These guidelines recommend that:
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations.
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes.
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay.
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
· Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment).
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
· Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
· Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction.
HEV belongs to the hepeviridae family and its prevalence has increased over the last decade. To date, four genotypes have been known to infect humans. Few patient with HEV will develop chronic hepatitis and ultimately fibrosis of liver.
Diagnosis is made by PCR of HEV RNA or antigen detection. Donor with HEV still can donate and is not a contraindication Prevention: Undercooked meat(particularly processed pork) should not be taken by the recipient Surveillance and Screening for HEV in Solid Organ Transplant Recipient
Recipients with raised liver transaminases or if patient is symptomatic, then HEV RNA or an antigen assay should be done (1C) .Not routinely done. Treatment of Acute Hepatitis E in a SOT-.
Around 30% of the patients spontaneously recover within 03 months ,so treatment is indicated in patients with severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic manifestations. Ribavirin is usually given as the first line treatment along with reduction of immunosuppression. Ribavirin can be stopped if two stool samples for HEV RNA are negative 01 month apart . Persistent HEV infection: Persistence of HEV RNA is detectable in blood or stool for more than three months despite being on treatment. Such patients are retreated with ribavirin but with higher doses and for longer duration(at least six months).
Hepatitis E Biology and Disease:
Recommend that:
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV. Infection in transplant recipients. Prevention of Hepatitis E in Solid Organ Transplant Recipients:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. Surveillance and Screening for HEV in Solid Organ Transplant Recipients:
Recommend that:
· Potential recipients of solid organ transplants do not need routine screening for HEV infection.
Unless indicated Pretransplantation, such as in an immunosuppressed individual with raised liver enzymes.
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. Treatment of Acute Hepatitis E:
In a Patient on the Transplant List We, suggest that:
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Management of HEV Infection in Solid Organ Transplant recipients:
Newly diagnosed or acute HEV infection suggest that:
· The initial management of includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed.
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. Persistent HEV infection:
Its recommend that:
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
· Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment).
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
Monitoring monthly with stool and plasma RNA, stop medication when negative two test one month6month.apart, SVR checked at 3 and 6 months.
Suggestion:
Monitoring viral load after one week of ribavirin.
Dose based on creatinine clearance.
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E:
Recommend that:
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs.
Suggest that:
· The detection of HEV viremia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant.
· Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Statements of Recommendation:
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
Transplant recipients travelling to countries where HEV is endemic should be advised to maintain good hand hygiene, drink boiled or bottled water only, and avoid raw or undercooked meat.
Blood product and transfusion:
donated blood in the UK has been universally screened for HEV using HEV-NAAT testing, as a cost-effectiveness analysis demonstrated that universal testing was more cost effective that selective testing. This is likely to significantly reduce the risk of transfusion acquired HEV.
PEG interferon:
Treatment could be considered in cases of ribavirin refractory HEV. Very close monitoring for rejection.
Guidelines for Hepatitis E & Solid Organ Transplantation Hepatitis E Biology and Disease
We recommend that:
1- Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection . (1B)
We suggest that:
2- All clinicians managing transplant recipients should receive specific training about HEV . (Not graded)
======================== Testing of Solid Organ Donors for Hepatitis E
We recommend that:
1- All solid organ donors are screened for HEV infection. (1C)
We suggest that:
1- The detection of HEV viraemia in a donor is not an absolute contra-indication for transplantation. (2C)
2- Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
====================================== Prevention of Hepatitis E in Solid Organ Transplant Recipients
We recommend that:
1- Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
========================== Surveillance and Screening for HEV in Solid Organ Transplant Recipients
We recommend that:
1- Potential recipients of solid organ transplants do not need routine screening for HEV infection. (D1)
2- Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
We suggest that:
1- Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
==================================== Treatment of Acute Hepatitis E in a Patient on the Transplant List
We suggest that:
1- Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
2- Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
========================================== Management of HEV Infection in Solid Organ Transplant recipients Newly diagnosed or acute HEV infection
We suggest that:
1- The initial management of newly diagnosed or acute HEV infection includes observation and monitoring , more than 30% will spontaneously clear the infection within three months. (2C)
2- A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV. (2C)
3- Early treatment with ribavirin may be considered in specific cases of acute hepatitis E , although evidence are limited. (2D)
Persistent HEV infection
We recommend that:
1- Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
2- Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response. (1C)
3- A baseline quantitative HEV RNA assessment is undertaken at the start of treatment. (1C)
4- Treatment with ribavirin should continue for at least three months, For most individuals 3-6 months . (1C)
5- Monthly HEV RNA testing is undertaken until stop of treatment. (1C)
6- Ribavirin is continued until stool tests are negative for HEV RNA on two. (1C)
7- A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
8- Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic a naemia is a common side effect. (1A)
9- PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
We suggest that:
1- Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment.(2C)
2- To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance. (2C)
3- Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin. (2D)
4- Routine baseline sequencing of HEV for mutations is not indicated. (2D)
5- PEG-interferon treatment may be considered in cases of ribavirin-refractory. (2D)
Summary of Hepatitis E in SOT (2017);
HEV is a hepeviridae family virus with different distribution in different continents with genotypes.
The most important G3 which causes infection.
It can be transmitted via donor organ, blood product too.
However, it’s not a contraindication for donation.
Acute HEV infection in SOT recipient requires no antiviral as majority will spontaneously resolve.
With infection the immunosuppression should be reduced, can increase the clearance of virus.
However, 60% of infection will persist. Diagnosis;
HEV RNA with PCR.
Usually all recipient and donor should doesn’t need to be screened. Prevention;
Recipient should not eat undercooked meat. Surveillance;
No need of routine.
If symptomatic or labs shows any raised transaminases then should tested aggressively and be treated as soon as possible. Management;
Observation,
General management,
Ribavirin is considered the first line of treatment.
Reduction of immunosuppression,
If persistent infection after three months of aggressive treatment in blood and for six month in stool.
Monthly HEV PCR for decision of stopping of ribavirin. Should be continued until two stool samples negative in a month apart.
Give a trail of re-treatment with ribavirin, if not responding consider it as refractory or resistant disease and start with Peg-interferon, with close monitoring of rejection as it can modulate the immune system.
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B).
Hepatitis E Biology and Disease
HEV RNA and/or antigen detection is recommended to be used in the diagnosis of HEV infection in transplant recipients
The managing transplant clinician is advised to have some training in the management of HEV infection as the incidence is on the rise
Solid Organ Donors for Hepatitis E
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues, and Organs (SaBTO)
The detection of HEV viremia is not an absolute contraindication to the donation of organs from a donor
Transplant recipients with HEV infection are managed like other normal population
Prevention of Hepatitis E in Solid Organ Transplant Recipients
The potential recipients of SOT must be counseled on the avoidance of undercooked pork or other meat before and after the procedure
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV infection, but with the exception of immunosuppressed with raised LFT
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay
The sample should be taken from the recipient before transplantation and be preserved for a minimum of one year for possible retrospective test
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Management of HEV Infection in Solid Organ Transplant recipients
The initial line of treatment in acute or newly diagnosed HEV infection is; observation, and monitoring of HEV RNA level, and liver enzymes
The next is the careful rejection of immunosuppressive while watching out for signs of rejection
Early administration of ribavirin is encouraged in patients with jaundice, coagulopathy, or extrahepatic manifestation
Treatment of persistent HEV infection
The presence of HEV RNA in a stool or blood sample for 3- months after the first test is positive is called persistent HEV infection
Ribavirin is used to achieve a sustained virological response
The ribavirin treatment should be for 3 months with a monthly check of plasma or stool HEV RNA viral load
The above treatment could be extended for another 3 months if no initial response
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment
Close monitoring to watch out for hemolytic anemia as ribavirin side effects
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. Although the risk of rejection is high in its use.
Hepatitis E Biology and Disease We recommend that:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Testing of Solid Organ Donors for Hepatitis E We recommend that:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients We recommend that:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients We recommend that:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Treatment of Acute Hepatitis E in a Patient on the Transplant List We suggest that:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Persistent HEV infection We recommend that:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Hepatitis E Biology and Disease Recommended: Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B) Suggested: All clinicians managing transplant recipients should receive specific training about HEV.
Testing of Solid Organ Donors for Hepatitis E Recommended: All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C) Suggested: – HEV viraemia in a donor is not an absolute contraindication for using organs from that donor, but need to inform the recipient for clinical management decisions post-transplant. (2C) – Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C) Prevention of Hepatitis E in SOT Recipients Written advice must be given regarding the risk of HEV from undercooked meat. (1D) Surveillance and Screening for HEV in SOT Recipients – No need of routine screening for HEV infection, except those with raised liver enzymes. (D1) – SOT recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV RNA. (1C) – A plasma sample taken at the time of transplantation should be stored for at least 1 year for retrospective testing for HEV or other infections. (2D) Treatment of Acute Hepatitis E in a Patient on the Transplant List – Individuals with unexplained acute on chronic hepatitis or acute liver failure should be tested for HEV. (2C) – Ribavirin is considered for patients of hepatitis E with cirrhosis, on liver transplant waiting list. (2D) Management of HEV Infection in Solid Organ Transplant recipients The initial management of acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes; >30% spontaneously clear the infection within 3months. Viral monitoring and antibody profile may help clinical decision-making. (2C) – Immunosuppression reduction is considered in patients with acute or persistent HEV. (2C) – Early treatment with ribavirin may be considered in specific cases of acute hepatitis E. (2D) Persistent HEV infection – HEV RNA is detectable in blood or stool for >3months after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C) – Ribavirin should be administered with the aim of sustained virological response. (1C) – A baseline quantitative HEV RNA on plasma and stool tested at the start of treatment. (1C) – Ribavirin therapy 3-6months administered for SOT recipients with persistent HEV infection. (1C) – HEV RNA in plasma and stool tested monthly – Ribavirin is continued until 2 stool tests (1month apart) are negative. (1C) – HEV RNA in stool and plasma tested at 3 months and 6 months, after stopping antiviral therapy – to look for SVR (1C) – Monitoring for anaemia during ribavirin therapy – dose reduction may be required if severe anaemia develops. Erythropoietin and/or blood transfusion may be indicated to allow continued antiviral therapy. (1A) – PEG-interferon should not be used as first line treatment in transplant recipients due to risk of rejection. (1D) – Quantitative assay of plasma HEV on day7 of Ribavirin treatment, determines the likely length of therapy. (2C) – To minimize treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance (CG formula). (2C) – Persistent HEV who relapse after first course of ribavirin à Re-treatment for 6months with ribavirin at higher dose tolerated. (2D) – PEG-interferon is indicated for cases with ribavirin-refractory persistent HEV infection. (2D) – Routine sequencing of HEV for mutations is not indicated (2D)
The incidence and prevalence of hepatitis E virus (HEV) infection has increased in many developed countries over the last decade. It has also been recognised that HEV infection can persist in immunosuppressed individuals, leading if left untreated to chronic hepatitis and significant liver fibrosis. Transplant recipients are therefore at risk of developing persistent HEV infection.
British Transplantation Society gave guidelines for Managment of SOT infected by Hepatis E-
Diagnosis– Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Testing of Donors– All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C).
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ .
Prevention of Hepatitis E in Solid Organ Transplant Recipients-Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipient- Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Treatment of Acute Hepatitis E in a SOT-The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations.
Persistent HEV infection- Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E:
All solid organ donors are screened for HEV but detection of viremia is not contraindication for transplantation. PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Education by written advice regarding the risk of HEV from undercooked meat before and after transplantation. (1D) SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS:
HEV is tested in an immunosuppressed individual with raised liver enzymes. (D1).
HEV using an HEV RNA or an antigen assay (C1). TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST:
HEV tested in patients with unexplained acute on chronic or acute liver failure
patients with cirrhosis who develop hepatitis E treated with ribavirin MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS: Newly Diagnosed or Acute HEV Infection:
1. Observation and Monitoring liver enzyme
2. Monitoring HEV RNA
3. Reduction of immunosuppression increase rate of clearance
4. To consider treatment with ribavirin in severe liver dysfunction or extrahepatic manifestation. Persistent HEV Infection:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with treatment for persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
● HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals
● All solid organ donors are screened for HEV fir Safety of Blood, Tissues and Organs
● Detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor
● A dvice to patients regarding the risk of HEV from undercooked meat before and after transplantation.
● Potential recipients of solid organ transplants do not need routine screening for HEV infection except when raised liver enzymes in immunosuppressed individual
● SOT recipients with raised liver transaminases or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay
● Keeping a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections.
● Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
● Ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
● Management of acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
● RI is considered in patients with acute or persistent HEV increases risk of rejection
● Ribavirin treatment in specific cases :
☆ Severe liver dysfunction
☆ Extra-hepatic manifestations
Persistent HEV infection
● It is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test
● Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained response (HEV RNA not detected in plasma and stool six months after completion of treatment)
● A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
● For most individuals 3-6 months of ribavirin treatment will suffice.
● Plasma and stool HEV RNA monthly until treatment stopping
● Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart
● HEV RNA testing plasma and stool samples at three and six months after stopping antiviral therapy.
● Haemolytic anaemia is a common SEs during ribavirin therapy which may require dose reduction or Epoetin therapy and/or blood transfusion
● PEG-interferon increases risk of rejection
● HEV RNA after seven days of ribavirin treatment predict response after three months of ribavirin treatment.
● Dosage of ribavirin is adapted to GFRe
● Patients who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at a higher dose
● Routine sequencing of HEV for mutation is not indicated prior to antiviral treatment
● PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
Hepatitis E Biology and Disease
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
· All clinicians managing transplant recipients should receive specific training about HEV.
Testing of Solid Organ Donors for Hepatitis E
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
· The detection of HEV viraemia in a donor is not an absolute contraindication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
· Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
· Individuals must receive written advice regarding the risk of HEV from undercooked meat before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. Except those immunosuppressed individuals with raised liver enzymes. (D1)
· SOT recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
· Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
· The initial management of acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
· Reduction in immunosuppression is considered in patients with acute or persistent HEV. (2C)
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E. (2D)
Persistent HEV infection
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
· Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response. (1C)
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
· Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart. (1C)
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
· Regular haemoglobin monitoring is conducted during ribavirin therapy, dose reduction may be required if anemia developed, and Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients due to risk of rejection. (1D)
· It is suggested to do quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
· To minimize treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
· Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
· PEG-interferon is indicated for cases with ribavirin-refractory persistent HEV infection. (2D)
HEV and SOT
HEV RNA and/ or Ag detection is used to diagnose HEV infection in transplant recipients since AB detection is not reliable in immunocompromised patients
DONOR
HEV should be looked for in all donor although it is NOT a contraindication
RECIPIENT
HEV AG and HEV RNA is detected in serum for diagnosis
Antibody is not detectable due to IS
EDUCATION
of recipient that water and undercooked pork can be the source
screening
recipients with elevated liver enzymes or symptoms suggestive of HEV infection should be tested for HEV using HEV RNA or an antigen assay
TREATMENT
1st step of management of SOTs with newly diagnosed or acute HEV infection is to monitor HEV RNA levels and the liver enzymes
since >30% of the cases will spontaneously clear the infection within 3 months
Reduction of IS is next step
Ribavarin is indicated in case of sever liver dysfunction
FOR PERSISTANT HEV INFECTION
HEV RNA in serum for more than 3 months after initial infection
ribavirin is used to achieve sustained virological response (i.e., undetectable HEV RNA in plasma or stool 6months after completion of treatment)
Duration 3-6 month with RNA monitoring as response to therapy
continued shedding of HEV in stool is a predictor of relapse following ribavirin treatment so treatment is continued till two monthly serum samples are negative
HEV RNA test (plasma and stool) is done at 3 and 6 months
Adverse effects due to Ribavarin
hemolytic anaemia is common
dose reduction is required to maintain Hb
Blood transfusion may be required
consider PEG-interferon in cases of ribavirin-refractory persistent HEV infection
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
We suggest that:
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
Hepatitis E Biology and Disease
We recommend that:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
We suggest that:
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
Testing of Solid Organ Donors for Hepatitis E
We recommend that:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
We suggest that:
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C) Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
We recommend that:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
We recommend that:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1) Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
We suggest that:
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
We suggest that:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C) Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
We suggest that:
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C) Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
We recommend that:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C) Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C) A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C) Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C) Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C) Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C) A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C) Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
We suggest that:
Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C) To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C) Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D) Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D) PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
HEV RNA +/- Ag detection used to diagnose HEV in transplant recipients.
Testing of solid organ donors for HEP E.
All recipients should be screened and those with viraemia managed acording to recommendations of other infected people.
Prevention of HEP E in SOT recipients;
People should be educated on risk of Hep E from poorly cooked meat esp processed pork.
Those with elevated liver enzymes and immunosuppression should be screened for HEV using HEV RNA or Ag esp when transaminases are above upper limit or pt symptomatic.
Samples from recipients can be stored for 1 yr for future retrospective testing for infections when indicated.
Treatment of Acute Hep E in a pt on transplant list;
HEV testing should be done in those with unexplained acute on chronic liver injury.
Ribavirin tx should be given in those with cirrhosis and Hep E while on liver transplant list.
Mgt of HEV infection in SOT recipients.
> Newly dx or acute HEV infection;
Initial steps are monitoring HEV RNA levels and LFTS with 30% expected to clear with no intervention in 3/12.
RIS can be considered in those with rising HEV VL to try clear virus but with graft function monitoring.
Ribavirin tx to be used in those with severe liver failure or extra hepatic manifestation.
>Persistent HEV infection.
Diagnosed with HEV RNA in blood/stool for > 3/12 with increased liver enzymes or from 1st +VE HEV RNA tested.
Ribavirin initiated to try get undetectable HEV RNA in blood/stool 6/12 post treatment.
Baseline HEV RNA done at the initiation of tx.
Ribavirin given for 3-6/12 and monthly HEV RNA done until tx stopped. Ribavirin stopped when HEV RNA in stool neg x2 occasions,1/12 apart.
Hb should be monitored while on ribavirin to monitor for hemolytic anemia and dose reduction considered once Hb drops. EPO/Blood transfusion may be used to maintain tx and avoid dose reduction.
PEG interferon is a reserve drug hardly used in persistent infection due to risk of triggering organ rejection.
Quantitative testing of plasma samples done at seven days of treatment with ribavirin to determine duration of treatment.
Ribavirin is renal dosed to minimize SE.
Higher tolerated ribavirin dosages used in those with persistent HEV that relapse after initial tx of ribavirin for minimum 6/12.
PEG interferon can be considered in those with HEV infection refractory to ribavirin.
III. Guidelines for Hepatitis E & Solid Organ Transplantation
Summarise these guidelines
Hepatitis E biology and disease
– HEV RNA and/ or Ag detection is used to diagnose HEV infection in transplant recipients since AB detection is not reliable in immunocompromised patients
Testing of solid organ donors for Hepatitis E
– all solid organs should be screened for HEV
– detection of HEV viremia in a donor is not an absolute contraindication to organ donation
Prevention of Hepatitis E in SOT recipients
– educate patients on risk of pre- and post-transplant HEV infection from undercooked meat (especially processed pork)
Surveillance and screening for Hepatitis E in SOT recipients
– routine pre-transplant HEV screening is not recommended in all potential SOT recipients unless in an immunosuppressed patient with elevated liver enzymes
– SOT recipients with elevated liver enzymes or symptoms suggestive of HEV infection should be tested for HEV using HEV RNA or an antigen assay
– a plasma sample can be taken at the time of transplantation and stored for at least 1 year to allow for retrospective testing for HEV and other infections among transplant recipients
Treatment of acute Hepatitis E in a patient on the transplant list
– test patients with unexplained acute on chronic or acute liver failure for HEV
Management of HEV infection in SOT recipients
Newly diagnosed or acute HEV infection
– 1st step of management of SOTs with newly diagnosed or acute HEV infection is to monitor HEV RNA levels and the liver enzymes since >30% of the cases will spontaneously clear the infection within 3 months
– reduction in immunosuppression may be considered in patients with acute or persistent HEV -this helps with viral clearance but may increase the risk of rejection if not well assessed
– consider early treatment with ribavirin especially in patients with acute hepatitis E who develop severe liver dysfunction (coagulopathy, jaundice) or extra-hepatic manifestations
Persistent HEV infection
– persistent HEV infection is diagnosed when HEV RNA is detectable in plasma or stool for >3months after onset of symptoms, elevated liver transaminases, or from a first positive HEV RNA test
– in patients with persistent HEV infection, ribavirin is used to achieve sustained virological response (i.e., undetectable HEV RNA in plasma or stool 6months after completion of treatment)
– obtain baseline quantitative HEV RNA (plasma and stool) before initiating treatment
– duration of treatment is 3-6months of ribavirin but monthly HEV RNAs are done until a decision is made to stop treatment
– continue ribavirin until stool tests are negative for HEV RNA on two occasions one month apart since continued shedding of HEV in stool is a predictor of relapse following ribavirin treatment
– HEV RNA test (plasma and stool) is done at 3 and 6 months after stopping antiviral therapy to assess for sustained virological clearance
– hemolytic anaemia is a common side effect of ribavirin hence regular HB monitoring ought to be done and where necessary ribavirin dose may be reduced to maintain an adequate Hb level
– if this is not feasible, erythropoietin and/ or blood transfusion should be considered
– PEG-interferon is associated with a moderate risk of precipitating organ rejection hence should not be used as 1st line therapy for treatment of persistent HEV infection
– a repeat HEV RNA test can be done after 7days of ribavirin treatment to help predict the chance of achieving sustained virological clearance after 3months of ribavirin treatment – this helps determine the likely duration of treatment
– the dose of ribavirin should be renal adjusted to minimize treatment-related side effects
– patients who relapse after the 1st course of ribavirin should be retreated for at least 6months with ribavirin but at higher doses as tolerated
– baseline sequencing for HEV mutations is not routinely done before initiating antiviral therapy
– consider PEG-interferon in cases of ribavirin-refractory persistent HEV infection
British Transplantation Society Guidelines Guidelines for Hepatitis E & Solid Organ Transplantation. Hepatitis E Biology and Disease
-For diagnosis of HEV post kidney transplant HEV RNA is indicated but antibody detection is unreliable(1B).
-Clinicians following transplant recipients should be well trained about HEV as its prevalence is increasing and the clinical consequences of infection can be significant. Testing of Solid Organ Donors for Hepatitis E -Al solid organ donors should be screened for HEV .(1C)
-The detection of HEV viremia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
-HEV infection via organ transplantation will be treated according to current guidelines. Prevention of Hepatitis E in Solid Organ Transplant Recipients.
Recipients should be counselled about the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. Surveillance and Screening for HEV in Solid Organ Transplant Recipients.
-Routine screening for HEV infection post-transplant is not indicated unless in special situation such as an immunosuppressed individual with raised liver enzymes with using an HEV RNA or an antigen
assay. (D1)
-Preserving a plasma sample at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D) Treatment of Acute Hepatitis E in a Patient on the Transplant List –Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D) Management of HEV Infection in Solid Organ Transplant recipients
– Observation and monitoring of HEV RNA levels and liver enzymes of newly diagnosed or acute HEV infection in solid organ transplant recipients is considered the proper management plan (2C)
-Reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations. (2D) Persistent HEV infection.
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months. (1C)
-Individuals with persistent HEV infection receive treatment with ribavirin till HEV RNA not detected in plasma and stool six months after completion of treatment. (1C)
-Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection with monthly HEV RNA screening (1C)
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, and sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
-HBG should be reviewed as Ribavirin lead to hemolytic anemia which can be treated by reduction of the dose with epiotin or blood transfusion (1A)
-Better to avoid PEG-interferon as there is a moderate risk of precipitating organ rejection, unless in cases of ribavirin-refractory persistent HEV (1D)
-Following the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. (2C)
-Ribavirin dose should be adjusted according to e GFR. (2C)
-HEV elapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
Summary
This is British Transplantation Society Guidelines for Hepatitis E & Solid Organ Transplantation 2017
Hepatitis E Biology and Disease Recommendation
– HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients (1B)
Testing of Solid Organ Donors for Hepatitis E Recommendation
– All solid organ donors must be screened for HEV (1C)
Suggestion
– HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but need to inform (2C)
– HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients Recommendation
– There is risk of HEV from undercooked meat (particularly processed pork) before and after transplantation so individual need written advice (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients Recommendation
– Testing for HEV is indicated pretransplantation, in an immunosuppressed individual with raised liver enzymes. (D1)
– Recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Suggestion
– Recipients have a plasma sample are stored for a minimum of one year at transplantation that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List Suggestion
– Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients Newly diagnosed or acute HEV infection Suggestion
– Observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
– Reduction in immunosuppression is considered in patients with acute or persistent HEV, but the risk of rejection should be monitored (2C)
– Early treatment with ribavirin may be considered in who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations (2D)
Persistent HEV infection Recommendation
– In this HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
– Persistent HEV infection should receive treatment with ribavirin with the aim of achieving sustained virological response (1C)
– A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
– Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
– Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
– Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart (1C)
– A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
– Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
– PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Suggestion
– Quantitative testing of a plasma HEV RNA sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
– The dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
– Persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
– Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
– PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Hepatitis E Virus Biology And DiseaseRecommendation
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. Suggestion
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
Introduction Hepatitis E virus (HEV) belongs to the genus Hepevirus in the Hepeviridae family and infects humans and a range of animal hosts. Four major HEV genotypes infect humans (G1 to G4) and are remarkable in their associated divergences, leading HEV to be aptly described as having ‘two faces’.
G1 and G2 are restricted to the human host. G1 occurs in Asia and Africa, with G2 reported from Mexico and also Africa. G3 has a worldwide distribution and is associated with infection in humans, pigs and other mammalian species; in contrast, G4 only infects humans and pigs, principally in South East Asia.
G4 also occurs in pigs in India, and occasionally in Europe. EpidemiologyHEV G1 and G2 viruses remain major public health concerns in resource poor settings, where HEV is thought to be responsible for >50% of cases of viral hepatitis. The virus is transmitted via the faecaloral route through the consumption of contaminated food and water. Person-to-person spread is not common. Case control studies using food based questionnaires show an association between the consumption of pork products and HEV infection in England. National surveys have shown that 93% of UK pigs are HEV antibody positive, with 20% having detectable HEV RNA in either plasma or caecal samples at time of slaughter. HEV replication The hepatitis E virion is a spherical particle that is icosahedral in symmetry and has spikes on the capsid surface. The genome is a single-stranded. The life cycle of HEV remains poorly understood, mainly because of the lack of efficient in vitro culture methods. The viral particles concentrate on the surface of hepatocytes, bind to an undefined receptor and are internalised. Following uncoating, the genomic RNA is released and translated in the cytoplasm into the non-structural proteins. Clinical featuresThe clinical features of acute HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure and are influenced greatly by genotype and by the age and gender of the patient. Symptoms, if they occur, include general malaise, abdominal pain, anorexia, nausea and fever and are followed by the onset of jaundice accompanied by dark urine, pale stools and pruritis. Most infections are self-limiting. Persistent infection leading to chronic hepatitis has been reported in immunosuppressed populations including solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals. A number of extrahepatic manifestations linked both to acute and to persistent hepatitis E infection have been reported, including thrombocytopenia, glomerulonephritis, acute pancreatitis, acute thyroiditis, brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, neuromyopathy, and vestibular neuritis. Diagnosis of Hepatitis EAcute hepatitis E cannot be clinically distinguished from other causes of acute hepatitis. Diagnosis of HEV infection can be undertaken using methods for detecting antibody, antigen and RNA. Antigen ELISAs are less sensitive than molecular methods; however, they provide a more rapid and accessible method for identifying current HEV infection. Testing of solid organ donors for Hepatitis ERecommendation
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations.
