introduction· Hepatitis B recurrence after liver transplantation is associated with biochemical or clinical evidence of active disease and can occur in those without prior CHB (HBcAb negative).
· The risk of developing de novo hepatitis B in recipients depends on their hepatitis B serological status and prophylactic measures used.
Review of Literature
· Treatment should be started at diagnosis to control viral replication and stabilize graft function, based on prior treatment and prophylaxis history. E
· entecavir and tenofovir are safe and effective in prophylaxis treatment, but not recommended in patients previously treated with lamivudine.
Recommendation· Lifelong antiviral therapy is recommended for HBV recurrence or de novo hepatitis B post-liver transplantation.
MONITORING FOR HBV RECURRENCE OR DE NOVO INFECTION POST-LIVER TRANSPLANTATION
Introduction· Monitoring post-transplant patients to detect HBV infection in a timely manner.
Review of Literature
· Monitoring of virological, serological, and clinical markers of infection post-transplantation is essential to evaluate prophylaxis efficacy.
· Non-adherence increases the risk of recurrence, so monitoring should consist of both HBV DNA quantification and HBsAg testing.
Recommendation· Monitoring intervals should be shortened in cases of non-adherence.
HEPATITIS B VACCINATION AND SOLID ORGAN TRANSPLANTATION
Rationale for Vaccination
· HBV vaccination is important to protect solid-organ recipients from HBV infection.
Renal Transplantation
· HBV infection is an important consideration in potential renal transplant recipients, with a higher risk of all-cause mortality and graft loss.
· HBV vaccination is recommended in HBV seronegative patients with end-stage renal disease to increase the use of HBcAb-positive kidneys and reduce the risk of reactivation.
Timing of Vaccination
· HBV vaccination is highly immunogenic in healthy individuals but is less effective in patients with organ failure and immunosuppressed.
· Vaccination should be considered early in the course of the disease, as the response to the HBV vaccine is suboptimal in pre-transplant and post-transplant periods.
Vaccination Method
· The usual vaccination schedule is three intramuscular doses of the HBV vaccine, but higher-dose formulations are available for end-stage renal disease.
Summarise these guidelines
-All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb.All HBsAg positive patients should
Tests for HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
– Any potential transplant recipients and donor found to be HBcAb positive but HBsAg negative must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection.
-Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre and liver transplantation must be considered .
– Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation.
– Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely.
We suggest that
– Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines.
-Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits.
-All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level.
– Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
-All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection.
-The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient.
-When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely.
-If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient .
3. the HBV non-immune recipient.
-HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative.
– If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient.
-All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation.
-The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation .
– HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
-HBsAg positive donors should not be used for HBV/HDV co-infected recipients.
-A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation.
-Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected.
-Recipients with HBcAb positive alone are at risk of HBV reactivation post-non-liver transplant and could be considered for 6-12 months course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy.
– Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
-HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen.
– All prospective solid organ transplant recipients who are HBV naive must be vaccinated and the response documented.
-Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice.
-Renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered .
-In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
Guidelines for Hepatitis B & Solid Organ Transplantation
This guideline is the first British Transplantation Society (BTS) guideline on the management of hepatitis B in the transplant setting.
HBV Biology and Disease:
• All HBsAg positive patients undergoing transplant work up should be assessed regarding hepatitis B status serology (HBeAg, HBeAb and HDV Ab) – and HBV DNA levels plus HDV RNA because it can only infect people who are also infected by the hepatitis B virus (HBV) .
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B:
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma:
Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
1. The HBsAg-positive recipient.
2. The HBV-immune recipient .
3.The HBv-non-immune recipient.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation :
Preventing Recurrence of HBV Post-Transplantation:
1. HBV DNA positive at time of transplant,
2. HBeAg positive patients
3.Those transplanted for hepatocellular carcinoma
4.Those who are HIV co-infected.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
Monitoring for HBV Recurrence or De Novo Infection:
HBV Vaccination and Solid Organ Transplantation
HBV Biology and disease Introduction Hepatitis B virus (HBV) is a hepatotrophic DNA virus, it belongs to the hepadnaviridae family. It is estimated to infect 257 million people worldwide and results in approximately 600,000 deaths every year due to complications of end-stage liver disease and hepatocellular carcinoma (HCC). Most of chronic HBV infection results from vertical transmission from mother to child or horizontal transmission through unsafe medical practice. Adult-to-adult transmission can also occur through sexual, nosocomial or blood borne routes. In adults, less than 10% progressed to chronic infection.
Virology and phases of infection HBV has a party circular double stranded DNA genome. It is converted to covalently closed circular DNA (cccDNA), which forms the template for the production of virions and ongoing infection. There are phases of the illness and they influence patient management:
Serological and virological testing The cornerstone for the diagnosis of HBV infection is the testing for HBV surface antigen (HBsAg). Any individuals who are HBsAg positive should be considered to have active infection and will require post-transplant treatment to control viral replication. They should also have HBV DNA levels measured to determine the status of the infection and help classify their current disease phase.
Testing for HBV core antibody (HBcAb) indicates whether or not an individual has been exposed to HBV in the past. Those who have spontaneously cleared the virus from the blood will be HBsAg negative but HBcAb positive. Testing for HBV surface antibody (HBsAb) is helpful to assess the veracity of the host immune response against HBV. Patients who have been vaccinated against HBV are HBcAb negative but HBsAb positive. Those who have spontaneously cleared HBV are HBsAg negative but HBcAb positive and generally HBsAb positive.
It is important to note that cccDNA remains permanently present in the hepatocytes of individuals who have cleared HBsAg from blood. Immunosuppression of these individuals with past infection can therefore result in the reactivation of HBV and the re-emergence of HBsAg.
Reactivation of HBV HBV reactivation is defined as the reappearance of markers of active HBV replication in a patient with previously controlled HBV infection, or an increase in levels of replication compared to previous levels. Reactivation may result from loss of immune control of HBV or lack of antiviral efficacy due to the emergence of antiviral resistant variants.
Hepatitis Delta co-infectionHepatitis delta (HDV) is a hepatotropic replication deficient single stranded covalently closed circular RNA virus that hijacks the HBV replication machinery within hepatocytes to facilitate its viral replication. It cannot exist in isolation. Virions are coated in HBsAg. It is estimated that around 5% of HBV infected patients worldwide are co-infected with HDV. A diagnosis of past or current HDV co-infection is dependent on the finding of serum HDV IgG positivity. Active HDV co-infection is confirmed by HDV RNA positivity. Indeed, HDV RNA should be performed in all cases of suspected HDV co-infection rather than relying on serology alone. HDV is either acquired at the time of infection with HBV or can occur as a super-infection. HDV co-infection results in more rapid progression of liver disease to cirrhosis and HCC, especially as it is difficult to treat.
Recommendations
Indications for transplantation for HBV related diseaseAcute Hepatitis BMore than 95-99% of adults who acquire acute HBV (AHB) will recover spontaneously and seroconvert to HBsAb without antiviral therapy. Approximately 1% of cases of AHB progress to fulminant hepatitis, which is characterized by a very high mortality rate (up to 80%), often requiring liver transplantation (OLT).
Antiviral treatment is indicated in certain subgroups of patients:
Recommendations
Chronic hepatitis B The goal of treatment in chronic HBV (CHB) infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC) and death. Current treatment guidelines consider NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis.
Decompensated cirrhosis Studies have shown that patients with untreated CHB have a 8 to 20% incidence of developing cirrhosis, and patients with untreated decompensated cirrhosis have poor prognosis. Prolonged and adequate suppression of HBV DNA with antiviral agents can prevent progression to decompensation and may even enable regression of fibrosis and the reversal of cirrhosis.
Hepatocellular carcinoma HCC represents more than 90% of primary liver cancers. A large proportion of HCC related mortality is due to chronic viral hepatitis.
Several factors are known to increase the risk of HCC among individuals with HBV infection:
Surveillance should be offered to patients with CHB who remain at risk of HCC development due to baseline factors. Treatment of HCC is similar to that in other causes of HCC. Liver transplantation is an established treatment option. For listing for OLT for HCC, the following criteria must be satisfied:
Recommendations
Hepatitis B and other (non-liver) transplantationIntroductionHepatitis B virus (HBV) infection is a major risk factor for hepatic dysfunction in solid organ transplant (SOT) recipients. Immunosuppressive therapy used in the SOT setting can modify the natural history of HBV infection leading to progressive liver damage, including fulminant hepatitis, and resulting in significant morbidity and mortality.
Impact of transplantation on HBV Both the adaptive and innate immune responses are important for the control of HBV infection. Reactivation of HBV is well described in association with the use of immunosuppressive agents such as B-cell depleting agents (e.g. rituximab), anthracycline derivatives, TNF-alpha inhibitors, cytokine inhibitors and tyrosine kinase inhibitors.
Impact of HBV infection on transplant outcomes HBV infection is associated with more frequent and rapid progression to cirrhosis and hepatocellular carcinoma in SOT recipients, thus contributing to higher mortality. Hepatitis associated with HBV reactivation can lead to liver failure, especially in patients with cirrhosis. HBV may also cause de novo membranous glomerulonephritis, potentially impacting on renal function after transplantation. With the introduction of effective antiviral therapy, post-transplant patient and graft survival rates have improved significantly.
Prevalence of HBV infection in SOT The prevalence of chronic HBV infection (HBsAg positive, HBcAb positive) or past HBV infection (HBsAg negative, HBcAb positive) amongst SOT recipients varies according to geographical regions of the world, following a similar pattern to HBV prevalence in the general population. The prevalence of past HBV infection in the SOT setting is not well reported, but will be generally higher than that of CHB. All patients likely to require SOT must be screened for HBV infection at the earliest opportunity, ideally before the administration of blood products or immunosuppression.
Risk of HBV infection in the SOT recipient The overall risk of HBV reactivation/de novo infection in a SOT recipient without antiviral treatment/prophylaxis is dependent upon the donor and recipient HBV status.
Management of SOT recipient with CHB or past HBV CHBV and past HBV are not contraindications for solid organ transplantation. With the introduction of effective HBV vaccinations and antiviral therapy, SOT can be carried out safely in patients with CHB or past HBV infection.
Non-liver SOT recipients with advanced liver disease Patients with advanced liver disease requiring transplantation of non-liver organs can experience hepatic decompensation following transplantation and need careful assessment by a multidisciplinary team including a liver specialist. Combined transplantation may be considered where appropriate.
Recommendations
Pre-transplant management of HBV in individuals being considered for transplantationLiver TransplantationSince the implementation of oral antiviral agents and effective vaccination programmes, liver transplantation for decompensated hepatitis B (HBV) cirrhosis has become less common. HCC complicating HBV remains a prevalent indication for liver transplantation (OLT). The first line antiviral therapy for patients with decompensated cirrhosis is tenofovir or entecavir monotherapy, which are preferred due to their potency and high barrier to resistance.
Non-liver solid organ transplantation As part of the work up for non-liver solid organ transplantation, patients should be screened for hepatitis B carriage. Pre-transplant suppression for patients with HBsAg positive disease should be given with tenofovir or entecavir to avoid progression of liver disease with immune suppression after transplantation.
Recommendations
Use of HBcAb antibody positive or HBsAg positive donors in solid organ transplantationIntroductionIt is recognised that the use of solid organs from donors with core antibodies (in the absence of HBsAg and regardless of the presence or absence of HBsAb) can transmit HBV infection to the organ recipient. The risk of transmission is very high for liver transplantation and much lower for transplantation of kidneys and thoracic organs. Transmission of infection is associated with the development of recipient HBsAg positivity, with an almost inevitable progression to chronic infection, and with high levels of HBV viral replication (typically serum HBeAg positivity with high titres of HBV DNA). This transmission has been called de novo HBV infection.
Recommendations
Core Antibody Positive Donation for Liver RecipientsDe novo HBV infection denotes the development in the recipient of serum HBsAg positivity, and is associated with the use of core antibody positive liver donation, regardless of the HBsAb donor status. The ideal recipient of the core antibody positive donation is the HBsAg positive recipient. Such a recipient will receive prophylaxis to prevent graft reinfection by HBV, and the same prophylaxis will prevent de novo infection. Published series demonstrate the potential for antiviral prophylaxis to reduce the risk of de novo infection. Most series have examined the use of lamivudine, HBIg or the combination to reduce the risk of de novo infection. The preferred treatment of de novo infection is with tenofovir and the stopping of lamivudine.
Recommendations
HBsAg Positive Donation for Liver RecipientsHBsAg positive liver donation may be considered for any recipient, including non-immune HBsAg negative recipients. This is possible because antiviral treatment with entecavir or tenofovir can reliably suppress HBV replication to prevent HBV-related liver disease in the recipient after liver transplantation. When considering the use of the liver from an HBsAg positive donor, the transplant surgeon should be confident that the liver does not have significant HBV-related fibrotic damage.
Recommendations
Core Antibody Positive Donation for Non-Liver Solid Organ RecipientsDonation of non-liver solid organs from the core antibody positive donor is rarely associated with de novo infection of the recipient. With such a low risk for de novo infection, it is hard to demonstrate a benefit of antiviral prophylaxis. Pre-transplant recipient HBV immunity appears to protect against de novo infection.
HBsAg Positive Donation for Non-Liver RecipientsThe donation of non-liver solid organs from an HBsAg positive donor to an HBsAg positive recipient can be undertaken as long as antivirals are used to suppress HBV after transplantation. Transplantation of a non-liver solid organ from an HBsAg positive donor to a non-immune recipient will result in chronic infection of the recipient.
Recommendations
Management of co-infection (HDV, HCV, HIV) in the liver transplant recipientManagement of HBV/HDV Co-InfectionHBV/HDV infection is typically associated with an aggressive chronic hepatitis with progression to cirrhosis and liver failure. HBV replication is relatively suppressed, so the majority of co-infected patients will be HBeAg negative with relatively low levels of serum HBV DNA. The only available antiviral therapy for HBV/HDV co-infection is alpha interferon, but response rates are disappointing, and are further reduced in patients with cirrhosis. HDV/HBV infection is unresponsive to treatment with nucleoside analogues. There is no proven effective treatment for recurrent (or acquired) graft HBV/HDV infection, and rapid progression to cirrhosis is likely.
Management of HBV/HIV Co-InfectionThe management of HBV/HIV co-infection has been aided by the availability of tenofovir which provides potent monotherapy against HBV infection, and is also a frequent component of combination antiretroviral therapy.
Recommendations
Preventing recurrence of HBV post-transplantationIntroductionHepatitis B virus (HBV) recurrence after liver transplantation is defined as the reappearance of circulating hepatitis B surface antigen (HBsAg), with or without detectable HBV DNA. Without appropriate prophylactic treatment, HBV recurrence is almost universal.
Hepatitis B Surface Antigen Positive RecipientsThe prevention of post-transplant HBV recurrence in HBsAg positive patients begins before transplantation. The HBV DNA viral load at the time of transplantation is a key determinant in the risk of HBV recurrence. All patients on the transplant waiting list should therefore be treated with antivirals with the aim of achieving an undetectable HBV DNA level. Following transplantation, prophylactic treatment of HBV recurrence should be with a combination of HBIG and NA antivirals. Although HBV/HDV co-infected patients have been shown to have reduced rates of HBV recurrence, there are very limited treatment options for delta hepatitis and thus HBV/HDV co-infected patients are often managed as high risk.
