1. A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. He was on prednisolone, MMF, and tacrolimus. During the first 1.5 years after transplantation, he developed CMV reactivation, primary EBV infection, and BK-virus viremia. Almost 3 years after transplantation at a routine check-in 2011, ALT (94 U/L) and AST (55 U/L) were found to be elevated. Kidney function was stable with an eGFR of 80 mL/min. Liver enzymes remained slightly increased in 2012 and 2013. No clear relation could be found with drugs. HCV and HBV PCR were negative. Repeated testing for BK, EBV and CMV DNA was negative. After temporary normalization, liver enzymes increased again with an ALT of 117 U/L. At that point, HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analysed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
What is the prevalence of HEV in solid organ transplantation?
171 Comments
Mohammed Sobair
How would you manage this case?
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.(1)
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. (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.
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
What is the prevalence of HEV in solid organ transplantation?
In developing world Nepal and Bangladesh indicate antibody prevalence rates of 47%
and 50%.
Developed World:
from 1% to 50%.
References:
1-BTS Guideline of hepatitis E and solid organ transplantifectio.2017
The diagnosis in chronic HE infection in a post kidney transplant recipient…..I would reduce the immunosuppression of the patient…I will reduce the CNI as there as studies showing that CNI enhances the viral HEV replication….MMF on the other hand has shown to have anti proliferative activities on the virus and hence I would like to continue MMF and low dose steroids…I would closely monitor for graft rejection by serial creatinine monitoring…WE have to monitor for blood HEV clearance and Stool HEV clearance regularly to see for spontaneous remission of the virus if possible…
Antiviral therapy with Ribavirin 600-800mg/day is recommended….the dosage is tiitrated according to the creatinine clearance…
duration of treatment is 3 months..CBC and liver function tests have to be monitored during treatment…the other treatment available is pegylated interferon but it may have immunomodulator effect and it may enhance rejection…
The prevalence of HEV infection is higher in SOT patients as compared to non transplant as high as 20%
The patient is known to be renal transplant recipient diagnosed with HEV infection.
Management would start by reduction of immunosuppressive doses, withholding antimetabolites as MMF, minimizing CNI doses to maintain low levels or even switch to another mTORi would be better.
Using antiviral regimen as ribavirin is the best tolerated by most of patients. The patient has normal renal function profile, hence no need for renal adjustment with optimum dose for 4 weeks at least with regular monitoring of viral load, CBC, liver enzymes mainly.
Special attention to the common side effects as they could be non-specific in the form of fatigue, fever or headache. Moreover severe side effects as hemolytic anaemia or severe GIT manifestations could need dose modification.
The co-administration of statins aids to initiate early response as it minimizes viral load as well.
Prevalence of HEV for organ transplants as liver: 27.2%, kidney 12.8%, and lung 5.6%.
HEV-3 and -4 can cause chronic infection in patients receiving immunosuppressive agents .
● Reducing Immunosuppressive Therapy
** Factors that progress infection to chronicity are :
☆ Low CD4 and CD8 counts at the time of HEV infection
☆ A shorter time since transplantation
☆ A shorter time from an acute rejection
☆ The use of tacrolimus
☆ A lower T-cell response and inflammatory response
☆ Patients that are heavily immunosuppressed
** Immunosuppressive drugs (cyclosporine A, tacrolimus, sirolimus, and everolimus, increase HEV replication but only mycophenolic acid can decrease HEV replication in vitro .
** HEV clearance occurred in 30% SOT patients with chronic HEV infection after reducing immunosuppressive therapies that principally targeted T-cells
** A reduction in immunosuppressive therapy seems to be the first-line therapeutic option
● Two-thirds of patients remain those need an effective antiviral therapy :
☆ Pegylated Interferon
For three months and the sustained virological response (SVR) at six months was 100% but it increases the risk of acute rejection due to its immunostimulatory effect
☆ Ribavirin
** Ribavirin as a monotherapy has become the treatment of choice for chronic HEV infection.
** The recommended dose 600 to 800 mg/day
** In patients with impaired kidney function, ribavirin dose should be adapted to kidney function
** Three months after initiating ribavirin therapy, if HEV RNA is negative in both the sera and stools, ribavirin can be stopped.