Suggestion
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant.
Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals.
IntroductionAlthough HEV is normally acquired through the oral (enteral) route, it can be transmitted at the time of solid organ transplantation, either with the transplanted organ or through blood components from an HEV-infected donor. Solid organ donors The detection of viraemia is unlikely to be an absolute contra-indication to use of an organ from a donor, but will inform clinical management decisions post-transplant. Living solid organ donors In the setting of living donation, it is recommended that potential donors be provided with dietary advice regarding avoidance of HEV infection. If HEV viraemia is detected in the potential donor, then living organ donation should be deferred until such time that laboratory testing confirms spontaneous resolution of HEV infection (plasma and stool HEV RNA not detected) in the otherwise healthy potential donor. HEV donor testing Although the potential for donor-transmitted HEV infection will exist, the risk is considered small both in terms of the likely incidence of such an event and the consequences of transmitted infection in the post-transplant setting when this is detected early and managed appropriately.
Management of Transplant Recipients who Receive an Organ from an HEV Viraemic DonorThe most appropriate management of the transplant recipient who receives an organ from a donor that is later identified to have HEV viraemia, and is therefore at risk of becoming persistently infected with HEV, is not known. Prevention of hepatitis E infection in solid organ transplant recipientsRecommendation
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Dietary advice It has been established that HEV G3, the prevalent genotype in developed countries, is a dietary acquired zoonosis with a number of animal species being the reservoir including pigs, wild boar, deer and rabbits. Consumption of raw or inadequately cooked pork or game meat from an animal viraemic at the time of slaughter is believed to be the major source of infection. Studies have demonstrated that infectious HEV can survive for long periods (more than one month) in food products, particularly when stored at 4°C. HEV is also not easily inactivated by cooking and can remain infectious when cooked at temperatures of less than 80° C for less than two minutes. HEV is also not inactivated when heated to 56° C or 60 °C even for long periods (1 hour), which is the approximate temperature of the central portion of meat when cooked rare. Therefore, considerable evidence implicates the consumption of undercooked meat (predominantly porcine) products in the recent rise in the cases of HEV in Europe. Ensuring pork, and other meat that may be from HEV-infected animals, is adequately cooked is one method that could reduce the risk of HEV infection in transplant recipients and the general population. In contrast to the above, the major route of transmission of HEV G1 and G2 is the faecal-oral route. Transplant recipients travelling to countries where HEV is endemic should be advised to maintain good hand hygiene, drink boiled or bottled water only, and avoid raw or undercooked meat. Transfusion of blood productsFrom April 2017, donated blood in the UK has been universally screened for HEV using HEV-NAAT testing, as a cost-effectiveness analysis demonstrated that universal testing was more cost effective that selective testing. This is likely to significantly reduce the risk of transfusion acquired HEV. Immunization against HEVPrevention of HEV infection is potentially possible through immunisation. Recombinant vaccines developed from genotype 1 HEV have shown efficacy in trials in China. Further studies would be required to test the efficacy of this vaccine, its durability of immune response, and ultimately its cost-effectiveness before further use could be recommended. Surveillance and screening for HEV in solid organ transplant recipientsRecommendation
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes.
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay.
Suggestion
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infection.
Screening for HEV in Patients awaiting TransplantationScreening for HEV in patients awaiting transplantation would involve testing for HEV in all potential transplant recipients. The majority of HEV infections in immunocompetent individuals are asymptomatic and achieve prompt seroconversion. There are no apparent health consequences of this asymptomatic infection and this does not lend support to screening all individuals for HEV pre-transplantation. However, there may be specific instances where testing potential transplant recipients for HEV before transplantation may be appropriate, such as in individuals who are immunosuppressed pre-transplant but have raised liver enzymes, or individuals with clinical features to suggest current or recent HEV infection, as this may alter their management.
Post-transplant Screening or Surveillance for HEV in Solid Organ Transplant RecipientsA number of studies have tried to estimate the prevalence of HEV in transplant recipients. The prevalence of detectable HEV RNA among transplant recipients in these studies, indicating current viraemia, ranged from 0-3.2%. The transplant patient may acquire HEV in two ways: through diet, which is a continuing cumulative risk measured by the attack rate in the population; and through the receipt of substances of human origin (SOHO) including organs and blood components, which is a temporally constrained risk, but also defined by the attack rate in the population. Given that HEV can become chronic in transplant recipients and can cause associated morbidity, screening options to consider include:
Test all transplant recipients annually using HEV RNA or HEV Antigen testing
Test transplant recipients for HEV RNA who have raised liver enzymes or symptoms suggestive of HEV (e.g. neurological symptoms).
Treatment of acute hepatitis E in a patient on the transplant list
Recommendation
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Acute HEV in Cirrhotic Patients on the Transplant ListAcute HEV infection in a patient on a transplant waiting list might be identified through abnormalities in ‘routine’ liver enzymes or due to a symptomatic presentation with liver dysfunction. Symptomatic presentation is recognised to be more frequent in older patients, often with underlying chronic liver disease or alcohol excess. n the presence of pre-existing cirrhosis and liver dysfunction acute symptomatic HEV infection can precipitate acute on chronic liver failure (ACLF), which is associated with a mortality of approximately 50% at three months after hospital admission. In this scenario there is a rationale to treating HEV. Case series describe patients with cirrhosis and liver dysfunction that worsened with HEV infection and were subsequently treated with ribavirin. Treatment with ribavirin appeared safe, although dose reduction in ribavirin was required for anaemia in some patients, with treatment duration ranging up to one month. The natural history of HEV infection in immunocompetent individuals is for spontaneous seroconversion and it is unclear whether ribavirin treatment speeds this process. HEV infection occurring in a patient on the liver transplant waiting list is not an absolute contraindication to transplantation.
Treatment of Patients with Acute Liver Failure due to Acute Hepatitis EAcute liver failure is a syndrome characterised by severe liver dysfunction (jaundice, coagulopathy and hepatic encephalopathy) on a background of a previously ‘normal’ liver. HEV is a common cause of acute hepatitis, but rarely causes fulminant liver failure. There are reports of successful transplantation for HEV-associated acute liver failure.
Management of HEV infection in solid organ transplant recipientsSuggestion
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
Dynamic viral monitoring and antibody profiling may help clinical decision-making.
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed.
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited.
Persistent HEV InfectionRecommendation
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
Individuals with treatment for persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment).
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction.
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
Suggestion
Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of ribavirin treatment.
To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation.
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.
Routine baseline sequencing of HEV for mutations is not indicated before antiviral treatment as the significance of such mutations has not been determined.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
Management of Acute HEV Infection Post-transplantationThe current natural history data suggest that acute HEV infection in solid organ transplant recipients does not require specific antiviral treatment at the outset in the majority of cases, as a significant proportion of patients will spontaneously clear the infection. The initial management of acute infection in solid organ transplant recipients should include careful observation and monitoring of HEV RNA levels, serology, and liver enzymes. Where possible, a reduction in immunosuppression should be considered. If HEV RNA clearance from the blood and stool has not been achieved by three months then persistent infection is likely to occur and the patient should be managed as having persistent HEV infection. There may be specific cases where early antiviral therapy with ribavirin is indicated, such as patients who develop severe liver dysfunction (jaundice and coagulopathy), although evidence for this is currently limited. It has recently been recognised that HEV infection (acute and persistent) has been associated with extrahepatic syndromes, particularly neurological manifestations, such as Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis. Renal (glomerulonephritis with and without cryoglobulinaemia), cardiac (myocarditis), and autoimmune extrahepatic manifestations (e.g. thyroiditis and thrombocytopenia) have also been described. Although it has not been proven, a few case reports have suggested that ribavirin treatment may improve the natural history of these extra hepatic manifestations.
Treatment of Persistent Hepatitis E Post-transplantationFollowing acute infection with HEV G3, the infection persists in approximately 60% of solid organ transplant recipients leading to persistent HEV infection. This can cause a chronic hepatitis that can progress rapidly (3-5 years) to cirrhosis. Efforts to treat HEV should begin after three months of infection. As HEV infection is frequently asymptomatic in transplant recipients, clinicians should have a high index of suspicion for the infection and should investigate raised liver enzymes of any degree with reflex HEV testing. Persistent HEV infection can be misdiagnosed as drug-induced liver injury, rejection (in liver transplants) or graft versus host disease, so careful assessment is needed of all liver enzyme abnormalities in transplant recipients.
Individuals with persistent HEV infection (documented or estimated duration of infection of greater that three months) should be treated with the aim of achieving a sustained virological response. Persistent HEV infection occurs mainly in heavily immunosuppressed individuals, particularly those on T cell suppressing drugs. Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV.
Ribavirin is an antiviral medication that has been used for many years in combination with pegylated interferon for the treatment of hepatitis C. More recently, ribavirin has been shown to have antiviral activity against HEV. It remains unknown what the optimum treatment duration and dose of ribavirin should be. The dose has to be adjusted as per the renal function. The most frequent side effect of ribavirin is a haemolytic anaemia. Approximately 40% of transplant recipients with persistent HEV relapse after three months of treatment with ribavirin. There are a few reports of successful treatment of persistent HEV with PEG-interferon. Sofosbuvir is a pangenotypic nucleotide analog licensed for the treatment
Summary
HEV belongs to the hepeviridae family and there are 4 genotypes that infect humans.
Genotype 1 and 2 occurs more commonly in developing countries and are transmitted in the fecal-oral route.
Genotype 3 and 4 mainly in developed countries transmitted via consumption of contaminated meat.
Clinical features of acute HEV infection range from asymptomatic, mild hepatitis to fulminant hepatic failure.
The clinical presentation mainly determined by the genotype, age and gender of the patient.
Most acute infection are self limiting.
Persistent infection mainly occurs in immunosuppressed patients.
Main genotype associated with persistent infection is G3.
HEV infection should be diagnosed via HEV RNA and antigen test, antibodies are not reliable in immunosuppressed patients.
There is risk of solid organ transmission of HEV either through the transplanted organ or blood products, thus all donors should be screened for HEV.
Presence of HEV infection in the donor is not an absolute contraindication for donation.
Living donors should be counselled against raw/undercooked meat and HEV NAAT testing should be done 4 weeks prior to donation.
Deceased donors results for HEV NAAT may not be available at the time of organ donation however this should not influence decision on use of the organ.
Prevention of HEV infection is possible through vaccination, however the only available vaccine is against G1 and only available in China.
Acute HEV infection in SOT recipients requires no antivirals as majority will spontaneously resolve.
Immunosuppressive therapy may be reduced to aid in clearance of the virus.
60% of acute infections will persist.
Ribavirin is a guanosine analogue which inhibits HEV replication.
Optimal duration and dosage is not well defined, however most studies have reported doses between 200-1200mg/day with a median dose of 600mg/day.
A baseline stool and plasma HEV RNA should be done at initiation then on regular intervals of 1 ,2 and 3 months.
Treatment should be stopped when 2 plasma and stool sample 1 month apart are negative for HEV RNA.
Treatment failure could be due to mutations rendering ribavirin resistance, insufficient treatment duration and insufficient dosage due to adverse effects.
Patients with treatment failure majority will respond to prolonged treatment of ribavirin even in mutations.
Pegylated interferon is a second line treatment incase of ribavirin refractory cases.
Further clinical studies are required on the use of sofosbuvir in treatment of HEV infection.
Summarise these guidelines Definitions of Hepatitis E used in this Guideline:
– Hepatitis E :Clinical hepatitis caused by acute HEV infection.
– Acute HEV :Acute infection with HEV that may or may not be symptomatic.
-Persistent HEV :HEV RNA detectable for three months or more.
– Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
-All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations.
-The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant.
-Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals.
– Individuals must receive written advice regarding the risk of HEV from undercooked meat before and after transplantation.
-Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes and test for HEV using an HEV RNA or an antigen assay.
-Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
-The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
-A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed.
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited.
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
– Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response.
– Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
– A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral treatment.
– PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
-Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.
● Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
Testing of Solid Organ Donors for Hepatitis E
● All solid organ donors are screened for HEV in line with the UK Advisory Committee for the (SaBTO) recommendations. (1C)
●The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
●Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
● Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
● Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
●Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (C1)
● Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
●Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
(2C)
●Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E
When on the liver transplant waiting list. (2D)
———————————————————–
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
● The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (C2)
●A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
●Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
●Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
●Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
●A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
●Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
● Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
●Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
● A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNAatthree and six months after stopping antiviral therapy. (1C)
●Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
●PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
●Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
● To minimize treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
● Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
● Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
●PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.(2D)
HEV infection : is frequently encountered in immune compromised patients particularly kidney transplant recipient with significant morbidity and mortality .
Awareness of its parthenogenesis and symptomatically is highly recommended in kidney transplant practice. Generally its recommend to screen all SOT donors for HEV infections.
Owing to immune suppression post transplantation, suspected recipients infected with HEV must be investigated with PCR for RNA and viral antigen.
The Transplant recipient must be alerted to risk of attracting HEV from under-cooked pork meat. HEV infection is a contraindication for kidney donation. When to survay for HEV:
Its not recommended to routinely screen the transplant candidate for HEV .However is indicative to investigate for HEV in patients who is immune suppressed and whose reported to have abnormal liver function test result. Management of HEV infection post transplantations:
Whenever acute fulminant hepatitis or acute on chronic hepatitis is diagnosed, HEV screening has to be implemented . Ribavirin is indicated for liver cirrhosis patient with HEV infection in liver transplantation candidate. Post transplantation HEV infection:
1] First step in management is vigilant observant approach . with close follow up of HEV RNA and liver function . HEV RNA is performed on plasma and stool . 30% spontaneous infection clearance during the first 3 months post infection.persistent EBV infection is was reported.
2] Ribavirin is indicated in severe acute hepatitis featuring severe joundice and coagulopathy.
3] Persistent HEV infection is indicative of continuing positive HEV RNA detected in plasma and or particularly in stool.
4] Ribavirin is implicated for 3-6 months . Recurrence of HEV infection is treated with higher doses of Ribavirin for 6 months.
5] Sustained recovery is featuring negative HEV RNA for 6 months from stopping the medications
6] Ribavirine might be associated with hemolytic anemia suppression.
7] Two negative successive stool tests for HEV RNA is indicative of HEV clearance.
8] Peg-Interferone may be indicated in refractory HEV infection
*Guidelines for Hepatitis E & Solid Organ Transplantation Hepatitis E Biology and Disease:
* Virus specific tests ( HEV RNA and or antigen test ) are recommended to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
* All clinicians should receive training about HEV as its prevalence is increasing and its clinical consequences can be significant as suggested by the guideline .
Testing of Solid Organ Donors for Hepatitis E
All solid organ donors should be screened for HEV viraemia, and individuals who become infected through transplantation should be managed according to SaBTO ( UK Advisory Committee for the Safety of Blood, Tissues and Organs ) recommendations.
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Individuals should receive written advice regarding HEV risk from undercooked meat before and after transplantation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
HEV infection screening is not recommended in potential recipients of solid organ transplants but a plasma sample can taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections.
Treatment of Acute Hepatitis E in a Patient on the Transplant
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list .
Management of HEV Infection in Solid Organ Transplant recipients: Newly diagnosed or acute HEV infection:
The initial management of HEV infection in solid organ transplant recipients includes observation and monitoring of RNA levels and liver enzymes, dynamic viral monitoring and antibody profiling, strategic reduction in immunosuppression, and early treatment with ribavirin.
Persistent HEV infection :
Persistent HEV infection is defined as detectable HEV RNA in the blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test,which should be treated with ribavirin for at least three months with monthly follow up of HEV RNA till the stop of treatment . .
After stopping antiviral therapy follow up of plasma and stool samples for HEV RNA will be at three and six months .
Regular haemoglobin monitoring is conducted during ribavirin therapy, adequate haemoglobin concentration should be maintained to allow continued antiviral therapy without avoidable drug reduction with epoetin therapy and/or blood transfusion .
PEG-interferon carries a moderate risk of organ rejection, which is why it should not be used as the first line for the treatment of persistent HEV in transplant recipients.
HEV RNA level should be assessed after seven days of ribavirin treatment which may help in prediction of achieving sustained virological response after three months of treatment.
NRibavirin dosage is adapted according to creatinine clearance to minimize its side-effects,
No significance mutations of HEV has been determined so baseline sequencing for mutations is not indicated prior to antiviral treatment .
BTS guidelines 2017 Diagnosis/ Prevention and treatment of HEV in organ transplant:
Screening for HEV infection is mandatory to do in all organ transplant and it’s not contraindicated for transplant but need good evaluation and treatment.
HEV RNA and/or antigen detection in plasma and stool must be used to diagnose HEV infection in transplant recipients. Prevention of Hepatitis E in Solid Organ Transplant Recipients:
Counselling regarding risk of infection during transplant and writing consent should be done. Treatment of Acute Hepatitis E :
All patients of organ transplant with unexplained acute or chronic liver failure should be treated with ribavirin for eradication of hepatitis E virus.
Also should be observation and monitoring of HEV RNA levels and liver enzymes during treatment.
However, reduction of immunosuppression is considered in patients with acute or persistent HEV as this help for viral clearance, but carry risk of rejection so should be monitoring drug level in lower limit.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart. Persistent of HEV:
If HEV RNA and liver enzymes persist should be continue ribavirin for at least three months for solid organ transplant.
Monthly HEV RNA testing in plasma and stool to detect clearance of virus and blood count is mandatory to do to avoid side effects of ribavirin as hemolytic anemia is common with ribavirin.
PEG-interferon is second line in case of persistent HEV but carrying high risk of organ transplant rejection. HEV genotype:
G1 and G2 are restricted to the human host.
G1 occurs in Asia and Africa, where G2 occur in Mexico and also Africa. G3 has a worldwide distribution and is associated with infection in humans, pigs and other mammalian species.
G4 only infects humans and pigs, principally in South East Asia; G4 also occurs in pigs in India, and occasionally in Europe. Transmission of HEV infection:
By feco-oral
blood transfusion or organ derived ClinicalFeatures Acute Hepatitis E
Range from asymptomatic to mild hepatitis to fulminate hepatic failure.
In pregnant women in third trimester with hepatitis E carrying risk of stillbirth and apportion and poor outcome reach to death. Persistent HEV Infection:
It’s lead to chronic hepatitis in immunosuppressed patients with solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals and carry risk of liver cirrhosis. Extra-hepatic manifestation:
It’s including thrombocytopenia, glomerulonephritis, acute pancreatitis, acute thyroiditis and Guillain-Barré syndrome. Diagnosis of HEV:
HEV RNA in plasma and stool
HEV incubation period of 2-6 weeks.
The anti-HEV IgM titres increase rapidly and then disappear.
Anti-HEV IgG antibodies are detected shortly after the IgM and continue to rise into the convalescence period, remaining detectable for months to years.
Antigen detection by ELISAs has been used recently for the diagnosis of HEV infection. Treatment of persistent HEV infection:
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of patients with persistent HEV.
Calcinurine inhibitors and mTor inhibitors may potentially exacerbate viral replication but MMF may inhibit viral replication while, steroid not effects on viral replication.
Dose of ribavirin 12 mg/kg for 12 weeks.
BTS guidelines recommendations for hepatitis E and SOT 2017:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
All solid organ donors are screened for HEV.
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor.
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV infection.
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay.
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Treatment of Acute Hepatitis E in SOT Patients
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making.
Reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed.
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations.
Persistent HEV infection
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment).
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect.
Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction.
To minimize treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation.
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
Hepatitis E Biology and Disease
Detection of HEV RNA and/or antigen is required in order to diagnose infection in transplant recipients because antibody testing is inaccurate (1B). It is strongly advised that all transplant physicians receive training on HEV as well as the clinical repercussions of the virus.
Testing of Solid Organ Donors for Hepatitis E
It is advised that all solid organ donors undergo HEV screening (1C).
HEV viremia in a donor does not necessarily rule out donation. (2C)
HEV infection acquired through transplantation is treated similarly to other chronically infected people. (2C)
Hepatitis E Prevention in SOT Recipients
It is urged that all SOTR be informed of the risk of HEV from undercooked meat (1D)
Surveillance and Testing for HEV in SOT Recipients
Regular recipient testing is not advised. Nonetheless, it is recommended for immunocompromised patients with elevated levels of liver enzymes. (D1)
Assessing recipients for HEV (RNA or an antigen) if they exhibit symptoms and have elevated liver enzyme levels (1C)
Upon transplantation, collect and keep the plasma of the recipient for at least one year to allow testing for HEV and other infections. (2D)
Management of Acute Hepatitis E in a Patient on the Transplant Waiting List
Anyone with unexplained acute, chronic, or acute liver failure must be screened for HEV. Listed individuals with cirrhosis who develop hepatitis E must have ribavirin treatment (2D)
Management of HEV Infection in SOT recipient
Initial treatment of acute HEV infection in recipients consists of observation and monitoring of HEV RNA levels and liver enzymes (30% of cases resolve spontaneously). In acute or persistent HEV, decreasing immunosuppression may aid in viral clearance; nevertheless, the risk of rejection must be carefully evaluated. Although the evidence is sparse, ribavirin can be explored early in severe liver dysfunction or extrahepatic symptoms. (2D)
Approach to persistent HEV infection
HEV RNA in blood or stool lasting >3 months following symptoms, elevated liver enzymes, or the first positive HEV RNA test indicates HEV infection. Ribavirin treatment promotes sustained virological response (C) (no detectable HEV RNA in plasma or stool 6 months after therapy completion). (1C)
HEV RNA in plasma and stool should be measured before treatment. (1C) Ribavirin treatment should last three months (mostly 3-6 months) (1C)
HEV RNA (plasma and stool) monitoring monthly to determine therapy duration (1C)
– Ribavirin is used until stool tests reveal HEV RNA-negative twice a month (1C)
– HBE RNA testing at 3 and 6 months post-antiviral therapy can determine sustained virological response (plasma and stool). (1C) Ribavirin dose can be lowered if hemolytic anemia occurs(1A)
PEG-interferon can cause rejection, hence it shouldn’t be utilized first. (1D) – Plasma HEV RNA is recommended after 7 days of Ribavirin therapy to predict sustained virological response after three months (2C) – Ribavirin dose should be adjusted to creatinine clearance to prevent adverse effects. (2C) HEV relapse after ribavirin should be treated for at least 6 months at a higher dose if tolerated. (2D) – Ribavirin-refractory chronic HEV infection, PEG-interferon treatment may be considered with close monitoring for rejection. (2D)
III. Guidelines for Hepatitis E & Solid Organ Transplantation Summarise these guidelines. Biology & Disease Recommendations:
HEV RNA &/or antigen detection used for diagnosis in TX (1B) Suggestions:
Specific training about HEV for clinicians managing transplant recipients (Not graded). Testing in SOT donors: Recommendations:
screening in line with the UK Advisory Committee for SaBTO recommendations. (1C) Suggestions:
HEV viraemia is not an absolute contra-indication to donation. (2C)
HEV transmitted via TX managed according to recommendations pertaining to other persistently infected individuals. (2C) Prevention in SOT recipients Recommendations:
written advice given regarding the risk of HEV from undercooked meat. (1D) Surveillance & Screening in SOT recipients Recommendations:
no need for routine screening for HEV infection. Testing may be indicated prêt-TX in an immunosuppressed individual with raised liver enzymes. (D1)
SOT recipients with liver transaminases > upper limit of normal or symptoms are tested using HEV RNA or an antigen assay. (1C) Suggestions:
Sample taken at the time of TX & stored for a minimum of 1 year to retrospectively test for HEV or other infections. (2D) Treatment of Acute Hepatitis E in a Patient on the Transplant List Suggestions:
In unexplained acute on chronic or acute liver failure, test for HEV. (2C)
Ribavirin in cirrhotic who develop hepatitis E when on the liver TX waiting list. (2D) Management of HEV Infection in SOT recipients Newly diagnosed or acute HEV infection Suggestions:
The initial management: observation & monitoring of HEV RNA levels & liver enzymes as > 30% will clear the infection within 3 months. Viral monitoring & antibody profiling help clinical decision-making. (2C)
Reduction in IS considered in acute or persistent HEV. (2C)
Ribavirin may be considered in specific cases of acute hepatitis E: severe liver dysfunction or extrahepatic manifestations. (2D) Persistent HEV infection Recommendations:
Diagnosed when HEV RNA is detectable for > 3 months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Ribavirin for persistent HEV infection. (1C)
A baseline HEV RNA (both plasma & stool) at the start of treatment. (1C)
Ribavirin continued for at least 3 months for SOT recipients. (1C)
Monthly HEV RNA testing while on treatment. (1C)
Ribavirin until stool tests are negative on 2 occasions 1 month apart. (1C)
A test of sustained virological response at 3 & 6 months after stopping antiviral. (1C)
Regular Hb monitoring during ribavirin therapy (HA is a common side effect). Dose reduction may be required. Epoetin therapy &/or blood transfusion may be indicated to allow continued antiviral therapy. (1A)
PEG-interferon should not be used as first line treatment (risk of precipitating organ rejection). (1D) Suggestions:
Check change in plasma HEV RNA after 7 days of ribavirin treatment to predict the chance of achieving sustained virological response after 3 months of treatment. (2C)
Ribavirin dose adjusted to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
Relapse after a first course of ribavirin is re-treated for at
least 6 months with ribavirin at higher dose range. (2D)
Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral. (2D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. (2D)
Guidelines for Hepatitis E & Solid Organ Transplantation
Summary
HEV infection in self limiting but can be an issue in immune compromised patients.
Mainly spreads by eating undercooked food , especially pork meat.
It can be Acute, persistent or chronic.
Diagnosis of HEV is by HEV PCR or by antigen in blood and stools
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO)
Positive HEV is not an absolute contraindication for donation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV infection
Other indications include-
Immunosuppressed individual with raised liver enzymes
If liver enzymes are raised after transplant
Treatment of HEV infection post transplant
Initial treatment- Observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
Dynamic viral monitoring and antibody profiling may help clinical decision-making
A strategic reduction in immunosuppression
Early treatment with ribavirin-
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice
Monitoring
Monthly HEV RNA testing in plasma and stool whilst on treatment
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients
Guidelines for Hepatitis E & Solid Organ Transplantation
Summary:
· Clinical hepatitis caused by acute HEV infection
· Acute HEV infection may be asymptomatic
· Persistent HEV: HEV RNA detectable for ≥ 3monthsin stool or blood (after onset of symptoms as jaundice or 1st time detection of viral RNA).
· Mode of transmission; undercooked pork, blood transfusion.
· Prevention;
o avoid undercooked pork.
o Recombinant vaccines developed from genotype 1 HEV have shown efficacy and licensed in China, but not elsewhere in the world.
· SOT recipients:
o Not routine, but indicated if elevated liver enzymes
o HEV specific tests as HEV RNA and/or antigen detectionmust be used, as antibody detection is unreliable in such immunosuppressed individuals.
o Management of acute hepatitis E;
§ Reduction of IS especially CNI and mTORi (but take care of rejection).
§ Close monitoring of HEV RNA levels and liver enzymes is essential as > 30% will spontaneously.
§ Treatment is indicated only in cirrhotic patients or those with severe liver dysfunction 9jaundice and coagulopathy).