Hepatitis B Core Antibody Positive RecipientsHepatitis B core antibody (HBcAb) positivity, with or without HBsAb, with negative HBsAg and negative HBV DNA is indicative of past HBV infection. When the immune system is therapeutically suppressed in the context of non-liver solid organ transplantation, there is potential for HBV reactivation.
Following liver transplantation, patients with occult HBV infection should be managed in the same way as HBsAg positive patients.
Hepatitis B Core Antibody Positive DonorsOrgans from donors chronically infected with HBV are not routinely used at present. However, single-centre case series exist of HBsAg positive donor livers used either in patients who are HBsAg positive with HBV-related liver disease or in HBcAb positive recipients. In these cases, HBV recurrence is 100% and there is persistence of HBsAg. In carefully selected patients with appropriate consent, the use of HBsAg positive donor organs may be a useful strategy to further expand the donor pool.
Recommendations
Treatment of HBV recurrence or de novo hepatitis b post solid organ transplantationIntroductionHepatitis B recurrence after liver transplantation (OLT) is defined as detectable hepatitis B surface antigen (HbsAg) and/or detectable viral load (HBV DNA) after transplantation for complications of chronic hepatitis B. In chronic hepatitis B (CHB) infection, spontaneous eradication of hepatitis B virus (HBV) from the host is rare. Even after hepatitis B surface antigen (HBsAg) seroconversion, it is likely that HBV persists within the host due to a stable pool of covalently-closed circular HBV DNA. Despite the removal of the liver, HBV may persist in extrahepatic sites and the circulation in sufficient quantities to re-infect the donor graft. Recurrence of hepatitis B represents a failure of preventative strategies to mitigate this risk.
De novo hepatitis B infection after OLT is defined as newly detectable HbsAg, and/or detectable HBV DNA, in those without prior CHB (HBcAb negative). The main risk of de novo hepatitis B after OLT is in those who receive allografts from donors who are hepatitis B core antibody (HBcAb) positive.
Review of literature HBV recurrence after OLT represents a failure of prophylaxis. Some of the reasons of recurrence include viral resistance and patient adherence. Other significant risk factors include detectable HBV DNA levels at the time of transplantation, hepatocellular carcinoma, or HIV. Immunosuppression taken by all post-transplant patients increases levels of HBV replication and progression of liver disease with HBV recurrence. The therapeutic goal once recurrent or de novo hepatitis is diagnosed is control of viral replication (suppression of HBV DNA) and stabilisation of graft function. In deciding on the type of treatment, it is important to establish the individual’s prior treatment and prophylaxis history. Due to increasing evidence of lamivudine resistance in patients post-transplantation, lamivudine is not recommended for treatment of hepatitis B recurrence or de novo hepatitis B. For patients who have previously been exposed to lamivudine and not responded, tenofovir should be offered as first line therapy.
Recommendations
Monitoring for HBV recurrence or de novo infection post liver transplantationIntroductionTo prevent graft dysfunction secondary to recurrent hepatitis B infection, monitoring of virological, serological, and clinical markers of infection post-transplantation is essential to evaluate prophylaxis efficacy. There are no randomised trials comparing different intervals of monitoring for recurrence of HBV infection post-liver transplant. Non-transplant patients receiving immunoprophylaxis against HBV recurrence during high-risk immunosuppression are typically monitored for reactivation, but guidelines do not indicate an ideal monitoring interval. Three-monthly monitoring is recommended for those at low risk of HBV recurrence taking immunosuppressive therapy without HBV prophylaxis. It is recommended to monitor for recurrence more frequently in the first year post-OLT, where failure of prophylaxis is more likely to manifest. Although both recurrent and de novo infection are conventionally defined by the reappearance of HBsAg, it is recommended that monitoring should consist of both HBV DNA quantification and HBsAg testing.
Recommendations
Hepatitis B vaccination and solid organ transplantationRationale for VaccinationImmunosuppressed solid-organ recipients develop a more severe and rapidly progressive HBV infection upon acquisition of HBV. It is especially important to prevent this in areas where there is a high prevalence of HBV infection amongst the organ donor pool, as donors may transmit HBV infection to recipients. HBV vaccination may provide protection against donor-derived HBV infection.
Liver transplantation Donor-derived infection Liver donors with serological evidence of past resolved HBV infection (i.e. HBsAg negative, HBcAb positive) may transmit HBV infection to recipients. Successful pre-transplant HBV vaccination can substantially reduce the risk of de novo HBV infection to around 10% and, with additional HBV prophylaxis, this risk can almost be entirely eliminated. This may allow recipients to access the full donor pool.
Recurrent HBV HBV vaccination cannot currently be recommended as a routine alternative strategy for the prevention of HBV recurrence after liver transplantation. Further work is required to define the optimal patient and vaccine characteristics.
Renal transplantation HBV infection is also an important consideration in potential renal transplant recipients. HBV vaccination is recommended in HBV seronegative patients with end-stage renal disease. In part, this is in order to increase the use of HBcAb positive kidneys amongst those who mount a protective HBsAb response. Also, in patients with resolved past resolved infection (HBcAb positive), vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation.
Timing of vaccination In healthy individuals, HBV vaccine is highly immunogenic. Upon administration of a series of three doses of HBV vaccine (either plasma-derived or recombinant), healthy subjects will develop HBsAb in the vast majority of cases. In the pre-transplant period, the immunogenicity of the HBV vaccine has been shown to be less potent. In patients who are not yet at the stage of requiring liver transplantation, higher HBV vaccination efficacy of around 90% has been reported in patients with chronic hepatitis C. An association between the severity of renal impairment and lack of response to the HBV vaccine has been shown, therefore, vaccination should be considered early in the course of disease. While the response to HBV vaccine may be suboptimal in the pre-transplant period, it is even more disappointing in the post-transplant period.
Vaccination method In healthy individuals, the usual vaccination schedule is a series of three intramuscular doses of HBV vaccine which are administered at baseline, one and six months. In patients with end-stage liver disease, the response to standard-dose HBV vaccinations is lower. These patients may benefit from a high-dose HBV vaccine. Similarly, patients with end-stage renal disease, particularly those on dialysis, demonstrate a poorer response to the standard-dose regimen. If HBV vaccination has to be given after solid-organ transplantation, the standard vaccine schedule with standard-dose vaccines at 0, 1 and 6 months is recommended.
Recommendations
Summary
HBV infection is one of the common chronic progressive viral infections and can cause chronic liver damage and cirrhosis, HBV vaccination should be adopted and applied to all to prevent the disease
This guideline was reviewed and written by experts in the field and contain different level of recommendation to help and guide decision-making in regard to kidney transplantation workup in those specific group of patients, published in 2016 contain 12 chapters with many recommendations varies in the level of evidence from strong evidence of 1 A level to moderate of B level, and weak or limited evidence at C and D levels.
Introduction
HBV DNA virus belongs to the Hepadnaviridae virus group, its major human antigen was first discovered in 1966 and according to WHO data, HBV infected more than 257 million with estimated annual death of around 600,000 due to advanced liver cirrhosis and complicated HCC, despite the vaccination programs against HBV still there is growing infections worldwide.
HBV transmission
Vertical transmission from mother to child and 90% can progress to chronic infection before 5 years old.Horizontal transmission due to unsafe medical work, adult to adult transmission, through sexual transmission, nosocomial and contaminated blood and blood products, IV drug abuse, < 10% in adults can progress to chronic infection.
Virology and Phases of Infection
HBV is a double-stranded DNA virus with no straight hepatoxicity effect, but rather compound interaction with the host immune system through inflammation, fibrosis, and cancer axis that defined the effect of chronic HBV infection. chronic carrier status refers to the failure to stand an innate and adaptive immune response during the primary infection. This complex interaction resulted in different and overlapping different phases of viral effects on the patient’s illness and management. These phases refer to patients’ hepatitis B e antigen (HBeAg) and hepatitis B e antibody (HBeAb)
status, alanine aminotransferase (ALT) levels, and HBV DNA quantification.
1.HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
categorized by HBeAg positive and HBeAb negative with HBV DNA viral loads generally >10 7logs IU/mL.The ALT level is in the normal range and a liver biopsy (if performed) shows no or minimal inflammation or fibrosis. However, in this phase there’s no true immune tolerance in fact there is ongoing cytotoxic T-cell activity
Treatment is really indicated in this phase.
2.HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” “Immune active” or “immune elimination phase”).
Patients in this phase are HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive
chronic infection this phase is asymptomatic, there is immune-mediated damage to the liver with resultant inflammation and fibrosis that can progress to cirrhosis in those with prolonged, unrecognized inflammation. Antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis.
1. HBe Antigen Negative Chronic Infection (previously called “inactive phase”).
This phase is characterized by HBeAg negativity, HBeAb positivity with normal ALT levels, and HBV DNA levels being characteristically <2000 IU/mL. but the rate of seroconversion depends on the age, genotype
Those > 40 years with genotype have a higher chance for seroconversion.
2. HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).
Usually associated with fluctuation in the level of ALT and lead to increased risk of cirrhosis and needs treatment with antiviral.
Serological and Virological Testing
1.HBV serological profile Interpretation
HBsAg negative, HBcAb negative, and HBsAb negative indicate no evidence of current or past, controlled HBV infection.
No immunity to HBV.
2.HBsAg negative, HBcAb negative, & HBsAb positive indicate vaccination with immunity
3.HBsAg positive indicates active infection HBsAg positive, HBcAb positive, IgM HBcAb positive, HBsAb negative
acute HBV infection (window period), or non-specific reactivity (false positive). This is mainly applicable to donors who may have received blood products
4.HBcAb positive with all other markers negative (‘core alone’) may indicate past HBV infection, HBsAg negative, HBcAb positive, and HBsAb positive again indicate past infection with good immunity.
HB ‘core alone’ positive profile in the recipient needs further workup including a history of blood products and risk factors for HBV, full HBV
serological markers, and HBV DNA (+/- follow-up testing) to explain the patient’s HBV status.
Reactivation of HBV
Reactivation may be asymptomatic or accompanied by a flare of hepatitis in previously minimal or inactive disease, demonstrating clinically with
acute hepatitis which can progress to acute liver failure and even death if untreated
reactivation risk depends on the HBV status and the type of immunosuppression and the underlying patient condition, lack of immune response, or resistance to the antiviral therapy.
All patients being worked up for solid organ transplantation must be tested for
HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant workup must have the following
tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
Any potential transplant recipients found to be HBcAb positive but HBsAg negative
(past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure)
must have HBV DNA testing to eliminate the opportunity of occult HBV infection. (1C)
Hepatitis Delta Co-Infection
Co-infection with HBV in > 5%, can worsen the course of progressive chronic liver disease cirrhosis, HCC, diagnosis by positive serology test for HDV IgG, and confirmation of co-infection with HDV BY HDV RNA positive test >2000IU/ML
Acute HBV infection
acute HBV infection is self-limiting in the majority up 95-99% even without treatment, only 1% can progress to fulminant hepatic failure with a high mortality rate of> 80% and the need for OLT.
Acute Fulminant hepatitis B
• Severe AHB – based on the presence of at least two of the following criteria:
– bilirubin >100 µmol/L
– international normalized ratio (INR) ≥1.6
– hepatic encephalopathy.
Early initiation of antiviral will hasten the recovery, shortening the disease course, preventing complications, and improving transplant-free survival in severe AHB,
treatment with tenofovir or entecavir should be strongly considered.
Chronic hepatitis B infection
The main goal for treating CHB infection is to prevent disease progression to cirrhosis, hepatocellular carcinoma (HCC), and death
NAs or pegylated-interferon (PEG-IFN) as first-line treatment for CHB in patients
with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine
aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis
Antiviral treatment has two objectives:
1. Improvement of liver function
2. Decreased risk of HBV recurrence after transplantation
Tenofovir TFV and entecavir ETV are currently the first-line agents, with superior potency and higher barrier to Lamivudine resistance (4). Both are well tolerated with good safety profiles more effective in the suppression of viral duplication and rapid in the clearance of viral load, not nephrotoxic and have an exceptional resistance profile, can be used at even higher doses in decompensated liver cirrhosis 1 mg instead of 0.5mg daily, can be used indefinitely with 3 months monitoring for the SVR BY HBV PCR
Any persistent viremia after 6-12 months of treatment consider treatment failure and consider alternative therapy
HBV-related decompensated liver cirrhosis with A MELD score of >20 was the most important predictor of mortality and should be listed for OLT. If
HBV DNA is detectable at any level, and ETV or TFV should be started as soon as possible [4]. Rendering HBV DNA undetectable before OLT decreases the risk of recurrence of HBV in
the graft
Hepatocellular carcinoma Hcc
For listing OLT for HCC, the following criteria must be satisfied [57]:
• A single tumor ≤5 cm in diameter, or
• Up to 5 separate tumors, all ≤3 cm, or
• Single tumor >5 cm and ≤7 cm diameter, where there has been no evidence of tumor progression, no extra-hepatic spread, and no new nodule formation over a six month
period. Loco-regional therapy +/- chemotherapy may be given during that time. Sustained viral response with antiviral therapy
Impact of Transplantation on HBV
immunosuppressive therapy used in SOT can modify the natural history of HBV infection its believed this is due to disruption of the host immune response and perhaps with enhanced replication of HBV facilitated by some drugs.Rapamycin (mTOR inhibitor) has been shown to enhance HBV production by inducing cellular autophagy.
Steroids enhance viral replications by their effect on the viral genome and both prednisolone and azathioprine increased intracellular viral DNA and RNA levels by approximately two-fold and four-fold respectively.
ciclosporin did not alter the levels of viral RNA or DNA. However, a combination of all three immunosuppressive agents increased the level of intracellular viral DNA eightfold, indicating an additive effect
Impact of HBV Infection on Transplant Outcome
HBV infection is associated with more frequent and rapid progression to cirrhosis and
hepatocellular carcinoma in SOT recipients, thus contributing to higher mortality and inferior survival before the era of antiviral prophylaxis
HBsAg positivity to be a risk factor for death in renal transplant recipients up to 94 % in some reports.
Also increased the risk of denovo membranous nephropathy.
Recent studies in kidney and heart transplant recipients with CHB without cirrhosis have reported excellent outcomes with antiviral therapy alone. In another recent study from Canada, HBV reactivation occurred in 4.1% of non-liver SOT patients with evidence of past HBV infection, with a median time to HBV reactivation of 4.7 years and even < than 2.5% in those with HBsABs with improved 5-year survival up to 82%.
Prevalence of HBV Infection in SOT
The pattern of HBV infection is similar to the general population and it’s overall reduced worldwide due to the improvement in vaccination and screening programs in addition to the development of infection control policies the prevalence of CBV infection depends on geographical areas Like is more in developing countries and the prevalence varies between 2-20% in HD populations while it’s even lower 0-10% in developed countries.