** If HEV RNA remains positive in the stools after three months, even if it is negative in the sera, ribavirin therapy should be prolonged for an additional three months.
** If HEV viremia increases after ceasing ribavirin therapy, a longer course of ribavirin 6 months, can be proposed.
** In patients who present with a relapse under ribavirin or who are resistant to ribavirin, there is no alternative, except for liver-transplant patients for whom pegylated interferon can be proposed.
● The main adverse effect is hemolytic anemia ( up to 40 %)
Others:
Insomnia, dyspnea, lack of concentration, emotional lability, and irritability, feeling tired, headache, nausea, fever, muscle pains, and an irritable mood.
Nassim Kamar, Sébastien Lhomme, Florence Abravanel, Olivier Marion, Jean-Marie Peron, Laurent Alric, and Jacques Izopet . Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis . Viruses. 2016 Aug; 8(8): 222.
the use of RBV for the treatment of an HEV infection in organ transplant patients is effective, and the recommendation of 12 weeks of therapy being adequate in terms of efficacy. Nevertheless, there are important issues that urgently need to be assessed, such as the optimal duration of therapy and drug dosage of RBV, as well the development of new drugs with a high safety profile https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022260/
This patient has chronic hepatitis E infection that can be transmitted either by infected meat or by infected organ transplant and blood components. For management, immunosuppression should be reduced. Ribavirin should be started for at least 3 months until HEV RNA becomes negative.
Regular test for liver eczema is essential as well. The dose of ribavirin depends on Cr Cl. for patients with Cr Cl, more than 50 ml/min 200 mg Q 8h is administered. Ribavirin side effects include hemolytic anemia, GI disorders, dermatological side effects, and general symptoms like fatigue, and fever headache. Hence, regular monitoring for CBC. is important. Prevalence of HEV for each organ transplant liver: 27.2%, kidney 12.8%, and lung 5.6%.
How would you manage this case? · Hepatitis E virus (HEV) infection is underdiagnosed. Most patients with HEV recover completely but immunosuppressed patients may have a more severe course. · HEV infection is either acute (< 3 months) or chronic (persist for more than 6 months). · Diagnosis of HEV infection in SOT depends on detection of HEV PCR in the blood or stoolas serology results are altered by immunosuppression · Management: · In our case we have chronic HEV infection. · Immunosuppression management: keep MMF (may be associated with lower risk of HEV infection) and steroids, but I will reduce Tacrolimus being associated with high risk of HEV infection. · Antiviral treatment: start ribavirin therapy for 3 months since the patient has chronic HEV infection. If relapse occur, the treatment should be restarted with a higher dose and for 6 months. Dose is 600-1000 mg/day, adjusted according to body weight and creatinine clearance · Blood HEV PCR should be done after 1 week of therapy to predict the duration of the therapy, the ribavirin is continued until 2 consecutive PCR results in the stool are negative one month apart · During therapy monitor liver enzymes and hemoglobin level every 2 weeks as Ribavirin can cause hemolytic anemia. · After stopping Ribavirin treatment, ensure sustained viral response (SVR) by repeating the viral load every 3 months using blood or stool PCR for 6 months.
What is the prevalence of HEV in solid organ transplantation? · In solid organ transplant is 4-20%. This increases with age, and demographic variables being higher in Africa and Asia.
References: 1. Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, et al. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec; 29(12):1134-1142. 2. Aggarwal A, Perumpail RB, Tummala S, Ahmed A. Hepatitis E virus infection in the liver transplant recipients: Clinical presentation and management. World J Hepatol. 2016; 8:117 3. Guidelines for Hepatitis E & Solid Organ Transplantation. BTS guidelines 2018
How would you manage this case? transplant recipient severely immunocompromised with history of multiple viral infection (CMV reactivation, primary EBV infection, and BK-virus viremia) presented with unexplained elevation of liver function, later on diagnosed with chronic HEV infection. management:while managing patients with solid organ transplants, benefits of treatment need to be weighed against risks of rejection. Reduction of immunosuppression is considered the first-line approach, allowing HEV clearance in about one-third of patients. Ribavirin, an anti-viral agent, is considered in patients with severe acute or acute on chronic liver failure. acts by inhibiting HEV viral replication and increases the expression of interferon stimulating genes leading to immune modulation It can be given as for 3 months, 600 mg / day. Ribavirin is also used successfully to treat HEV-associated membranoproliferative glomerulonephritis in a solid organ transplant recipient. In patients with detectable HEV RNA in the serum and/or in the stool, at the end of three months, ribavirin monotherapy can be continued for an additional three months. the use of IFNα is not recommended among other solid organ transplant recipients due to the risk of graft rejection. Sofosbuvir was ineffective in achieving sustained virological response.