§ Those cases should be treated with ribavirin.
o Management of Persistent HEV;
§ baseline quantitative HEV RNA PCR on both plasma and stool before start of therapy.
§ Treatment with ribavirin for 3-6 months, to achieve sustained virological response (HEV RNA not detected in plasma and stool 6 months after end of treatment).
§ Treatment is continued until stool PCR is negative for HEV RNA on 2 occasions, 1 month apart, as continued shedding of HEV in stool indicates high risk for relapse.
§ ↓ viral titer 7 days after start ribavirin has good prognostic value.
§ Follow up CBC (as anemia is adverse effect, treated by blood transfusion and ESA therapy).
§ Relapse is treated with longer 6 month course of ribavirin with higher doses as tolerated.
§ PEG-interferon is not preferred as it increases risk of allograft rejection, except in cases of ribavirin-refractory persistent HEV.
· All potential donors should be screened for HEV, HEV viraemia in a donor is not an absolute contra-indication but needs MDT.
The article deals with guidelines for Hepatitis E virus (HEV) infection and solid organ transplantation (SOT) published by the British Transplantation Society in 2017.
HEV Biology ant disease: HEV has 4 major genotypes (G1 to G4), with G1 and G2 being restricted to human host. The major route of transmission is feco-oral route. But it can be transmitted through blood components and solid organ transplant. Diagnosis of HEV infection requires detection of antibody, antigen or RNA, as it is clinically indistinguishable from other causes of acute hepatitis.
HEV RNA and/or antigen test must be used for diagnosing HEV infection in transplant recipients (as antibody testing is unreliable in immunosuppressed patients). Transplant specialists should be trained about HEV infection and its management.
Testing of solid organ donors for HEV: The major route of transmission is feco-oral route. But it can be transmitted through blood components and solid organ transplant including liver and renal transplant. Although the risk is very low, all solid organ donors must be screened for HEV. Potential living donors should be provided with dietary advice with respect to avoiding HEV and should undergo HEV-NAAT within 4 weeks of organ donation, which if positive, should defer transplant till stool and plasma HEV RNA is negative. In urgent situations, transplantation can go ahead even with a positive HEV result of donor. Recipients who develop HEV through transplant must be managed as per standard protocol.
Prevention of HEV in SOT recipients: Written dietary advice must be provided to prospective SOT recipients regarding avoiding undercooked/ raw meat (especially processed pork), maintaining adequate hand hygiene, drink boiled or bottled water while travelling to HEV endemic regions. Donated blood is also screened for HEV-NAAT. Vaccination against HEV needs further testing before recommendation.
Surveillance and screening for HEV in SOT: Routine HEV screening of prospective SOT recipients is not required. Screening with HEV RNA or an antigen assay may be done in pre-transplant immunosuppressed patients/ post-transplant with raised liver enzymes or with clinical symptoms. A plasma sample of SOT recipients at the time of transplant can be stored for minimum 1 year for retrospective testing, if the need arises.
Treatment of acute HEV in a patient on the transplant list: Patients with unexplained acute liver failure, or acute on chronic liver failure should be tested for HEV, and those having cirrhosis on liver transplant waiting list, if develop HEV, must be treated with ribavirin (in whim the mortality risk is significant). Patients with HEV associated acute liver failure can be treated with ribavirin (with dose titration as per GFR, and careful monitoring).
Management of HEV infection in SOT recipients:
Acute HEV: Newly diagnosed or acute HEV infection in SOT recipient would require observation, HEV RNA, serology and liver enzyme monitoring as >30% will spontaneously recover within 3 months. Reduction in immunosuppression (CNI and mTOR inhibitors increase HEV replication while MMF inhibit HEV replication) may be considered, but risk of rejection should be assessed. Early treatment with ribavirin may be given in patients with severe hepatic dysfunction (jaundice and coagulopathy), or extra-hepatic manifestations (neurological – Guillian Barre Syndrome, encephalitis, glomerulonephritis, myocarditis, thyroiditis etc).
Persistent HEV infection: When HEV RNA is persistent in blood or stool for >3 months, then persistent HEV infection is diagnosed. 15% of such patients may develop cirrhosis in 3-5 years. Such patients should be given ribavirin (after testing a baseline HEV RNA pre-treatment)with median dosage of 600 mg/day for at least 3 months (majority 3-6 months. Plasma HEV RNA can be tested on day 7 of treatment which might help in predicting the length of treatment required. Monthly testing of plasma and stool HEV should be done and treatment should be stopped once 2 consecutive negative stool results (1 month apart) are obtained. The target is to achieve SVR (sustained virological response) defined as absence of HEV RNA in plasma and stool at 6 months after treatment completion. Post-treatment HEV RNA in plasma and stool should be done at 3 and 6 months after stopping treatment. Ribavirin is associated with hemolytic anemia, hence dose should be adjusted as per creatinine clearance, and regular hemoglobin monitoring should be done, and erythropoietin or blood transfusion might be required. Pegylated interferon is not used as first-line due to risk of precipitating rejection, but may be used in ribavirin-refractory persistent HEV infection. Those who relapse after ribavirin treatment can be retreated with higher doses for minimum 6 months. Use of sofosbuvir in HEV requires further studies.
I like your well structured detailed summaryin relation to each advice in relation to the type of disease and corresponding treatment. I appreciate your strategy in relation to Hep E infection and transplant.
Guidelines for Hepatitis E & Solid Organ Transplantation
Introduction:
Hepatitis E is a herpesvirus, infects humans and mammals (pigs), with 4 genotypes, with geographic variations, it is responsible of >50% viral hepatitis worldwide, transmitted via feco-oral route, G3 and 4 transmitted from animal reservoir, or by transfusion of blood products, the prevalence increased with age, mortality observed in pregnant women and children’s < 2 years of age, Hepatitis E V infection is either acute (< 3 months), persistent (3-6 months) or chronic (persist for more than 6 months) Hepatitis E Biology and Disease:
HEV RNA and/or antigen detection, must be used to diagnose infection in transplant recipients as antibody is unreliable (1B)
Training for all transplant physician about HEV and the clinical consequences is recommended. (Not graded) Clinical features:
Acute infection(<3 months), usually asymptomatic, but may present with mild hepatitis, rarely presents with a fulminant hepatitis, with high mortality in 3rd trimester of pregnant women of 25% in G1, with fetal comorbidities. – incubation period 2-6 weeks.
Persistent infection (3-6 months), chronic hepatitis (>6months)usually seen in immunocompromised patients, and seen with G3, and rare in G1, once infected, 60% of solid organ transplant recipients fail to clear the virus and are at risk of developing chronic hepatitis.
Extra-hepatic Manifestations, These include thrombocytopenia, glomerulonephritis, acute pancreatitis acute thyroiditis, and neuropathologist have also been described including brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, vestibular neuritis.
Testing of Solid Organ Donors for Hepatitis E:
All solid organ donors recommended to be screened for HEV (1C)
HEV viremia in a donor is not an absolute contra-indication for donation. (2C)
HEV infection through transplantation is managed as other persistently infected individuals. (2C)
Prevention of Hepatitis E in SOT Recipients:
It is recommended for all SOTR to be advised about the risk of HEV from undercooked meat (1D) Surveillance and Screening for HEV in SOT Recipients:
Routine recipients screening is not recommended. However, it is indicated in immunocompromised with high liver enzymes. (D1)
Testing recipients for HEV (RNA or an antigen) if they have symptoms and have high liver enzymes (1C)
Collect and stored plasma of recipient upon transplantation for at least one year to allow testing for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List:
Any individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Listed individuals with cirrhosis who develop hepatitis E to be treated with ribavirin (2D) Management of HEV Infection in SOT recipient:
Acute HEV infection(<3months):
Initial management in recipients includes observation and monitoring of HEV RNA levels and liver enzymes (spontaneously resolve in 30 %). (2C)
In acute/ persistent HEV, reducing immunosuppression may help viral clearance, carefully assess risk of rejection. (2C)
Ribavirin cab be considered early in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence is limited. (2D)
Persistent HEV infection(3-6 months):
It is diagnosed if HEV RNA is detectable in blood or stool for >3 months after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Sustained virological response is the aim when treat with ribavirin (no detectable HEV RNA in plasma and stool 6 months after therapy completion) (1C)
Before starting treatment HEV RNA on both plasma and stool is recommended as a baseline. (1C)
Ribavirin treatment should continue for minimum 3 months (mostly 3-6 months) (1C)
Monthly monitoring of HEV RNA (plasma and stool) to guide therapy duration (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart (1C)
Assess sustained virological response at 3 and 6 months after stopping antiviral therapy by testing HBE RNA (plasma and stool). (1C)
Monitor for hemolytic anemia during ribavirin therapy, if occurred ribavirin dose can be reduced. Epoetin therapy and/or blood transfusion can be considered to avoid dose reduction (1A)
PEG-interferon associated with risk of rejection, so should not be used as first line for the treatment (1D)
Plasma HEV RNA is recommended after 7 days of Ribavirin therapy, as it may predict sustained virological response after three months (2C)
Ribavirin dose should be adjusted to creatinine clearance to reduce side effects. (2C)
HEV relapse after ribavirin course should be re-treated for at least 6 months aiming a higher dose if tolerated. (2D)
Routine testing HEV mutations is not indicated prior to antiviral treatment (2D)
Ribavirin- refractory persistent HEV infection, PEG-interferon treatment may be considered with close monitoring for rejection. (2D)
I appreciate level of recommendation in relation to each advice in relation to the type of disease and corresponding treatment. I appreciate your strategy in relation to Hep E infection and transplant.
HEV infection is usually self-limited, but in immunosuppressed patients it may have a more severe course
The main route of transmission is through ingestion of undercooked meat (mainly pork), so all transplant recipients should be informed to avoid this type of food
HEV infection is either acute (< 3 months), persistent (3-6 months) or chronic (persist for more than 6 months)
Diagnosis of HEV infection in SOT should be settled by detection of PCR and/or Ag in blood or stool and not by serology as it may be altered by immunosuppression
Screening of all donors is recommended, and HEV is not absolute contraindication for donation
Indications of the HEV testing in renal transplant recipient
Before transplantation only if the patient has unexplained elevated liver enzymes and is immunosuppressed
After transplantation if there is elevation of liver enzymes acute or chronic liver failure
It is better to have a blood sample at the time of transplantation to be frozen for at least 1 year
Treatment of HEV after transplantation
Observation since > 30 % will have spontaneous viral clearance within 3 months
Cautious reduction of immunosuppression according to the immunological risk of the patient
Antiviral therapy (ribavirin) for 3-6 months which is indicated in case of persistent (> 3 months) or severe (liver failure or extrahepatic manifestations ) infection, if relapse occur the treatment should be restarted again with higher dose and for 6 months
Monitoring
In patients not on antiviral, monitoring of PCR monthly is recommended
If antiviral therapy is given, blood and stool PCR should be done after the first week of therapy as it will predict the duration of therapy, the treatment then is continued till disappearance of the virus from stool in 2 consecutive samples 1 month apart
Monitoring of ribavirin induced hemolytic anemia is recommended and the dose is adjusted according to hemoglobin level
After clearance of viremia it is recommended to monitor the PCR /3 months for 6 months , if still no viremia, this means sustained virological response
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B).
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded
Testing of Solid Organ Donors for Hepatitis E:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients:
Newly diagnosed or acute HEV infection:
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral
monitoring and antibody profiling may help clinical decision-making. (2C)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achievingsustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the
start of treatment. (1C)
Treatment with ribavirin should continue for atleast three months for solid organ transplant
recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin
treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop
treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month
apart, as continued shedding of HEV in stool is an important factor predicting relapse after
ribavirin treatment. (1C)
A test of sustained virological response is conducted by testing plasma and stool samples for
HEV RNA at three and six months after stopping antiviral therapy. (1C)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. EpoetinNtherapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
HEPATITIS E VIRUS BIOLOGY AND DISEASE:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
Individuals who become infected with HEV through transplantation are managed accordingo recommendations pertaining to other persistently infected individuals. (2C)
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation ,such as in an immunosuppressed individual with raised liver enzymes. (D1
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (C1)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infection. (2D)
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (C2)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV Infection:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with treatment for persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
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.
Guidelines for Hepatitis E & Solid Organ Transplantation Introduction
hepatitis E virus (HEV) infection has increased in many developed countries over the last decade.
It implicated in immunosuppressed individuals and if untreated can change to chronic hepatitis E virus infection . Transplant recipients are therefore at risk of developing persistent HEV infection. Hepatitis E Biology and Disease
HEV infection in transplant recipients must be investigated by HEV RNA as antibody detection is unreliable in immunosuppressed individuals. (1B)
The clinician in transplantation should be knows and training about HEV infection . Testing of Solid Organ Donors for Hepatitis E .
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations (1C).
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant (2C) .
Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C). Prevention of Hepatitis E in Solid Organ Transplant Recipients
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D). Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV
infection. There may be specific instances where testing for HEV is indicated pre
transplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C).
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections.(2D) Treatment of Acute Hepatitis E in a Patient on the Transplant List
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV(2C) .
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D) Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
A strategic reduction in immunosuppression is considered in patients with acute or
persistent HEV as this may facilitate viral clearance, but the risk of rejection should be
carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra hepatic manifestations, although evidence for this recommendation is currently limited. (2D) Persistent HEV infection
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving
sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic
anaemia is a common treatment-related side effect. Ribavirin dose reduction may be
required during treatment to maintain an adequate haemoglobin concentration. Epoetin
therapy and/or blood transfusion may be indicated to allow continued antiviral therapy
without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in
transplant recipients as there is a moderate risk of precipitating organ rejection. (1D) Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.(2D)
Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral
treatment as the significance of mutations has not been determined. (2D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Guidelines for Hepatitis E & Solid Organ Transplantation
1. Hepatitis E Biology and Disease We recommend that:
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B) We suggest that:
· All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded) 2. Testing of Solid Organ Donors for Hepatitis E We recommend that:
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C) We suggest that:
· The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
· Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C) 3. Prevention of Hepatitis E in Solid Organ Transplant Recipients We recommend that:
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D) 4. Surveillance and Screening for HEV in Solid Organ Transplant Recipients We recommend that:
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pre- transplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C) We suggest that:
· Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D) 5. Treatment of Acute Hepatitis E in a Patient on the Transplant List We suggest that:
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D) 6. Management of HEV Infection in Solid Organ Transplant recipients A. Newly diagnosed or acute HEV infection We suggest that:
· The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C) · A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra- hepatic manifestations, although evidence for this recommendation is currently limited. (2D) B. Persistent HEV infection We recommend that:
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
· Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
· Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
· Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D) We suggest that:
· Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
· To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
· Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Hepatitis E Biology and Disease
-HEV RNA and/or antigen detection are recommended for diagnosis of HEV infection in transplant recipients due to inadequate Ab response. Solid organ donors testing for HEV
Is done for all solid organ donors according to UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. Hepatitis E prevention in SOT Recipients
Individuals must be educated about HEV infection risks including consuming undercooked meat pre and post transplant. HEV screening and surveillance in SOT recipients
-It is not routinely indicated in all cases ,only in certain cases as immunosuppressed ones with elevated liver enzymes using HEV RNA or an antigen assay.
-It is suggested that recipients need a plasma sample taken at transplantation time and stored for a minimum of 1 year then tested retrospectively for HEV or other infections. Acute Hepatitis E in a Patient on the Transplant List treatment
-Cases with chronic or acute liver failure need HEV testing
– Ribavirin therapy is recommended for cases having cirrhosis with hepatitis E awaiting on the liver transplant waiting list. HEV Infection in SOT recipients mangement Newly diagnosed or acute HEV infection
-Dynamic HEV RNA monitoring, Ab profiling and liver enzymes follow up can aid decision-making as 30% can spontaneously get cured within 3 months.
-Cautious reduction of immunosuppression can be done with assessing rejection risk.
-HEV viraemia is not an absolute contraindication for organ donation, but subjected to clinical decision.
-There is limited evidence for using ribavirin for those with acute hepatitis E ,severe liver dysfunction and extrahepatic manifestations Persistent HEV infection
-It is diagnosed when HEV RNA is noticed in blood or stool for >3 months after symptoms onset, elevated liver enzymes, or from the first positive HEV RNA test
-Treated with Ribavirin to attain sustained viral response mostly for 3-6 months, till HEV RNA stool tests for HEV RNA are negative on 2 occasions one month apart.
-A baseline quantitative HEV RNA level need to be detected in plasma and stool as treatment starts.
-HEV RNA testing in plasma and stool on monthly bases is needed till stopping treatment decision is taken.
-HEV RNA testing at 3 and 6 months after stopping antiviral therapy is essential to assess sustained virological response.
-Ribavirin can cause haemolytic anemia managed by dose reduction ,Epoetin therapy and/or blood transfusion
-Peg INF is not used to organ rejection risk. It is suggested
– to adjust Ribavirin dose according to creatinine clearance
-cases with relapse after ribavirin therapy need retreatment for 6 months at least ,need re-treatment with ribavirin at higher dose range.
-Ribavirin-refractory persistent HEV infection can be treated with PEG INF along with caution for rejection.
Hepatitis E and SOT Hepatitis E Biology and Disease We recommend
Virus-specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in Tx recipients as antibody detection is unreliable in immunosuppressed individuals. (1B).
We suggest
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical sequences of infection can be significant. (not graded)
Testing of SOD for HBE We recommend
All SOD have screened for HEV in line with UK Advisory Committee for the safety of Blood, Tissue, and Organs (SaBTO) recommendation. (1C)
We suggest
The detection of HE viremia in a donor is not a contraindication to use organs from that donor but will inform clinical management post-Tx. (2C)
Individuals who become infected with HEV through Tx are managed according to the recommendations pertaining to other persistently infected individuals. (2C)
Prevention of HE in SOT recipients we recommend
Individuals should receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after Tx. (1D)
Surveillance and screening for HEV in SOT recipients W recommend
HEV screening is indicated in immunosuppressed patients with raised liver enzymes pre-transplantation. (1D)
SOT recipients with elevated liver enzymes or symptoms suggestive of HEV infection are tested for HEV antigen and HEV RNA. (1C)
We suggest
Transplant recipients have stored plasma samples at the time of transplantation for a minimum of 1 year that can be tested retrospectively for HEV or other infections. (2D)
Treatment of acute HE infection in a patient on the transplant list We suggest
Individuals with unexplained acute on chronic liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Treatment of HEV infection in SOT recipients Newly diagnosed or acute HEV infection We suggest
The initial management of newly diagnosed or acute infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes. (2C)
An immunosuppressant reduction is advised if acute or persistent infection as it facilitates viral clearance, but the risk of rejection should e assessed carefully. (2C)
Early treatment t with ribavirin should be started in cases (of severe liver dysfunction, or extrahepatic manifestation, with limited evidence. (2D)
Persistent HEV infection We recommend
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first +ve HEV RNA test. (1C)
Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving a virological response. (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment duration ranged from 3-6 months with ribavirin for SOT. (1C)
Ribavirin is continued until HEV RNA stool is negative for 2 consecutive tests 1 month apart. (1C)
A test for virological response is conducted by testing plasma and stool samples for HEV RNA at 3 and 6 months after stopping antiviral therapy. (1C)
Hemoglobin monitoring to avoid hemolytic anemia a side effect of ribavirin therapy with epoetin or blood transfusion to avoid ribavirin dose reduction. (1A)
PEG-interferon should not be used as first-line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
We suggest
Assess level of HEV RNA after 7 days after starting ribavirin. (2C)
Adjusted renal dose according to CrCl to minimise the side effects. (2C)
PEG-interferon in ribavirin-refractory persistent HEV infection, with monitoring risk of rejection. (2D)
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.
Guidelines for Hepatitis E & Solid Organ Transplantation
Hepatitis E Biology and Disease
· The prevalence of HEV is increasing and the clinical consequences of infection can be significant.
· It is recommended that HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients
Testing of Solid Organ Donors for Hepatitis E
· All solid organ donors are screened for HEV
· It is suggested the detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor. Prevention of Hepatitis E in Solid Organ Transplant Recipients
· Individuals must receive written advice regarding the risk of HEV from undercooked meat.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
· It is recommended that not all potential recipients of solid organ transplants are screened for HEV infection.
· It is tested for example in an immunosuppressed individual with raised liver enzymes.
They suggested that transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. Treatment of Acute Hepatitis E in a Patient on the Transplant List
· It is suggested that individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. Management of HEV Infection in Solid Organ Transplant recipients Newly diagnosed or acute HEV infection It is suggested that:
· The initial management of acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as spontaneous clearance can occur within three months
· Reduction in immunosuppression is considered in patients with acute or persistent HEV
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E.
Persistent HEV infection It is recommended that
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after acute infection.
· Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response.
· For most individuals 3-6 months of ribavirin treatment will suffice.
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. It is suggested that:
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range.