Risk of HBV Infection in the SOT Recipient
All donors and recipients should be screened for possible active or Chronic HBV infection and risk of reactivation after SOT, and the risk of reactivation or denovo infection depends on the donor and recipient HBV status and the use of antiviral prophylaxis after transplantation, as shown in table 4 from the guideline .those with high titer antiHBsAB considered low risk for reactivation however breakthrough reactivation still can occur Hence post-transplant anti-HBsAb monitoring is not routinely recommended to predict the risk of reactivation. However, donors with HBsAg positive, anti-HBc positive to recipients with HBsAg positive, anti-HBc positive are considered the highest risk for HBV reactivation/infection without antiviral treatment
All HBsAg-positive individuals being considered for liver transplantation should be
treated with either tenofovir or entecavir before transplantation, aiming for an
undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive
must have liver disease staging and suppression of HBV DNA by either tenofovir or
entecavir before transplantation if there is a standard clinical indication. (1B)
The kidneys, heart, and lungs from the HBcAb-positive organ donor can be used for
any recipient, and the risk of de novo HBV infection is low. (1A)
If need demands, the non-liver solid organs of the HBsAg positive organ donor can
be used for any recipient, after an individualized assessment of risk and benefit. (2C)
• When an HBcAb-positive donor is used, lamivudine prophylaxis may be given for six
months after transplantation, although the risk of transmission is very low. (2c)
Summary
Patients undergoing pre-transplantation workup should have HBsAg, HBsAb and HBcAb.
Patients with positive HBsAg should have HBeAg, and DNA levels for HDV and HBV.
Recipients and donors with positive HBcAb positive and negative HBsAg should have HBV and HDV DNA to exclude occult infection.
Patients with fulminant hepatitis B liver failure should be referred for liver transplantation.
Early antivirals will promote their recovery and shorten disease duration.
Patients with decompensated cirrhosis should be initiated on antivirals regardless of ALT, DNA levels and e antigen status.
High HBV DNA in chronic hepatitis B untreated are associated with progression to liver cirrhosis and hepatocellular carcinoma.
HBV and non-liver SOT transplantation is associated with increased risk of hepatic dysfunction and rapid progression to cirrhosis and HCC.
Donors with HBcAb positive non-liver SOT may be accepted due to low risk of reactivation, lamivudine prophylaxis may be given for 6 months.
Donors with HBsAg positive may also donate to recipients who are HBsAg positive as long as antiviral prophylaxis is given.
HBV/HDV co-infection is associated with aggressive hepatitis and progression to cirrhosis and liver failure.
HBV recurrence is defined as reappearance of HBsAg with or without detectable HBV DNA.
HBcAb positive alone may indicates past infection.
HBcAb positive alone may also indicate occult infection.
HBV vaccination should be offered to all SOT recipients.
I note that you have explained how evidence of past infection of HBV in relation to the decision -making necessary for transplantation.
. For all D& R ….. HBsAg , HBsAb & HBcAb should be done
. HBsAg positive + HBsAb positive + HBcAb positive……. Acute infection
. HBcAb positive …….past infection
. HBsAb posive …….vaccination
. If HBsAg + HBsAb positive …….require HBeAg, HBeAb, HBV DNA & HBD Ab testing
. if HDV Ab positive or suspicious ……require HDV RNA
. HDV co infection with HBV
. All patents with viral positive ….require a multidisciplinary team discussion
I make note of your interpretation of serological testing. Short and sweet.
This guideline outlines the transplantation of solid organs in the context of HBV infection.
It advocates the assessment for HBV and HDV infection whenever HBcAb is detected in the work up before transplantation. As HBcAb is indicative of previous infection that might have progressed to Chronic HBV infection or had resolved previously. Other markers of infection must be explored similarly including HBsAg, anti HBsAb, HBeAg, anti HBeAb, in addition to HBV DNA and HDV.
In the setting of active infection with HBV, it is suggested to treat the patient properly with Tenofovir and Entecavir.
Treatment of HBV infection depends on detecting markers of replication and activity.
Markers involved in assessment includes HBeAg, HBeAb, ALT, HBV PCR copies, and liver fibrosis. Accordingly categorizing the result into HBV infection vs HBV Hepatitis.
In the presence of HBeAg, HBV DNA copies of more than 200000 and normal ALT is corresponding to minimal hepatic inflammation and categorized as HBV infection. In this situation its not warranted to commence treatment.
On the other hand, when HBeAg is positive with or without HBeAb , HBV copies of more than 2000 and elevated ALT is congruent with hepatitis and hepatic fibrosis. It’s indicative to start treatment with Tenofovir and Entecavir.
Transplanting a kidney from HBcAb positive is indicative to undertake prophylactic treatment with Lamivudine.
When donor is HBsAg positive, the SOT can be performed to HBV infected , but not HDV /HBV infected patient.
Next is immunized recipient.
Last is HBsAg negative patient.
Occult HBV infection : when HBsAg is negative and HBV DNA is positive.
Life long treatment is indicated for those at high risk of recurrence including
HBeAg positive.
HBV DNA positive
Transplant for HCC.
Transplant for Acute haptic failure
I make note of your interpretation of serological testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your summary.
II. Guidelines for Hepatitis B & Solid Organ Transplantation
Summarise these guidelines.
HBV Biology & Disease
Recommendations:
• Pre-TX All SOT patients tested for HBsAg, HBsAb & HBcAb. (1B)
• HBsAg +ve patients must have: HBeAg, HBeAb & HDV Ab serology, & HBV DNA levels. (1B)
• HDV RNA done if HDV serology is +ve or equivocal. (1B)
• If HBcAb +ve but HBsAg -ve (past infection), HBV DNA & HDV serology done to exclude occult HBV or HDV infection. (1B)
• Donors HBcAb +ve but HBsAg -ve (past HBV exposure) must have HBV DNA test to exclude occult HBV infection. (1C)
============================
Indications for TX for HBV-Related Disease
Acute Fulminant Hepatitis B
Recommendations:
• Management in a specialist liver centre. (1C)
• Liver TX according to UK listing criteria defined by NHSBT. (1A)
Suggestions:
• Early antiviral treatment with NA promote recovery, shorten disease duration & improve TX free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis & HCC
Recommendations:
• Decompensated cirrhosis treated in specialist liver units as the use of antiviral is complex & patients may need liver TX. (1C)
• Urgent antiviral may be required in decompensated cirrhosis & detectable HBV DNA. Entecavir & tenofovir are the 1stline agents & used indefinitely. (1A)
Suggestions:
• Listing for liver TX if hepatitis B cirrhosis & a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
============================
HBV & Non-Liver TX
Suggestions:
• Careful consideration of the potential risks and benefits. (2C)
============================
Pre-TX Management of HBV
Recommendations:
• Treatment with either tenofovir or entecavir before TX, aiming for an undetectable HBV DNA level. (1B)
• Non-liver SOT who are HBsAg +ve must have liver disease staging & suppression of HBV DNA by tenofovir or
entecavir before TX. (1B)
============================
Use of HBcAb +ve or HBsAg +ve Donors
General Recommendations
Suggestions:
• Appropriate matching of recipient with a donor +ve for HBsAg or HBcAb discussed with a specialist in viral hepatitis. (2C)
• Recipients counselled about the possibility of receiving a liver from a donor with past or current HBV infection.
(Not graded)
HBcAb +ve donation for liver recipients
Recommendations
• The HBcAb +ve (HBsAg +ve) donor liver used for any recipient. (1C)
• If liver from a HBcAb +ve donor is given to HBsAg+ve recipient, the standards to prevent HBV reactivation are adopted. (1B)
• If liver from a HBcAb +ve donor is given to a HBV immune or non-immune recipient, lamivudine is given & continued indefinitely. (1A)
Suggestions:
• HBcAb +ve donor liver allocated in the following order:
1. HBsAg-+ve recipient
2. HBV-immune recipient (naturally immune & vaccine-induced)
3.HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
Recommendations
• HBsAg +ve donor livers can be given to HBsAg +ve recipients, as long as the recipient is known to be HDV -ve. (1C)
• HBsAg +ve liver can be given to HBsAg –ve patient on urgent demand. (1D)
• Recipients of a liver from HBsAg +ve donor treated with entecavir or tenofovir. (1B)
• Use of HBIg is not recommended. (1C)
HBcAb +ve & HBsAg +ve Donation for Non-Liver SOT Recipients
Recommendations
• Kidneys, heart & lungs from HBcAb +ve organ donor can be used for any recipient (risk of de novo HBV infection is low). (1A)
Suggestions:
• Non-liver organs of HBsAg +ve donor can be used for any recipient, after assessin risk & benefit. (2C)
• If HBcAb +ve donor used, lamivudine is given for 6 months after TX. (2C)
============================
Management of Co-Infection (HDV, HCV, HIV) & TX
Recommendations
• HBV/HDV recipients given HBIg/NA prophylaxis. (1C)
• HBsAg +ve donors not to be used for HBV/HDV co-infected recipients. (1C)
• MDT plan of management of each of the HIV & HBV infections before TX. (1D)
• HBIg used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. (1C)
Suggestions:
• HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of TX. (2C)
============================
Preventing Recurrence of HBV Post-Transplantation
Recommendations
• For HBsAg +ve individuals at high risk of recurrence, HBIg &/or a potent NA is recommended from the time of TX to prevent HBV reinfection post-liver TX. (1B)
Suggestions:
• Early withdrawal of HBIG or use of HBIG-free prophylaxis in recipients at low risk for post-TX HBV recurrence. (2C)
• Life-long HBIG & a potent NA for patients at high risk for HBV recurrence:
• Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver TX & could be given a limited (6-12 months) course of prophylactic antiviral treatment. (2B)
============================
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Recommendations
• Review of adherence with NA prophylaxis.Resistance testing at a specialist laboratory. (1C)
• Lifelong antiviral for all with HBV recurrence or de novo hepatitis B post-liver TX. (1C)
Entecavir or Tenofovir are first line treatment. Tenofovir if there is previous lamivudine exposure. (1B)
============================
Monitoring for HBV Recurrence or De Novo Infection
Recommendations
• HBV DNA & HBsAg monitored every 3 months 1styear & then every 6 months in HBsAg +ve liver TX recipients or patients receiving a graft from a HBcAb +ve donor. (1C)
• Monitoring intervals shortened in cases of non-adherence. (Not graded)
============================
HBV Vaccination & SOT
Recommendations
• All prospective HBV naive SOT recipients must be vaccinated & the response documented. (1C)
Suggestions:
• Amongst liver recipients transplanted for HBV, vaccination cannot currently be recommended as routine. (2C)
• Amongst KTX recipients who are HBcAb +ve, if HBsAb are <100 IU/mL, then vaccination considered to boost the protective titre & minimise the risk of reactivation. (2C)
• All prospective SOT recipients should receive a high dose, accelerated vaccine schedule. (2C)
• If initial HBV vaccination schedule failed, a second series given. (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
BTS recommendations for hepatitis B and solid organ transplantation 2018:
Pre-transplant management of HBV:
Use of HBcAb Positive or HBsAg Positive Donors:
1- The HBsAg-positive recipient
2- The HBV-immune recipient (including both naturally immune and vaccine-
induced immunity)
3- The HBV non-immune recipient.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
Preventing Recurrence of HBV Post-Transplantation
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
Monitoring for HBV Recurrence or De Novo Infection:
HBV Vaccination and Solid Organ Transplantation
I make note of your interpretation of serological and genotyping testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your well-structured reply that is a very clinically oriented summary.
Introduction
HBV is a Hepadnaviridae hepatotrophic DNA virus.
The World Health Organization estimates that 257 million people worldwide are infected with it, causing 600,000 deaths annually from end-stage liver disease and hepatocellular cancer (HCC).
Despite the immunization protocol, HBV infection from vertical transfer from mother to child or horizontal transmission from unsafe medical practice is rising.
Up to 90% of infants infected develop chronic infection, while 30% of pre-five-year-olds do.
Sexual, nosocomial, and blood-borne adult-to-adult transmission can occur (the latter often in intravenous drug users). Less than 10% persistent infection.
HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
HBV DNA viral loads are typically >107 log IU/mL, and HBeAg positivity is associated with an absence of HBeAb. Manifest between the ages of 20 and 30. Liver biopsy showing modest inflammation and fibrosis but normal ALT levels. There’s no need for medical treatment.
HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” or “immune active” or “immune elimination phase”).
HBeAg positive with persistent or intermittent increase in ALT and fluctuating HBV DNA levels that are typically lower than HBeAg positive chronic infection. Asymptomatic inflammation and fibrosis caused by the immune system leading to liver cirrhosis. May result in decompensated cirrhosis of the liver or abrupt liver failure. Antiviral therapy for patients with prolonged phase and severe liver fibrosis as determined by liver biopsy.
HBe Antigen Negative Chronic Infection (previously called “inactive phase”)
HBV DNA levels are typically <2000 IU/mL with negative HBeAg, positive HBeAb, and normal ALT values. Age at HBV acquisition affects the rate of HBe antigen seroconversion, which results in the establishment of chronic HBeAg-negative infection. HBV genotype also has a major influence: for example, people with genotype B seroconvert more than those with genotype C. In children under the age of three, the annual seroconversion rate is above 2%, whereas in early adulthood, the rate is 12%. Up to 8% of patients may have reversion to e antigen positive, however the underlying mechanism is unclear. The risk of developing cirrhosis and/or HCC is significantly increased in people who have later HBeAg seroconversion . This is particularly true for individuals over the age of 40 and could be due to a lifetime of exposure to subclinical hepatic inflammation.
HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”)
HBV DNA levels lower than HBeAg +ve hepatitis, often >2000 IU/mL and commonly >20,000 IU/Ml.There is an increase in serum ALT levels, which is highly variable. Damage to the liver can quickly lead to cirrhosis and HCC. Serum HBV DNA levels have been demonstrated to directly correlate with the risk of HCC in such patients through long-term follow-up studies. Antiviral treatment is the mainstay of treatment.
Indications for Transplantation for HBV-Related Disease
Acute fulminant hepatitis B patients should be treated in a liver center. (1C)
Fulminant hepatitis B patients should consider liver transplantation.
Consider tenofovir or entecavir for early nucleoside analogue (NA) antiviral treatment. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma guidelines
Specialist liver units should treat hepatitis B-related decompensated cirrhosis (1C)
Decompensated cirrhosis patients with HBV DNA need prompt NA antiviral treatment (s). First-line antivirals entecavir and tenofovir should be taken forever. (1A) Patients with hepatitis B cirrhosis and a UKELD score >49 or HCC within UK NHSBT guidelines should be listed for liver transplantation. (2A)
Selection of donor and recipient Guidelines
Before being considered for liver transplantation, potential patients must be treated with entecavir or tenofovir and reach undetectable HBV DNA levels.
Recipients should be counseled if a donor has a history of or is currently infected with HBV.
Donor livers with negative HBsAg and positive HBcAb can be used for liver transplantation, but lamivudine should be administered prophylactically beginning at the time of transplantation and continuing permanently.
HBsAg-positive donor livers may be transplanted into HBsAg-positive recipients who are HDV-negative.
In emergency instances, HBsAg-positive livers can be transplanted to HBsAg-negative recipients, providing they begin treatment with entecavir or tenofovir immediately after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
From the moment of transplantation, HBV/HDV recipients must undergo HBIg/NA prophylaxis. HBV/HDV co-infected patients cannot receive organs from HBsAg-positive donors – HBV infection treatment must involve a hepatologist. Hepatitis B immunoglobulins as HBV prophylaxis if HIV antivirals are discontinued prior to surgery. After HIV antiviral medication is reinstated, HBV prophylaxis will be identical to HBV prophylaxis.
Preventing Recurrence of HBV Post-Transplantation
Using HBIg and/or a NA beginning at the time of transplantation. In instances with low risk for post-transplant HBV recurrence, HBIg-free regimens can be utilized. -In cases with high risk, HBIg and NA can be used for life.