What is the prevalence of HEV in solid organ transplantation? HEV genome 3 related infection is associated with solid organ transplant recipients and immunocompromised patients. Recent data demonstrates HEV seroprevalence rates ranging from < 1% up to 52% in Europe. Karthik Kovvuru, Nicholas Carbajal, Abhinandan Reddy Pakanati.Renal manifestations of hepatitis E among immunocompetent and solid organ transplant recipients.World J Hepatol. 2022 Mar 27; 14(3): 516–524
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment
Modification of immunosuppression–
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV. Evidence suggests that calcineurin and mTOR inhibitors may contribute to persistence of HEV replication in hepatocytes and the development of persistent HEV, whereas corticosteroids appear to have no effect on viral replication, and mycophenolate may have an inhibitory HEV replication in vitro. Therefore, strategic modification of immunosuppression might help with viral clearance. It is important to recognise that changes in immunosuppression can precipitate rejection in more immunogenic individuals so the risk of rejection versus the potential benefits of modification of immunosuppression must be carefully balanced.
Antiviral therapy
Ribavirin-
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 achievingsustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment). Dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation.
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.
What is the prevalence of HEV in solid organ transplantation?
The prevalence of HEV infection in solid organ transplant (SOT) recipients varies by countries and transplanted organs. Meta-analysis demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients
This is a case of chronic HEV infection> 6 months detectable RNA. 1- detailed history and clinical examination 2- laboratories for , CBC, KFT, Urinalysis, LDH, liver function (albumin, INR), gamma GT, alkaline phosphatase, and bilirubin, and a quantitative stool HEV PCR(as baseline) 3- ultrasound abdomen, for any organomegaly, and CXR. Treatment: 1. Reduction of immunosuppression 2. Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 6 months after stopping the Ribavirin) 3. Adjust dose to GFR monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function. 4. Failure of treatment: repeat the course with high dose Ribavern but observe for side effect as above 5. in cases of ribavirin-refractory persistent HEV infection ,PEG-interferon treatment may be considered. However, it carries a risk of rejection. Prevalence of HEV in SOT The pooled estimated prevalence of HEV infection in SOT patients was 20.2% The pooled estimated prevalence of HEV infection for each organ transplant was as follows: Liver : 27.2% Kidney : 12.8 % Heart : 12.8% Lung 5.6%
About 30% of patients undergo HEV clearance in the first 3 months, as the patient has already gone through this phase, it is necessary to decrease immunosuppression.
If the patient has progression of liver dysfunction, treatment with Ribavarin will be necessary.
What is the prevalence of HEV in solid organ transplantation?
The prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients). The prevalence of HEV infection is two-fold more common in middle-income countries compared to high-income countries.
REFERENCE:
– Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
How would you manage this?
This is a case of chronic HEV in a immunocompromissed recipient.
The main stay of management is reduction of immunosuppression, anti-viral therapy, reduction of immunosuppression may decrease the infection/ viral load by 30%.
To follow the treatment response the sustained viral response.
Which is monitored by PCR test.
Monitor side effect of drugs, treatment can be done using ribavirine (600mg/day for three months) for HEV infection.
If not responding can be given pegylated interferon alpha.
Monitoring and prevention of rejection, as the treatment may take more than six months for clearance of infection.
Drug modification like switching from tacrolimus to cyclosporine can improve outcomes of infection. Prevalence of HEV in Solid Organ Transplantation.
Usually initially it present with IgM antibodies positivity which shows acute infection, if anti- IgG positive shows chronic infection and persists for years.