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
Summarise these guidelines
This is the first British Transplantation Society (BTS) guideline of hepatitis E in the transplant setting [Guidelines for Hepatitis E & Solid Organ Transplantation (SOT), April 2017]
Definitions of Hepatitis E (in this Guideline): Hepatitis E: Clinical hepatitis caused by acute HEV infection Acute HEV: Acute infection with HEV that may or may not be symptomatic Persistent HEV: HEV RNA detectable for three months or more
HEPATITIS E VIRUS BIOLOGY AND DISEASE Introduction
o Genus Hepevirus (Hepeviridae family)
o Infects humans and animals
o Four genotypes:
1. G2: only in human (occurs in Asia and Africa)
2. G2: only in human (Mexico and Africa)
3. G3: humans, pigs and other mammalian species (worldwide distribution)
4. G4: humans and pigs (principally in South East Asia)
Epidemiology Developing World
o Responsible for >50% of cases of viral hepatitis
o Transmitted via the faecal oral route (contaminated food and water)
o Mainly young adults (15 and 39 years) and slightly common in male
o Prevalence rates is 47% and 50% in Nepal and Bangladesh respectively (no differences noted by gender)
Developed World
o HEV G3 and G4 are zoonotic infections (pork products and game meat)
o More in males (> 50 years)
o Seroprevalence: 1%-50%
Hepatitis E Virus in England
o Genotype 3 virus (group 1 and group 2)
o Seroprevalence rates in the general population are high (~13%)
o 93% of UK pigs are HEV antibody positive (20% having detectable HEV RNA)
Transfusion Transmitted HEV
o Seroprevalence rates range from 6%-46% in blood donors
o In the UK, universal screening of all blood components for HEV is now recommended by the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO)
Clinical Features Acute Hepatitis E
o Range from asymptomatic infection to mild hepatitis to fulminant liver failure (influenced greatly by genotype, age, gender of the patient)
o Symptoms include general malaise, abdominal pain, anorexia, nausea and fever and are (followed by jaundice with dark urine, pale stools and pruritis)
o Most infections are self-limiting
o Mortality rate in the developing world is 0.5 – 4% (G1 virus). In pregnancy mortality rate is 25%, particularly in the third trimester. Spontaneous abortion, stillbirth and neonatal death also increased. Infection is associated with G1 and not with G3 infection
o In patients with underlying liver disease may lead to decompensation and a poor outcome
Persistent HEV Infection
o Can leads to chronic hepatitis in immunosuppressed populations including solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals
o All infection is G3 with the exception of one G4 (47) and one G7 (camelid) (48) virus
o No reports of G1 and G2 viruses
o Clinical features are often unremarkable (liver transaminases are usually only very modestly raised and few patients present with any symptoms)
o In SOT, 60% fail to clear the virus and are at risk of developing chronic hepatitis. Liver biopsy shows rapid progression of liver fibrosis with 10% of patients progressing to cirrhosis over a few years
o Factors associated with failure to clear HEV include low leucocyte, total lymphocyte and T-cell counts
o In the HIV patients, they have low CD4 counts. Viral clearance following treatment is associated with the recovery of CD4 levels and can present as an immune reconstitution hepatitis
Extrahepatic Manifestations
o In both acute and persistent hepatitis E infection
o Include thrombocytopenia, glomerulonephritis, acute pancreatitis, acute thyroiditis, and neuropathologies (brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, neuromyopathy, and vestibular neuritis)
Diagnosis of Hepatitis E
For acute hepatitis, use antibody, antigen and RNA methods (cannot be clinically distinguished from other causes of acute hepatitis)
Incubation period is 2-6 weeks (after this, first initial short-lived IgM response followed by more durable IgG antibodies)
Enzyme immunoassays or rapid immunochromatographic kits for the detection of specific IgM antibodies
Antigen ELISAs are less sensitive than molecular methods (but they provide a more rapid and accessible method for identifying current HEV infection)
HEV RNA can be detected a few weeks before the onset of clinical symptoms in both blood and stool samples
The diagnosis of persistent hepatitis E infection is challenging as infections are usually asymptomatic (detection of the virus itself, either through HEV RNA testing or HEV antigen testing, as antibody detection in the immunosuppressed population is not a reliable marker of infection)
Statements of Recommendation
o We recommend that virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
o We suggest that all clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E Introduction
o HEV can be transmitted at the time of SOT, either with the transplanted organ or through blood components from an HEV-infected donor
o Pre-transplant immunosuppression may allow potential recipients to become persistently infected before transplantation, and acute infection may also occur in the potential transplant recipient
Living Solid Organ Donors
o Dietary advice to avoid of HEV infection
o Screening with HEV-NAAT within four weeks of organ donation
o If HEV viraemia is detected, living organ donation should be deferred until laboratory testing confirms spontaneous resolution of HEV infection (plasma and stool HEV RNA not detected)
o In situations of great urgency (paediatric living liver donation), that life saving donation may still be considered from individuals known to be viraemic, although the risk to the donor in this situation is not known
HEV Donor Testing
o In deceased organ donation, HEV-NAAT results should be available between 24 and 28 hours after transplantation to inform ongoing clinical management of the recipient
o The absence of HEV-NAAT test results will not, and should not, influence decisions regarding the use of organs
o The identification of deceased donors with HEV viraemia is important, even after transplantation has occurred, because it allows for appropriate posttransplant recipient monitoring, the possible modification of immunosuppressive therapy, or the use of antiviral therapy for those recipients that do not spontaneously clear the virus
Management of Transplant Recipients who Receive an Organ from an HEV Viraemic Donor
o Not known
o Individuals who become persistently infected with HEV through transplantation, recommended to be managed according to recommendations pertaining to other persistently infected individuals
Statements of Recommendation
o We recommend that all solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
o We suggest that the detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
o We suggest that individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS Dietary Advice
o Infectious HEV can survive for long periods (more than one month) in food products, particularly when stored at 4°C
o Not easily inactivated by cooking and can remain infectious when cooked at temperatures of < 80° C for less than two minutes
o Not inactivated when heated to 56° C or 60 °C even for long periods (1 hour)
Transfusion of Blood Products
o From April 2017, donated blood in the UK are screened for HEV using HEV-NAAT testing
o Overall prevalence is 1 in 2848 (study in England, G3). The transmission rate is 42% in viraemic (HEV RNA), which equates to an approximate rate of transmission of 1 in 5000 transfusions
Immunisation against HEV
o Possible through immunization
o Recombinant G1 vaccines in China (Hecolin®, Xiamen Innovax Biotech)
Statements of Recommendation
o We recommend that individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS Post-transplant Screening or Surveillance for HEV in SOT Recipients
Seroprevalence rates is 8.3%-43% for anti-HEV antibodies (HEV RNA ranged from 0-3.2%)
The transplant patient may acquire HEV in two ways:
1. through diet, which is a continuing cumulative risk
2. through the receipt of substances of human origin (SOHO) including organs and blood components, which is a temporally constrained risk
Options for screening/surveillance could potentially be offered:
1. Test all transplant recipients annually using HEV RNA or HEV Antigen testing (insufficient evidence to support and this would be a costly intervention)
2. Test transplant recipients for HEV RNA who have raised liver enzymes or symptoms suggestive of HEV (e.g. neurological symptoms)
Statements of Recommendation
o We recommend that potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pre-transplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
o We recommend that SOT recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
o We suggest that transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST Acute HEV in Cirrhotic Patients on the Transplant List
o In pre-existing cirrhosis and liver dysfunction acute symptomatic HEV infection can precipitate acute on chronic liver failure (ACLF), which is associated with a mortality of approximately 50% at three months
o Treatment with ribavirin is safe, although dose reduction in ribavirin was required for anaemia in some patients, with treatment duration ranging up to one month
o HEV infection occurring in a patient on the liver transplant waiting list is not an absolute contraindication to transplantation
Treatment of Patients with Acute Liver Failure due to Acute Hepatitis E
o Acute liver failure is characterised by severe liver dysfunction (jaundice, coagulopathy and hepatic encephalopathy) on a background of a previously ‘normal’ liver
o HEV is a common cause of acute hepatitis, but rarely causes fulminant liver failure
o The role of ribavirin in HEV-associated acute liver failure is not known
o Treat with ribavirin in patients with HEV viremia and liver failure (renal dose reduction)
o There are reports of successful transplantation for HEV-associated acute liver failure
Statements of Recommendation
o We suggest that individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
o We suggest that treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS Management of Acute HEV Infection Post-transplantation
o If HEV RNA not cleared from the blood and stool by three months, persistent infection is likely to occur and the patient should be managed as having persistent HEV infection
o HEV infection (acute and persistent) can be associated with extrahepatic syndromes, particularly neurological manifestations (Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis, Renal (glomerulonephritis with and without cryoglobulinaemia), cardiac (myocarditis), and autoimmune extrahepatic manifestations (e.g. thyroiditis and thrombocytopenia)
Treatment of Persistent Hepatitis E Post-transplantation
o Following acute infection with HEV G3, the infection persists in approximately 60% of SOT recipients leading to persistent HEV infection. This can cause a chronic hepatitis that can progress rapidly (3-5 years) to cirrhosis in approximately 15% of infected SOT recipients
o Persistent HEV infection should be treated with the aim of clearing HEV from the blood and stool
Chronic HEV infection:
o Detectable HEV RNA in the blood and/ or stool for greater than six months (treat after 3 months)
o The most common symptom is fatigue (jaundice is rare)
o Neurological symptoms can also occur
o Typically ALT levels are between 200-300 U/L in transplant recipients, but patients with may also present with minimally raised liver enzymes or enzymes within the upper normal range
o Persistent HEV infection can be misdiagnosed as drug-induced liver injury, rejection (in liver transplants) or graft versus host disease
Modification of immunosuppression:
Lead to clearance of HEV infection in 30% of individuals with persistent HEV In vitro effect:
o ciclosporin increased HEV viral replication in a dose-dependent manner and may therefore potentiate infection with HEV
o Tacrolimus increased HEV replication in a cell culture model (at high dosages)
o mTOR inhibitors potentiate HEV replication
o Corticosteroids had no effect
o mycophenolate inhibit HEV replication. This effect was potentiated with the addition of ribavirin
Ribavirin:
o Reduce HEV replication in vitro by reducing intracellular pools of GTPPEG-interferon
o A guanosine analogue and may also act as a nucleoside inhibitor, inhibiting replicating HEV RNA
o Sustained virological response (HEV RNA negative six months post-treatment) varies from 63-82%
o Persisting HEV in the stool, even after clearance from the blood suggests ongoing HEV infection
o Dose ranges from 200-1200 mg per day (a median dosage of 600 mg/day)
o Dose regimen according to the creatinine clearance calculated by the Cockcroft-Gault equation
o Side effects: haemolytic anaemia is the most one and required intervention in 40% (dose reduction, epoetin or blood transfusion). Regular monitoring of haemoglobin on treatment, initially every two weeks until the haemoglobin has reached nadir then monthly thereafter. Dose reduction is recommended when the haemoglobin falls below 100 g/L
o Treatment failure with ribavirin treatment: 40% with persistent HEV relapse after three months of treatment
o Reasons for treatment failure include:
1. dose reduction due to side effects
2. insufficient duration of treatment to clear HEV from both blood and stool
3. G1634R mutation
o The majority of patients who relapse will respond to a longer course of treatment
o Treat until the HEV RNA is negative in blood and stool on two tests at least one month apart (6 months or longer)
PEG-interferon
o A few reports of successful treatment of persistent HEV (75% sustained virological response)
o Well known to increase the risk of rejection in transplant recipients
o Considered in ribavirin refractory HEV, particularly if associated with ribavirin resistance mutations (close monitoring for rejection)
Sofosbuvir
o A pangenotypic nucleotide analog (licensed for the treatment of HCV)
o In a recent study, suggested that inhibit HEV RNA replication in an experimental model of HEV
Statements of Recommendation Newly diagnosed or acute HEV infection
o We suggest that the initial management of newly diagnosed or acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
o We suggest that a strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
o We suggest that early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
o We recommend that persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
o We recommend that individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
o We recommend that a baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
o We recommend that treatment with ribavirin should continue for at least three months for SOT recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
o We recommend that monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
o We recommend that ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
o We recommend that a test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
o We recommend that regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
o We recommend that PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
o We suggest that assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
o We suggest that to minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
o We suggest that patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
o We suggest that routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
o We suggest that PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
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 E Biology and Disease
– HEV RNA and/or antigen detection, must be used to diagnose infection in transplant recipients as antibody is unreliable (1B)
– Training for all transplant physician about HEV and the clinical consequences is recommended. (Not graded)
Testing of Solid Organ Donors for Hepatitis E
– All solid organ donors recommended to be screened for HEV (1C)
– HEV viremia in a donor is not an absolute contra-indication for donation. (2C)
– HEV infection through transplantation is managed as other persistently infected individuals. (2C)
Prevention of Hepatitis E in SOT Recipients
-It is recommended for all SOTR to be advised about the risk of HEV from undercooked meat (1D)
Surveillance and Screening for HEV in SOT Recipients
-Routine recipients screening is not recommended. However, it is indicated in immunocompromised with high lever enzymes. (D1)
– Testing recipients for HEV (RNA or an antigen) if they have symptoms and have high liver enzymes (1C)
– Collect and stored plasma of recipient upon transplantation for at least one year to allow testing for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
-Any individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
– Listed individuals with cirrhosis who develop hepatitis E to be treated with ribavirin (2D)
Management of HEV Infection in SOT recipient: Acute HEV infection
-Initial management in recipients includes observation and monitoring of HEV RNA levels and liver enzymes ( spontaneously resolve in 30 %). (2C)
– In acute/ persistent HEV, reducing immunosuppression may help viral clearance, carefully assess risk of rejection. (2C)
-Ribavirin cab be considered early in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence is limited. (2D)
Persistent HEV infection
– It is diagnosed if HEV RNA is detectable in blood or stool for >3 months after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
– Sustained virological response is the aim when treat with ribavirin (no detectable HEV RNA in plasma and stool 6 months after therapy completion) (1C)
– Before starting treatment HEV RNA on both plasma and stool is recommended as a baseline. (1C)
– Ribavirin treatment should continue for minimum 3 months (mostly 3-6 months) (1C)
– Monthly monitoring of HEV RNA (plasma and stool) to guide therapy duration (1C)
– Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart (1C)
– Assess sustained virological response at 3 and 6 months after stopping antiviral therapy by testing HBE RNA (plasma and stool). (1C)
– Monitor for hemolytic anemia during ribavirin therapy, if occurred ribavirin dose can be reduced. Epoetin therapy and/or blood transfusion can be considered to avoid dose reduction (1A)
– PEG-interferon associated with risk of rejection, so should not be used as first line for the treatment (1D)
– Plasma HEV RNA is recommended after 7 days of Ribavirin therapy, as it may predict sustained virological response after three months (2C)
– Ribavirin dose should be adjusted to creatinine clearance to reduce side effects. (2C)
– HEV relapse after ribavirin course should be re-treated for at least 6 months aiming a higher dose if tolerated. (2D)
-Routine testing HEV mutations is not indicated prior to antiviral treatment (2D)
– Ribavirin-refractory persistent HEV infection, PEG-interferon treatment may be considered with close monitoring for rejection. (2D)
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.
DEFINTIONS OF HEPATITIS E USED IN THIS GUIDELINES ;
————————————————————————————-
1-Hepatitis E ;
Clinical hepatitis caused by acute HEV infection.
2-Acute HEV;
Acute infection with HEV that may or may not be symptomatic
3-Persistent HEV;
HEV RNA detectable for three months or more.
VIRUS SPECIIC TESTS ;
—————————————————————————
The guidelines recommend using HEV RNA and/or antigen detection to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B).
The guidelines suggest that ;All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded).
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E;
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The guidelines recommend screening of all solid organ donors for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C).
Also it suggest that;
1-The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
2- Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C).
PREVENTION OF HEPATITIS E IN SOLID ORGAN TRANSPLANT RECIPIENTS ;
————————————————————————————————————-
The guidelines recommend that: Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D).
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENT ;
————————————————————————————————
The guidelines recommend that:In the potential recipients ;
1-no need to perform screening for HEV infection if there is no raised liver enzyme (D1).
2- Testing for HEV using an HEV RNA or an antigen assay when liver transaminases are above the upper limit of normal or symptoms suggestive of HEV infection (1C) .
The guidelines suggest that:
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D).
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST ;
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The guidelines suggest that:
1-In the presence of unexplained acute on chronic or acute liver failure individuals should be screened for HEV. (2C)
2-Treatment with ribavirin should be offered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D).
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS ;
————————————————————————————————————
1-Newly diagnosed or acute HEV infection;
————————————————————–
The guidelines suggest that:
A-The initial management includes observation and monitoring of HEV RNA levels and liver enzymes.(2C).
B- Reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
C-Ribavirin may be considered in specific cases of acute hepatitis E or extra- hepatic manifestations. (2D).
PERSISTENT HEV INFECTION ;
———————————————–
The guidelines recommend that:
1-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
2-Individuals with persistent HEV infection should receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
3-A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
4-The duration of treatment with ribavirin should be at least three months for solid organ transplant recipients with persistent HEV infection(1C)
5- Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
6-Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
7- PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
The guidelines suggest that:
1-quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
2-To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance. (2C)
3-Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.
(2D)
4-Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
5-PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
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.
Guidelines regarding Hepatitis E and Solid Organ Transplantation
The following recommendations have been made by the British Transplantation Society regarding hepatitis E in the setting of solid organ transplantation because of the disease burden that leads to significant liver fibrosis.
It is recommended that virus specific tests such as HEV RNA and antigen detection are to be used to diagnosis HEV infection in transplant recipients. This is because antibody detection alone is unreliable in individuals who are immunosuppressed.
Clinicians in the transplant team need specific training on managing HEV since its prevalence is on the rise and the clinical consequences significant.
All donors are to be tested for HEV. Although it is not an absolute contraindication, it will help make informed decisions for the transplant team.
In terms of prevention, individuals need to receive written advice regarding the risk of HEV from under cooked meat, especially pork.
Potential recipients do not need routine screening for HEV, except in cases where the patient has raised liver enzymes.
Patients with unexplained acute or acute on chronic liver failure should be tested for HEV.
Ribavirin is to considered for patients with cirrhosis who develop hepatitis E when put on the waiting list.
Initial management of acute HEV infection in SOTRs includes observation and monitoring of HEV RNA levels and liver enzymes. This kind of viral monitoring and antibody profiling can help clinical decision making.
Persistent HEV infection is diagnosed when HEV RNA is detected in blood or stool for more than 3 months after the initial onset of relevant symptoms, raised liver enzymes, or from the first HEV RNA test that was positive.
3-6 months ribavirin treatment is recommend in cases of persistent HEV infection.
Regular Hb monitoring is to be done during ribavirin therapy because hemolytic anemia is a side effect.
Blood transfusion may be needed during ribavirin therapy.
Ribavirin refractory cases may be treated with PEG interferon.
Introduction: Hepatitis E is a hepevirus, infects humans an mammals (pigs), with 4 genotyps, with geographic variations, it is responsible of >50% viral hepatitis worldwide, transmitted via feco-oral route, G3 and 4 transmitted from animal reservoir, or by transfusion of blood products, the prevalence increased with age, mortality observed in pregnant women and childrens < 2 years of age.
Clinical features: Acute infection – usually asymptomatic, but may present with mild hepatitis, rarely presents with a fulminant hepatitis, with high mortality in 3rd trimester of pregnant women of 25% in G1, with fetal comorbidities.- incubation period 2-6 weeks. Persistent infection – chronic hepatitis usually seen in immunocompromised patients, and seen with G3,and rare in G1, Once infected, 60% of solid organ transplant recipients fail to clear the virus and are at risk of developing chronic hepatitis. Extrahepatic Manifestations – These include thrombocytopenia, glomerulonephritis, acute pancreatitis acute thyroiditis, and neuropathologies have also been described including brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, vestibular neuritis.
Diagnosis: Antibodies titer (ELISA) of IgM and IgG – identify acute infections. HEV RNA, and antigen testing – identify persistent disease and in immunocompromised patients
Definitions of Hepatitis E: Hepatitis E= Clinical hepatitis caused by acute HEV infection. Acute HEV= Acute infection with HEV that may or may not be symptomatic. Persistent HEV= HEV RNA detectable for three months or more. Hepatitis E Biology and Disease: HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Testing of Solid Organ Donors for Hepatitis E: All solid organ donors screened for HEV. (1C) HEV viraemia in a donor is not an absolute contraindication to organ donation, but will inform clinical management decisions post-transplant. (2C) Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C) Prevention of Hepatitis E in Solid Organ Transplant Recipients: Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D) Vaccination is an option for disease prevention in china, not approved elsewhere. Surveillance and Screening for HEV in Solid Organ Transplant Recipients: Recipients of solid organ transplants do not need routine screening for HEV infection, may be indicated pretransplantation, in an immunosuppressed individual with raised liver enzymes.(1D) Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C) Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D) Treatment of Acute Hepatitis E in a Patient on the Transplant List: Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C) Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients: Newly diagnosed or acute HEV infection- The initial management of newly diagnosed or acute HEV infection is observation and monitoring of HEV RNA levels and liver enzymes, > 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C) A reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C) Early treatment with ribavirin may be considered in: (1) patients who develop severe liver dysfunction (jaundice and coagulopathy). (2) extrahepatic manifestations.(2D)
Persistent HEV infection- Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C) Individuals with persistent HEV infection, receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C) A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C) Treatment with ribavirin should continue for at least 3 months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment.(1C) Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C) Usually treatment with ribavirin is stopped at 3 month when two HEV RNA negative for two occasion one month apart.(1C) Sustained virological response, by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C) Haemolytic anaemia is a common treatment-related side effect, hence frequent (Hgb) monitoring is a must. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A) PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D) Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment.(2C) The dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation- reduce side effects (2C) Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D) or in combination with sofosbuvir. Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment. (2D) PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D) Mycophenolate inhibits viral replication, but m-TOR and CNI potentiate viral replication.
Guidelines for Hepatitis E & Solid Organ Transplantation
Hepatitis E Biology and Disease
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
Testing of Solid Organ Donors for Hepatitis E
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV infection.
There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections.
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect.
Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration.
Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment.
We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required.
To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.
Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
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.
III. Guidelines for Hepatitis E & Solid Organ Transplantation
Introduction
HEV is a virus that infects humans and a range of animal hosts, with four major genotypes: G1, G2, G3, and G4.
The epidemiological picture, transmission routes and reservoirs, as well as clinical features and outcome differ depending on the region.
Epidemiology
HEV G1 and G2 viruses are major public health concerns in resource poor settings, where they are transmitted via the faecal-oral route through the consumption of contaminated food and water.
There is a striking age-related clinical picture with disease mainly reported from young adults between the age of 15 and 39 years with a slight male preponderance.
In the developed world, HEV G3 and G4 are zoonotic infections, being transmitted to humans from an animal reservoir.
Surveillance of hepatitis E shows a remarkably consistent demographic picture with the majority of clinical cases reported in males over the age of 50 years.
Enhanced surveillance data from England collected over ten years indicates that the infection is dynamic in the population, suggesting fluctuations in risk over time.
Parallel molecular characterisation indicates genotype 3 virus to be linked to indigenous infection in England with two phylogenetically distinct clades,.
Seroprevalence rates in the general population are high at ~13% with data from modelling work and extrapolation of HEV-infected donors indicating that up to 200 000 HEV infections occur per year and that these account for around 600-800 cases of hepatitis in England.
National surveys have shown that 93% of UK pigs are HEV antibody positive, with 20% having detectable HEV RNA in either plasma or caecal samples at time of slaughter.
Persistent HEV infections are increasingly recognised, reflecting increased awareness and testing.
The management of these patients is varied and where patients are being treated, Ribavirin is the drug of choice.
EXECUTIVE SUMMARY OF RECOMMENDATIONS Hepatitis E Biology and Disease
We recommend that:
Virus specific tests must be used to diagnose HEV infection in transplant recipients.
We suggest that:
Clinicians should receive training about HEV as its prevalence is increasing and its clinical consequences can be significant.
Testing of Solid Organ Donors for Hepatitis E We recommend that:
Testing of solid organ donors for Hepatitis E can inform clinical management decisions post-transplant, and individuals who become infected through transplantation should be managed according to SaBTO recommendations.
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Prevention of Hepatitis E in transplant recipients requires written advice before and after transplantation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Transplant recipients should not need routine screening for HEV infection, but should have a plasma sample taken at the time of transplantation and stored for one year to be tested retrospectively for HEV or other infections.
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Treatment with ribavirin is recommended for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Management of HEV Infection in Solid Organ Transplant recipients Newly diagnosed or acute HEV infection
The initial management of HEV infection in solid organ transplant recipients should include observation and monitoring of RNA levels and liver enzymes, strategic reduction in immunosuppression, and early treatment with ribavirin.
Persistent HEV infection
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection.
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
Regular haemoglobin monitoring is conducted during ribavirin therapy.
Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction.
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
We suggest that:
Quantitative testing of plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of treatment.
To minimise treatment-related side-effects, dosage is adapted according to creatinine clearance.
PEG-interferon treatment may be considered, but requires close monitoring for rejection.
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E Statements of Recommendation
The detection of HEV viraemia in a donor should inform clinical management decisions post-transplant, and individuals who become infected through transplantation should be managed according to SaBTO recommendations.
The detection of HEV viraemia in a donor should inform clinical management decisions post-transplant.
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
Individuals must receive written advice regarding HEV risk from undercooked meat before and after transplantation.
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS Statements of Recommendation
Potential recipients of solid organ transplants should not need routine screening for HEV infection, but should be tested for HEV using an HEV RNA or antigen assay.
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST Statements of Recommendation
Treatment with ribavirin is recommended for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
The initial management of HEV infection in solid organ transplant recipientsincludes observation and monitoring of HEV RNA levels and liver enzymes, dynamic viral monitoring and antibody profiling, strategic reduction in immunosuppression, and early treatment with ribavirin.
Persistent HEV infection should be diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
Treatment should continue for at least three months for persistent HEV infection, with 3-6 months of ribavirin for most individuals.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, and a test of sustained virological response is conducted at three and six months after stopping antiviral therapy.
Regular haemoglobin monitoring is conducted during treatment to maintain an adequate haemoglobin concentration, and Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection, but requires very close monitoring for rejection.
The Hepatitis E virus belongs to the family of Hepaviridea and is known to infect both humans and animals. It has four genotypes (G1-G4) with G1 and G2 being the major public health concerns, particularly in the developing world, while G3 and G4 are in the developed world.
Executive Summary of Recommendations
Hepatitis E Biology and Disease
HEV RNA and/or antigen detection is recommended to be used in the diagnosis of HEV infection in transplant recipients
The managing transplant clinician is advised to have some training in the management of HEV infection as the incidence is on the rise
Solid Organ Donors for Hepatitis E
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues, and Organs (SaBTO)
The detection of HEV viremia is not an absolute contraindication to the donation of organs from a donor
Transplant recipients with HEV infection are managed like other normal population
Prevention of Hepatitis E in Solid Organ Transplant Recipients
The potential recipients of SOT must be counseled on the avoidance of undercooked pork or other meat before and after the procedure
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV infection, but with the exception of immunosuppressed with raised LFT
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay
The sample should be taken from the recipient before transplantation and be preserved for a minimum of one year for possible retrospective test
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Management of HEV Infection in Solid Organ Transplant recipients
The initial line of treatment in acute or newly diagnosed HEV infection is; observation, and monitoring of HEV RNA level, and liver enzymes
The next is the careful rejection of immunosuppressive while watching out for signs of rejection
Early administration of ribavirin is encouraged in patients with jaundice, coagulopathy, or extrahepatic manifestation
Treatment of persistent HEV infection
The presence of HEV RNA in a stool or blood sample for 3- months after the first test is positive is called persistent HEV infection
Ribavirin is used to achieve a sustained virological response
The ribavirin treatment should be for 3 months with a monthly check of plasma or stool HEV RNA viral load
The above treatment could be extended for another 3 months if no initial response
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment
Close monitoring to watch out for hemolytic anemia as ribavirin side effects
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. Although the risk of rejection is high in its use.
Hepatitis E: clinical hepatitis caused by acute HEV infection.
Acute HEV: acute infection with HEV that may or may not symptomatic.
Persistent HEV infection: detection of HEV RNA for 3 months or more after onset of symptoms, increased liver enzymes or first positive HEV RNA test.
Diagnosis of HEV infection done by RNA &/or Ag detection in transplant recipients( Ab not reelable in immunosuppressed patients)
All clinicians deal with HEV infection management should be trained specifically for acute or persistent HEV infection due to increase prevalence of infection & significant sequels.
All SOT donors screened for HEV according SaBTO recommendation.
Detection of HEV viremia in donors is not an absolute contraindication for donation.
SOT recipients should receive written advice about the risk of HEV infection from undercooked meat before & post transplantation.
Screening for HEV in SOT recipients:
Routine screening for HEV not needed but it may be indicated in immunosuppressed patients with increased liver enzymes
Patients with increased liver enzymes or symptoms suggest HEV infection should be tested for RNA or Ags.
Plasma samples of recipients taken at transplant time & stored for 1 year to be tested retrospectively for HEV or any other infection.
Treatment of acute hepatitis E in patients on transplant list:
Any patients with unexplained acute on chronic or acute hepatic failure should be tested for HEV.
Patients with cirrhosis & hepatitis E on waiting list treated with ribavirin.
Management of HEV infection in SOT recipients:
Newly diagnosed acute HEV infection need monitoring of RNA & liver enzymes (>30% of cases resolved spontaneously).
Careful reduction of immunosuppression can assist in viral clearance but risk of rejection should be assessed.
Ribavirin used in:
severe liver dysfunction.
extra hepatic manifestation.
Ribavirine used in treatment of persistent HEV infection to achieve sustained virology response (undetected RNA 6 months after treatment completion).
Stool & plasma RNA measured at starting of treatment (baseline).
Treatment of persistent HEV infection should be 3-6 months with monthly RNA testing in stool till treatment discontinuation( 2 stool sample 1 month apart negative to decide stop treatment).
Sustained viral response done by testing stool & plasma RNA at 3 & 6 moths after treatment discontinuation.
During ribavirin use, regular Hb monitoring is advised.
Peg-INF should not be used as first line treatment of persistent HEV infection treatment with increased risk of rejection.
Measurement of HEV RNA after 7 days of ribavirin treatment may predict length of treatment required.
Dose of ribavirin modified according estimated CC equation.
Relapse of persistent HEV infection should be treated with higher dose of ribavirin if tolerated.
In cases of ribavirin resistant, PEG INF can be used in treatment of persistent HEV infection with very close monitor for rejection.
HEV RNA and/or antigen test is recommended for the diagnosis of HEV infection(1B)
Training for management of HEV infection is essential(not graded)
Testing of solid organ donor for HEV
All donors must be screened according to UK advisory committee for the safety of blood, tissue, and organ recommendation(1C)
Donor HEV viremia should not preclude transplantation but the transplant team must be aware about this for making appropriate clinical decision(2C)
Prevention of hepatitis E in solid organ transplantation (SOT)
Patients must be informed in written to avoid under cooked meat e.g., processed pork due risk of HEV infection(1D)
Surveillance and screening for HEN in SOT
HEV screening is not a routine transplant assessments (1D)
HEV RNA / Antigen test is indicated for those with abnormal liver function test (1C)
Transplant plasma sample may be kept for at least one year for the purpose of future testing for any infection(2D)
Treatment of acute HEV in a patient on the transplant list
Ribavirin can be use to treat HEV infection on top of liver cirrhosis for a patient on the liver transplant list(2D)
Management of HEV in SOT
A.Newly diagnosed infection
Follow up & monitoring (HEV RNA, LFTs) because > 30% will clear the virus spontaneously with 3 months(2C)
Reduction of immune suppression is an option but this should be weighted against the risk of rejection(2C)
Ribivirin may be considered in those with Jaundice, coagulopathy or extra-hepatic features(2D)
B.Persistent infection
The presence of HEV in the plasma or stool for > 3 months after infection(1C)
Treat with ribavirin for 2 to 6 months to attain sustained virological response which is defined as an absence of the virus from the plasma or stool at 3 and 6 months after the treatment(1C)
Monitor HEV RNA plasma or stool on monthly bases to guide the treatment plan(1C)
Stop ribavirin after two consecutive negative stop samples for HEV RNA one month apart(1C) . The reappearance of HEV RNA is an indicator of viral relapse
Hemoglobin should be monitored regularly because ribavirin may induced hemolytic anemia. You may reduce the dose or consider the use of erythropeotin and or blood transfusion to keep going with ribavirin treatment(1A)
Check plasma HEV RNA after 7 days to decide on the duration of treatment(2C)
Ribavirin dose is adjusted according to eGFR to reduce the side effects(2C)
Case of replase are retreated again with higher doses of ribavirin for at least 6 months specially if tolerated well(2D)
Ribavirin-refractory persistent HEV infection: you may consider the use of PEG-interferon therapy but the risk of rejection will go up and therefore, the patient will need close monitoring.
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.
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
Definitions of Hepatitis E used in this Guideline Hepatitis E Clinical hepatitis caused by acute HEV infection Acute HEV Acute infection with HEV that may or may not be symptomatic Persistent HEV HEV RNA detectable for three months or more
Acute Hepatitis E
The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure and are influenced greatly by genotype and by the age and gender of the patient.
Symptoms (general malaise, abdominal pain, anorexia, nausea and fever and are followed by the onset of jaundice accompanied by dark urine, pale stools and pruritis.) Most infections are self-limiting. Data reported mainly from the G1 virus in the developing world suggest a mortality rate of between 0.5 – 4%
. This increases markedly to approximately 25% among pregnant women, particularly in the third trimester . Spontaneous abortion, stillbirth and neonatal death are also increased. This poor outcome of infection during pregnancy appears only to be associated with G1 infection and is seen not with G3 infection.