For people with a history of HBV infection who are at risk of HBV reactivation following a non-liver transplant, a limited (6-12 month) course of preventive antiviral therapy may be recommended.
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Lifelong antiviral therapy in the form of Entecavir or Tenofovir is recommended as first-line therapy. HBV DNA and HBsAg should be tested every three months for the first year, and then every six months thereafter (1C)
Solid Organ Transplantation and HBV Vaccination
HBV-naive solid organ transplant candidates must be vaccinated (time allowed) and their reaction monitored. (1C) If HBsAb are <100 IU/mL in HBcAb-positive renal transplant recipients, immunization may reduce reactivation risk. (2C) Solid organ transplant candidates should receive high-dose, expedited vaccines. (2C) Provide a second HBV immunization series to nonresponders. (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding treatment.
Introduction:
Hepatitis B Virus (HBV) is a hepatotrophic DNA virus that belongs to the Hepadnaviridae family of viruses.
It is a major human pathogen and is estimated by the World Health Organisation to infect 257 million people worldwide, and results in an estimated 600,000 deaths every year through complications of end stage liver disease and hepatocellular carcinoma (HCC).
The number of individuals who are chronically infected with HBV is increasing, despite the vaccination protocol, chronic HBV infection result from either vertical transmission from mother to child or horizontal transmission through unsafe medical practice.
Infection in infants results in chronic infection in up to 90% of cases, whereas approximately 30% of children infected before the age of five develop chronic infection.
Adult-to-adult transmission can also occur through sexual, nosocomial or blood borne transmission (the latter often in intravenous drug users). Results in less than 10% chronic infection.
HBe Antigen Positive Chronic Infection (previously called “non-inflammatory” or “immune tolerant phase”).
HBeAg positive and HBeAb negative with HBV DNA viral loads generally >107 log IU/mL.
Occur during the first 20-30 years of life.
Normal ALT level, and no or mild inflammation and fibrosis by liver biopsy.
No treatment needed.
HBe Antigen Positive Chronic Hepatitis (previously called “inflammatory” or “immune active” or “immune elimination phase”).
HBeAg positive with persistent or intermittent elevation in ALT and fluctuating HBV DNA levels that are generally lower than those with HBeAg positive chronic infection.
Asymptomatic, but immune mediated inflammation and fibrosis leading to liver cirrhosis.
May lead to decompensated liver cirrhosis or acute liver failure.
Anti viral therapy for prolonged phase and those with advanced liver fibrosis by biopsy.
HBe Antigen Negative Chronic Infection (previously called “inactive phase”).
HBeAg negativity, HBeAb positivity with normal ALT levels and HBV DNA levels being characteristically <2000 IU/mL. HBe antigen seroconversion rates, leading to the development of HBeAg negative chronic infection, are determined by the age at the time of acquisition of HBV. HBV genotype also has a significant influence: for example, those with genotype B seroconvert more than those with genotype C [16]. The annual seroconversion rate is ><2% in children younger than three years of age, whereas the equivalent rate is 12% in early adulthood [2]. Reversion to e antigen positivity can occur in up to 8% of patients but the mechanism behind this is poorly understood [17]. Individuals who undergo later HBeAg seroconversion have a much higher likelihood of developing cirrhosis and/or HCC [18]. This is especially true aged >40 years old and may reflect the lifetime exposure to subclinical hepatic inflammation.
HBe Antigen Negative Chronic Hepatitis (previously called “immune escape phase”).
HBV DNA levels >2000 IU/mL and frequently >20,000 IU/Ml, usually lower than HBeAg +ve hepatitis.
Serum ALT levels are raised and can fluctuate significantly.
Liver damage can progress rapidly towards cirrhosis and HCC.
Long term follow-up studies have shown that the risk of HCC is directly correlated to serum HBV DNA levels in such patients.
Antiviral therapy forms the cornerstone of management
Recommendations:
– All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B).
– All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B).
– HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B).
– Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B).
– All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C).
Indications for Transplantation for HBV-Related Disease:
Acute Fulminant Hepatitis B
– Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C).
– Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A).
– Early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B).
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
– Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C).
– Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A).
– Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
– Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
– All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B).
– Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B).
Use of HBcAb Positive or HBsAg Positive Donors General Recommendations
– The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C).
– All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded).
HBcAb positive donation for liver recipients
– The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C).
– When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B).
– When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A).
– If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient.
2. the HBV-immune recipient.
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
– HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C).
– If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D).
– All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B).
– Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C).
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
– The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A).
– If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C).
– When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C).
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
– HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C).
– HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C).
– A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D).
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period.
– After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C).
– For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C).
Preventing Recurrence of HBV Post-Transplantation
– HBsAg positive individuals are at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B).
– Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C).
– Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; (HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected) although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B).
– Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B).
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
– All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C).
– Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C).
– Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B).
Monitoring for HBV Recurrence or De Novo Infection
– HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C).
– Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded).
HBV Vaccination and Solid Organ Transplantation
– All prospective solid organ transplant recipients who are HBV naive must be vaccinated and the response documented. (1C).
– Liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C).
– Renal transplant recipients who are HBcAb positive, if HBsAb are < 100 IU/ml, vaccination should be done to boost the titer and minimize the risk of reactivation.(2C).
– All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C).
– Those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C).
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding treatment.
Summary of Guidelines
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb
HBsAg positive– They should unergo HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
HDV positive or equivocal– Perform HDV RNA testing
HBcAb positive but HBsAg negative- HBV DNA and HDV serology testing to exclude occult HBV or HDV infection
HBcAb but HBsAg negative– Perform HBV DNA testing to exclude the possibility of occult HBV infection
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 (The United Kingdom Model for End-Stage Liver Disease)or with HCC within criteria.
HBV and Other (Non-Liver) Transplantation
Consider for combined transplantation after careful consideration of the potential risks and benefits
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication.
HBcAb Positive or HBsAg Positive Donors
All recipients should be counselled
HBcAb positive donation for liver recipients
Can be allocated to –
HBsAg Positive Donation for Liver Recipients
Can be donated to HBsAg positive recipients only.
Preventing Recurrence of HBV Post-Transplantation
Those at high risk of recurrence should have combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT-
Check adherence with NA prophylaxis
Lifelong antiviral therapy with Entecavir or Tenofovir
HBV Vaccination and SOT
All prospective HBV naive must be vaccinated
Renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/ml.
I make note of your interpretation of serological testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your summary.I note that you have explained how a donor with evidence of past infection of HBV in relation to the decision -making necessary for transplantation.
Summary:
· During work up for recipient with SOT: must be tested for HBsAg, HBsAb and HBcAb (1B)
ü If HBsAg +ve: we must do: HBeAg, HBeAb, HBV PCR (markers of active disease) and HDV Ab serology.
ü If HDV serology is positive or equivocal: we must do HDV RNA (PCR).
ü If HBcAb positive and HBsAg negative (past infection): must do HBV PCR and HDV serology to exclude occult HBV or HDV infection.
· Donors (positive for HBcAb but HBsAg negative) (indicating past HBV exposure) must have HBV PCR testing to exclude occult HBV infection.
· Liver transplantation in HBV infection is either:
o Fulminant hepatic failure (Early treatment with nucleot(s)ide analogues (NA) as tenofovir or entecavir may promote recovery, shorten disease duration and improve transplant free survival).
o Chronic decompensated liver disease (with life-long antiviral as (tenofovir or entecavir).
· For SOT as kidney in HBV positive recipients:
o Treatment with 1st line antiviral therapy as (tenofovir or entecavir) must be completed before transplantation, till undetectable HBV DNA level.
· Use of HBcAb Positive or HBsAg Positive Donors (? past infection) for kidney transplantation:
o can be used for any recipient, after counseling of the recipient.
o If HBcAb positive donor is used, prophylaxis for 6 months post- transplantation with lamivudine may be given, but the risk of transmission is very low.
· While In liver transplantation:
o Positive for positive as (HBsAg positive is used only for HBsAg positive recipients and in emergency situations for those with HBsAg negative).
o The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient.
· HBV Recurrence or De Novo Hepatitis B after liver transplantation:
o Monitoring is indicated in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor.
o Monitor by HBV DNA and HBsAg every 3 months in the first year and thereafter every 6 months regardless prophylaxis regimen.
o HBV recurrence: check adherence to NA prophylaxis.
o Resistance testing in special lab.
o Lifelong antiviral therapy is recommended for -liver transplantation.
o Entecavir or Tenofovir are recommended as first line treatment. Tenofovir is used in case of previous lamivudine exposure
· HBV vaccination in renal transplantation:
o All HBV naive potential SOT recipients must be vaccinated (time permitting) and the response documented.
o Renal transplant recipients who are HBcAb positive, if HBsAb are < 100 IU/ml should receive booster dose to prevent reactivation post transplantation.
o If patient fails to respond to the initial HBV vaccine, a second series should be given.
I like your well structured detailed summary.
I note that you have explained how a donor with evidence of past infection of HBV in relation to the decision -making necessary for transplantation.
Thanks dear professor
HBV Biology and Disease
——————————
• All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb and HBcAb. (1B)
• All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
• Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Phases of Chronic Hepatitis B Infection
———————————————-
HBeAg positive chronic infection
HBeAg status Positive
HBeAb status Negative
ALT levels Normal
HBV DNA Levels Very high
Histological liver damage None
HBeAg positive chronic hepatitis
HBeAg status Positive
HBeAb status Neg or pos
ALT levels high
HBV DNA Levels Usually high
Histological liver damage Yes
HBeAg negative chronic infection
HBeAg status Negative
HBeAb status positive
ALT levels Normal
HBV DNA Levels <2000 IU/mL
Histological liver damage None
HBeAg negative chronic hepatitis
HBeAg status Negative
HBeAb status positive
ALT levels high
HBV DNA Levels >2000 – >20000 IU/mL
Histological liver damage Yes
HBV serological profiles and interpretation
——————————————————————–
No evidence of current or past, controlled HBV infection. No immunity to HBV.
HBsAg negative
HBcAb negative
HBsAb negative
Evidence of past HBV infection and immunity.
HBsAg negative
HBcAb positive
HBsAb positive
Evidence of vaccine-induced immunity.
HBsAg negative
HBcAb negative
HBsAb positive
Consistent with acute HBV infection.
(Note: IgM HBcAb may be positive in HBV reactivation)
HBsAg positive
HBcAb positive
IgM HBcAb positive
HBsAb negative
Evidence of chronic HBV, if confirmed on two samples six months apart
HBsAg positive
HBcAb positive
IgM HBcAb negative
HBsAb negative
HBeAg positive/negative
HBeAb negative/positive
past, controlled infection;
resolving acute infection (window period);
or occult chronic infection.
HBsAg negative
HBcAb positive
HBsAb negative
Antiviral treatment is indicated in
—————————————-
A- • Fulminant hepatitis B
B- • Severe AHB – based on the presence of at least two of the following criteria: – bilirubin >100 µmol/L – international normalised ratio (INR) ≥1.6 – hepatic encephalopathy
C- • Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
D- • Immunocompromised host
The criteria for listing for liver transplantation
———————————————————————–for acute liver failure related to hepatitis B must include
A- hepatic encephalopathy and:
B- Prothrombin time >100 seconds
or INR >6.5
or
C- • Any three from:
– age >40 or <10 years
– jaundice to encephalopathy time >7 days
– serum bilirubin >300 µmol/L
– prothrombin time >50 seconds or INR >3.5
Antiviral Treatment
——————————
•1- As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
. 2- Current treatment guidelines consider NAs or (PEG-IFN) as first-line treatment for CHB in patients with serum HBV DNA levels >2000 IU/mL in combination with elevated alanine aminotransferase (ALT) levels and/or with moderate/severe liver inflammation and/or fibrosis
3- Decompensated Hepatitis B Cirrhosis and
—————————————————-Hepatocellular Carcinoma
——————————-
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units. (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
———————————————————————
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive
———————————————–Donors
————-
: • The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
• The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
• If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity)
3. the HBV non-immune recipient. (2C)
HBcAb Positive and HBsAg Positive Donation
—————————————————-for Non-Liver Solid Organ Recipients
———————————————————-
• The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
• If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
• When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Preventing Recurrence of HBV Post-
—————————————- -Transplantation:
—————————
• In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B):
• Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
• Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
• Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo
————————————————–Hepatitis B after Solid Orgast Transplantation
—————————————————-
• Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
• Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo
—————————————————Infection
————
• HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
HBV Vaccination and Solid Organ
—————————————Transplantation
——————
• All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
• Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
• All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
• In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I note that you have explained how a donor with evidence of past infection of HBV in relation to the decision -making necessary for transplantation.
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding treatment.
Summary
HBV Biology and Disease
For recipient of solid organ transplant
• all receipient of solid organ transplant must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
• if recipient found to be HBsAg positive the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
•if HDV serology is positive or equivoca HDV RNA testing must be performed. (1B)
• if recipient found to be HBcAb positive but HBsAg negative (past infection) do HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
For donor
• All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) do HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B guidelines they recommend that:
• Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver center. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B
• As early antiviral treatment with nucleot(s)ide analogues (NA), treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
guidelines recommend that:
• Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units (1C)
• Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
they suggest that
• Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
Selection of donor and recipient
Guidelines recommend that
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
-HBV/HDV recipients need to receive a combination of HBIg/NA prophylaxis from time of transplantation.
– HBV/HDV co-infected recipients cannot receive organs from HBsAg positive donors
-hepatologist need to be involved in HBV infection treatment.
-HBIg as HBV prophylaxis if HIV antivirals are stopped in the peri-operative period. After HIV antiviral treatment is reintroduced the HBV prophylaxis will be the same as that used for HBV .
Preventing Recurrence of HBV Post-Transplantation
By using HBIg and/or a NA from the time of transplantation.
-For low risk cases for post-transplant HBV recurrence, HBIg free regimen can be used
-For high risk cases HBIg and NA can be used lifelong
– For those with past HBV infection are at risk of HBV reactivation post-non-liver transplant can be considered for a limited (6-12 months) course of prophylactic antiviral treatment.
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
-lifelong antiviral therapy in the forum of Entecavir or Tenofovir are advised as first line treatment
Monitoring for HBV Recurrence or de novo infection
HBV Vaccination and Solid Organ Transplantation
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I note that you have explained how a donor with evidence of past infection of HBV in relation to the decision -making necessary for transplantation.