Otherwise, HEV infection seen in liver transplantation is around 3-28%,
Pooled estimated prevelance for each solid organ transplant is around
Liver 27.2%,
Kidney 12.8%,
Heart 12.8%, and
Lung 5.6%.
After confirming the presence of HEV RNA in stool or plasma , treatment should start by reduction of immunosuppressant and follow the patient for 3 months unless there’s severe infection, in such case Ribavirin therapy should start.
The dose vary from 600-1000mg /day adjusted according to body weight and GFR.
There’s no consensus about the duration of treatment, but a period of 6months is adopted.
The drug should be monitored after the first week then monthly by CBC and RFT .
The drug is continued till 2 consecutive sample of stool or plasma are negative with one month a part.
The drug SE include hemolytic anemia, skin rash , GIT symptoms,headache.
The prevalence of HEV in solid organ transplantation is 20.2% , with heightest prevalence in liver and lower in lung transplantation, in kidney its 12.2%.
Referece:
BTS guideline 2017.
This DBD recipient in 2008, had intense immunosuppression, indicated by post-transplant CMV, EBV and BKV infection. Repeated deranged LFT, and evaluation detected 5years post-renal transplant infection with HEV genotype3. As the previous stored sample also detected HEVRNA and IGM antibody, and persistent IgG anti-HEV, it indicates Chronic HEV infection with reactivation due to intense immunosuppression with off and on LFT derangement. Management: Reduction of prednisone and tacrolimus to minimum level. Monitoring Tac levels, RFT for rejection, CBC, LFT and Liver ultrasound.
Tab Ribavirin PO 200mg 3-5times daily – dose adjusted to Creatinine Clearance.
The dose should be adjusted according to creatinine clearance if CrCl >50 ml/min no dose adjustment needed, CrCl 30-50 ml/min 200 mg alternative with 400 mg every other day, CrCl <30 ml/min 200mg OD, Follow up by CBC monthly if Hb is less than 8.5 g/dl, WBC less than 1,000, platelets less than 50,000 then stop ribavirin. 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 therapy. · The pooled estimated prevalence of HEV infection in SOT patients was 20.2%, and the prevalence in different organs was as follows: 1. Liver (27.2%) 2. Kidney (12.8%). 3. Heart (12.8%), 4. Lung (5.6%). Response to ProF Ahmed Halawa’s questions What are the side effects of ribavirin?
Most important side effect is anaemia – occur in 10-13% – (haemolysis + bone marrow suppression) – dose-dependent à when Ribavirin >1.2 g daily for > 10 days given and in case of renal impairment Other adverse effects: Leukopenia, Neutropenia, Thrombocytopenia – <10% Generalised malaise, weakness, nausea, diarrhoea Hyperbilirubinemia, lactic acidosis, Hyperuricemia Hypocalcaemia, Hypomagnesemia Standard dose of Ribavirin and factors affecting dosing standard dose is 600-1200 mg daily (Available 200 mg capsule) According to body weight < 50 kg: 200 mg in the morning; 400 mg in the evening. 50-60 kg: 400 mg twice daily. >60 Kg: 400 mg in the morning; 600 mg in the evening. Ribavirin dosage in CKD and transplant patients? In transplant recipients – start with 200mg twice a day to thrice a day (400-600mg/day) Can titrate the dose according to adverse effect and tolerance. serum creatinine should be monitored every month and Ribavirin dose need to be adjusted according to GFR (creatinine clearance (CrCl) · CrCl >50ml – no dose modification required · Moderate renal impairment (CrCl) 30 – 50 ml/min à 600 mg daily – 200 mg alternating with 400 mg every other day (to start with) · Severe renal impairment (CrCl) <30 ml/min à 200 -400 mg daily – lower dose if serum creatine is >2 mg/dl à <200mg/day · End-stage renal disease (ESRD) à 200 mg daily – starting with lower dose (200 mg 3 times weekly), then increase to 200mg daily, if no side effects – Patient on regular haemodialysis: use 200 mg 3 times weekly To check for CBC every month – dose modification needed if severe anaemia develops In cardiac patient – with haemoglobin drop of > 2 gm after 1 month of treatment à reduce dose to 600 mg daily – if hemoglobin is <12 g/dL after reduction of the dose treatment should be temporary stopped – once haemoglobin increase > 12g à dose increased gradually by 200 mg a day In non-cardiac patient, – if haemoglobin <10 g/dL after treatment à reduce dose to 600 mg daily – if haemoglobin increase the dose can be increased gradually by 200 mg a day · If hemoglobin is <8.5 g/dL at any time stop ribavirin · Leukopenia WBC <1,000, neutrophils <500, platelets <50,000 : stop treatment permanently References 1. Brennan BJ, Wang K, Blotner S, et al. Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment. Antimicrob Agents Chemother. 2013; 57(12): 6097-105. Doi :10.1128/AAC.00608-13 2. Ribavirin, In: Aronson JK (ed.), Meyler’s Side Effects of Drugs (Sixteenth Edition), Elsevier, 2016. p.115-129. 3. De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res 2018 Apr; 130: 308-315. doi: 10.1016/j.phrs. 2018.02.030. 4. British Transplantation Society. Guidelines for Hepatitis E and Solid Organ Transplantation, 1st ed.; British Transplantation Society: Macclesfield, UK, 2017; Available online: https://bts.org.uk/wp-content/uploads/2017/06/BTS_HEV_Guideline-FINAL.pdf 5. Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant. 2019 Sep;33(9):e13514. doi: 10.1111/ctr.13514. 6. Up to date
Above is a case of chronic HEV infection with genotype 3.Firstly,stool and plasma sample for PCR for HEV RNA should be sent, then reduction of immunosuppression i.e., steroids and anti-metabolite should be decreased followed by Tacrolimus .Close monitoring of graft function is must due to increase chances of rejection ,then Ribavirin in renal adjusted dose should be started timely for early virological clearance and that can be checked by doing monthly PCR on stool and plasma sample. Its dose varies from 600-1200 mg/day and no consensus about the duration is being mentioned in the literature , however,it is continued till the two consecutive stool tests are negative for HEV RNA one month apart. Generally duration is 3-6 months and no dosage adjustment required for GFR >50ml/min. But patient should be monitored for the side effects like hemolytic anemia, leucopenia, thrombocytopenia and GI disturbances .In resistant cases, Peg interferon is the option.
What is the prevalence of HEV in solid organ transplantation?
The pooled prevalence of HEV infection in solid organ transplantation is 20.2% , however, varies with different organ transplantation – Liver (27.2%)having highest prevalence followed by kidney (12.8%).and heart(12.8%), and then lung(5.6%).Both acute and chronic HEV infection can occur and according to one study -70% of the patients with acute infection develop chronic infection
REFERENCES:
1-Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254.
2-Guidelines for Hepatitis E & Solid OrganTransplantation. BTS guidelines 2018
. WHO estimates that HEV causes 20 million new infections annually, with more than 3 million cases of acute hepatitis and over 55,000 deaths.
· Genotype 3 is prevalent in Western countries, as well as in Asia and North America.
· patients with solid organ transplantation may develop chronic HEV infection.
Management
· Reduction of immunosuppression. First, reduce Tacrolimus.
· Antiviral therapy: a 12-week course of ribavirin monotherapy with a dose 600 to 1000 mg daily, in two divided doses.
· Monitoring for toxicity: CBC, creatinine with eGFR, liver enzymes, and bilirubin levels at week 4 of treatment. Then CBC at weeks 8 and 12 to evaluate for anemia associated with ribavirin.
· For those who develop anemia, the dose of ribavirin can be adjusted based on the severity and comorbidities.
· If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated.
· If HEV is detectable in serum and/or stools at week 12, ribavirin therapy should be extended for an additional 12 weeks. What is the prevalence of HEV in solid organ transplantation?
In a prospective cohort of 700 solid organ transplant recipients, 5 % acquired HEV infection, of whom 47 % developed a chronic infection
Management
The first step is reduction of immunosupression and preferably CNI and glucocorticoids.
This patient would require Ribavirin , as there is active hepatitis and the period of observation for three months usually recommended does not apply to this patient.
It can be given for atleast three months which can be extended to six months depending upon the response. Close monitoring should be done and cure should be considered if two consecutive stool PCR are negative one month apart.
The side effects of Ribavirin should be considered specially hemolytic anemia.