Persistent HEV Infection Persistent infection leading to chronic hepatitis has been reported in immunosuppressed populations including solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals With the exception of one G4 and one G7
. Liver transaminases are usually only very modestly raised and few patients present with any symptoms
Once infected, 60% of solid organ transplant recipients fail to clear the virus and are at risk of developing chronic hepatitis
Liver biopsy shows rapid progression of liver fibrosis with 10% of patients progressing to cirrhosis over a few years
Factors such as low leucocyte, total lymphocyte and T-cell counts are associated with failure to clear HEV
In the HIV setting, patients who develop chronic infection have low CD4 counts
Viral clearance following treatment in HIV-infected individuals is associated with the recovery of CD4 levels and can present as an immune reconstitution hepatitis
Extrahepatic Manifestations linked both to acute and to persistent hepatitis E infection have been reported. These include thrombocytopenia, glomerulonephritis, acute pancreatitis and acute thyroiditis -brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, neuromyopathy, and vestibular neuritis
With regards to solid organ donation
the Committee recommends that all organ donors be individually screened for hepatitis E viraemia. The detection of viraemia is unlikely to be an absolute contra-indication to use of an organ from a donor
In the setting of living donation, it is recommended that potential donors be provided with dietary advice regarding avoidance of HEV infection and that screening with HEV-NAAT be undertaken within four weeks of organ donation
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D
Modification of immunosuppression
Persistent HEV infection occurs mainly in heavily immunosuppressed individuals, particularly those on T cell suppressing drugs.
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV
Different classes of immunosuppressant drugs have different effects on HEV replication
ciclosporin increased HEV viral replication in a dose-dependent manner and may therefore potentiate infection with HEV
Tacrolimus also increased HEV replication in a cell culture model; however, this effect was only seen at high dosages.
mTOR inhibitors also appeared to potentiate HEV replication
. Corticosteroids had no effect on HEV replication
mycophenolate was shown to inhibit HEV replication
This effect was potentiated with the addition of ribavirin.
As antibody detection is inconsistent in immunosuppressed transplant patients, we propose virus-specific testing, such as HEV RNA and/or antigen detection to identify HEV infection. (1B)
We recommend that all transplant doctors get HEV (acute and persistent) training due to its rising frequency and serious clinical repercussions.
Solid Organ Donor Hepatitis E Testing:
The UK Advisory Committee for the Safety of Blood, Tissues, and Organs (SaBTO) recommends screening all solid organ donors for HEV. (1C)
We propose that: HEV viremia in a donor is not an absolute contraindication to organ usage but will guide clinical treatment choices post-transplant. (2C)
HEV-transplanted patients are treated like other chronically infected patients. (2C)
Solid Organ Transplant Hepatitis E Prevention:
Before and after transplantation, individuals should get written counseling on HEV risk from undercooked meat, especially processed pork. (1D)
HEV screening in solid organ transplant recipients:
We advise against HEV screening for solid organ transplant candidates. In immunosuppressed patients with elevated liver enzymes, pretransplantation HEV testing may be advised. (D1)
HEV RNA or antigen assays are performed on solid organ transplant patients with elevated liver transaminases or HEV symptoms. (1C)
We recommend that transplant patients have a plasma sample collected upon transplantation and preserved for a year to screen for HEV or other infections.
(2D)
Acute Hepatitis E Therapy in Transplant Candidates:
We recommend HEV testing for unexplained acute or chronic liver failure.
(2C)
Hepatitis E in liver transplant candidates with cirrhosis may be treated with ribavirin. (2D)
HEV Infection Treatment in Solid Organ Transplant Recipients:
Recent HEV infection
As more than 30% of solid organ transplant patients may spontaneously eliminate HEV infection within three months, we recommend monitoring HEV RNA levels and liver enzymes. Real-time viral surveillance and antibody profiling may aid clinical decision-making. (2C)
In individuals with acute or chronic HEV, reducing immunosuppression may help viral clearance, although the risk of rejection must be addressed. (2C)
Acute hepatitis E patients with severe liver dysfunction (jaundice and coagulopathy) or extrahepatic symptoms may benefit from early ribavirin therapy, although the available data is weak. (2D)
HEV infection that persists:
HEV infection may continue if HEV RNA is found in blood or stool for more than three months after relevant symptoms, raised liver enzymes, or the first positive HEV RNA test. (1C)
Ribavirin is given to those with persistent HEV infection (greater than three months) (HEV RNA is not found in plasma or stool six months after treatment completion). (1C)
At the start of treatment, plasma, and stool are measured for quantitative HEV RNA. (1C)
Chronic HEV patients with solid organ transplants should take ribavirin for three months. Ribavirin is usually used for 3–6 months. (1C)
Monthly plasma and stool HEV RNA testing continues until treatment is stopped. (1C)
Ribavirin is continued until two stool tests are negative for HEV RNA, one month apart, to prevent a recurrence. (1C)
For sustained virological response, plasma and stool samples are examined for HEV RNA three and six months after stopping antiviral therapy. (1C)
Ribavirin may cause hemolytic anemia, hence, hemoglobin testing is done often. Ribavirin dose reduction may be needed to maintain hemoglobin throughout treatment. Blood transfusions or epoetin therapy may be needed to extend antiviral treatment without decreasing medication. (1A)
Due to a moderate risk of organ rejection, transplant patients with chronic HEV should not use PEG-interferon as a first-line treatment. (1D)
Guidelines for Hepatitis E & Solid Organ Transplantation: 1-Hepatitis E virus Biology and Disease: Recommendation;
-Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B) Suggestion;
-All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded) 2-Testing of Solid Organ Donors for Hepatitis E: Recommendation;
-All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C) Suggestion;
-The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
-Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C) 3-Prevention of Hepatitis E infection in Solid Organ Transplant Recipients: Recommendation;
-Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D) 4-Surveillance and Screening for HEV in Solid Organ Transplant Recipients: Recommendation;
-Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
-Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C) Suggestion;
-Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D) 5-Treatment of Acute Hepatitis E in a Patient on the Transplant List: Suggestion;
-Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
-Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D) 6-Management of HEV Infection in Solid Organ Transplant recipients: Newly diagnosed or acute HEV infection; Suggestion;
-The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
-A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D) Persistent HEV infection; Recommendation;
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
-Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
-A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
-Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
-Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
-A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
-Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
-PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D) Suggestion;
-Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment, and therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
-To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
-Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
-Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
-PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Guidelines for Hepatitis E & Solid Organ Transplantation, British Transplantation Society Guidelines, 2017
· We recommend that: Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients:
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. However, testing for HEV is indicated pre-transplantation in an immunosuppressed individual with raised liver enzymes. (D1)
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
For Newly diagnosed or acute HEV infection:
· The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes. More than 30% will spontaneously clear the infection within three months. (2C
· A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D
Persistent HEV infection
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
· Individuals with persistent HEV infection (infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
During Ribavirin Rx measures should include:
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C) Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
· Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
· Quantitative testing of a plasma sample to be taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
· To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
These guidelines recommend that:
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations.
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes.
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay.
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
· Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment).
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
· Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
· Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction.
HEV belongs to the hepeviridae family and its prevalence has increased over the last decade. To date, four genotypes have been known to infect humans. Few patient with HEV will develop chronic hepatitis and ultimately fibrosis of liver.
Diagnosis is made by PCR of HEV RNA or antigen detection. Donor with HEV still can donate and is not a contraindication
Prevention: Undercooked meat(particularly processed pork) should not be taken by the recipient
Surveillance and Screening for HEV in Solid Organ Transplant Recipient
Recipients with raised liver transaminases or if patient is symptomatic, then HEV RNA or an antigen assay should be done (1C) .Not routinely done.
Treatment of Acute Hepatitis E in a SOT-.
Around 30% of the patients spontaneously recover within 03 months ,so treatment is indicated in patients with severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic manifestations. Ribavirin is usually given as the first line treatment along with reduction of immunosuppression. Ribavirin can be stopped if two stool samples for HEV RNA are negative 01 month apart .
Persistent HEV infection: Persistence of HEV RNA is detectable in blood or stool for more than three months despite being on treatment. Such patients are retreated with ribavirin but with higher doses and for longer duration(at least six months).
Hepatitis E Biology and Disease:
Recommend that:
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV. Infection in transplant recipients.
Prevention of Hepatitis E in Solid Organ Transplant Recipients:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients:
Recommend that:
· Potential recipients of solid organ transplants do not need routine screening for HEV infection.
Unless indicated Pretransplantation, such as in an immunosuppressed individual with raised liver enzymes.
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay.
Treatment of Acute Hepatitis E:
In a Patient on the Transplant List We, suggest that:
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Management of HEV Infection in Solid Organ Transplant recipients:
Newly diagnosed or acute HEV infection suggest that:
· The initial management of includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed.
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited.
Persistent HEV infection:
Its recommend that:
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
· Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment).
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
Monitoring monthly with stool and plasma RNA, stop medication when negative two test one month6month.apart, SVR checked at 3 and 6 months.
Suggestion:
Monitoring viral load after one week of ribavirin.
Dose based on creatinine clearance.
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E:
Recommend that:
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs.
Suggest that:
· The detection of HEV viremia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant.
· Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals.
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Statements of Recommendation:
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
Transplant recipients travelling to countries where HEV is endemic should be advised to maintain good hand hygiene, drink boiled or bottled water only, and avoid raw or undercooked meat.
Blood product and transfusion:
donated blood in the UK has been universally screened for HEV using HEV-NAAT testing, as a cost-effectiveness analysis demonstrated that universal testing was more cost effective that selective testing. This is likely to significantly reduce the risk of transfusion acquired HEV.
PEG interferon:
Treatment could be considered in cases of ribavirin refractory HEV. Very close monitoring for rejection.
Guidelines for Hepatitis E & Solid Organ Transplantation
Hepatitis E Biology and Disease
We recommend that:
1- Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection . (1B)
We suggest that:
2- All clinicians managing transplant recipients should receive specific training about HEV . (Not graded)
========================
Testing of Solid Organ Donors for Hepatitis E
We recommend that:
1- All solid organ donors are screened for HEV infection. (1C)
We suggest that:
1- The detection of HEV viraemia in a donor is not an absolute contra-indication for transplantation. (2C)
2- Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
======================================
Prevention of Hepatitis E in Solid Organ Transplant Recipients
We recommend that:
1- Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
==========================
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
We recommend that:
1- Potential recipients of solid organ transplants do not need routine screening for HEV infection. (D1)
2- Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
We suggest that:
1- Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
====================================
Treatment of Acute Hepatitis E in a Patient on the Transplant List
We suggest that:
1- Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
2- Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
==========================================
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
We suggest that:
1- The initial management of newly diagnosed or acute HEV infection includes observation and monitoring , more than 30% will spontaneously clear the infection within three months. (2C)
2- A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV. (2C)
3- Early treatment with ribavirin may be considered in specific cases of acute hepatitis E , although evidence are limited. (2D)
Persistent HEV infection
We recommend that:
1- Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
2- Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response. (1C)
3- A baseline quantitative HEV RNA assessment is undertaken at the start of treatment. (1C)
4- Treatment with ribavirin should continue for at least three months, For most individuals 3-6 months . (1C)
5- Monthly HEV RNA testing is undertaken until stop of treatment. (1C)
6- Ribavirin is continued until stool tests are negative for HEV RNA on two. (1C)
7- A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
8- Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic a naemia is a common side effect. (1A)
9- PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
We suggest that:
1- Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment.(2C)
2- To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance. (2C)
3- Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin. (2D)
4- Routine baseline sequencing of HEV for mutations is not indicated. (2D)
5- PEG-interferon treatment may be considered in cases of ribavirin-refractory. (2D)
Summary of Hepatitis E in SOT (2017);
HEV is a hepeviridae family virus with different distribution in different continents with genotypes.
The most important G3 which causes infection.
It can be transmitted via donor organ, blood product too.
However, it’s not a contraindication for donation.
Acute HEV infection in SOT recipient requires no antiviral as majority will spontaneously resolve.
With infection the immunosuppression should be reduced, can increase the clearance of virus.
However, 60% of infection will persist.
Diagnosis;
HEV RNA with PCR.
Usually all recipient and donor should doesn’t need to be screened.
Prevention;
Recipient should not eat undercooked meat.
Surveillance;
No need of routine.
If symptomatic or labs shows any raised transaminases then should tested aggressively and be treated as soon as possible.
Management;
Observation,
General management,
Ribavirin is considered the first line of treatment.
Reduction of immunosuppression,
If persistent infection after three months of aggressive treatment in blood and for six month in stool.
Monthly HEV PCR for decision of stopping of ribavirin. Should be continued until two stool samples negative in a month apart.
Give a trail of re-treatment with ribavirin, if not responding consider it as refractory or resistant disease and start with Peg-interferon, with close monitoring of rejection as it can modulate the immune system.
Summarise these guidelines
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B).
Hepatitis E Biology and Disease
Solid Organ Donors for Hepatitis E
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Management of HEV Infection in Solid Organ Transplant recipients
Treatment of persistent HEV infection
Hepatitis E Biology and Disease We recommend that:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Testing of Solid Organ Donors for Hepatitis E We recommend that:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients We recommend that:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients We recommend that:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Treatment of Acute Hepatitis E in a Patient on the Transplant List We suggest that:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Persistent HEV infection We recommend that:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Summarize These Guidelines
EXECUTIVE SUMMARY OF RECOMMENDATIONS
Hepatitis E Biology and Disease
Recommended: Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Suggested: All clinicians managing transplant recipients should receive specific training about HEV.
Testing of Solid Organ Donors for Hepatitis E
Recommended: All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
Suggested:
– HEV viraemia in a donor is not an absolute contraindication for using organs from that donor, but need to inform the recipient for clinical management decisions post-transplant. (2C)
– Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in SOT Recipients
Written advice must be given regarding the risk of HEV from undercooked meat. (1D)
Surveillance and Screening for HEV in SOT Recipients
– No need of routine screening for HEV infection, except those with raised liver enzymes. (D1)
– SOT recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV RNA. (1C)
– A plasma sample taken at the time of transplantation should be stored for at least 1 year for retrospective testing for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
– Individuals with unexplained acute on chronic hepatitis or acute liver failure should be tested for HEV. (2C)
– Ribavirin is considered for patients of hepatitis E with cirrhosis, on liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
The initial management of acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes; >30% spontaneously clear the infection within 3months. Viral monitoring and antibody profile may help clinical decision-making. (2C)
– Immunosuppression reduction is considered in patients with acute or persistent HEV. (2C)
– Early treatment with ribavirin may be considered in specific cases of acute hepatitis E. (2D)
Persistent HEV infection
– HEV RNA is detectable in blood or stool for >3months after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
– Ribavirin should be administered with the aim of sustained virological response. (1C)
– A baseline quantitative HEV RNA on plasma and stool tested at the start of treatment. (1C)
– Ribavirin therapy 3-6months administered for SOT recipients with persistent HEV infection. (1C)
– HEV RNA in plasma and stool tested monthly – Ribavirin is continued until 2 stool tests (1month apart) are negative. (1C)
– HEV RNA in stool and plasma tested at 3 months and 6 months, after stopping antiviral therapy – to look for SVR (1C)
– Monitoring for anaemia during ribavirin therapy – dose reduction may be required if severe anaemia develops. Erythropoietin and/or blood transfusion may be indicated to allow continued antiviral therapy. (1A)
– PEG-interferon should not be used as first line treatment in transplant recipients due to risk of rejection. (1D)
– Quantitative assay of plasma HEV on day7 of Ribavirin treatment, determines the likely length of therapy. (2C)
– To minimize treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance (CG formula). (2C)
– Persistent HEV who relapse after first course of ribavirin à Re-treatment for 6months with ribavirin at higher dose tolerated. (2D)
– PEG-interferon is indicated for cases with ribavirin-refractory persistent HEV infection. (2D)
– Routine sequencing of HEV for mutations is not indicated (2D)
The incidence and prevalence of hepatitis E virus (HEV) infection has increased in many developed countries over the last decade. It has also been recognised that HEV infection can persist in immunosuppressed individuals, leading if left untreated to chronic hepatitis and significant liver fibrosis. Transplant recipients are therefore at risk of developing persistent HEV infection.
British Transplantation Society gave guidelines for Managment of SOT infected by Hepatis E-
Diagnosis– Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Testing of Donors– All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C).
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ .
Prevention of Hepatitis E in Solid Organ Transplant Recipients-Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipient- Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Treatment of Acute Hepatitis E in a SOT-The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations.
Persistent HEV infection- Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment.Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E:
All solid organ donors are screened for HEV but detection of viremia is not contraindication for transplantation.
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Education by written advice regarding the risk of HEV from undercooked meat before and after transplantation. (1D)
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS:
HEV is tested in an immunosuppressed individual with raised liver enzymes. (D1).
HEV using an HEV RNA or an antigen assay (C1).
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST:
HEV tested in patients with unexplained acute on chronic or acute liver failure
patients with cirrhosis who develop hepatitis E treated with ribavirin
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Newly Diagnosed or Acute HEV Infection:
1. Observation and Monitoring liver enzyme
2. Monitoring HEV RNA
3. Reduction of immunosuppression increase rate of clearance
4. To consider treatment with ribavirin in severe liver dysfunction or extrahepatic manifestation.
Persistent HEV Infection:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with treatment for persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Guidelines for Hepatitis E & Solid Organ Transplantation
Testing for SOT donors and recipients
Prevention of Hepatitis E
Surveillance and screening
Treatment of Acute Hepatitis E in a Patient on Transplant list
Management of HEV infection post transplantation
Newly diagnosed
Persistent HEV infection (HEV RNA is detectable in blood or stool > 3 months)
● HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals
● All solid organ donors are screened for HEV fir Safety of Blood, Tissues and Organs
● Detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor
● A dvice to patients regarding the risk of HEV from undercooked meat before and after transplantation.
● Potential recipients of solid organ transplants do not need routine screening for HEV infection except when raised liver enzymes in immunosuppressed individual
● SOT recipients with raised liver transaminases or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay
● Keeping a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections.
● Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
● Ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
● Management of acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
● RI is considered in patients with acute or persistent HEV increases risk of rejection
● Ribavirin treatment in specific cases :
☆ Severe liver dysfunction
☆ Extra-hepatic manifestations
Persistent HEV infection
● It is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test
● Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained response (HEV RNA not detected in plasma and stool six months after completion of treatment)
● A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
● For most individuals 3-6 months of ribavirin treatment will suffice.
● Plasma and stool HEV RNA monthly until treatment stopping
● Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart
● HEV RNA testing plasma and stool samples at three and six months after stopping antiviral therapy.
● Haemolytic anaemia is a common SEs during ribavirin therapy which may require dose reduction or Epoetin therapy and/or blood transfusion
● PEG-interferon increases risk of rejection
● HEV RNA after seven days of ribavirin treatment predict response after three months of ribavirin treatment.
● Dosage of ribavirin is adapted to GFRe
● Patients who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at a higher dose
● Routine sequencing of HEV for mutation is not indicated prior to antiviral treatment
● PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
Hepatitis E Biology and Disease
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
· All clinicians managing transplant recipients should receive specific training about HEV.
Testing of Solid Organ Donors for Hepatitis E
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
· The detection of HEV viraemia in a donor is not an absolute contraindication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
· Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
· Individuals must receive written advice regarding the risk of HEV from undercooked meat before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. Except those immunosuppressed individuals with raised liver enzymes. (D1)
· SOT recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
· Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
· The initial management of acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
· Reduction in immunosuppression is considered in patients with acute or persistent HEV. (2C)
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E. (2D)
Persistent HEV infection
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
· Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response. (1C)
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
· Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart. (1C)
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
· Regular haemoglobin monitoring is conducted during ribavirin therapy, dose reduction may be required if anemia developed, and Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients due to risk of rejection. (1D)
· It is suggested to do quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
· To minimize treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
· Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
· PEG-interferon is indicated for cases with ribavirin-refractory persistent HEV infection. (2D)
HEV and SOT
HEV RNA and/ or Ag detection is used to diagnose HEV infection in transplant recipients since AB detection is not reliable in immunocompromised patients
DONOR
HEV should be looked for in all donor although it is NOT a contraindication
RECIPIENT
HEV AG and HEV RNA is detected in serum for diagnosis
Antibody is not detectable due to IS
EDUCATION
of recipient that water and undercooked pork can be the source
screening
recipients with elevated liver enzymes or symptoms suggestive of HEV infection should be tested for HEV using HEV RNA or an antigen assay
TREATMENT
1st step of management of SOTs with newly diagnosed or acute HEV infection is to monitor HEV RNA levels and the liver enzymes
since >30% of the cases will spontaneously clear the infection within 3 months
Reduction of IS is next step
Ribavarin is indicated in case of sever liver dysfunction
FOR PERSISTANT HEV INFECTION
HEV RNA in serum for more than 3 months after initial infection
ribavirin is used to achieve sustained virological response (i.e., undetectable HEV RNA in plasma or stool 6months after completion of treatment)
Duration 3-6 month with RNA monitoring as response to therapy
continued shedding of HEV in stool is a predictor of relapse following ribavirin treatment so treatment is continued till two monthly serum samples are negative
HEV RNA test (plasma and stool) is done at 3 and 6 months
Adverse effects due to Ribavarin
hemolytic anaemia is common
dose reduction is required to maintain Hb
Blood transfusion may be required
consider PEG-interferon in cases of ribavirin-refractory persistent HEV infection
HEPATITIS E VIRUS BIOLOGY AND DISEASE
Statements of Recommendation
We recommend that:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
We suggest that:
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
Hepatitis E Biology and Disease
We recommend that:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
We suggest that:
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
Testing of Solid Organ Donors for Hepatitis E
We recommend that:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
We suggest that:
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C) Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
We recommend that:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
We recommend that:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1) Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
We suggest that:
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
We suggest that:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C) Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
We suggest that:
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C) Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
We recommend that:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C) Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C) A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C) Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C) Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C) Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C) A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C) Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
We suggest that:
Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C) To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C) Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D) Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D) PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Guidelines for Hepatitis E & Solid Organ Transplantation
Testing for SOT donors and recipients
Prevention of Hepatitis E
Surveillance and screening
Treatment of Acute Hepatitis E in a Patient on Transplant list
Management of HEV infection post transplantation
Newly diagnosed
Persistent HEV infection (HEV RNA is detectable in blood or stool > 3 months)
GUIDELINES FOR HEP E AND SOT.
HEP E Biology and disease.
Testing of solid organ donors for HEP E.
Prevention of HEP E in SOT recipients;
Treatment of Acute Hep E in a pt on transplant list;
Mgt of HEV infection in SOT recipients.
> Newly dx or acute HEV infection;
>Persistent HEV infection.
III. Guidelines for Hepatitis E & Solid Organ Transplantation
Summarise these guidelines
Hepatitis E biology and disease
– HEV RNA and/ or Ag detection is used to diagnose HEV infection in transplant recipients since AB detection is not reliable in immunocompromised patients
Testing of solid organ donors for Hepatitis E
– all solid organs should be screened for HEV
– detection of HEV viremia in a donor is not an absolute contraindication to organ donation
Prevention of Hepatitis E in SOT recipients
– educate patients on risk of pre- and post-transplant HEV infection from undercooked meat (especially processed pork)
Surveillance and screening for Hepatitis E in SOT recipients
– routine pre-transplant HEV screening is not recommended in all potential SOT recipients unless in an immunosuppressed patient with elevated liver enzymes
– SOT recipients with elevated liver enzymes or symptoms suggestive of HEV infection should be tested for HEV using HEV RNA or an antigen assay
– a plasma sample can be taken at the time of transplantation and stored for at least 1 year to allow for retrospective testing for HEV and other infections among transplant recipients
Treatment of acute Hepatitis E in a patient on the transplant list
– test patients with unexplained acute on chronic or acute liver failure for HEV
Management of HEV infection in SOT recipients
– 1st step of management of SOTs with newly diagnosed or acute HEV infection is to monitor HEV RNA levels and the liver enzymes since >30% of the cases will spontaneously clear the infection within 3 months
– reduction in immunosuppression may be considered in patients with acute or persistent HEV -this helps with viral clearance but may increase the risk of rejection if not well assessed
– consider early treatment with ribavirin especially in patients with acute hepatitis E who develop severe liver dysfunction (coagulopathy, jaundice) or extra-hepatic manifestations
– persistent HEV infection is diagnosed when HEV RNA is detectable in plasma or stool for >3months after onset of symptoms, elevated liver transaminases, or from a first positive HEV RNA test
– in patients with persistent HEV infection, ribavirin is used to achieve sustained virological response (i.e., undetectable HEV RNA in plasma or stool 6months after completion of treatment)
– obtain baseline quantitative HEV RNA (plasma and stool) before initiating treatment
– duration of treatment is 3-6months of ribavirin but monthly HEV RNAs are done until a decision is made to stop treatment
– continue ribavirin until stool tests are negative for HEV RNA on two occasions one month apart since continued shedding of HEV in stool is a predictor of relapse following ribavirin treatment
– HEV RNA test (plasma and stool) is done at 3 and 6 months after stopping antiviral therapy to assess for sustained virological clearance
– hemolytic anaemia is a common side effect of ribavirin hence regular HB monitoring ought to be done and where necessary ribavirin dose may be reduced to maintain an adequate Hb level
– if this is not feasible, erythropoietin and/ or blood transfusion should be considered
– PEG-interferon is associated with a moderate risk of precipitating organ rejection hence should not be used as 1st line therapy for treatment of persistent HEV infection
– a repeat HEV RNA test can be done after 7days of ribavirin treatment to help predict the chance of achieving sustained virological clearance after 3months of ribavirin treatment – this helps determine the likely duration of treatment
– the dose of ribavirin should be renal adjusted to minimize treatment-related side effects
– patients who relapse after the 1st course of ribavirin should be retreated for at least 6months with ribavirin but at higher doses as tolerated
– baseline sequencing for HEV mutations is not routinely done before initiating antiviral therapy
– consider PEG-interferon in cases of ribavirin-refractory persistent HEV infection
British Transplantation Society Guidelines
Guidelines for Hepatitis E & Solid Organ Transplantation.
Hepatitis E Biology and Disease
-For diagnosis of HEV post kidney transplant HEV RNA is indicated but antibody detection is unreliable(1B).
-Clinicians following transplant recipients should be well trained about HEV as its prevalence is increasing and the clinical consequences of infection can be significant.
Testing of Solid Organ Donors for Hepatitis E
-Al solid organ donors should be screened for HEV .(1C)
-The detection of HEV viremia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
-HEV infection via organ transplantation will be treated according to current guidelines.
Prevention of Hepatitis E in Solid Organ Transplant Recipients.
Recipients should be counselled about the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients.
-Routine screening for HEV infection post-transplant is not indicated unless in special situation such as an immunosuppressed individual with raised liver enzymes with using an HEV RNA or an antigen
assay. (D1)
-Preserving a plasma sample at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
–Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
– Observation and monitoring of HEV RNA levels and liver enzymes of newly diagnosed or acute HEV infection in solid organ transplant recipients is considered the proper management plan (2C)
-Reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations. (2D)
Persistent HEV infection.