HBV BIOLOGY AND DISEASE ;
————————————————————-
The guidelines recommend that:
1-All transplant candidates must be tested for HBsAg, HBsAb (absolute titres) and HBcAb . (1B)
2- All HBsAg positive transplant candidates must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
3-Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
4-All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
5-HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
HBV and other (NONE-LIVER) TRANSPLANTATION;
————————————————————————–
The guidelines suggest that;
Candidates with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
PER-TRANSPLANT MANAGEMENT OF HBV IN INDIVIDUAL BEING CONSIDERED OR TRANSPLANTATION ;
——————————————————————————————————-
The guidelines recommend that:
1-All HBsAg positive candidates being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
2-Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
USE OF HBcAb POSITIVE or HBsAg POSITIVE DONORS;
——————————————————————————————
The guidelines suggested that:
1-The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
2-All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb POSITIVE and HBsAg POSITIVE DONATION FOR NON-LIVER SOLID ORGAN RECIPIENTS ;
———————————————————————————————————-
The guidelines recommend that:
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
The guidelines suggest that:
1- If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
2-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
MANAGEMENT of CO-INFECTION (HDV, HCV, HIV) and TRANSPLANTATION ;
——————————————————————————————————-
The guidelines recommend that:
1- HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
2- HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
3-A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
4-HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
The guidelines suggest that:
For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
PREVENTING RECURRENCE of HBV POST TRANSPLANTATION;
—————————————————————————————–
The guidelines recommend that:
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
The guidelines suggest that:
1-Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
2- Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are;
a- HBV DNA positive at time of transplant.
b- HBeAg positive patients.
c- Those transplanted for hepatocellular carcinoma
d- Those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
3- Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
TREATMENT of HBV RECURRENCE or De Novo Hepatitis B after SOLID ORGAN TRANSPLANTATION ;
———————————————————————————————————
The guidelines recommend that;
1-All candidates with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
2-Lifelong antiviral therapy is recommended for all candidates with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
3-Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
MONITORING for HBV RECCURRENCE or De Novo INFECTION;
——————————————————————————————————-
The guidelines recommend that;
1-HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
2-Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
HBV VACCINATION and SOLID ORGAN TRANSPLANTATION ;
—————————————————————————————————–
The guidelines recommend that;
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
The guidelines suggest that;
1-Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
2- Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
3-All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
4- In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
Guidelines for Hepatitis B & Solid Organ Transplantation
HBV Biology and Disease:
Any SOT candidates should be tested for HBsAg, HBs Ab & HBc Ab (1B).
All SOT candidates with HBsAg +ve should be tested for HBe Ag, HBe Ab, HDV Ab & HBV DNA level, (1B).
Positive or equivocal HDV serology patients must undergo HDV RNA, (1B).
All potential donor or recipients with HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
Indications for Transplantation for HBV-Related Disease:
Acute Fulminant Hepatitis B:
Recommendations:
Must be managed in a specialist liver Center (1C)
Liver transplantation must be considered in patients with fulminant hepatitis B (1A)
Suggestion:
As early antiviral treatment with NA may promote recovery, shorten disease duration, and improve transplant free survival in severe Acute HBV, treatment with Tenofovir or Entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Recommendations:
Should be treated in specialist liver units as antiviral therapy is complex and patients may be needing liver Tx (1C)
If HBV DNA is detectable; urgent antiviral treatment with NA(s). Entecavir and Tenofovir are the first line antiviral agents and should be continued indefinitely (1A)
Suggestions:
Listing for liver Tx; in HBV cirrhosis and UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
Suggestion:
Advanced HBV-related liver disease requiring another SOT to be considered for combined transplantation (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Recommendation:
All HBsAg +ve individuals should be treated before transplantation (with Tenofovir or Entecavir), aiming for an undetectable HBV DNA level (1B)
HBsAg +ve individuals undergoing non-liver SOT must have liver disease staging and suppression of HBV DNA by either Tenofovir or Entecavir before transplantation (1B)
Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations:
Matching a recipient with donor +ve for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
All recipients should be counselled about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients:
Recommendation:
If liver comes from HBcAb donor
– It can be used for any potential liver recipient. (1C)
– if recipient HBsAg +ve , measures to prevent HBV reactivation should be adopted (1B)
– Prophylactic Lamivudine should be given at the time of transplantation, and should be continued indefinitely, if recipient HBV immune or non-immune (1A)
Suggestion:
If other waiting list priorities permit, the HBcAb positive donor liver should be allocated in the following order:
-The HBsAg-positive recipient
-The HBV-immune recipient
-The HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
Recommendation:
Can be given to HBsAg positive recipients, with HDV negative. (1C)
If urgency demands, can be given to an HBsAg negative patient. (1D)
All recipients must be treated with Entecavir or Tenofovir from the time of transplantation. (1B)
Use of HBIg rarely achieves HBsAg negativity and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
Recommendation:
The kidneys, heart and lungs can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion:
-If need demands, HBsAg positive organs can be used for any recipient (individualized risk assessment) (2C)
-When a HBcAb positive donor is used, Lamivudine prophylaxis may be given for 6 months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Recommendations:
– HBV/HDV recipients; should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
– HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
– Peri-operative management plan of the HIV and HBV infections should be agreed by the MDT (1D)
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
Suggestion:
– For HBV/HDV recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
Recommendation:
– In HBsAg positive individuals; the use of HBIg and/or a potent NA at the time of transplantation. (1B)
Suggestion:
– Early withdrawal of HBIG or HBIG-free prophylaxis in low risk recipients (2C)
– Life-long combination HBIG and NA for individual at high risk for HBV recurrence (2B)
– Post-non-liver transplant with past HBV infection (HBcAb positive alone) are considered for (6-12 months) course of prophylactic antiviral treatment; with monitoring for recurrence (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Recommendation:
– Review of adherence with NA prophylaxis and test for resistance (1C)
– Lifelong antiviral therapy for all individuals with HBV recurrence or de novo HBV (1C)
– Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
Recommendation:
– HBV DNA and HBsAg every 3 months in the first year and then every 6 months (1C)
– Shorter interval if non-adherence is suspected. (Not graded)
HBV Vaccination and Solid Organ Transplantation
Recommendation:
• All HBV naïve recipients must be vaccinated, and the response documented. (1C)
Suggestion:
Liver recipients transplanted for HBV; vaccination cannot recommend as routine. (2C)
Renal recipients if HBsAb are <100 IU/mL, vaccination is recommended. (2C)
All recipients should receive a high dose, accelerated vaccine schedule. (2C)
Second vaccination series considered if fail non -response documented (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
I make note of your interpretation of virology reports in relation to timings of test and viral load pertaining to HBV infections
I like your detailed well-structured summary.
Summary of the Guidelines
Guidelines for Hepatitis B & Solid Organ Transplantation
1. HBV Biology and Disease
i. All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
ii. All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
iii. HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
iv. Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
v. All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
2. Indications for Transplantation for HBV-Related Disease
a) Acute Fulminant Hepatitis B.
The criteria for listing for liver transplantation for acute liver failure related to hepatitis B must include hepatic encephalopathy and:
i. Prothrombin time >100 seconds or INR >6.5 or
ii. Any three from:
· age >40 or <10 years
· jaundice to encephalopathy time >7 days
· serum bilirubin >300 μmol/L
· prothrombin time >50 seconds or INR >3.5
b) Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma.
3. HBV and Other (Non-Liver) Transplantation: it is suggested that;
· Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
4. Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
a) All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
b) Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
5. Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations; We suggest that:
a) The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
b) All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
6. HBcAb positive donation for liver recipients
We recommend that:
a) The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
b) When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
c) When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
We suggest that
If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
a) the HBsAg-positive recipient
b) the HBV-immune recipient (including both naturally immune and vaccine-induced immunity)
c) the HBV non-immune recipient. (2C)
7. HBsAg Positive Donation for Liver Recipients
We recommend that:
a) HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
b) If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
c) All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
d) Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
8. HBsAg Positive Donation for Liver Recipients
We recommend that:
a) HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
b) If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
c) All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
d) Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
9. HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
We recommend that:
· The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
We suggest that:
· If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
· When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
10.Management of Co-Infection (HDV, HCV, HIV) and Transplantation
We recommend that:
a. HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
b. HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
c. A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
d. HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
We suggest that:
· For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
11.Chapter 9: Preventing Recurrence of HBV Post-Transplantation
We recommend that:
· In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
We suggest that:
a) Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
b) Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
c) Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
12.Chapter 10: Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
We recommend that
a) All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
b) Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
c) Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
13.Monitoring for HBV Recurrence or De Novo Infection
We recommend that
a) HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
b) Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
14.HBV Vaccination and Solid Organ Transplantation
We recommend that
· All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
We suggest that
a) Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
b) Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
c) All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
d) In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
15.Antiviral treatment is indicated in certain subgroups of patients with AHB:
a) Fulminant hepatitis B
b) Severe AHB – based on the presence of at least two of the following criteria:
· bilirubin >100 μmol/L
· international normalised ratio (INR) ≥1.6
· hepatic encephalopathy
c) Protracted disease course – persistent symptoms or marked jaundice for more than four weeks after presentation
d) Immunocompromised host
Therapy should be continued for at least three months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss.
I like your well structured detailed summary.
I appreciate your understanding of a range of genotyping tests in HBV infection.
· Summarise these guidelines
Guidelines for Hepatitis B and solid organ transplantation were published in March 2018 by the British Transplantation Society. Its chapters included the following:
Hepatitis B virus (HBV) biology and disease: HBV is a hepatotrophic DNA virus with majority of infections occurring due to unsafe medical practices and vertical transmission. Chronic infection rate in infants, children, and adults is approximately 90%, 30%, and 10% respectively. Four different phases of HBV infection (depending on HBe antigen, HBe antibody, alanine aminotransferase levels, and HBV DNA levels) include HBe antigen positive chronic infection, HBe antigen chronic hepatitis, HBe antigen negative chronic infection, and HBe antigen negative chronic hepatitis. HBsAg testing is cornerstone for HBV infection diagnosis. It is recommended that:
· Test for HBsAg, Anti HBs antibody titres, and anti HBc antibody for all patients being worked up for solid organ transplantation.
· For all potential transplant recipients:
o If HBsAg positive, then test for HBe antigen, Anti HBe antibody, HBV DNA levels, and anti HDV antibody serology.
o If HDV serology is positive or equivocal, get HDV RNA testing
o If HBc antibody positive, get HBV DNA and HDV serology testing done (to rule out occult HBV and HDV infection).
· For all potential organ donors:
o If HBsAg negative and HBc antibody positive, get HBV DNA testing (to rule out occult HBV infection).
Indications for transplantation for HBV related disease: 95-99% of acute HBV infection will recover spontaneously. 1% will progress to fulminant hepatitis with up to 80% mortality.
Acute Hepatitis B: Antiviral treatment is required in fulminant hepatitis B, severe acute HBV infection, immunocompromised patients, and in protracted disease course. Liver transplant should be considered in all patients with fulminant hepatitis. Criteria for listing include hepatic encephalopathy with either prothrombin time, PT >100 seconds (or INR>6.5), or 3 out of 4 criteria including age (>40 or <10 years), serum bilirubin (>300 micromol/L), PT (>50 seconds, or INR >3.5), or jaundice to encephalopathy time >7 days.
Fulminant hepatic failure with HBV infection must be managed in a specialist liver centre and early antiviral treatment with nucleot(side analogues (NA), tenofovir or entecavir should be considered.
Chronic Hepatitis B: In patients with chronic HBV infection with increased ALT and HBV DNA >2000 U/ml, NAs or pegylated IFN should be used for treatment.
Decompensated cirrhosis: Patients should be treated in specialist liver unit, and may require antiviral treatment with listing for liver transplant in patients with UKELD score > 49 (predicted 1-year liver disease mortality without transplantation >9%) or UKELD score < 49 with a variant syndrome (diuretic resistant ascites or chronic hepatic encephalopathy).
Hepatocellular carcinoma (HCC): HCC is associated with males, older, Asian or African, positive family history, higher HBV DNA levels, longer duration of infection, cirrhosis, alcohol and tobacco exposure. HCC treatment involves resection if small, single lesion with well-preserved levier function, but is associated with high recurrence rates of 50% and 70% at 3 and 5 years. Liver transplant is indicated if single HCC < 5 cm, or upto 5 tumors with size < 3 cm, or 5-7 cm size without any progression in 6 months. Tumor rupture, AFP >1000, extra-hepatic spread, and macroscopic vascular invasion are contra-indications for transplant.
HBV and other (non-liver) transplantation: Reactivation of HBV is seen with immunosuppression, with 50-94% rates of reactivation after renal transplant. Patients with chronic HBV infection or past HBV infection can undergo solid organ transplantation, and if have HBV-related liver disease, should be considered for combined transplantation after multidisciplinary assessment.
Pre-transplant management of HBV in individuals being considered for transplantation: For liver transplantation, all prospective recipients, who are HBsAg positive, should be treated with antivirals. Tenofovir (in cases of lamuvidine resistance) or entecavir (in cases of adefovir resitance) should be given in doses modified as per creatinine clearance to achieve undetectable HBV DNA levels pre-transplant. For non-liver transplantation in HBsAg positive patient, liver disease should be staged and tenofovir or entecavir should be given (avoid interferon). Monitor HBV DNA levels in HBsAg negative patients with positive HBcAb.
Use of HBcAb positive or HBsAg positive donors in SOT: Appropriate matching of a transplant recipient with a donor positive for HBsAg or HBcAb should be discussed with viral hepatitis specialist, and the recipient should be counselled accordingly.
HBcAb positive liver donor: It should be allocated in order of HBsAg positive patient, then HBV-immune recipient, and last to HBV non-immune recipient. For HBsAg negative liver transplant recipients, if donor is HBV core antibody (HBcAb) positive, then it can be used under cover of prophylactic lamivudine to be given indefinitely (due to increased rates of HBsAg seroconversion, ranging upto 80%). In case of HBsAg positive recipient, standard treatment protocol with HBIg prophylaxis (to prevent HBV reactivation) will suffice.
HBsAg positive liver donor: Such a donor can donate to any recipient (HBsAg negative or HBsAg positive with HDV negative status) who must be treated with entecavir and tenofovir (due to reliable HBV suppression). HBIg use is not recommended as it rarely achieves HBsAg negativity.
HBcAb positive and HBsAg positive non-liver donor: HBcAb positive non-liver organ can be given to any recipient (with lamivudine prophylaxis for 6 months), while HBsAg positive non-liver donor can donate to any recipient. HBsAg positive recipient will be on antivirals, while HBV immune recipients may or may not be given prophylactic antivirals (long-term monitoring for HBsAg appearance would be required). HBV non-immune recipients should be given antivirals.
Management of co-infection (HDV, HCV, HIV) and transplantation: Upto 10% HBV infections have HDV co-infection. HBV/HDV recipients should receive combination HBIg/NA prophylaxis from the time of transplantation. HBsAg positive donors should not be used for HBV/HDV co-infected recipients. There is no effective treatment for recurrent (or acquired) graft HBV/HDV infection, and it rapidly leads to cirrhosis. HCV co-infection will warrant HCV treatment using DAAs, while there is no effect on HBV treatment due to HCV co-infection. HIV con-infection management becomes easy due to tenofovir, which is part of anti-HIV treatment protocols. A multidisciplinary plan for the peri-operative management of each of the HIV and HBV infections should be created and adhered to. HBIg could be used as HBV prophylaxis in the perioperative period.
After post-operative re-introduction of HIV antiviral treatment, HBV prophylaxis approach remains same. For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but only after 24 months of transplant.
Preventing HBV recurrence post-transplantation: Risk factors for recurrence in HBsAg positive recipients include positive HBV DNA, HIV positivity, HDV co-infection, HBeAg positivity, and associated HCC. Such patients should receive HBIg (intravenous 5000 unit/day on alternate days for 1 week) and/or NAs (tenofovir or entecavir) from time of liver-transplant which could be given life-long. Low-risk patienrs (HBeAg negative and HBV DNA negative) can be considered for early HBIg withdrawal, or HBIg –free regimen. HBcAb positive recipient could be considered for 6-12 months of prophylactic antiviral (lamivudine) treatment (or can be monitored for HBV recurrence).