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months. (1C)
-Individuals with persistent HEV infection receive treatment with ribavirin till HEV RNA not detected in plasma and stool six months after completion of treatment. (1C)
-Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection with monthly HEV RNA screening (1C)
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, and sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
-HBG should be reviewed as Ribavirin lead to hemolytic anemia which can be treated by reduction of the dose with epiotin or blood transfusion (1A)
-Better to avoid PEG-interferon as there is a moderate risk of precipitating organ rejection, unless in cases of ribavirin-refractory persistent HEV (1D)
-Following the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. (2C)
-Ribavirin dose should be adjusted according to e GFR. (2C)
-HEV elapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
Summary
This is British Transplantation Society Guidelines for Hepatitis E & Solid Organ Transplantation 2017
Hepatitis E Biology and Disease
Recommendation
– HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients (1B)
Testing of Solid Organ Donors for Hepatitis E
Recommendation
– All solid organ donors must be screened for HEV (1C)
Suggestion
– HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but need to inform (2C)
– HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Recommendation
– There is risk of HEV from undercooked meat (particularly processed pork) before and after transplantation so individual need written advice (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Recommendation
– Testing for HEV is indicated pretransplantation, in an immunosuppressed individual with raised liver enzymes. (D1)
– Recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Suggestion
– Recipients have a plasma sample are stored for a minimum of one year at transplantation that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Suggestion
– Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients Newly diagnosed or acute HEV infection
Suggestion
– Observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
– Reduction in immunosuppression is considered in patients with acute or persistent HEV, but the risk of rejection should be monitored (2C)
– Early treatment with ribavirin may be considered in who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations (2D)
Persistent HEV infection
Recommendation
– In this HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
– Persistent HEV infection should receive treatment with ribavirin with the aim of achieving sustained virological response (1C)
– A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
– Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
– Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
– Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart (1C)
– A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
– Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
– PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Suggestion
– Quantitative testing of a plasma HEV RNA sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
– The dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
– Persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
– Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
– PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Hepatitis E Virus Biology And DiseaseRecommendation
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
Suggestion
Introduction Hepatitis E virus (HEV) belongs to the genus Hepevirus in the Hepeviridae family and infects humans and a range of animal hosts. Four major HEV genotypes infect humans (G1 to G4) and are remarkable in their associated divergences, leading HEV to be aptly described as having ‘two faces’.
G1 and G2 are restricted to the human host. G1 occurs in Asia and Africa, with G2 reported from Mexico and also Africa. G3 has a worldwide distribution and is associated with infection in humans, pigs and other mammalian species; in contrast, G4 only infects humans and pigs, principally in South East Asia.
G4 also occurs in pigs in India, and occasionally in Europe.
Epidemiology HEV G1 and G2 viruses remain major public health concerns in resource poor settings, where HEV is thought to be responsible for >50% of cases of viral hepatitis. The virus is transmitted via the faecaloral route through the consumption of contaminated food and water. Person-to-person spread is not common. Case control studies using food based questionnaires show an association between the consumption of pork products and HEV infection in England. National surveys have shown that 93% of UK pigs are HEV antibody positive, with 20% having detectable HEV RNA in either plasma or caecal samples at time of slaughter.
HEV replication The hepatitis E virion is a spherical particle that is icosahedral in symmetry and has spikes on the capsid surface. The genome is a single-stranded. The life cycle of HEV remains poorly understood, mainly because of the lack of efficient in vitro culture methods. The viral particles concentrate on the surface of hepatocytes, bind to an undefined receptor and are internalised. Following uncoating, the genomic RNA is released and translated in the cytoplasm into the non-structural proteins.
Clinical featuresThe clinical features of acute HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure and are influenced greatly by genotype and by the age and gender of the patient. Symptoms, if they occur, include general malaise, abdominal pain, anorexia, nausea and fever and are followed by the onset of jaundice accompanied by dark urine, pale stools and pruritis. Most infections are self-limiting. Persistent infection leading to chronic hepatitis has been reported in immunosuppressed populations including solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals. A number of extrahepatic manifestations linked both to acute and to persistent hepatitis E infection have been reported, including thrombocytopenia, glomerulonephritis, acute pancreatitis, acute thyroiditis, brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, neuromyopathy, and vestibular neuritis.
Diagnosis of Hepatitis EAcute hepatitis E cannot be clinically distinguished from other causes of acute hepatitis. Diagnosis of HEV infection can be undertaken using methods for detecting antibody, antigen and RNA. Antigen ELISAs are less sensitive than molecular methods; however, they provide a more rapid and accessible method for identifying current HEV infection.
Testing of solid organ donors for Hepatitis ERecommendation
Suggestion
IntroductionAlthough HEV is normally acquired through the oral (enteral) route, it can be transmitted at the time of solid organ transplantation, either with the transplanted organ or through blood components from an HEV-infected donor.
Solid organ donors The detection of viraemia is unlikely to be an absolute contra-indication to use of an organ from a donor, but will inform clinical management decisions post-transplant.
Living solid organ donors In the setting of living donation, it is recommended that potential donors be provided with dietary advice regarding avoidance of HEV infection. If HEV viraemia is detected in the potential donor, then living organ donation should be deferred until such time that laboratory testing confirms spontaneous resolution of HEV infection (plasma and stool HEV RNA not detected) in the otherwise healthy potential donor.
HEV donor testing Although the potential for donor-transmitted HEV infection will exist, the risk is considered small both in terms of the likely incidence of such an event and the consequences of transmitted infection in the post-transplant setting when this is detected early and managed appropriately.
Management of Transplant Recipients who Receive an Organ from an HEV Viraemic DonorThe most appropriate management of the transplant recipient who receives an organ from a donor that is later identified to have HEV viraemia, and is therefore at risk of becoming persistently infected with HEV, is not known.
Prevention of hepatitis E infection in solid organ transplant recipientsRecommendation
Dietary advice It has been established that HEV G3, the prevalent genotype in developed countries, is a dietary acquired zoonosis with a number of animal species being the reservoir including pigs, wild boar, deer and rabbits. Consumption of raw or inadequately cooked pork or game meat from an animal viraemic at the time of slaughter is believed to be the major source of infection. Studies have demonstrated that infectious HEV can survive for long periods (more than one month) in food products, particularly when stored at 4°C. HEV is also not easily inactivated by cooking and can remain infectious when cooked at temperatures of less than 80° C for less than two minutes. HEV is also not inactivated when heated to 56° C or 60 °C even for long periods (1 hour), which is the approximate temperature of the central portion of meat when cooked rare. Therefore, considerable evidence implicates the consumption of undercooked meat (predominantly porcine) products in the recent rise in the cases of HEV in Europe. Ensuring pork, and other meat that may be from HEV-infected animals, is adequately cooked is one method that could reduce the risk of HEV infection in transplant recipients and the general population. In contrast to the above, the major route of transmission of HEV G1 and G2 is the faecal-oral route. Transplant recipients travelling to countries where HEV is endemic should be advised to maintain good hand hygiene, drink boiled or bottled water only, and avoid raw or undercooked meat.
Transfusion of blood products From April 2017, donated blood in the UK has been universally screened for HEV using HEV-NAAT testing, as a cost-effectiveness analysis demonstrated that universal testing was more cost effective that selective testing. This is likely to significantly reduce the risk of transfusion acquired HEV.
Immunization against HEVPrevention of HEV infection is potentially possible through immunisation. Recombinant vaccines developed from genotype 1 HEV have shown efficacy in trials in China. Further studies would be required to test the efficacy of this vaccine, its durability of immune response, and ultimately its cost-effectiveness before further use could be recommended.
Surveillance and screening for HEV in solid organ transplant recipientsRecommendation
Suggestion
Screening for HEV in Patients awaiting TransplantationScreening for HEV in patients awaiting transplantation would involve testing for HEV in all potential transplant recipients. The majority of HEV infections in immunocompetent individuals are asymptomatic and achieve prompt seroconversion. There are no apparent health consequences of this asymptomatic infection and this does not lend support to screening all individuals for HEV pre-transplantation. However, there may be specific instances where testing potential transplant recipients for HEV before transplantation may be appropriate, such as in individuals who are immunosuppressed pre-transplant but have raised liver enzymes, or individuals with clinical features to suggest current or recent HEV infection, as this may alter their management.
Post-transplant Screening or Surveillance for HEV in Solid Organ Transplant RecipientsA number of studies have tried to estimate the prevalence of HEV in transplant recipients. The prevalence of detectable HEV RNA among transplant recipients in these studies, indicating current viraemia, ranged from 0-3.2%. The transplant patient may acquire HEV in two ways: through diet, which is a continuing cumulative risk measured by the attack rate in the population; and through the receipt of substances of human origin (SOHO) including organs and blood components, which is a temporally constrained risk, but also defined by the attack rate in the population. Given that HEV can become chronic in transplant recipients and can cause associated morbidity, screening options to consider include:
Recommendation
Acute HEV in Cirrhotic Patients on the Transplant ListAcute HEV infection in a patient on a transplant waiting list might be identified through abnormalities in ‘routine’ liver enzymes or due to a symptomatic presentation with liver dysfunction. Symptomatic presentation is recognised to be more frequent in older patients, often with underlying chronic liver disease or alcohol excess. n the presence of pre-existing cirrhosis and liver dysfunction acute symptomatic HEV infection can precipitate acute on chronic liver failure (ACLF), which is associated with a mortality of approximately 50% at three months after hospital admission. In this scenario there is a rationale to treating HEV. Case series describe patients with cirrhosis and liver dysfunction that worsened with HEV infection and were subsequently treated with ribavirin. Treatment with ribavirin appeared safe, although dose reduction in ribavirin was required for anaemia in some patients, with treatment duration ranging up to one month. The natural history of HEV infection in immunocompetent individuals is for spontaneous seroconversion and it is unclear whether ribavirin treatment speeds this process. HEV infection occurring in a patient on the liver transplant waiting list is not an absolute contraindication to transplantation.
Treatment of Patients with Acute Liver Failure due to Acute Hepatitis EAcute liver failure is a syndrome characterised by severe liver dysfunction (jaundice, coagulopathy and hepatic encephalopathy) on a background of a previously ‘normal’ liver. HEV is a common cause of acute hepatitis, but rarely causes fulminant liver failure. There are reports of successful transplantation for HEV-associated acute liver failure.
Management of HEV infection in solid organ transplant recipientsSuggestion
Persistent HEV InfectionRecommendation
Suggestion
Management of Acute HEV Infection Post-transplantationThe current natural history data suggest that acute HEV infection in solid organ transplant recipients does not require specific antiviral treatment at the outset in the majority of cases, as a significant proportion of patients will spontaneously clear the infection. The initial management of acute infection in solid organ transplant recipients should include careful observation and monitoring of HEV RNA levels, serology, and liver enzymes. Where possible, a reduction in immunosuppression should be considered. If HEV RNA clearance from the blood and stool has not been achieved by three months then persistent infection is likely to occur and the patient should be managed as having persistent HEV infection. There may be specific cases where early antiviral therapy with ribavirin is indicated, such as patients who develop severe liver dysfunction (jaundice and coagulopathy), although evidence for this is currently limited. It has recently been recognised that HEV infection (acute and persistent) has been associated with extrahepatic syndromes, particularly neurological manifestations, such as Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis. Renal (glomerulonephritis with and without cryoglobulinaemia), cardiac (myocarditis), and autoimmune extrahepatic manifestations (e.g. thyroiditis and thrombocytopenia) have also been described. Although it has not been proven, a few case reports have suggested that ribavirin treatment may improve the natural history of these extra hepatic manifestations.
Treatment of Persistent Hepatitis E Post-transplantationFollowing acute infection with HEV G3, the infection persists in approximately 60% of solid organ transplant recipients leading to persistent HEV infection. This can cause a chronic hepatitis that can progress rapidly (3-5 years) to cirrhosis. Efforts to treat HEV should begin after three months of infection. As HEV infection is frequently asymptomatic in transplant recipients, clinicians should have a high index of suspicion for the infection and should investigate raised liver enzymes of any degree with reflex HEV testing. Persistent HEV infection can be misdiagnosed as drug-induced liver injury, rejection (in liver transplants) or graft versus host disease, so careful assessment is needed of all liver enzyme abnormalities in transplant recipients.
Individuals with persistent HEV infection (documented or estimated duration of infection of greater that three months) should be treated with the aim of achieving a sustained virological response. Persistent HEV infection occurs mainly in heavily immunosuppressed individuals, particularly those on T cell suppressing drugs. Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV.
Ribavirin is an antiviral medication that has been used for many years in combination with pegylated interferon for the treatment of hepatitis C. More recently, ribavirin has been shown to have antiviral activity against HEV. It remains unknown what the optimum treatment duration and dose of ribavirin should be. The dose has to be adjusted as per the renal function. The most frequent side effect of ribavirin is a haemolytic anaemia. Approximately 40% of transplant recipients with persistent HEV relapse after three months of treatment with ribavirin.
There are a few reports of successful treatment of persistent HEV with PEG-interferon. Sofosbuvir is a pangenotypic nucleotide analog licensed for the treatment
Summary
HEV belongs to the hepeviridae family and there are 4 genotypes that infect humans.
Genotype 1 and 2 occurs more commonly in developing countries and are transmitted in the fecal-oral route.
Genotype 3 and 4 mainly in developed countries transmitted via consumption of contaminated meat.
Clinical features of acute HEV infection range from asymptomatic, mild hepatitis to fulminant hepatic failure.
The clinical presentation mainly determined by the genotype, age and gender of the patient.
Most acute infection are self limiting.
Persistent infection mainly occurs in immunosuppressed patients.
Main genotype associated with persistent infection is G3.
HEV infection should be diagnosed via HEV RNA and antigen test, antibodies are not reliable in immunosuppressed patients.
There is risk of solid organ transmission of HEV either through the transplanted organ or blood products, thus all donors should be screened for HEV.
Presence of HEV infection in the donor is not an absolute contraindication for donation.
Living donors should be counselled against raw/undercooked meat and HEV NAAT testing should be done 4 weeks prior to donation.
Deceased donors results for HEV NAAT may not be available at the time of organ donation however this should not influence decision on use of the organ.
Prevention of HEV infection is possible through vaccination, however the only available vaccine is against G1 and only available in China.
Acute HEV infection in SOT recipients requires no antivirals as majority will spontaneously resolve.
Immunosuppressive therapy may be reduced to aid in clearance of the virus.
60% of acute infections will persist.
Ribavirin is a guanosine analogue which inhibits HEV replication.
Optimal duration and dosage is not well defined, however most studies have reported doses between 200-1200mg/day with a median dose of 600mg/day.
A baseline stool and plasma HEV RNA should be done at initiation then on regular intervals of 1 ,2 and 3 months.
Treatment should be stopped when 2 plasma and stool sample 1 month apart are negative for HEV RNA.
Treatment failure could be due to mutations rendering ribavirin resistance, insufficient treatment duration and insufficient dosage due to adverse effects.
Patients with treatment failure majority will respond to prolonged treatment of ribavirin even in mutations.
Pegylated interferon is a second line treatment incase of ribavirin refractory cases.
Further clinical studies are required on the use of sofosbuvir in treatment of HEV infection.
Summarise these guidelines
Definitions of Hepatitis E used in this Guideline:
– Hepatitis E :Clinical hepatitis caused by acute HEV infection.
– Acute HEV :Acute infection with HEV that may or may not be symptomatic.
-Persistent HEV :HEV RNA detectable for three months or more.
– Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
-All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations.
-The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant.
-Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals.
– Individuals must receive written advice regarding the risk of HEV from undercooked meat before and after transplantation.
-Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes and test for HEV using an HEV RNA or an antigen assay.
-Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
-The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
-A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed.
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited.
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test.
– Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response.
– Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice.
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
– A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral treatment.
– PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
-Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.
HepatitisE Biology and Disease
● Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
Testing of Solid Organ Donors for Hepatitis E
● All solid organ donors are screened for HEV in line with the UK Advisory Committee for the (SaBTO) recommendations. (1C)
●The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
●Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients
● Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
● Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
●Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (C1)
● Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
●Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
(2C)
●Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E
When on the liver transplant waiting list. (2D)
———————————————————–
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
● The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (C2)
●A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
●Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
●Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
●Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
●A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
●Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
● Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
●Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
● A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNAatthree and six months after stopping antiviral therapy. (1C)
●Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
●PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
●Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
● To minimize treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
● Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
● Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
●PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.(2D)
HEV infection : is frequently encountered in immune compromised patients particularly kidney transplant recipient with significant morbidity and mortality .
Awareness of its parthenogenesis and symptomatically is highly recommended in kidney transplant practice.
Generally its recommend to screen all SOT donors for HEV infections.
Owing to immune suppression post transplantation, suspected recipients infected with HEV must be investigated with PCR for RNA and viral antigen.
The Transplant recipient must be alerted to risk of attracting HEV from under-cooked pork meat.
HEV infection is a contraindication for kidney donation.
When to survay for HEV:
Its not recommended to routinely screen the transplant candidate for HEV .However is indicative to investigate for HEV in patients who is immune suppressed and whose reported to have abnormal liver function test result.
Management of HEV infection post transplantations:
Whenever acute fulminant hepatitis or acute on chronic hepatitis is diagnosed, HEV screening has to be implemented .
Ribavirin is indicated for liver cirrhosis patient with HEV infection in liver transplantation candidate.
Post transplantation HEV infection:
1] First step in management is vigilant observant approach . with close follow up of HEV RNA and liver function . HEV RNA is performed on plasma and stool . 30% spontaneous infection clearance during the first 3 months post infection.persistent EBV infection is was reported.
2] Ribavirin is indicated in severe acute hepatitis featuring severe joundice and coagulopathy.
3] Persistent HEV infection is indicative of continuing positive HEV RNA detected in plasma and or particularly in stool.
4] Ribavirin is implicated for 3-6 months . Recurrence of HEV infection is treated with higher doses of Ribavirin for 6 months.
5] Sustained recovery is featuring negative HEV RNA for 6 months from stopping the medications
6] Ribavirine might be associated with hemolytic anemia suppression.
7] Two negative successive stool tests for HEV RNA is indicative of HEV clearance.
8] Peg-Interferone may be indicated in refractory HEV infection
*Guidelines for Hepatitis E & Solid Organ Transplantation
Hepatitis E Biology and Disease:
Testing of Solid Organ Donors for Hepatitis E
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Treatment of Acute Hepatitis E in a Patient on the Transplant
Management of HEV Infection in Solid Organ Transplant recipients: Newly diagnosed or acute HEV infection:
Persistent HEV infection :
BTS guidelines 2017
Diagnosis/ Prevention and treatment of HEV in organ transplant:
Screening for HEV infection is mandatory to do in all organ transplant and it’s not contraindicated for transplant but need good evaluation and treatment.
HEV RNA and/or antigen detection in plasma and stool must be used to diagnose HEV infection in transplant recipients.
Prevention of Hepatitis E in Solid Organ Transplant Recipients:
Counselling regarding risk of infection during transplant and writing consent should be done.
Treatment of Acute Hepatitis E :
All patients of organ transplant with unexplained acute or chronic liver failure should be treated with ribavirin for eradication of hepatitis E virus.
Also should be observation and monitoring of HEV RNA levels and liver enzymes during treatment.
However, reduction of immunosuppression is considered in patients with acute or persistent HEV as this help for viral clearance, but carry risk of rejection so should be monitoring drug level in lower limit.
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
Persistent of HEV:
If HEV RNA and liver enzymes persist should be continue ribavirin for at least three months for solid organ transplant.
Monthly HEV RNA testing in plasma and stool to detect clearance of virus and blood count is mandatory to do to avoid side effects of ribavirin as hemolytic anemia is common with ribavirin.
PEG-interferon is second line in case of persistent HEV but carrying high risk of organ transplant rejection.
HEV genotype:
G1 and G2 are restricted to the human host.
G1 occurs in Asia and Africa, where G2 occur in Mexico and also Africa. G3 has a worldwide distribution and is associated with infection in humans, pigs and other mammalian species.
G4 only infects humans and pigs, principally in South East Asia; G4 also occurs in pigs in India, and occasionally in Europe.
Transmission of HEV infection:
By feco-oral
blood transfusion or organ derived
ClinicalFeatures
Acute Hepatitis E
Range from asymptomatic to mild hepatitis to fulminate hepatic failure.
In pregnant women in third trimester with hepatitis E carrying risk of stillbirth and apportion and poor outcome reach to death.
Persistent HEV Infection:
It’s lead to chronic hepatitis in immunosuppressed patients with solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals and carry risk of liver cirrhosis.
Extra-hepatic manifestation:
It’s including thrombocytopenia, glomerulonephritis, acute pancreatitis, acute thyroiditis and Guillain-Barré syndrome.
Diagnosis of HEV:
HEV RNA in plasma and stool
HEV incubation period of 2-6 weeks.
The anti-HEV IgM titres increase rapidly and then disappear.
Anti-HEV IgG antibodies are detected shortly after the IgM and continue to rise into the convalescence period, remaining detectable for months to years.
Antigen detection by ELISAs has been used recently for the diagnosis of HEV infection.
Treatment of persistent HEV infection:
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of patients with persistent HEV.
Calcinurine inhibitors and mTor inhibitors may potentially exacerbate viral replication but MMF may inhibit viral replication while, steroid not effects on viral replication.
Dose of ribavirin 12 mg/kg for 12 weeks.
12 mg/kg ribavarin dose seems to be higher
BTS guidelines recommendations for hepatitis E and SOT 2017:
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Treatment of Acute Hepatitis E in SOT Patients
Persistent HEV infection
I note that you have explained how evidence of past infection impacts the decision-making necessary for transplantation.
Hepatitis E Biology and Disease
Detection of HEV RNA and/or antigen is required in order to diagnose infection in transplant recipients because antibody testing is inaccurate (1B). It is strongly advised that all transplant physicians receive training on HEV as well as the clinical repercussions of the virus.
Testing of Solid Organ Donors for Hepatitis E
It is advised that all solid organ donors undergo HEV screening (1C).
HEV viremia in a donor does not necessarily rule out donation. (2C)
HEV infection acquired through transplantation is treated similarly to other chronically infected people. (2C)
Hepatitis E Prevention in SOT Recipients
It is urged that all SOTR be informed of the risk of HEV from undercooked meat (1D)
Surveillance and Testing for HEV in SOT Recipients
Regular recipient testing is not advised. Nonetheless, it is recommended for immunocompromised patients with elevated levels of liver enzymes. (D1)
Assessing recipients for HEV (RNA or an antigen) if they exhibit symptoms and have elevated liver enzyme levels (1C)
Upon transplantation, collect and keep the plasma of the recipient for at least one year to allow testing for HEV and other infections. (2D)
Management of Acute Hepatitis E in a Patient on the Transplant Waiting List
Anyone with unexplained acute, chronic, or acute liver failure must be screened for HEV. Listed individuals with cirrhosis who develop hepatitis E must have ribavirin treatment (2D)
Management of HEV Infection in SOT recipient
Initial treatment of acute HEV infection in recipients consists of observation and monitoring of HEV RNA levels and liver enzymes (30% of cases resolve spontaneously). In acute or persistent HEV, decreasing immunosuppression may aid in viral clearance; nevertheless, the risk of rejection must be carefully evaluated. Although the evidence is sparse, ribavirin can be explored early in severe liver dysfunction or extrahepatic symptoms. (2D)
Approach to persistent HEV infection
HEV RNA in blood or stool lasting >3 months following symptoms, elevated liver enzymes, or the first positive HEV RNA test indicates HEV infection. Ribavirin treatment promotes sustained virological response (C) (no detectable HEV RNA in plasma or stool 6 months after therapy completion). (1C)
HEV RNA in plasma and stool should be measured before treatment. (1C) Ribavirin treatment should last three months (mostly 3-6 months) (1C)
HEV RNA (plasma and stool) monitoring monthly to determine therapy duration (1C)
– Ribavirin is used until stool tests reveal HEV RNA-negative twice a month (1C)
– HBE RNA testing at 3 and 6 months post-antiviral therapy can determine sustained virological response (plasma and stool). (1C) Ribavirin dose can be lowered if hemolytic anemia occurs(1A)
PEG-interferon can cause rejection, hence it shouldn’t be utilized first. (1D) – Plasma HEV RNA is recommended after 7 days of Ribavirin therapy to predict sustained virological response after three months (2C) – Ribavirin dose should be adjusted to creatinine clearance to prevent adverse effects. (2C) HEV relapse after ribavirin should be treated for at least 6 months at a higher dose if tolerated. (2D) – Ribavirin-refractory chronic HEV infection, PEG-interferon treatment may be considered with close monitoring for rejection. (2D)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
III. Guidelines for Hepatitis E & Solid Organ Transplantation
Summarise these guidelines.
Biology & Disease
Recommendations:
HEV RNA &/or antigen detection used for diagnosis in TX (1B)
Suggestions:
Specific training about HEV for clinicians managing transplant recipients (Not graded).
Testing in SOT donors:
Recommendations:
screening in line with the UK Advisory Committee for SaBTO recommendations. (1C)
Suggestions:
HEV viraemia is not an absolute contra-indication to donation. (2C)
HEV transmitted via TX managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention in SOT recipients
Recommendations:
written advice given regarding the risk of HEV from undercooked meat. (1D)
Surveillance & Screening in SOT recipients
Recommendations:
no need for routine screening for HEV infection. Testing may be indicated prêt-TX in an immunosuppressed individual with raised liver enzymes. (D1)
SOT recipients with liver transaminases > upper limit of normal or symptoms are tested using HEV RNA or an antigen assay. (1C)
Suggestions:
Sample taken at the time of TX & stored for a minimum of 1 year to retrospectively test for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Suggestions:
In unexplained acute on chronic or acute liver failure, test for HEV. (2C)
Ribavirin in cirrhotic who develop hepatitis E when on the liver TX waiting list. (2D)
Management of HEV Infection in SOT recipients
Newly diagnosed or acute HEV infection
Suggestions:
The initial management: observation & monitoring of HEV RNA levels & liver enzymes as > 30% will clear the infection within 3 months. Viral monitoring & antibody profiling help clinical decision-making. (2C)
Reduction in IS considered in acute or persistent HEV. (2C)
Ribavirin may be considered in specific cases of acute hepatitis E: severe liver dysfunction or extrahepatic manifestations. (2D)
Persistent HEV infection
Recommendations:
Diagnosed when HEV RNA is detectable for > 3 months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Ribavirin for persistent HEV infection. (1C)
A baseline HEV RNA (both plasma & stool) at the start of treatment. (1C)
Ribavirin continued for at least 3 months for SOT recipients. (1C)
Monthly HEV RNA testing while on treatment. (1C)
Ribavirin until stool tests are negative on 2 occasions 1 month apart. (1C)
A test of sustained virological response at 3 & 6 months after stopping antiviral. (1C)
Regular Hb monitoring during ribavirin therapy (HA is a common side effect). Dose reduction may be required. Epoetin therapy &/or blood transfusion may be indicated to allow continued antiviral therapy. (1A)
PEG-interferon should not be used as first line treatment (risk of precipitating organ rejection). (1D)
Suggestions:
Check change in plasma HEV RNA after 7 days of ribavirin treatment to predict the chance of achieving sustained virological response after 3 months of treatment. (2C)
Ribavirin dose adjusted to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
Relapse after a first course of ribavirin is re-treated for at
least 6 months with ribavirin at higher dose range. (2D)
Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral. (2D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. (2D)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
Guidelines for Hepatitis E & Solid Organ Transplantation
Summary
HEV infection in self limiting but can be an issue in immune compromised patients.
Mainly spreads by eating undercooked food , especially pork meat.