Treatment of HBV recurrence or De novo HBV after SOT: Recurrence implies detectable HBsAg or HBV DNA after transplant in chronic HBV infection. De novo infection implies newly detectable HBsAg or HBV DNA after transplant in those without chronic hepatitis B infection. Patients with HBV recurrence should be assessed for adherence with NA prophylaxis and should be treated with antivirals (entecavir or tenofovir – especially in case of prior lamivudine exposure) lifelong. Resistance testing should be undertaken at a specialist laboratory.
Monitoring of HBV recurrence or de novo infection: HBV DNA and HBsAg should be checked every 3 months for 1 year, and then 6 monthly in HBsAg positive recipient or HBcAb positive donor. The frequency can be increased in case of non-adherence.
Hepatitis B vaccination and SOT: All prospective SSOT recipients should be vaccinated with a high-dose accelerated vaccination schedule and response should be documented (with second series administration, if no response), as successful vaccination decreases risk of de novo infection to 10%. Vaccination for liver transplant recipients (for HBv) is not currently recommended routinely. In HBcAb positive kidney transplant recipients, If HBsAb is <100 IU/ml, then vaccination should be done to increase the antibody levels.
I like your detailed well-structured summary.
I note that
you have explained how to choose a donor with evidence of past infection in
relation to the decision -making necessary for transplantation.
Guidelines for Hepatitis B and Solid Organ Transplantation
Summary of the Guidelines
HBV Biology and Disease
Indication for transplantation for HBV-related disease
Acute fulminant HB
We recommend
We suggest
Decompensated Hepatitis B cirrhosis and HCC
We recommend
We suggest
HBV and other non-liver transplantation
We suggest
Pre-transplantation management of HBV in individuals being considered for transplantation
We recommend
Use of HBcAb-positive or HBsAg-positive donors
We suggest that
HBcAb positive donation for liver recipients
We recommend that
We suggest that
HBsAg +ve donation for liver recipients
We recommend that
HBcAb +ve and HBsAg +ve donation for non-liver SOT
We recommend that
We suggest that
Management of Co-infection (HDV, HCV, HIV) and transplantation
We recommend that
We suggest
preventing recurrence of HBV post-Tx
We recommend
We suggest
Treatment of HBV recurrence or De Novo HBV infection after SOT
We recommend
Monitor HBV recurrence or de novo infection
We recommend
HBV vaccination and SOT
We recommend
We suggest
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
Summarise these guidelines
This is the first British Transplantation Society (BTS) guideline of hepatitis B in the transplant setting [Guidelines for Hepatitis B & Solid Organ Transplantation (SOT)], March 2018
HBV Biology and Disease
o All patients being worked up for SOT must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
o All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
o HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
o Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
o All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Phases of Chronic Hepatitis B Infection: (rely on the patient’s HBeAg and HBeAb status, ALT levels, and HBV DNA quantification)
1. HBeAg positive chronic infection: HBeAg positive, HBeAb negative, ALT levels normal, HBV DNA levels very high – classically in the millions, and no histological liver damage (treatment is rarely indicated)
2. HBeAg positive chronic hepatitis: HBeAg positive, HBeAb can be positive or negative, ALT levels is high, HBV DNA Levels usually high, and with histological liver damage with progression to cirrhosis possible (antiviral therapy is indicated if this phase is prolonged or there is evidence of significant liver fibrosis)
3. HBeAg negative chronic infection: HBeAg negative, HBeAb positive, ALT levels normal, HBV DNA Levels <2000 IU/mL, and no histological liver damage (generally not require therapy, regular follow-up is mandatory as reactivation and the development of HBeAg negative chronic hepatitis occurs in 25%)
4. HBeAg negative chronic hepatitis: HBeAg negative, HBeAb usually positive, ALT levels high, HBV DNA Levels >2000 IU/mL and frequently >20000 IU/mL, and with histological liver damage and progression to cirrhosis possible (needs antiviral therapy)
The titre of HBsAb can be variable and levels above 10 miu/mL are protective
HB core alone (HBcAb positive with all other markers negative):
*May indicate
1. past HBV infection
2. passively acquired antibodies (blood transfusion)
3. acute HBV infection (window period)
4. or non-specific reactivity (false positive)
*This is particularly relevant in donors who may have received blood products (HBsAb and HBeAb antibodies may also be passively transferred from blood products)
*HB core alone in the recipient must be further investigated before transplantation (any history of blood products and risk factors for HBV, full HBV serological markers, and HBV DNA (+/- follow-up testing) to clarify the patient’s HBV status)
*Immunosuppression in individuals with past infection can result in the reactivation of HBV and the re-emergence of HBsAg
Reactivation of HBV:
Reappearance of markers of active HBV replication in a patient with previously controlled HBV infection, or an increase in levels of replication compared to previous levels
Depends on:
1. Baseline HBV status
2. Underlying condition
3. Type of immunosuppressive therapy
4. and host immunity
May result from:
1. Loss of immune control of HBV
2. or lack of antiviral efficacy due to the emergence of antiviral resistant variants
May be asymptomatic or associated with a flare of hepatitis in previously minimal or inactive disease, manifesting clinically with acute hepatitis which can progress to acute liver failure and even death if untreated
Serological and virological profile of reactivation may vary depending on the pre-existing profile in the patient
HBV reactivation can occur in:
1. Chronic hepatitis B virus ((exacerbation of chronic hepatitis B virus). The risk of is higher
2. Past HBV (reactivation of past HBV). Reactivation is more likely to occur in those with low or undetectable HBsAb levels and may be preceded by a fall in HBsAb levels over time
3. Patients who were HBeAg negative or had undetectable serum HBV DNA prior to transplant
Hepatitis Delta Co-Infection:
Cannot exist in isolation (Virions are coated in HBsAg)
o Around 5% of HBV infected patients worldwide are co-infected with HDV
o Is more prevalent in South America, Turkey, Eastern Europe and Sub-Saharan Africa (low prevelance in Asia despite the large numbers of HBV-infected people in this continent)
o Either acquired at the time of infection with HBV or can occur as a super-infection
o HDV co-infection results in more rapid progression of liver disease to cirrhosis and HCC, especially as it is difficult to treat
o In cases of HDV co-infection where HBV DNA levels are above 2000 IU/mL or fluctuate above this level, it is generally recommended that HBV replication is inhibited with nucleoside analogues
o A diagnosis of past or current HDV co-infection is dependent on the finding of serum HDV IgG positivity
o Active HDV co-infection is confirmed by HDV RNA positivity
o HDV RNA should be performed in all cases of suspected HDV co-infection rather than relying on serology alone
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
o Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
o Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by NHSBT. (1A)
o As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe acute hepatitis B, treatment with tenofovir or entecavir should be strongly considered. (2B)
*> 95-99% of adults who acquire acute HBV (AHB) will recover spontaneously and seroconvert to HBsAb without antiviral therapy (1% of cases of AHB progress to fulminant hepatitis, which is characterised by a very high mortality rate (up to 80%), often requiring liver transplantation (OLT))
Indications of antiviral treatment include:
1. Fulminant hepatitis B
2. Severe AHB – two of the following criteria: bilirubin >100 µmol/L, INR ≥1.6, hepatic encephalopathy
3. Protracted disease course – persistent symptoms or marked jaundice for more than 4 weeks after presentation
4. Immunocompromised host
Prompt antiviral administration in patients with severe or fulminant AHB:
1. Shorten disease duration
2. Promote recovery
3. Improve survival
*Antiviral treatment should be started early
*Treatment should be continued for at least 3 months after seroconversion to HBsAb or 12 months after anti-HBe seroconversion without HBsAg loss
Fulminant hepatitis B:
Liver transplantation should be considered in all patients
The criteria for listing for liver transplantation: hepatic encephalopathy and
prothrombin time >100 seconds or INR >6.5
or any three from: age >40 or <10 years/ jaundice to encephalopathy time >7 days/serum bilirubin >300 µmol/L/ PT >50 seconds or INR >3.5
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
o Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C)
o Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
o Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
Chronic Hepatitis B (CHB):
o The goal of treatment is to prevent disease progression to cirrhosis, HCC and death
o First-line treatment is NAs or pegylated-interferon (PEG-IFN) with serum HBV DNA levels >2000 IU/mL in combination with elevated ALT levels and/or with moderate/severe liver inflammation and/or fibrosis
Decompensated Cirrhosis:
o Poor prognosis in untreated patients (14-35% 5-year survival, compared with 84% in the compensated state)
o Should be treated in specialised liver units
o Start oral NAs, irrespective of serum ALT, HBV DNA and e antigen status (Interferon is contraindicated in cirrhosis because of the risk of potentially life-threatening complications)
Objectives of antiviral treatment:
1. Improvement of liver function
2. Decreased risk of HBV recurrence after transplantation
Criteria for consideration of OLT in the UK include:
1. A projected one year liver disease mortality without transplantation of >9%, predicted by a United Kingdom Model for End-Stage Liver Disease (UKELD) score of ≥ 49 2
2. A variant syndrome (e.g. diuretic resistant ascites or chronic hepatic encephalopathy) in those with a UKELD of <49
Hepatocellular Carcinoma (HCC):
50-60% due to HBV (can occur without cirrhosis, but the majority (70-90%) develops in cirrhotic livers)
Risk factors of HCC in patients with HBV infection:
1. Demographic – male gender, older age, Asian or African ancestry, family history of HCC
2. Viral – higher HBV DNA levels, genotype (C>B), pre-core mutations, longer duration of infection, co-infection with HCV, HIV and HDV
3. Clinical – cirrhosis
4. Environmental – alcohol, tobacco, aflatoxin exposure
HCC surveillance:
1. Six-monthly abdominal ultrasound scans even if HBV DNA is adequately suppressed
2. Serum alpha-fetoprotein (AFP): controversial, six-monthly
Treatment:
Similar to that in other causes of HCC
In non-cirrhotic: resection is the treatment of choice for a single lesion
In a cirrhotic liver: treatment depends on the size of the lesions, the number of lesions, and the serum AFP concentration. Surgical resection is the first line treatment for patients with solitary HCC and well-preserved liver function
Recurrence is 50% at three years and 70% at five years reported
Liver transplantation: absolute contraindications include
1. Tumor rupture
2. AFP >1000 iu/mL
3. Extra-hepatic spread
4. Macroscopic vascular invasion
Liver transplantation: listing
1. A single tumor ≤5 cm diameter
2. Up to 5 separate tumors, all ≤3 cm
3. Single tumor >5 cm and ≤7 cm diameter, with no evidence of tumor progression, no extra-hepatic spread and no new nodule formation over a six month period. Loco-regional therapy +/- chemotherapy may be given during that time
HBV and Other (Non-Liver) Transplantation
o Patients with advanced HBV-related liver disease requiring another organ transplant are considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
Impact of Transplantation on HBV:
o Although some immunosuppressive drugs exhibit anti-HBV properties in vitro, when used in combination with other drugs in the SOT setting, they usually have a net immunosuppressive effect, thus promoting HBV replication
Impact of HBV Infection on Transplant Outcome:
HBsAg positivity is a risk factor for death in renal transplant recipients
HBV may cause de novo membranous glomerulonephritis, potentially impacting on renal function after transplantation
CHB without cirrhosis have excellent outcomes with antiviral therapy alone
HBV reactivation occurred in 4.1% of non-liver SOT patients with evidence of past HBV infection, with a median time to HBV reactivation of 4.7 years () study from Canada. The overall five-year survival was 82%
Risk of HBV Infection in the SOT Recipient:
o The overall risk of HBV reactivation/de novo infection in a SOT recipient without antiviral treatment/prophylaxis is dependent upon the donor and recipient HBV status
Management of SOT Recipient with CHB or Past HBV:
o CHBV and past HBV are not contraindications for SOT
o Should be be referred to a specialist in viral hepatitis for full evaluation
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
o All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
o Individuals undergoing non-liver SOT who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors
o The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
o All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients:
o The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
o When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
o When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
o If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order: 1. the HBsAg-positive recipient 2. The HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. The HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients:
o HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
o If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
o All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
o Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
o The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
o If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit.
o When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
*Use of solid organs from donors with core antibodies (in the absence of HBsAg and regardless of the presence or absence of HBsAb) can transmit HBV infection to the organ recipient (the risk of transmission is very high for liver transplantation and much lower for transplantation of kidneys and thoracic organs)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
o HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
o HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
o A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
o HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
o For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
o In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
o Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
o Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
o Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
o All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
o Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
o Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Definition of hepatitis B recurrence after liver transplantation: detectable HbsAg and/or detectable viral load (HBV DNA) after transplantation for complications of chronic hepatitis B
Definition of de novo hepatitis B infection after OLT: newly detectable HbsAg, and/or detectable HBV DNA, in those without prior CHB (HBcAb negative)
Risk factors of recurrence:
1. Viral resistance (and previous treatment regimens)
2. Patient non-adherence
3. Detectable HBV DNA levels at the time of transplantation
4. Hepatocellular carcinoma
5. HIV
6. Immunosuppression
Monitoring for HBV Recurrence or De Novo Infection
o HBV DNA and HBsAg should be monitored every 3 months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
o Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
Increase the risk of recurrence after liver transplant (OLT):
1. Transplantation for HCC
2. HBeAg positivity pre-OLT
3. HBV viral load >100,000 IU/mL at the time of transplantation
4. Non-adherence (Male gender, lack of social support and mental illness)
HBV Vaccination and Solid Organ Transplantation
o All potential SOT recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
o Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
o Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
o All prospective SOT recipients should receive a high-dose, accelerated vaccine schedule. (2C)
o In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
Timing of Vaccination:
o A series of three doses of HBV vaccine (either plasma-derived or recombinant)
o Healthy subjects will develop HBsAb (with protective serum titres of >10 U/L) in 95-99%
o Poor response in patients with ESRD (60-90%)
o There is an association between the severity of renal impairment and lack of response to the HBV vaccine, therefore, vaccination should be considered early in the course of disease)
o The response to HBV vaccine may be suboptimal in the pre-transplant period and disappointing in the post-transplant period (may be related to immune suppression)
o The loss of protective immunity was significantly more frequent in patients with lower HBsAb titres at the time of transplantation (<100 U/L) compared with those patients with higher titres
Vaccination Method:
o Available recombinant vaccines are HBvaxPro (standard dose 10 µg), Engerix-B (standard dose 20 µg) and Fendrix (standard dose 20 µg)
o Higher-dose vaccine formulations are available for use in patients with ESRD [HBvaxPro® (40 µg/mL standard dose 40 µg) and Fendrix® (40 µg/mL, standard dose 20 µg)]
o An accelerated regimen with 4 doses of the vaccine (HBvaxPro and Engerix-B 40 µg or Fendrix 20µg) given at 0, 1, 2 and 6 months is recommended in ESRD
o If HBV vaccination given after SOT, the standard vaccine schedule with standard-dose vaccines at 0, 1 and 6 months is recommended
o HBsAb titres should be measured 1-3 months after the completion of the vaccination schedule
o In those who fail to respond to the initial vaccination schedule ( antibody titres ⩽10 IU/L), a further vaccine schedule should be administered
Renal Transplantation:
o Significantly higher all-cause mortality (relative risk 2.21, 95% CI 1.56-3.14) and all-cause graft loss (relative risk 1.44, 95% CI 1.26-1.63) in renal transplant recipients with HBV
o Reactivation in patients with past resolved HBV infection (i.e. HBsAg negative/HBcAb positive is around 6.5% (particularly amongst recipients without HBsAb at the time of renal transplantation)
o Transmission of HBV is universal after use of renal grafts from HBsAg positive donors (may also occur from donors who are only HBcAb positive)
o HBV vaccination is recommended in HBV seronegative patients with ESRD
o In patients with past resolved infection (HBcAb positive), vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation
I make note of your interpretation of virology reports in relation to timings of test and viral load pertaining to HBV infections.