It can be Acute, persistent or chronic.
Diagnosis of HEV is by HEV PCR or by antigen in blood and stools
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO)
Positive HEV is not an absolute contraindication for donation.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV infection
Other indications include-
Immunosuppressed individual with raised liver enzymes
If liver enzymes are raised after transplant
Treatment of HEV infection post transplant
Initial treatment- Observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months.
Dynamic viral monitoring and antibody profiling may help clinical decision-making
A strategic reduction in immunosuppression
Early treatment with ribavirin-
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice
Monitoring
Monthly HEV RNA testing in plasma and stool whilst on treatment
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients
I like your well structured detailed summary.
I appreciate the need for RNA levels to assess effectiveness of treatment of by ribavarin.
Guidelines for Hepatitis E & Solid Organ Transplantation
Summary:
· Clinical hepatitis caused by acute HEV infection
· Acute HEV infection may be asymptomatic
· Persistent HEV: HEV RNA detectable for ≥ 3months in stool or blood (after onset of symptoms as jaundice or 1st time detection of viral RNA).
· Mode of transmission; undercooked pork, blood transfusion.
· Prevention;
o avoid undercooked pork.
o Recombinant vaccines developed from genotype 1 HEV have shown efficacy and licensed in China, but not elsewhere in the world.
· SOT recipients:
o Not routine, but indicated if elevated liver enzymes
o HEV specific tests as HEV RNA and/or antigen detection must be used, as antibody detection is unreliable in such immunosuppressed individuals.
o Management of acute hepatitis E;
§ Reduction of IS especially CNI and mTORi (but take care of rejection).
§ Close monitoring of HEV RNA levels and liver enzymes is essential as > 30% will spontaneously.
§ Treatment is indicated only in cirrhotic patients or those with severe liver dysfunction 9jaundice and coagulopathy).
§ Those cases should be treated with ribavirin.
o Management of Persistent HEV;
§ baseline quantitative HEV RNA PCR on both plasma and stool before start of therapy.
§ Treatment with ribavirin for 3-6 months, to achieve sustained virological response (HEV RNA not detected in plasma and stool 6 months after end of treatment).
§ Treatment is continued until stool PCR is negative for HEV RNA on 2 occasions, 1 month apart, as continued shedding of HEV in stool indicates high risk for relapse.
§ ↓ viral titer 7 days after start ribavirin has good prognostic value.
§ Follow up CBC (as anemia is adverse effect, treated by blood transfusion and ESA therapy).
§ Relapse is treated with longer 6 month course of ribavirin with higher doses as tolerated.
§ PEG-interferon is not preferred as it increases risk of allograft rejection, except in cases of ribavirin-refractory persistent HEV.
· All potential donors should be screened for HEV, HEV viraemia in a donor is not an absolute contra-indication but needs MDT.
I appreciate your strategy in relation to Hep E infection and transplant.
Thanks dear professor
The article deals with guidelines for Hepatitis E virus (HEV) infection and solid organ transplantation (SOT) published by the British Transplantation Society in 2017.
HEV Biology ant disease: HEV has 4 major genotypes (G1 to G4), with G1 and G2 being restricted to human host. The major route of transmission is feco-oral route. But it can be transmitted through blood components and solid organ transplant. Diagnosis of HEV infection requires detection of antibody, antigen or RNA, as it is clinically indistinguishable from other causes of acute hepatitis.
HEV RNA and/or antigen test must be used for diagnosing HEV infection in transplant recipients (as antibody testing is unreliable in immunosuppressed patients). Transplant specialists should be trained about HEV infection and its management.
Testing of solid organ donors for HEV: The major route of transmission is feco-oral route. But it can be transmitted through blood components and solid organ transplant including liver and renal transplant. Although the risk is very low, all solid organ donors must be screened for HEV. Potential living donors should be provided with dietary advice with respect to avoiding HEV and should undergo HEV-NAAT within 4 weeks of organ donation, which if positive, should defer transplant till stool and plasma HEV RNA is negative. In urgent situations, transplantation can go ahead even with a positive HEV result of donor. Recipients who develop HEV through transplant must be managed as per standard protocol.
Prevention of HEV in SOT recipients: Written dietary advice must be provided to prospective SOT recipients regarding avoiding undercooked/ raw meat (especially processed pork), maintaining adequate hand hygiene, drink boiled or bottled water while travelling to HEV endemic regions. Donated blood is also screened for HEV-NAAT. Vaccination against HEV needs further testing before recommendation.
Surveillance and screening for HEV in SOT: Routine HEV screening of prospective SOT recipients is not required. Screening with HEV RNA or an antigen assay may be done in pre-transplant immunosuppressed patients/ post-transplant with raised liver enzymes or with clinical symptoms. A plasma sample of SOT recipients at the time of transplant can be stored for minimum 1 year for retrospective testing, if the need arises.
Treatment of acute HEV in a patient on the transplant list: Patients with unexplained acute liver failure, or acute on chronic liver failure should be tested for HEV, and those having cirrhosis on liver transplant waiting list, if develop HEV, must be treated with ribavirin (in whim the mortality risk is significant). Patients with HEV associated acute liver failure can be treated with ribavirin (with dose titration as per GFR, and careful monitoring).
Management of HEV infection in SOT recipients:
Acute HEV: Newly diagnosed or acute HEV infection in SOT recipient would require observation, HEV RNA, serology and liver enzyme monitoring as >30% will spontaneously recover within 3 months. Reduction in immunosuppression (CNI and mTOR inhibitors increase HEV replication while MMF inhibit HEV replication) may be considered, but risk of rejection should be assessed. Early treatment with ribavirin may be given in patients with severe hepatic dysfunction (jaundice and coagulopathy), or extra-hepatic manifestations (neurological – Guillian Barre Syndrome, encephalitis, glomerulonephritis, myocarditis, thyroiditis etc).
Persistent HEV infection: When HEV RNA is persistent in blood or stool for >3 months, then persistent HEV infection is diagnosed. 15% of such patients may develop cirrhosis in 3-5 years. Such patients should be given ribavirin (after testing a baseline HEV RNA pre-treatment) with median dosage of 600 mg/day for at least 3 months (majority 3-6 months. Plasma HEV RNA can be tested on day 7 of treatment which might help in predicting the length of treatment required. Monthly testing of plasma and stool HEV should be done and treatment should be stopped once 2 consecutive negative stool results (1 month apart) are obtained. The target is to achieve SVR (sustained virological response) defined as absence of HEV RNA in plasma and stool at 6 months after treatment completion. Post-treatment HEV RNA in plasma and stool should be done at 3 and 6 months after stopping treatment. Ribavirin is associated with hemolytic anemia, hence dose should be adjusted as per creatinine clearance, and regular hemoglobin monitoring should be done, and erythropoietin or blood transfusion might be required. Pegylated interferon is not used as first-line due to risk of precipitating rejection, but may be used in ribavirin-refractory persistent HEV infection. Those who relapse after ribavirin treatment can be retreated with higher doses for minimum 6 months. Use of sofosbuvir in HEV requires further studies.
I like your well structured detailed summary in relation to each advice in relation to the type of disease and corresponding treatment. I appreciate your strategy in relation to Hep E infection and transplant.
Guidelines for Hepatitis E & Solid Organ Transplantation
Introduction:
Hepatitis E is a herpesvirus, infects humans and mammals (pigs), with 4 genotypes, with geographic variations, it is responsible of >50% viral hepatitis worldwide, transmitted via feco-oral route, G3 and 4 transmitted from animal reservoir, or by transfusion of blood products, the prevalence increased with age, mortality observed in pregnant women and children’s < 2 years of age, Hepatitis E V infection is either acute (< 3 months), persistent (3-6 months) or chronic (persist for more than 6 months)
Hepatitis E Biology and Disease:
HEV RNA and/or antigen detection, must be used to diagnose infection in transplant recipients as antibody is unreliable (1B)
Training for all transplant physician about HEV and the clinical consequences is recommended. (Not graded)
Clinical features:
Acute infection(<3 months), usually asymptomatic, but may present with mild hepatitis, rarely presents with a fulminant hepatitis, with high mortality in 3rd trimester of pregnant women of 25% in G1, with fetal comorbidities. – incubation period 2-6 weeks.
Persistent infection (3-6 months), chronic hepatitis (>6months)usually seen in immunocompromised patients, and seen with G3, and rare in G1, once infected, 60% of solid organ transplant recipients fail to clear the virus and are at risk of developing chronic hepatitis.
Extra-hepatic Manifestations, These include thrombocytopenia, glomerulonephritis, acute pancreatitis acute thyroiditis, and neuropathologist have also been described including brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, vestibular neuritis.
Testing of Solid Organ Donors for Hepatitis E:
All solid organ donors recommended to be screened for HEV (1C)
HEV viremia in a donor is not an absolute contra-indication for donation. (2C)
HEV infection through transplantation is managed as other persistently infected individuals. (2C)
Prevention of Hepatitis E in SOT Recipients:
It is recommended for all SOTR to be advised about the risk of HEV from undercooked meat (1D)
Surveillance and Screening for HEV in SOT Recipients:
Routine recipients screening is not recommended. However, it is indicated in immunocompromised with high liver enzymes. (D1)
Testing recipients for HEV (RNA or an antigen) if they have symptoms and have high liver enzymes (1C)
Collect and stored plasma of recipient upon transplantation for at least one year to allow testing for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List:
Any individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Listed individuals with cirrhosis who develop hepatitis E to be treated with ribavirin (2D)
Management of HEV Infection in SOT recipient:
Acute HEV infection(<3months):
Initial management in recipients includes observation and monitoring of HEV RNA levels and liver enzymes (spontaneously resolve in 30 %). (2C)
In acute/ persistent HEV, reducing immunosuppression may help viral clearance, carefully assess risk of rejection. (2C)
Ribavirin cab be considered early in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence is limited. (2D)
Persistent HEV infection(3-6 months):
It is diagnosed if HEV RNA is detectable in blood or stool for >3 months after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Sustained virological response is the aim when treat with ribavirin (no detectable HEV RNA in plasma and stool 6 months after therapy completion) (1C)
Before starting treatment HEV RNA on both plasma and stool is recommended as a baseline. (1C)
Ribavirin treatment should continue for minimum 3 months (mostly 3-6 months) (1C)
Monthly monitoring of HEV RNA (plasma and stool) to guide therapy duration (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart (1C)
Assess sustained virological response at 3 and 6 months after stopping antiviral therapy by testing HBE RNA (plasma and stool). (1C)
Monitor for hemolytic anemia during ribavirin therapy, if occurred ribavirin dose can be reduced. Epoetin therapy and/or blood transfusion can be considered to avoid dose reduction (1A)
PEG-interferon associated with risk of rejection, so should not be used as first line for the treatment (1D)
Plasma HEV RNA is recommended after 7 days of Ribavirin therapy, as it may predict sustained virological response after three months (2C)
Ribavirin dose should be adjusted to creatinine clearance to reduce side effects. (2C)
HEV relapse after ribavirin course should be re-treated for at least 6 months aiming a higher dose if tolerated. (2D)
Routine testing HEV mutations is not indicated prior to antiviral treatment (2D)
Ribavirin- refractory persistent HEV infection, PEG-interferon treatment may be considered with close monitoring for rejection. (2D)
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. I appreciate your strategy in relation to Hep E infection and transplant.
HEV infection is usually self-limited, but in immunosuppressed patients it may have a more severe course
The main route of transmission is through ingestion of undercooked meat (mainly pork), so all transplant recipients should be informed to avoid this type of food
HEV infection is either acute (< 3 months), persistent (3-6 months) or chronic (persist for more than 6 months)
Diagnosis of HEV infection in SOT should be settled by detection of PCR and/or Ag in blood or stool and not by serology as it may be altered by immunosuppression
Screening of all donors is recommended, and HEV is not absolute contraindication for donation
Indications of the HEV testing in renal transplant recipient
Treatment of HEV after transplantation
Monitoring
I like your well structured detailed summary.
I appreciate the need for RNA levels to monitor the effectiveness of treatment of Hep E.
Hepatitis E Biology and Disease:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B).
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded
Testing of Solid Organ Donors for Hepatitis E:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Surveillance and Screening for HEV in Solid Organ Transplant Recipients:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients:
Newly diagnosed or acute HEV infection:
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral
monitoring and antibody profiling may help clinical decision-making. (2C)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achievingsustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the
start of treatment. (1C)
Treatment with ribavirin should continue for atleast three months for solid organ transplant
recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin
treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop
treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month
apart, as continued shedding of HEV in stool is an important factor predicting relapse after
ribavirin treatment. (1C)
A test of sustained virological response is conducted by testing plasma and stool samples for
HEV RNA at three and six months after stopping antiviral therapy. (1C)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. EpoetinNtherapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
HEPATITIS E VIRUS BIOLOGY AND DISEASE:
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E:
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
Individuals who become infected with HEV through transplantation are managed accordingo recommendations pertaining to other persistently infected individuals. (2C)
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS:
Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation ,such as in an immunosuppressed individual with raised liver enzymes. (D1
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (C1)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infection. (2D)
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (C2)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV Infection:
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with treatment for persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
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
Guidelines for Hepatitis E & Solid Organ Transplantation
Introduction
hepatitis E virus (HEV) infection has increased in many developed countries over the last decade.
It implicated in immunosuppressed individuals and if untreated can change to chronic hepatitis E virus infection . Transplant recipients are therefore at risk of developing persistent HEV infection.
Hepatitis E Biology and Disease
HEV infection in transplant recipients must be investigated by HEV RNA as antibody detection is unreliable in immunosuppressed individuals. (1B)
The clinician in transplantation should be knows and training about HEV infection .
Testing of Solid Organ Donors for Hepatitis E .
All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations (1C).
The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant (2C) .
Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C).
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D).
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Potential recipients of solid organ transplants do not need routine screening for HEV
infection. There may be specific instances where testing for HEV is indicated pre
transplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C).
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections.(2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV(2C) .
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
A strategic reduction in immunosuppression is considered in patients with acute or
persistent HEV as this may facilitate viral clearance, but the risk of rejection should be
carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra hepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving
sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic
anaemia is a common treatment-related side effect. Ribavirin dose reduction may be
required during treatment to maintain an adequate haemoglobin concentration. Epoetin
therapy and/or blood transfusion may be indicated to allow continued antiviral therapy
without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in
transplant recipients as there is a moderate risk of precipitating organ rejection. (1D) Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.(2D)
Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral
treatment as the significance of mutations has not been determined. (2D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Summary of the Guidelines
Guidelines for Hepatitis E & Solid Organ Transplantation
1. Hepatitis E Biology and Disease
We recommend that:
· Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
We suggest that:
· All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
2. Testing of Solid Organ Donors for Hepatitis E
We recommend that:
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
We suggest that:
· The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
· Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
3. Prevention of Hepatitis E in Solid Organ Transplant Recipients
We recommend that:
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
4. Surveillance and Screening for HEV in Solid Organ Transplant Recipients
We recommend that:
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pre- transplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
We suggest that:
· Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
5. Treatment of Acute Hepatitis E in a Patient on the Transplant List
We suggest that:
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
6. Management of HEV Infection in Solid Organ Transplant recipients
A. Newly diagnosed or acute HEV infection
We suggest that:
· The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C) · A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra- hepatic manifestations, although evidence for this recommendation is currently limited. (2D)
B. Persistent HEV infection
We recommend that:
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
· Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
· Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
· Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
We suggest that:
· Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
· To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
· Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
Hepatitis E Biology and Disease
-HEV RNA and/or antigen detection are recommended for diagnosis of HEV infection in transplant recipients due to inadequate Ab response.
Solid organ donors testing for HEV
Is done for all solid organ donors according to UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations.
Hepatitis E prevention in SOT Recipients
Individuals must be educated about HEV infection risks including consuming undercooked meat pre and post transplant.
HEV screening and surveillance in SOT recipients
-It is not routinely indicated in all cases ,only in certain cases as immunosuppressed ones with elevated liver enzymes using HEV RNA or an antigen assay.
-It is suggested that recipients need a plasma sample taken at transplantation time and stored for a minimum of 1 year then tested retrospectively for HEV or other infections.
Acute Hepatitis E in a Patient on the Transplant List treatment
-Cases with chronic or acute liver failure need HEV testing
– Ribavirin therapy is recommended for cases having cirrhosis with hepatitis E awaiting on the liver transplant waiting list.
HEV Infection in SOT recipients mangement
Newly diagnosed or acute HEV infection
-Dynamic HEV RNA monitoring, Ab profiling and liver enzymes follow up can aid decision-making as 30% can spontaneously get cured within 3 months.
-Cautious reduction of immunosuppression can be done with assessing rejection risk.
-HEV viraemia is not an absolute contraindication for organ donation, but subjected to clinical decision.
-There is limited evidence for using ribavirin for those with acute hepatitis E ,severe liver dysfunction and extrahepatic manifestations
Persistent HEV infection
-It is diagnosed when HEV RNA is noticed in blood or stool for >3 months after symptoms onset, elevated liver enzymes, or from the first positive HEV RNA test
-Treated with Ribavirin to attain sustained viral response mostly for 3-6 months, till HEV RNA stool tests for HEV RNA are negative on 2 occasions one month apart.
-A baseline quantitative HEV RNA level need to be detected in plasma and stool as treatment starts.
-HEV RNA testing in plasma and stool on monthly bases is needed till stopping treatment decision is taken.
-HEV RNA testing at 3 and 6 months after stopping antiviral therapy is essential to assess sustained virological response.
-Ribavirin can cause haemolytic anemia managed by dose reduction ,Epoetin therapy and/or blood transfusion
-Peg INF is not used to organ rejection risk.
It is suggested
– to adjust Ribavirin dose according to creatinine clearance
-cases with relapse after ribavirin therapy need retreatment for 6 months at least ,need re-treatment with ribavirin at higher dose range.
-Ribavirin-refractory persistent HEV infection can be treated with PEG INF along with caution for rejection.
I like your well structured detailed summary. I appreciate your strategy in relation to Hep E infection and transplant.
Hepatitis E and SOT
Hepatitis E Biology and Disease
We recommend
We suggest
Testing of SOD for HBE
We recommend
We suggest
Prevention of HE in SOT recipients
we recommend
Surveillance and screening for HEV in SOT recipients
W recommend
We suggest
Treatment of acute HE infection in a patient on the transplant list
We suggest
Treatment of HEV infection in SOT recipients
Newly diagnosed or acute HEV infection
We suggest
Persistent HEV infection
We recommend
We suggest
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.
Thank you very much Prof.
Guidelines for Hepatitis E & Solid Organ Transplantation
Hepatitis E Biology and Disease
· The prevalence of HEV is increasing and the clinical consequences of infection can be significant.
· It is recommended that HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients
Testing of Solid Organ Donors for Hepatitis E
· All solid organ donors are screened for HEV
· It is suggested the detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor.
Prevention of Hepatitis E in Solid Organ Transplant Recipients
· Individuals must receive written advice regarding the risk of HEV from undercooked meat.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
· It is recommended that not all potential recipients of solid organ transplants are screened for HEV infection.
· It is tested for example in an immunosuppressed individual with raised liver enzymes.
They suggested that transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections.
Treatment of Acute Hepatitis E in a Patient on the Transplant List
· It is suggested that individuals with unexplained acute on chronic or acute liver failure should be tested for HEV.
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list.
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
It is suggested that:
· The initial management of acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as spontaneous clearance can occur within three months
· Reduction in immunosuppression is considered in patients with acute or persistent HEV
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E.
Persistent HEV infection
It is recommended that
· Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after acute infection.
· Individuals with persistent HEV infection receive treatment with ribavirin with the aim of achieving sustained virological response.
· For most individuals 3-6 months of ribavirin treatment will suffice.
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection.
It is suggested that:
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range.
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection.
I like your well structured detailed summary. I appreciate your strategy in relation to Hep E infection and transplant.
Summarise these guidelines
This is the first British Transplantation Society (BTS) guideline of hepatitis E in the transplant setting [Guidelines for Hepatitis E & Solid Organ Transplantation (SOT), April 2017]
Definitions of Hepatitis E (in this Guideline):
Hepatitis E: Clinical hepatitis caused by acute HEV infection
Acute HEV: Acute infection with HEV that may or may not be symptomatic
Persistent HEV: HEV RNA detectable for three months or more
HEPATITIS E VIRUS BIOLOGY AND DISEASE
Introduction
o Genus Hepevirus (Hepeviridae family)
o Infects humans and animals
o Four genotypes:
1. G2: only in human (occurs in Asia and Africa)
2. G2: only in human (Mexico and Africa)
3. G3: humans, pigs and other mammalian species (worldwide distribution)
4. G4: humans and pigs (principally in South East Asia)
Epidemiology
Developing World
o Responsible for >50% of cases of viral hepatitis
o Transmitted via the faecal oral route (contaminated food and water)
o Mainly young adults (15 and 39 years) and slightly common in male
o Prevalence rates is 47% and 50% in Nepal and Bangladesh respectively (no differences noted by gender)
Developed World
o HEV G3 and G4 are zoonotic infections (pork products and game meat)
o More in males (> 50 years)
o Seroprevalence: 1%-50%
Hepatitis E Virus in England
o Genotype 3 virus (group 1 and group 2)
o Seroprevalence rates in the general population are high (~13%)
o 93% of UK pigs are HEV antibody positive (20% having detectable HEV RNA)
Transfusion Transmitted HEV
o Seroprevalence rates range from 6%-46% in blood donors
o In the UK, universal screening of all blood components for HEV is now recommended by the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO)
Clinical Features
Acute Hepatitis E
o Range from asymptomatic infection to mild hepatitis to fulminant liver failure (influenced greatly by genotype, age, gender of the patient)
o Symptoms include general malaise, abdominal pain, anorexia, nausea and fever and are (followed by jaundice with dark urine, pale stools and pruritis)
o Most infections are self-limiting
o Mortality rate in the developing world is 0.5 – 4% (G1 virus). In pregnancy mortality rate is 25%, particularly in the third trimester. Spontaneous abortion, stillbirth and neonatal death also increased. Infection is associated with G1 and not with G3 infection
o In patients with underlying liver disease may lead to decompensation and a poor outcome
Persistent HEV Infection
o Can leads to chronic hepatitis in immunosuppressed populations including solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals
o All infection is G3 with the exception of one G4 (47) and one G7 (camelid) (48) virus
o No reports of G1 and G2 viruses
o Clinical features are often unremarkable (liver transaminases are usually only very modestly raised and few patients present with any symptoms)
o In SOT, 60% fail to clear the virus and are at risk of developing chronic hepatitis. Liver biopsy shows rapid progression of liver fibrosis with 10% of patients progressing to cirrhosis over a few years
o Factors associated with failure to clear HEV include low leucocyte, total lymphocyte and T-cell counts
o In the HIV patients, they have low CD4 counts. Viral clearance following treatment is associated with the recovery of CD4 levels and can present as an immune reconstitution hepatitis
Extrahepatic Manifestations
o In both acute and persistent hepatitis E infection
o Include thrombocytopenia, glomerulonephritis, acute pancreatitis, acute thyroiditis, and neuropathologies (brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, neuromyopathy, and vestibular neuritis)
Diagnosis of Hepatitis E
For acute hepatitis, use antibody, antigen and RNA methods (cannot be clinically distinguished from other causes of acute hepatitis)
Incubation period is 2-6 weeks (after this, first initial short-lived IgM response followed by more durable IgG antibodies)
Enzyme immunoassays or rapid immunochromatographic kits for the detection of specific IgM antibodies
Antigen ELISAs are less sensitive than molecular methods (but they provide a more rapid and accessible method for identifying current HEV infection)
HEV RNA can be detected a few weeks before the onset of clinical symptoms in both blood and stool samples
The diagnosis of persistent hepatitis E infection is challenging as infections are usually asymptomatic (detection of the virus itself, either through HEV RNA testing or HEV antigen testing, as antibody detection in the immunosuppressed population is not a reliable marker of infection)
Statements of Recommendation
o We recommend that virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
o We suggest that all clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E
Introduction
o HEV can be transmitted at the time of SOT, either with the transplanted organ or through blood components from an HEV-infected donor
o Pre-transplant immunosuppression may allow potential recipients to become persistently infected before transplantation, and acute infection may also occur in the potential transplant recipient
Living Solid Organ Donors
o Dietary advice to avoid of HEV infection
o Screening with HEV-NAAT within four weeks of organ donation
o If HEV viraemia is detected, living organ donation should be deferred until laboratory testing confirms spontaneous resolution of HEV infection (plasma and stool HEV RNA not detected)
o In situations of great urgency (paediatric living liver donation), that life saving donation may still be considered from individuals known to be viraemic, although the risk to the donor in this situation is not known
HEV Donor Testing
o In deceased organ donation, HEV-NAAT results should be available between 24 and 28 hours after transplantation to inform ongoing clinical management of the recipient
o The absence of HEV-NAAT test results will not, and should not, influence decisions regarding the use of organs
o The identification of deceased donors with HEV viraemia is important, even after transplantation has occurred, because it allows for appropriate posttransplant recipient monitoring, the possible modification of immunosuppressive therapy, or the use of antiviral therapy for those recipients that do not spontaneously clear the virus
Management of Transplant Recipients who Receive an Organ from an HEV Viraemic Donor
o Not known
o Individuals who become persistently infected with HEV through transplantation, recommended to be managed according to recommendations pertaining to other persistently infected individuals
Statements of Recommendation
o We recommend that all solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
o We suggest that the detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
o We suggest that individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
Dietary Advice
o Infectious HEV can survive for long periods (more than one month) in food products, particularly when stored at 4°C
o Not easily inactivated by cooking and can remain infectious when cooked at temperatures of < 80° C for less than two minutes
o Not inactivated when heated to 56° C or 60 °C even for long periods (1 hour)
Transfusion of Blood Products
o From April 2017, donated blood in the UK are screened for HEV using HEV-NAAT testing
o Overall prevalence is 1 in 2848 (study in England, G3). The transmission rate is 42% in viraemic (HEV RNA), which equates to an approximate rate of transmission of 1 in 5000 transfusions
Immunisation against HEV
o Possible through immunization
o Recombinant G1 vaccines in China (Hecolin®, Xiamen Innovax Biotech)
Statements of Recommendation
o We recommend that individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS
Post-transplant Screening or Surveillance for HEV in SOT Recipients
Seroprevalence rates is 8.3%-43% for anti-HEV antibodies (HEV RNA ranged from 0-3.2%)
The transplant patient may acquire HEV in two ways:
1. through diet, which is a continuing cumulative risk
2. through the receipt of substances of human origin (SOHO) including organs and blood components, which is a temporally constrained risk
Options for screening/surveillance could potentially be offered:
1. Test all transplant recipients annually using HEV RNA or HEV Antigen testing (insufficient evidence to support and this would be a costly intervention)
2. Test transplant recipients for HEV RNA who have raised liver enzymes or symptoms suggestive of HEV (e.g. neurological symptoms)
Statements of Recommendation
o We recommend that potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pre-transplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
o We recommend that SOT recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
o We suggest that transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST
Acute HEV in Cirrhotic Patients on the Transplant List
o In pre-existing cirrhosis and liver dysfunction acute symptomatic HEV infection can precipitate acute on chronic liver failure (ACLF), which is associated with a mortality of approximately 50% at three months
o Treatment with ribavirin is safe, although dose reduction in ribavirin was required for anaemia in some patients, with treatment duration ranging up to one month
o HEV infection occurring in a patient on the liver transplant waiting list is not an absolute contraindication to transplantation
Treatment of Patients with Acute Liver Failure due to Acute Hepatitis E
o Acute liver failure is characterised by severe liver dysfunction (jaundice, coagulopathy and hepatic encephalopathy) on a background of a previously ‘normal’ liver
o HEV is a common cause of acute hepatitis, but rarely causes fulminant liver failure
o The role of ribavirin in HEV-associated acute liver failure is not known
o Treat with ribavirin in patients with HEV viremia and liver failure (renal dose reduction)
o There are reports of successful transplantation for HEV-associated acute liver failure
Statements of Recommendation
o We suggest that individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
o We suggest that treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
Management of Acute HEV Infection Post-transplantation
o If HEV RNA not cleared from the blood and stool by three months, persistent infection is likely to occur and the patient should be managed as having persistent HEV infection
o HEV infection (acute and persistent) can be associated with extrahepatic syndromes, particularly neurological manifestations (Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis, Renal (glomerulonephritis with and without cryoglobulinaemia), cardiac (myocarditis), and autoimmune extrahepatic manifestations (e.g. thyroiditis and thrombocytopenia)
Treatment of Persistent Hepatitis E Post-transplantation
o Following acute infection with HEV G3, the infection persists in approximately 60% of SOT recipients leading to persistent HEV infection. This can cause a chronic hepatitis that can progress rapidly (3-5 years) to cirrhosis in approximately 15% of infected SOT recipients
o Persistent HEV infection should be treated with the aim of clearing HEV from the blood and stool
Chronic HEV infection:
o Detectable HEV RNA in the blood and/ or stool for greater than six months (treat after 3 months)
o The most common symptom is fatigue (jaundice is rare)
o Neurological symptoms can also occur
o Typically ALT levels are between 200-300 U/L in transplant recipients, but patients with may also present with minimally raised liver enzymes or enzymes within the upper normal range
o Persistent HEV infection can be misdiagnosed as drug-induced liver injury, rejection (in liver transplants) or graft versus host disease
Modification of immunosuppression:
Lead to clearance of HEV infection in 30% of individuals with persistent HEV
In vitro effect:
o ciclosporin increased HEV viral replication in a dose-dependent manner and may therefore potentiate infection with HEV
o Tacrolimus increased HEV replication in a cell culture model (at high dosages)
o mTOR inhibitors potentiate HEV replication
o Corticosteroids had no effect
o mycophenolate inhibit HEV replication. This effect was potentiated with the addition of ribavirin
Antiviral therapy:
1. Ribavirin:
2. PEG-interferon
3. Sofosbuvir
Ribavirin:
o Reduce HEV replication in vitro by reducing intracellular pools of GTPPEG-interferon
o A guanosine analogue and may also act as a nucleoside inhibitor, inhibiting replicating HEV RNA
o Sustained virological response (HEV RNA negative six months post-treatment) varies from 63-82%
o Persisting HEV in the stool, even after clearance from the blood suggests ongoing HEV infection
o Dose ranges from 200-1200 mg per day (a median dosage of 600 mg/day)
o Dose regimen according to the creatinine clearance calculated by the Cockcroft-Gault equation
o Side effects: haemolytic anaemia is the most one and required intervention in 40% (dose reduction, epoetin or blood transfusion). Regular monitoring of haemoglobin on treatment, initially every two weeks until the haemoglobin has reached nadir then monthly thereafter. Dose reduction is recommended when the haemoglobin falls below 100 g/L
o Treatment failure with ribavirin treatment: 40% with persistent HEV relapse after three months of treatment
o Reasons for treatment failure include:
1. dose reduction due to side effects
2. insufficient duration of treatment to clear HEV from both blood and stool
3. G1634R mutation
o The majority of patients who relapse will respond to a longer course of treatment
o Treat until the HEV RNA is negative in blood and stool on two tests at least one month apart (6 months or longer)
PEG-interferon
o A few reports of successful treatment of persistent HEV (75% sustained virological response)
o Well known to increase the risk of rejection in transplant recipients
o Considered in ribavirin refractory HEV, particularly if associated with ribavirin resistance mutations (close monitoring for rejection)
Sofosbuvir
o A pangenotypic nucleotide analog (licensed for the treatment of HCV)
o In a recent study, suggested that inhibit HEV RNA replication in an experimental model of HEV
Statements of Recommendation
Newly diagnosed or acute HEV infection
o We suggest that the initial management of newly diagnosed or acute HEV infection in SOT recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
o We suggest that a strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
o We suggest that early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection
o We recommend that persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
o We recommend that individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
o We recommend that a baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
o We recommend that treatment with ribavirin should continue for at least three months for SOT recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
o We recommend that monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
o We recommend that ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
o We recommend that a test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
o We recommend that regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
o We recommend that PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
o We suggest that assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
o We suggest that to minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
o We suggest that patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
o We suggest that routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
o We suggest that PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
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 E Biology and Disease
– HEV RNA and/or antigen detection, must be used to diagnose infection in transplant recipients as antibody is unreliable (1B)
– Training for all transplant physician about HEV and the clinical consequences is recommended. (Not graded)
Testing of Solid Organ Donors for Hepatitis E
– All solid organ donors recommended to be screened for HEV (1C)
– HEV viremia in a donor is not an absolute contra-indication for donation. (2C)
– HEV infection through transplantation is managed as other persistently infected individuals. (2C)
Prevention of Hepatitis E in SOT Recipients
-It is recommended for all SOTR to be advised about the risk of HEV from undercooked meat (1D)
Surveillance and Screening for HEV in SOT Recipients
-Routine recipients screening is not recommended. However, it is indicated in immunocompromised with high lever enzymes. (D1)
– Testing recipients for HEV (RNA or an antigen) if they have symptoms and have high liver enzymes (1C)
– Collect and stored plasma of recipient upon transplantation for at least one year to allow testing for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
-Any individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
– Listed individuals with cirrhosis who develop hepatitis E to be treated with ribavirin (2D)
Management of HEV Infection in SOT recipient:
Acute HEV infection
-Initial management in recipients includes observation and monitoring of HEV RNA levels and liver enzymes ( spontaneously resolve in 30 %). (2C)
– In acute/ persistent HEV, reducing immunosuppression may help viral clearance, carefully assess risk of rejection. (2C)
-Ribavirin cab be considered early in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence is limited. (2D)
Persistent HEV infection
– It is diagnosed if HEV RNA is detectable in blood or stool for >3 months after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
– Sustained virological response is the aim when treat with ribavirin (no detectable HEV RNA in plasma and stool 6 months after therapy completion) (1C)
– Before starting treatment HEV RNA on both plasma and stool is recommended as a baseline. (1C)
– Ribavirin treatment should continue for minimum 3 months (mostly 3-6 months) (1C)
– Monthly monitoring of HEV RNA (plasma and stool) to guide therapy duration (1C)
– Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart (1C)
– Assess sustained virological response at 3 and 6 months after stopping antiviral therapy by testing HBE RNA (plasma and stool). (1C)
– Monitor for hemolytic anemia during ribavirin therapy, if occurred ribavirin dose can be reduced. Epoetin therapy and/or blood transfusion can be considered to avoid dose reduction (1A)
– PEG-interferon associated with risk of rejection, so should not be used as first line for the treatment (1D)
– Plasma HEV RNA is recommended after 7 days of Ribavirin therapy, as it may predict sustained virological response after three months (2C)
– Ribavirin dose should be adjusted to creatinine clearance to reduce side effects. (2C)
– HEV relapse after ribavirin course should be re-treated for at least 6 months aiming a higher dose if tolerated. (2D)
-Routine testing HEV mutations is not indicated prior to antiviral treatment (2D)
– Ribavirin-refractory persistent HEV infection, PEG-interferon treatment may be considered with close monitoring for rejection. (2D)
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.
DEFINTIONS OF HEPATITIS E USED IN THIS GUIDELINES ;
————————————————————————————-
1-Hepatitis E ;
Clinical hepatitis caused by acute HEV infection.
2-Acute HEV;
Acute infection with HEV that may or may not be symptomatic
3-Persistent HEV;
HEV RNA detectable for three months or more.
VIRUS SPECIIC TESTS ;
—————————————————————————
The guidelines recommend using HEV RNA and/or antigen detection to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B).
The guidelines suggest that ;All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded).
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E;
—————————————————————————————–
The guidelines recommend screening of all solid organ donors for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C).
Also it suggest that;
1-The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
2- Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C).
PREVENTION OF HEPATITIS E IN SOLID ORGAN TRANSPLANT RECIPIENTS ;
————————————————————————————————————-
The guidelines recommend that: Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D).
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENT ;
————————————————————————————————
The guidelines recommend that:In the potential recipients ;
1-no need to perform screening for HEV infection if there is no raised liver enzyme (D1).
2- Testing for HEV using an HEV RNA or an antigen assay when liver transaminases are above the upper limit of normal or symptoms suggestive of HEV infection (1C) .
The guidelines suggest that:
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D).
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST ;
———————————————————————————————————–
The guidelines suggest that:
1-In the presence of unexplained acute on chronic or acute liver failure individuals should be screened for HEV. (2C)
2-Treatment with ribavirin should be offered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D).
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS ;
————————————————————————————————————
1-Newly diagnosed or acute HEV infection;
————————————————————–
The guidelines suggest that:
A-The initial management includes observation and monitoring of HEV RNA levels and liver enzymes.(2C).
B- Reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
C-Ribavirin may be considered in specific cases of acute hepatitis E or extra- hepatic manifestations. (2D).
PERSISTENT HEV INFECTION ;
———————————————–
The guidelines recommend that:
1-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
2-Individuals with persistent HEV infection should receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
3-A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
4-The duration of treatment with ribavirin should be at least three months for solid organ transplant recipients with persistent HEV infection(1C)
5- Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
6-Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
7- PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
The guidelines suggest that:
1-quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
2-To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance. (2C)
3-Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated.
(2D)
4-Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
5-PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
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
Guidelines regarding Hepatitis E and Solid Organ Transplantation
The following recommendations have been made by the British Transplantation Society regarding hepatitis E in the setting of solid organ transplantation because of the disease burden that leads to significant liver fibrosis.
I like your well structured detailed summary. I appreciate your strategy in relation to Hep E infection and transplant.
Summarise this article
Introduction:
Hepatitis E is a hepevirus, infects humans an mammals (pigs), with 4 genotyps, with geographic variations, it is responsible of >50% viral hepatitis worldwide, transmitted via feco-oral route, G3 and 4 transmitted from animal reservoir, or by transfusion of blood products, the prevalence increased with age, mortality observed in pregnant women and childrens < 2 years of age.
Clinical features:
Acute infection – usually asymptomatic, but may present with mild hepatitis, rarely presents with a fulminant hepatitis, with high mortality in 3rd trimester of pregnant women of 25% in G1, with fetal comorbidities.- incubation period 2-6 weeks.
Persistent infection – chronic hepatitis usually seen in immunocompromised patients, and seen with G3,and rare in G1, Once infected, 60% of solid organ transplant recipients fail to clear the virus and are at risk of developing chronic hepatitis.
Extrahepatic Manifestations – These include thrombocytopenia, glomerulonephritis, acute pancreatitis acute thyroiditis, and neuropathologies have also been described including brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, vestibular neuritis.
Diagnosis:
Antibodies titer (ELISA) of IgM and IgG – identify acute infections.
HEV RNA, and antigen testing – identify persistent disease and in immunocompromised patients
Definitions of Hepatitis E:
Hepatitis E= Clinical hepatitis caused by acute HEV infection.
Acute HEV= Acute infection with HEV that may or may not be symptomatic.
Persistent HEV= HEV RNA detectable for three months or more.
Hepatitis E Biology and Disease:
HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Testing of Solid Organ Donors for Hepatitis E:
All solid organ donors screened for HEV. (1C)
HEV viraemia in a donor is not an absolute contraindication to organ donation, but will inform clinical management decisions post-transplant. (2C)
Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients:
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
Vaccination is an option for disease prevention in china, not approved elsewhere.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients:
Recipients of solid organ transplants do not need routine screening for HEV infection, may be indicated pretransplantation, in an immunosuppressed individual with raised liver enzymes.(1D)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List:
Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients:
Newly diagnosed or acute HEV infection-
The initial management of newly diagnosed or acute HEV infection is observation and monitoring of HEV RNA levels and liver enzymes, > 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
A reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in: (1) patients who develop severe liver dysfunction (jaundice and coagulopathy). (2) extrahepatic manifestations.(2D)
Persistent HEV infection-
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Individuals with persistent HEV infection, receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
Treatment with ribavirin should continue for at least 3 months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment.(1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Usually treatment with ribavirin is stopped at 3 month when two HEV RNA negative for two occasion one month apart.(1C)
Sustained virological response, by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
Haemolytic anaemia is a common treatment-related side effect, hence frequent (Hgb) monitoring is a must. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment.(2C)
The dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation- reduce side effects (2C)
Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D) or in combination with sofosbuvir.
Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment. (2D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Mycophenolate inhibits viral replication, but m-TOR and CNI potentiate viral replication.
I like your well structured detailed summary. I appreciate your strategy in relation to Hep E infection and transplant.
Guidelines for Hepatitis E & Solid Organ Transplantation
Hepatitis E Biology and Disease
Testing of Solid Organ Donors for Hepatitis E
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
Persistent HEV infection
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.
III. Guidelines for Hepatitis E & Solid Organ Transplantation
Introduction
Epidemiology
====================================================================
EXECUTIVE SUMMARY OF RECOMMENDATIONS
Hepatitis E Biology and Disease
We recommend that:
We suggest that:
Testing of Solid Organ Donors for Hepatitis E
We recommend that:
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Management of HEV Infection in Solid Organ Transplant recipients
Newly diagnosed or acute HEV infection
Persistent HEV infection
We suggest that:
TESTING OF SOLID ORGAN DONORS FOR HEPATITIS E
Statements of Recommendation
PREVENTION OF HEPATITIS E INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
SURVEILLANCE AND SCREENING FOR HEV IN SOLID ORGAN TRANSPLANT RECIPIENTS
Statements of Recommendation
TREATMENT OF ACUTE HEPATITIS E IN A PATIENT ON THE TRANSPLANT LIST
Statements of Recommendation
MANAGEMENT OF HEV INFECTION IN SOLID ORGAN TRANSPLANT RECIPIENTS
====================================================================
I like your well structured detailed summary.
I appreciate the need for RNA levels to assess effectiveness of treatment of by ribavarin or PEG-IF
Many thanks Prof.Sharma
SUMMARY
Introduction
The Hepatitis E virus belongs to the family of Hepaviridea and is known to infect both humans and animals. It has four genotypes (G1-G4) with G1 and G2 being the major public health concerns, particularly in the developing world, while G3 and G4 are in the developed world.
Executive Summary of Recommendations
Hepatitis E Biology and Disease
Solid Organ Donors for Hepatitis E
Prevention of Hepatitis E in Solid Organ Transplant Recipients
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
Treatment of Acute Hepatitis E in a Patient on the Transplant List
Management of HEV Infection in Solid Organ Transplant recipients
Treatment of persistent HEV infection
I like your well structured detailed summary.
I appreciate the need for RNA levels to assess effectiveness of treatment of by ribavarin.
Hepatitis E: clinical hepatitis caused by acute HEV infection.
Acute HEV: acute infection with HEV that may or may not symptomatic.
Persistent HEV infection: detection of HEV RNA for 3 months or more after onset of symptoms, increased liver enzymes or first positive HEV RNA test.
Screening for HEV in SOT recipients:
Treatment of acute hepatitis E in patients on transplant list:
Management of HEV infection in SOT recipients:
I like your well structured detailed summary.
I appreciate the need for RNA levels to assess effectiveness of treatment of by ribavarin.
Recommendations & suggestions :(Level 1 = recommendation, level 2 is suggestion)
Hepatitis E Biology and Disease
Testing of solid organ donor for HEV
Prevention of hepatitis E in solid organ transplantation (SOT)
Surveillance and screening for HEN in SOT
Treatment of acute HEV in a patient on the transplant list
Management of HEV in SOT
A.Newly diagnosed infection
B.Persistent infection
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.
Thnx prof
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
Definitions of Hepatitis E used in this Guideline
Hepatitis E Clinical hepatitis caused by acute HEV infection
Acute HEV Acute infection with HEV that may or may not be symptomatic
Persistent HEV HEV RNA detectable for three months or more
Acute Hepatitis E
The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure and are influenced greatly by genotype and by the age and gender of the patient.
Symptoms (general malaise, abdominal pain, anorexia, nausea and fever and are followed by the onset of jaundice accompanied by dark urine, pale stools and pruritis.) Most infections are self-limiting. Data reported mainly from the G1 virus in the developing world suggest a mortality rate of between 0.5 – 4%
. This increases markedly to approximately 25% among pregnant women, particularly in the third trimester . Spontaneous abortion, stillbirth and neonatal death are also increased. This poor outcome of infection during pregnancy appears only to be associated with G1 infection and is seen not with G3 infection.
Persistent HEV Infection Persistent infection leading to chronic hepatitis has been reported in immunosuppressed populations including solid organ transplant recipients, patients with haematological disorders receiving chemotherapy, and HIV-infected individuals With the exception of one G4 and one G7
. Liver transaminases are usually only very modestly raised and few patients present with any symptoms
Once infected, 60% of solid organ transplant recipients fail to clear the virus and are at risk of developing chronic hepatitis
Liver biopsy shows rapid progression of liver fibrosis with 10% of patients progressing to cirrhosis over a few years
Factors such as low leucocyte, total lymphocyte and T-cell counts are associated with failure to clear HEV
In the HIV setting, patients who develop chronic infection have low CD4 counts
Viral clearance following treatment in HIV-infected individuals is associated with the recovery of CD4 levels and can present as an immune reconstitution hepatitis
Extrahepatic Manifestations linked both to acute and to persistent hepatitis E infection have been reported. These include thrombocytopenia, glomerulonephritis, acute pancreatitis and acute thyroiditis -brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, neuromyopathy, and vestibular neuritis
With regards to solid organ donation
the Committee recommends that all organ donors be individually screened for hepatitis E viraemia. The detection of viraemia is unlikely to be an absolute contra-indication to use of an organ from a donor
In the setting of living donation, it is recommended that potential donors be provided with dietary advice regarding avoidance of HEV infection and that screening with HEV-NAAT be undertaken within four weeks of organ donation
Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D
Modification of immunosuppression
Persistent HEV infection occurs mainly in heavily immunosuppressed individuals, particularly those on T cell suppressing drugs.
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV
Different classes of immunosuppressant drugs have different effects on HEV replication
ciclosporin increased HEV viral replication in a dose-dependent manner and may therefore potentiate infection with HEV
Tacrolimus also increased HEV replication in a cell culture model; however, this effect was only seen at high dosages.
mTOR inhibitors also appeared to potentiate HEV replication
. Corticosteroids had no effect on HEV replication
mycophenolate was shown to inhibit HEV replication
This effect was potentiated with the addition of ribavirin.
I appreciate your understanding about the need to modify immunosupression when infected with Hep E, well-supported by level of recommendation.
Hepatitis E Pathogenesis:
As antibody detection is inconsistent in immunosuppressed transplant patients, we propose virus-specific testing, such as HEV RNA and/or antigen detection to identify HEV infection. (1B)
We recommend that all transplant doctors get HEV (acute and persistent) training due to its rising frequency and serious clinical repercussions.
Solid Organ Donor Hepatitis E Testing:
The UK Advisory Committee for the Safety of Blood, Tissues, and Organs (SaBTO) recommends screening all solid organ donors for HEV. (1C)
We propose that: HEV viremia in a donor is not an absolute contraindication to organ usage but will guide clinical treatment choices post-transplant. (2C)
HEV-transplanted patients are treated like other chronically infected patients. (2C)
Solid Organ Transplant Hepatitis E Prevention:
Before and after transplantation, individuals should get written counseling on HEV risk from undercooked meat, especially processed pork. (1D)
HEV screening in solid organ transplant recipients:
We advise against HEV screening for solid organ transplant candidates. In immunosuppressed patients with elevated liver enzymes, pretransplantation HEV testing may be advised. (D1)
HEV RNA or antigen assays are performed on solid organ transplant patients with elevated liver transaminases or HEV symptoms. (1C)
We recommend that transplant patients have a plasma sample collected upon transplantation and preserved for a year to screen for HEV or other infections.
(2D)
Acute Hepatitis E Therapy in Transplant Candidates:
We recommend HEV testing for unexplained acute or chronic liver failure.
(2C)
Hepatitis E in liver transplant candidates with cirrhosis may be treated with ribavirin. (2D)
HEV Infection Treatment in Solid Organ Transplant Recipients:
Recent HEV infection
As more than 30% of solid organ transplant patients may spontaneously eliminate HEV infection within three months, we recommend monitoring HEV RNA levels and liver enzymes. Real-time viral surveillance and antibody profiling may aid clinical decision-making. (2C)
In individuals with acute or chronic HEV, reducing immunosuppression may help viral clearance, although the risk of rejection must be addressed. (2C)
Acute hepatitis E patients with severe liver dysfunction (jaundice and coagulopathy) or extrahepatic symptoms may benefit from early ribavirin therapy, although the available data is weak. (2D)
HEV infection that persists:
HEV infection may continue if HEV RNA is found in blood or stool for more than three months after relevant symptoms, raised liver enzymes, or the first positive HEV RNA test. (1C)
Ribavirin is given to those with persistent HEV infection (greater than three months) (HEV RNA is not found in plasma or stool six months after treatment completion). (1C)
At the start of treatment, plasma, and stool are measured for quantitative HEV RNA. (1C)
Chronic HEV patients with solid organ transplants should take ribavirin for three months. Ribavirin is usually used for 3–6 months. (1C)
Monthly plasma and stool HEV RNA testing continues until treatment is stopped. (1C)
Ribavirin is continued until two stool tests are negative for HEV RNA, one month apart, to prevent a recurrence. (1C)
For sustained virological response, plasma and stool samples are examined for HEV RNA three and six months after stopping antiviral therapy. (1C)
Ribavirin may cause hemolytic anemia, hence, hemoglobin testing is done often. Ribavirin dose reduction may be needed to maintain hemoglobin throughout treatment. Blood transfusions or epoetin therapy may be needed to extend antiviral treatment without decreasing medication. (1A)
Due to a moderate risk of organ rejection, transplant patients with chronic HEV should not use PEG-interferon as a first-line treatment. (1D)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
Guidelines for Hepatitis E & Solid Organ Transplantation:
1-Hepatitis E virus Biology and Disease:
Recommendation;
-Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals. (1B)
Suggestion;
-All clinicians managing transplant recipients should receive specific training about HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of infection can be significant. (Not graded)
2-Testing of Solid Organ Donors for Hepatitis E:
Recommendation;
-All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)
Suggestion;
-The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
-Individuals who become infected with HEV through transplantation are managed according to recommendations pertaining to other persistently infected individuals. (2C)
3-Prevention of Hepatitis E infection in Solid Organ Transplant Recipients:
Recommendation;
-Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D)
4-Surveillance and Screening for HEV in Solid Organ Transplant Recipients:
Recommendation;
-Potential recipients of solid organ transplants do not need routine screening for HEV infection. There may be specific instances where testing for HEV is indicated pretransplantation, such as in an immunosuppressed individual with raised liver enzymes. (D1)
-Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Suggestion;
-Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
5-Treatment of Acute Hepatitis E in a Patient on the Transplant List:
Suggestion;
-Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
-Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
6-Management of HEV Infection in Solid Organ Transplant recipients:
Newly diagnosed or acute HEV infection;
Suggestion;
-The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months. Dynamic viral monitoring and antibody profiling may help clinical decision-making. (2C)
-A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
-Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D)
Persistent HEV infection;
Recommendation;
-Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
-Individuals with persistent HEV infection (documented or estimated duration of infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
-A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
-Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
-Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C)
-Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
-A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
-Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
-PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
Suggestion;
-Assessment of the change in plasma HEV RNA after seven days of ribavirin treatment may help predict the chance of achieving sustained virological response after three months of ribavirin treatment, and therefore suggest quantitative testing of a plasma sample taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
-To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
-Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
-Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral treatment as the significance of mutations has not been determined. (2D)
-PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.
Guidelines for Hepatitis E & Solid Organ Transplantation, British Transplantation Society Guidelines, 2017
· We recommend that: Virus specific tests, including HEV RNA and/or antigen detection, must be used to diagnose HEV infection in transplant recipients as antibody detection is unreliable in immunosuppressed individuals.
· All solid organ donors are screened for HEV in line with the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. The detection of HEV viraemia in a donor is not an absolute contra-indication to use of an organ from that donor, but will inform clinical management decisions post-transplant. (2C)
Prevention of Hepatitis E in Solid Organ Transplant Recipients:
· Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation. (1D
Surveillance and Screening for HEV in Solid Organ Transplant Recipients
· Potential recipients of solid organ transplants do not need routine screening for HEV infection. However, testing for HEV is indicated pre-transplantation in an immunosuppressed individual with raised liver enzymes. (D1)
· Solid organ transplant recipients with liver transaminases above the upper limit of normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay. (1C)
Transplant recipients have a plasma sample taken at the time of transplantation and stored for a minimum of one year that could be tested retrospectively for HEV or other infections. (2D)
Treatment of Acute Hepatitis E in a Patient on the Transplant List
· Individuals with unexplained acute on chronic or acute liver failure should be tested for HEV. (2C)
· Treatment with ribavirin is considered for patients with cirrhosis who develop hepatitis E when on the liver transplant waiting list. (2D)
Management of HEV Infection in Solid Organ Transplant recipients
For Newly diagnosed or acute HEV infection:
· The initial management of newly diagnosed or acute HEV infection in solid organ transplant recipients includes observation and monitoring of HEV RNA levels and liver enzymes. More than 30% will spontaneously clear the infection within three months. (2C
· A strategic reduction in immunosuppression is considered in patients with acute or persistent HEV as this may facilitate viral clearance, but the risk of rejection should be carefully assessed. (2C)
· Early treatment with ribavirin may be considered in specific cases of acute hepatitis E, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although evidence for this recommendation is currently limited. (2D
Persistent HEV infection
Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool for more than three months after the onset of relevant symptoms, raised liver enzymes, or from the first positive HEV RNA test. (1C)
· Individuals with persistent HEV infection (infection of more than three months) receive treatment with ribavirin with the aim of achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). (1C)
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
· Treatment with ribavirin should continue for at least three months for solid organ transplant recipients with persistent HEV infection. For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
· PEG-interferon should not be used as first line for the treatment of persistent HEV in transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
During Ribavirin Rx measures should include:
· Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment. (1C) Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart, as continued shedding of HEV in stool is an important factor predicting relapse after ribavirin treatment. (1C)
· A test of sustained virological response is conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy. (1C)
· Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or blood transfusion may be indicated to allow continued antiviral therapy without avoidable drug reduction. (1A)
· Quantitative testing of a plasma sample to be taken at day seven of ribavirin treatment to help determine the likely length of treatment required. (2C)
· To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)
· Patients with persistent HEV who relapse after a first course of ribavirin are re-treated for at least six months with ribavirin at dosages toward the higher dose range, where tolerated. (2D)
I like your well structured detailed summary.
I appreciate level of recommendation in relation to each advice.