Your write-up is in a lot of details as if you are writing a chapter.
Guidelines for Hepatitis B & Solid Organ Transplantation (BTS)
HBV Biology and Disease
· All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb.
· All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels.
· HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal.
· Any potential transplant recipients or donor found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA testing to exclude occult HBV.
HBV and Other (Non-Liver) Transplantation
· It is suggested that all patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation.
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
· It is recommended that individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation.
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
· It is recommended that the kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low.
· It is suggested that when a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
· It is recommended that HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation.
· It is recommended that, a plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation.
Preventing Recurrence of HBV Post-Transplantation
· It is suggested that if HBsAg positive individuals are at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation.
· It is suggested that recipients with evidence of past HBV are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment. Or just monitoring for HBV recurrence without prophylaxis.
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
· It is recommended that lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation.
· Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure.
Monitoring for HBV Recurrence or De Novo Infection
HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor.
HBV Vaccination and Solid Organ Transplantation
· It is recommended that all prospective solid organ transplant recipients who are HBV naive must be vaccinated using a high-dose, accelerated vaccine schedule and the response documented.
· It is suggested that liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but not all.
· Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation.
· In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered.
I like your detailed well-structured summary.
I note that
you have explained how to choose a donor with evidence of past infection in
relation to the decision -making necessary for transplantation.
Summary
Introduction
Hepatitis B is an infectious disease that can lead to progressive liver damage and ultimately liver failure, requiring transplantation. The following are guideline recommendations for Hepatitis B in the setting of solid organ transplantation.
Guidelines and recommendations
I make note of your interpretation of virology reports in relation to timings of test and viral load pertaining to HBV infections
I like your
detailed well-structured summary.
HBV Biology and Disease
– All patients being worked up for SOT must be tested for HBsAg, HBsAb and HBcAb. (1B)
– All HBsAg +ve patients must have: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
– HDV RNA done if recipient HDV serology is positive or equivocal. (1B)
– All potential donor or recipients with HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Recommendations:
• Must be managed in a specialist liver center. (1C)
• Liver transplantation must be considered in patients with fulminant hepatitis B (1A)
Suggestion;
• As early antiviral treatment with NA may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Recommendations:
• Should be treated in specialist liver units as antiviral therapy is complex and patients may be need liver Tx (1C)
• If HBV DNA is detectable; urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
Suggestions:
• Listing for liver Tx; in HBV cirrhosis and UKELD score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
HBV and Other (Non-Liver) Transplantation
Suggestion:
• Advanced HBV-related liver disease requiring another SOT to be considered for combined transplantation (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Recommendation:
• All HBsAg +ve individuals should be treated before transplantation (with tenofovir or entecavir), aiming for an undetectable HBV DNA level. (1B)
• HBsAg +ve individuals undergoing non-liver SOT must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation (1B)
Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
Suggestion:
– Matching a recipient with donor +ve for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
– All recipients should be counselled about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients
Recommendation: Ife liver comes from HBcAb donor
– It can be used for any potential liver recipient. (1C)
– if recipient HBsAg +ve , meaures to prevent HBV reactivation should be adopted. (1B)
– Prophylactic lamivudine should be given at the time of transplantation, and should be continued indefinitely, if recipient HBV immune or non-immune (1A)
Suggestion:
– If other waiting list priorities permit, the HBcAb positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient
3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients
Recommendation:
– Can be given to HBsAg positive recipients, with HDV negative. (1C)
– If urgency demands, can be given to an HBsAg negative patient. (1D)
– All recipients must be treated with entecavir or tenofovir from the time of transplantation. (1B)
– Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
Recommendation:
– The kidneys, heart and lungs can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion:
-If need demands, HBsAg positive organs can be used for any recipient (individualized risk assessment )(2C)
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for 6 months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Recommendations:
– HBV/HDV recipients; should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
– HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
– Perioperative management plan of the HIV and HBV infections should be agreed by the MDT (1D)
– HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
Suggestion:
– For HBV/HDV recipients HBIg withdrawal from combination HBIg/NA prophylaxis can be considered, but not within 12 months of transplantation. (2C)
Preventing Recurrence of HBV Post-Transplantation
Recommendation:
– In HBsAg positive individuals; the use of HBIg and/or a potent NA at the time of transplantation. (1B)
Suggestion:
– Early withdrawal of HBIG or HBIG-free prophylaxis in low risk recipients (2C)
– Life-long combination HBIG and NA for individual at high risk for HBV recurrence (2B)
– Post-non-liver transplant with past HBV infection (HBcAb positive alone) are considered for (6-12 months) course of prophylactic antiviral treatment; with monitoring for recurrence (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Recommendation:
– Review of adherence with NA prophylaxis and test for resistance (1C)
– Lifelong antiviral therapy for all individuals with HBV recurrence or de novo HBV (1C)
– Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
Monitoring for HBV Recurrence or De Novo Infection
Recommendation:
– HBV DNA and HBsAg every 3 months in the first year and then every 6 months (1C)
– Shorter interval if non-adherence is suspected. (Not graded)
HBV Vaccination and Solid Organ Transplantation
Recommendation:
• All HBV naïve recipients must be vaccinated and the response documented. (1C)
Suggestion:
• Liver recipients transplanted for HBV, vaccination cannot recommended as routine. (2C)
• Renal recipients if HBsAb are <100 IU/mL, vaccination is recommended. (2C)
• All recipients should receive a high-dose, accelerated vaccine schedule. (2C)
• Second vaccination series considered if fail non response documented (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
Indications of transplantation for HBV-relaed disease:
Pre-transplant management of HBV infection in transplant candidates:
Use of HBcAb+ve or HBsAg+ve donors:
HBcA+ve & HBsAg+ve donors for non liver SOT recipients:
Management of co-infection(HDV, HCV,HIV) & transplantation:
Prevention recurrence of HBV infection post transplantation:
Treatment of HBV recurrence or de novo HBV after SOT:
Monitoring of HBV recurrence or de novo HBV infection:
HBV vaccination & SOT:
I make note of your interpretation of serological and molecular testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections
Summarise these guidelines
HBV Biology and Disease
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1BAll HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and hepatitis delta virus ( HDV ) Ab serology, and HBV DNA levels. (1B)
Hepatis delta virus (HDV) RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation.
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
Use of HBcAb Positive or HBsAg Positive Donors
The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C) • All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C) •
When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C) HBsAg positive donors should not be used for HBV/Hepatitis Delta Virus (HDV) co-infected recipients. (1C)
A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
HBIg (immunoglobulin )could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV mono infection. (1C).
Preventing Recurrence of HBV Post-Transplantation
In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent nucleoside analogue (NA ) is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
Life-long combination therapy with HBIG and a potent nucleoside analogue( NA) can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation.
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
HBV Vaccination and Solid Organ Transplantation
All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
Recommendations and suggestions: (Recommendations =1 , suggestions =2)
HBV Biology and Disease
Acute Fulminant HBV
Decompensated Hepatitis B cirrhosis and Hepatocelluar Carcinoma
HBV and other Transplantation (non- Liver)
Pretransplant Management of HBV in Individuals Being Considered for Transplantation
Use of HBcAb Positive or HBsAg Positive donors
HBcAb Positive donation for liver recipients
HBsAg Positive donation for Liver recipients
HBcAb Positive and HBsAg positive donation to Non-liver Solid Organ Recipients
Management of Co-infection (HDV,HCV, HIV) and Transplantation
Preventing recurrence of HBV posttransplant
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
Monitoring for HBV Recurrence or de novo infection
HBV Vaccination & SOT
I make note of your interpretation of serological and molecular testing reports pertaining to HBV infections in relation to timings in the natural history HBV infections. I like your summary.
Thnxs prof
HBV Biology and disease
It is recommended that
–HBsAg, HBsAb and HBcAb need to be tested for cases prepared for SOT.
– HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels need to be tested for HBsAg positive patients prepared for transplantation
– Potential recipients with positive or equivocal HDV serology need to have HDV RNA testing .
– HBV DNA and HDV serology testing is recommended for potential recipients having HBcAb positive and HBsAg negative to exclude occult HBV or HDV infection.
– HBV DNA test is needed for donors with positive HBcAb and negative HBsAg to exclude occult HBV infection
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
It is recommended for this group of patients to be manged at specialised centers , Giving antiviral therapy with nucleot(s)ide analogues (NA) can enhance recovery and transplant free survival in severe Acute hepatitis B, treatment with tenofovir or entecavir is highly recommended.
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
Those patients need to be treated in specialised liver units and start antiviral treatment with NA(s).
Cases having hepatitis B cirrhosis and a United Kingdom end stage liver disease score (UKELD ) score >49 or with HCC within criteria defined in the UK NHSBT guidelines can be considered for liver transplantation.
HBV and Other (Non-Liver) Transplantation
Combined transplantation can be considered for those with advanced HBV-related liver disease requiring another organ transplant
Pre-Transplant management of HBV for potential candidates for Transplantation
-HBsAg positive cases prepared for liver transplantation need to be
treated with tenofovir or entecavir before transplantation, to reach undetectable HBV DNA level.
– HBsAg positive candidates undergoing non-liver SOT need liver disease staging and HBV DNA suppression by tenofovir or
entecavir before transplantation .
HBcAb Positive or HBsAg Positive Donors
-There inclusion has to be evaluated with viral hepatitis specialist along with conselling.
-The HBcAb positive (HBsAg negative) donor liver can be offered for any possible liver recipient.
– HB c Ab positive donor can donate to HBsAg positive recipient, the standard preventive strategy for HBV reactivation has to be applied.
– Prophylactic lamivudine need to be started at transplantation and continued indefinitely, when a HBc Ab positive donor donates to a HBV immune or non-immune recipient.
-HBsAg positive liver donor can be given to HBsAg positive recipients if HDV is negative.
– HBsAg positive liver can be given to HBsAg negative patient in urgent cases.
– Hepatic recipients from HBsAg positive donor need to be treated with entecavir or tenofovir from the time of transplantation
– HBIg is rarely recommended.
– Kidneys, heart and lungs from the HBcAb positive donors can be donated to any recipient, as de novo HBV infection is low meanwhile lamivudine prophylaxis may be given for 6 months after transplantation.
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
-HBV/HDV recipients need to receive a combination of HBIg/NA prophylaxis from time of transplantation.
– HBV/HDV co-infected recipients cannot receive organs from HBsAg positive donors
-MDT need to be involved in HIV and HBV infection treatment.
-HBIg as HBV prophylaxis if HIV antivirals are stopped in the peri-operative period. After HIV antiviral treatment is reintroduced the HBV prophylaxis will be the same as that used for HBV monoinfection.
Preventing Recurrence of HBV Post-Transplantation
By using HBIg and/or a NA from the time of transplantation.
-For low risk cases for post-transplant HBV recurrence, HBIg free regimen can be used
-For high risk cases HBIg and NA can be used lifelong
– For those with past HBV infection are at risk of HBV reactivation post-non-liver transplant can be considered for a limited (6-12 months) course of prophylactic antiviral treatment.
Treatment of HBV Recurrence or De Novo Hepatitis B after SOT
-Adherence to prophylaxis has to be assessed and resistance has to be tested
-lifelong antiviral therapy in the forum of Entecavir or Tenofovir are adviced as first line treatment
Monitoring for HBV Recurrence or De Novo Infection
-HBV DNA and HBsAg need monitoring every 3 months in the first year and then every 6 months in HBsAg positive liver transplant recipients or recipients from a HBcAb positive donor.
-For cases with possible non adherence and self reporting cases monitoring intervals can be shortened.
HBV Vaccination and SOT
-All naïve candidates must be vaccinated.
-HBcAb positive cases if HBsAb are <100 IU/mL need vaccination.
SUMMARY
Executive summary and recommendations
Indications for Transplantation for HBV-Related Disease
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Use of HBcAb Positive or HBsAg Positive Donors
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients
The HBsAg donor should not be used in HBV/HDV co-infected recipients
Preventing the Recurrence of HBV Post-Transplantation
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation.
Monitoring for HBV Recurrence or De Novo Infection
HBV Vaccination and Solid Organ Transplantation
I like your well structured detailed summary.
I appreciate your interpretation in relation to the type of disease and corresponding mode of treatment indicated.
These guidelines represent consensus opinion from experts in the field of transplantation in the United Kingdom
For each recommendation the quality of evidence has been graded as:
A (high) -B (moderate) -C (low) -D (very low)
For each recommendation, the strength of recommendation has been indicated as one of: Level 1 (we recommend)
recommendation is a strong recommendation to do (or not do) something where the benefits clearly outweigh the risks (or vice versa) for most, if not all patients
-Level 2 (we suggest)
recommendation is a weaker recommendation, where the risks and benefits are more closely balanced or are more uncertain
– Not graded (where there is not enough evidence to allow formal grading
Hepatitis B virus (HBV) infection is a major risk factor for hepatic dysfunction in solid organ transplant (SOT) recipients
Reactivation of HBV is well described in association with the use of immunosuppressive agents such as B-cell depleting agents (e.g. rituximab), anthracycline derivatives, TNF- inhibitors, cytokine inhibitors and tyrosine kinase inhibitors
Ciclosporin has been shown to inhibit HBV replication
In a hydrodynamic injection mouse model, dexamethasone, ciclosporin and cyclophosphamide were shown to enhance HBV replication, whilst replication was terminated in mice treated with mycophenolate
Rapamycin (an mTOR inhibitor) has been shown to enhance HBV production by inducing cellular autophagy
The use of steroids can induce reactivation of HBV secondary to the stimulatory effect on the glucocorticoid-responsive enhancer region of the HBV genome
. Hepatitis associated with HBV reactivation can lead to liver failure, especially in patients with cirrhosis. Before the introduction of antiviral prophylaxis, the rates of HBV reactivation after renal transplantation ranged from 50 to 94%
post-transplant anti-HBsAb monitoring is not routinely recommended to predict the risk of reactivation.
We suggest that • Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C
All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
As early antiviral treatment with nucleot(s)ide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
We recommend that: • The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
We recommend that: In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
We recommend that HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
We recommend that • All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Amongst renal transplant recipients who are HBcAb positive, if HBsAb are <100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
II. Guidelines for Hepatitis B & Solid Organ Transplantation
====================================================================
Summarise these guidelines
HBV Biology and Disease
Indications for Transplantation for HBV-Related Disease
Acute Fulminant Hepatitis B
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma
HBV and Other (Non-Liver) Transplantation
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Use of HBcAb Positive or HBsAg Positive Donors
General Recommendations
HBcAb positive donation for liver recipients
HBsAg Positive Donation for Liver Recipients
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients can be used for any recipient, with low risk of infection and lamivudine prophylaxis for six months after transplantation.
===================================================================
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Preventing Recurrence of HBV Post-Transplantation
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ
Transplantation
Monitoring for HBV Recurrence or De Novo Infection
HBV Vaccination and Solid Organ Transplantation
I like your detailed well-structured summary.
I note that you have explained how to choose a donor with evidence of past infection in relation to the decision -making necessary for transplantation.
Many thanks for you Prof.Sharma
HBV Biology and Disease
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation
Use of HBcAb Positive or HBsAg Positive Donors
Management of Co-Infection (HDV, HCV, HIV) and Transplantation
Preventing Recurrence of HBV Post-Transplantation
Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation
Monitoring for HBV Recurrence or De Novo Infection
HBV Vaccination and Solid Organ Transplantation
Typing whole sentence in bold or typing in capitals amounts to shouting.
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding mode of treatment indicated.
HBV Biology and Disease:
We urge that: • All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titers), and HBcAb. (1B)
• All HBsAg-positive patients having transplant workups must have the following tests: HBeAg, HBeAb, HDV Ab serology, and HBV DNA levels. (1B)
• HDV RNA testing must be undertaken in possible transplant patients if HDV serology is positive or ambiguous. (1B)
• All prospective transplant patients found to be HBcAb positive but HBsAg negative (past infection) must undergo HBV DNA and HDV serology testing to eliminate occult HBV or HDV infection. (1B)
• All donors who are positive for HBcAb but HBsAg negative (prior HBV exposure) must undergo HBV DNA testing to eliminate the potential of hidden HBV infection. (1C)
HBV Transplantation Indications:
Hepatitis B Fulminant
• Hepatitis B-related fulminant liver failure should be treated in a liver center. (1C) NHSBT listing requirements require liver transplantation for fulminant hepatitis B patients. (1A)
Early antiviral therapy with nucleotide analogs (NA) may increase recovery, minimize illness duration, and improve transplant-free survival in severe AHB. Tenofovir or entecavir should be seriously explored. (2B)
Decompensated HBV Cirrhosis and Hepatocellular Carcinoma:
• Hepatitis B patients with decompensated cirrhosis should be treated in liver units since antiviral treatment is complicated and they may be candidates for liver transplantation. (1C)
• Decompensated cirrhosis patients with HBV DNA need prompt NA antiviral therapy (s). First-line antivirals entecavir and tenofovir should be taken forever. (1A)
We recommend listing individuals with hepatitis B cirrhosis and a UKELD score >49 or HCC under UK NHSBT guidelines for liver transplantation. (2A)
HBV and Non-Liver Transplantation:
• Patients with advanced HBV-related liver disease needing another organ transplant may consider combination transplantation after weighing the risks and benefits. (2C)
Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation :
We recommend that: • All HBsAg-positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
• Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
HBcAb/HBsAg Positive Donors: General Guidelines:
• A viral hepatitis expert should explore matching an organ recipient with an HBsAg or HBcAb donor. (2C)
• Potential recipients should be informed throughout the screening process that they may get a liver from a donor with HBV infection.
HBcAb-positive liver donation:
• Anybody may receive the HBcAb positive (HBsAg negative) donor’s liver. (1C)
When an HBsAg-positive receiver receives liver from a hepatitis B core antibody-positive donor, the conventional HBV reactivation prevention method should be used. (1B
) When a liver from an HBcAb-positive donor is transplanted to an HBV-immune or non-immune recipient, prophylactic lamivudine should be administered from transplantation and maintained permanently. (1A)
If other waiting list priorities allow, the hepatitis B core antibody-positive donor liver should be distributed as follows:
1- HBsAg-positive recipient
2. HBV-immune recipients (naturally and vaccine-induced)
3. HBV-nonimmune recipient. (2C)
HBsAg-positive liver donation:
• HDV-negative HBsAg-positive patients may receive donor’s livers. (1C)
• HBsAg-negative patients may get HBsAg-positive livers in an emergency. (1D)
• HBsAg-positive liver transplant patients must start entecavir or tenofovir treatment. (1B)
• HBIg seldom reduces HBsAg. (1C)
HBcAb/HBsAg Positive Donation for Non-Liver Solid Organ Recipients:
• The kidneys, heart, and lungs from the HBcAb-positive organ donor may be utilized by anybody without danger of de novo HBV infection. (1A)
• After an individual risk-benefit evaluation, the HBsAg-positive donor’s non-liver solid organs may be utilized for any recipient. (2C)
Lamivudine prophylaxis may be administered for six months following transplantation if the donor is HBcAb positive, even if the transmission is unlikely. (2C)
Transplantation and Co-Infection (HDV, HCV, HIV):
HBV/HDV patients should get combined HBV/NA prophylaxis from transplantation. (1C)
HBV/HDV co-infected recipients should not receive HBsAg-positive donors.
(1C)
• Before transplantation, the multidisciplinary team should agree on perioperative HIV and HBV care plans. (1D)
• HBIg may prevent HBV if HIV antivirals are halted during surgery. HBV prophylaxis after HIV antiviral therapy is the same as for HBV mono-infection transplantation. (1C)
• HBV/HDV-infected patients may contemplate HBIg withdrawal from combined HBIg/NA prophylaxis, but not within 12 months of transplantation. (2C)\sC
Post-Transplant HBV Prevention:
• HBIg and/or a powerful NA should be used after transplantation to prevent HBV reinfection in HBsAg-positive patients at high risk of recurrence. (1B)
• Low-risk post-transplant HBV recurrence patients may benefit from early HBIG withdrawal or HBIG-free prophylaxis.
(2C)
• Lifelong combination therapy with HBIG and a potent NA may be given to patients at high risk for HBV recurrence, such as those who are HBV DNA positive at transplant, HBeAg positive, transplanted for hepatocellular carcinoma, or HIV co-infected. Most of the data supporting this use come from retrospective studies in the lamivudine era. (2B)
• Patients with evidence of prior HBV infection (HBcAb positive alone) are at increased risk of HBV reactivation post-non-liver transplant and may benefit from a short (6–12 months) course of preventive antiviral medication. Monitoring for HBV recurrence is also appropriate. (2B)
Recurrence or De Novo Hepatitis B Therapy Following Solid Organ Transplantation:
• All post-liver transplant HBV recurrence patients should carefully assess NA prophylaxis adherence. Specialist labs should test for resistance. (1C)
• All post-liver transplantation HBV recurrence or de novo hepatitis B patients should get lifelong antiviral medication. (1C)
16 • Entecavir or Tenofovir should be used initially. Lamivudine-exposed patients should take tenofovir. (1B)
HBV recurrence/de novo infection monitoring:
HBsAg-positive liver transplant recipients or those getting grafts from HBcAb-positive donors should be examined for HBV DNA and HBsAg every three months in the first year and every six months afterward, regardless of therapy or prophylaxis. (1C)
HBV Vaccination and Solid Organ Transplantation:
• All HBV-naive prospective solid organ transplant patients should be vaccinated (time allows) and the reaction noted. (1C)
• Vaccination may help certain liver transplant patients generate protective serum titers of HBsAb, but it is not advised as a normal practice. (2C)
• If HBsAb is <100 IU/mL in HBcAb-positive kidney transplant patients, immunization may reduce the risk of reactivation. (2C)
• Solid organ transplant candidates should get high-dose, expedited vaccines. (2C)
• A second HBV vaccine series should be given to non-responders. (2C)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
Guidelines for Hepatitis B & Solid Organ Transplantation:
1-HBV Biology and Disease:
Recommendation;
–All patients being worked up for solid organ transplantation must be tested for HBsAg, HBsAb (absolute titres) and HBcAb. (1B)
–All HBsAg positive patients undergoing transplant work up must have the following tests: HBeAg, HBeAb and HDV Ab serology, and HBV DNA levels. (1B)
–HDV RNA testing must be performed in potential transplant recipients where HDV serology is positive or equivocal. (1B)
–Any potential transplant recipients found to be HBcAb positive but HBsAg negative (past infection) must have HBV DNA and HDV serology testing to exclude occult HBV or HDV infection. (1B)
–All donors who are positive for HBcAb but HBsAg negative (past HBV exposure) must have HBV DNA testing to exclude the possibility of occult HBV infection. (1C)
2-Indications for Transplantation for HBV-Related Disease:
Acute Fulminant Hepatitis B;
Recommendation;
-Individuals with fulminant liver failure associated with hepatitis B infection must be managed in a specialist liver centre. (1C)
-Liver transplantation must be considered in patients with fulminant hepatitis B in keeping with UK listing criteria defined by National Health Service Blood and Transplant (NHSBT). (1A)
Suggestion;
-As early antiviral treatment with nucleotide analogues (NA) may promote recovery, shorten disease duration and improve transplant free survival in severe AHB, treatment with tenofovir or entecavir should be strongly considered. (2B)
Decompensated Hepatitis B Cirrhosis and Hepatocellular Carcinoma;
Recommendation;
-Individuals with decompensated cirrhosis due to hepatitis B should be treated in specialist liver units as the application of antiviral therapy is complex and these patients may be candidates for liver transplantation. (1C)
-Individuals with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Entecavir and tenofovir are the first line antiviral agents and should be continued indefinitely. (1A)
Suggestion;
-Listing for liver transplantation should be considered in patients with hepatitis B cirrhosis and a United Kingdom end stage liver disease (UKELD) score >49 or with HCC within criteria defined in the UK NHSBT guidelines. (2A)
3-HBV and Other (Non-Liver) Transplantation:
Suggestion;
-Patients with advanced HBV-related liver disease requiring another organ transplant be considered for combined transplantation after careful consideration of the potential risks and benefits. (2C)
4-Pre-Transplant Management of HBV in Individuals Being Considered for Transplantation:
Recommendation;
-All HBsAg positive individuals being considered for liver transplantation should be treated with either tenofovir or entecavir before transplantation, aiming for an undetectable HBV DNA level. (1B)
-Individuals undergoing non-liver solid organ transplantation who are HBsAg positive must have liver disease staging and suppression of HBV DNA by either tenofovir or entecavir before transplantation if there is a standard clinical indication. (1B)
5-Use of HBcAb Positive or HBsAg Positive Donors:
General Recommendations;
Suggestion;
-The appropriate matching of an organ recipient with a donor positive for HBsAg or HBcAb should be discussed with a specialist in viral hepatitis. (2C)
-All potential recipients should be counselled during the assessment process about the possibility of receiving a liver from a donor with past or current HBV infection. (Not graded)
HBcAb positive donation for liver recipients;
Recommendation;
-The HBcAb positive (HBsAg negative) donor liver can be used for any potential liver recipient. (1C)
-When the liver comes from a hepatitis B core antibody positive donor and is given to an HBsAg positive recipient, the standard approach to prevent HBV reactivation should be adopted. (1B)
-When the liver comes from a HBcAb positive donor and is given to a HBV immune or non-immune recipient, prophylactic lamivudine should be given from the time of transplantation, and should be continued indefinitely. (1A)
Suggestion;
-If other waiting list priorities permit, the hepatitis B core antibody positive donor liver should be allocated in the following order:
1. the HBsAg-positive recipient
2. the HBV-immune recipient (including both naturally immune and vaccine-induced immunity) 3. the HBV non-immune recipient. (2C)
HBsAg Positive Donation for Liver Recipients;
Recommendation;
-HBsAg positive donor livers can be given to HBsAg positive recipients, as long as the recipient is known to be HDV negative. (1C)
-If urgency demands, the HBsAg positive liver can be given to an HBsAg negative patient. (1D)
-All recipients of a liver from an HBsAg positive donor must be treated with entecavir or tenofovir from the time of transplantation. (1B)
-Use of HBIg rarely achieves HBsAg negativity, and is not recommended. (1C)
HBcAb Positive and HBsAg Positive Donation for Non-Liver Solid Organ Recipients;
Recommendation;
-The kidneys, heart and lungs from the HBcAb positive organ donor can be used for any recipient, and the risk of de novo HBV infection is low. (1A)
Suggestion;
-If need demands, the non-liver solid organs of the HBsAg positive organ donor can be used for any recipient, after an individualised assessment of risk and benefit. (2C)
-When a HBcAb positive donor is used, lamivudine prophylaxis may be given for six months after transplantation, although the risk of transmission is very low. (2C)
6-Management of Co-Infection (HDV, HCV, HIV) and Transplantation:
Recommendation;
-HBV/HDV recipients should receive combination HBIg/NA prophylaxis from time of transplantation. (1C)
-HBsAg positive donors should not be used for HBV/HDV co-infected recipients. (1C)
-A plan for the perioperative management of each of the HIV and HBV infections should be agreed by the multidisciplinary team before transplantation. (1D)
-HBIg could be used as HBV prophylaxis if/when HIV antivirals are suspended in the peri-operative period. After HIV antiviral treatment is re-established, the approach to HBV prophylaxis is no different from that used for transplantation of HBV monoinfection. (1C)
Suggestion;
-For HBV/HDV infected recipients HBIg withdrawal from combination HBIg/nucleo(t)side analogues(NA) prophylaxis can be considered, but not within 12 months of transplantation. (2C)
7-Preventing Recurrence of HBV Post-Transplantation:
Recommendation;
-In HBsAg positive individuals deemed to be at high risk of recurrence, combination therapy with HBIg and/or a potent NA is recommended from the time of transplantation to prevent HBV reinfection post-liver transplant. (1B)
Suggestion;
-Early withdrawal of HBIG or even the use of HBIG-free prophylaxis can be considered in recipients who are at low risk for post-transplant HBV recurrence. (2C)
-Life-long combination therapy with HBIG and a potent NA can potentially be given to patients who were traditionally considered at high risk for HBV recurrence; namely those who are HBV DNA positive at time of transplant, HBeAg positive patients, those transplanted for hepatocellular carcinoma or those who are HIV co-infected; although most of the data supporting use in these groups come from retrospective studies in the lamivudine era. (2B)
-Recipients with evidence of past HBV infection (HBcAb positive alone) are at risk of HBV reactivation post-non-liver transplant and could be considered for a limited (6-12 months) course of prophylactic antiviral treatment; although monitoring for HBV recurrence is an equally acceptable strategy. (2B)
8-Treatment of HBV Recurrence or De Novo Hepatitis B after Solid Organ Transplantation:
Recommendation;
-All patients with HBV recurrence post-liver transplant should have a careful review of adherence with NA prophylaxis. Resistance testing should be undertaken at a specialist laboratory. (1C)
-Lifelong antiviral therapy is recommended for all individuals with HBV recurrence or de novo hepatitis B post-liver transplantation. (1C)
-Entecavir or Tenofovir are recommended as first line treatment. Tenofovir should be used if the patient has previous lamivudine exposure. (1B)
9-Monitoring for HBV Recurrence or De Novo Infection:
Recommendation;
-HBV DNA and HBsAg should be monitored every three months in the first year and thereafter every six months in HBsAg positive liver transplant recipients or individuals receiving a graft from a HBcAb positive donor, regardless of treatment or prophylaxis regimen. (1C)
-Monitoring intervals should be shortened in cases of self-reported or suspected non-adherence. (Not graded)
10-HBV Vaccination and Solid Organ Transplantation:
Recommendation;
-All prospective solid organ transplant recipients who are HBV naive must be vaccinated (time permitting) and the response documented. (1C)
Suggestion;
-Amongst liver recipients transplanted for HBV, vaccination can be considered as a strategy to develop protective serum titres of HBsAb in some recipients, but cannot currently be recommended as routine practice. (2C)
-Amongst renal transplant recipients who are HBcAb positive, if HBsAb are < 100 IU/mL, then vaccination should be considered to boost the protective titre of HBsAb and minimise the risk of reactivation. (2C)
-All prospective solid organ transplant recipients should receive a high-dose, accelerated vaccine schedule. (2C)
-In those who fail to respond to the initial HBV vaccination schedule, a second series should be administered. (2C)
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