Usual dose is 600 to 1000 mg
we can use 600 mg in Tx patients.
35 year old patient received cadaver transplant with early post transplant infections including BK, CMV, EPV.
Patient experienced elevation in liver enzymes in 2011 and more increase in 2012.
Genotype 3 HEV in 2013 with high HEV RNA and IgG and IgM
Persistent HEV infection more than 3 months
Management :
Full history and examination
Detection of baseline stool and plasma HEV RNA test
Reduction of immunosuppression is starred first especially MMF
Ribavirin 600 mg daily for at least 3 months.
Plasma and stool HEV are monitored every month. With initial 7 days monitor to check initial response.
If persistent HEV test after 3 months continue treatment till 6 months or till 2 tests 1 month apart are negative
If relapse post Ribavirin we shall repeat course of Ribavirin with higher dose and longer duration.
Side effects of Ribavirin may include Hemolytic anemia so check of Complete blood count regularly.
HEV infection is common in SOT recipients and accounts for 20.2%. It is at least two-fold higher in middle-income countries compared to high-income countries. The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants. More studies demonstrating the clinical impacts of HEV infection in SOT recipients, such as graft failure, rejection, and mortality, are warranted.
This renal transplant patient has chronic HEV, as previous samples when the liver enzymes were elevated revealed positive HEV RNA. Reduction of tacrolimus, MMF and prednisolone. Monitoring Tac levels and monitoring for rejection. Liver ultrasound and monitoring LFTs. Ribavirin dose ranging from 600-1000mg daily depending on the patient’s weight and CrCl. The dose should be adjusted according to creatinine clearance if CrCl >50 ml/min no dose adjustment needed, CrCl 30-50 ml/min 200 mg alternative with 400 mg every other day, CrCl <30 ml/min 200mg OD, Follow up by CBC monthly if Hb is less than 8.5 g/dl, WBC less than 1,000, platelets less than 50,000 then stop ribavirin. 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 therapy.
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%. The pooled estimated prevalence of HEV infection for each organ transplant was as follows: 1. Liver (27.2%) 2. Kidney (12.8%). 3. Heart (12.8%), 4. Lung (5.6%).
· WHO estimates that HEV causes 20 million new infections annually, with more than 3 million cases of acute hepatitis and over 55,000 deaths.
· Genotype 3 is prevalent in Western countries, as well as in Asia and North America.
· patients with solid organ transplantation may develop chronic HEV infection.
Management
· Reduction of immunosuppression. First, reduce Tacrolimus.
· Antiviral therapy: a 12-week course of ribavirin monotherapy with a dose 600 to 1000 mg daily, in two divided doses.
· Monitoring for toxicity: CBC, creatinine with eGFR, liver enzymes, and bilirubin levels at week 4 of treatment. Then CBC at weeks 8 and 12 to evaluate for anemia associated with ribavirin.
· For those who develop anemia, the dose of ribavirin can be adjusted based on the severity and comorbidities.
· If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated.
· If HEV is detectable in serum and/or stools at week 12, ribavirin therapy should be extended for an additional 12 weeks.
What is the prevalence of HEV in solid organ transplantation?
In a prospective cohort of 700 solid organ transplant recipients, 5 % acquired HEV infection, of whom 47 % developed a chronic infection
DIAGNOSIS of EBV infection can be established in this case as RNA is positive and ant HEV antibody are present
treatment
RIBAVARIN in GFR depending dosage is advised
200 mg capsule upto 800 mg per day if GFR is normal
Hemolytica anaemia is main adverse effect along with leucopenia , GI upset
Hb need monitoring every month
May need to stop the drug if Hb falls significantly like 2 gm per month
The managment of this case is ribavirin ,this medications need close monitoring for the Hb as one of the main side effect is anemia which is fatal specially in c ardiac patient .
Ribavirin is Exkret through renal for that need dose adjustment in case of renal impairment other wise will lead to ribavirin toxicity .
Because of its teratogenicity and emberiocidal effect of ribavirin it is conntraindicated in pregnency .
The dose of ribavirin is between 600 to 1000mg/day according to the body wt with adjustment according to the eGFR . once we satrted need close follow up for SE and will need monthly assessment of Hb .
If the Hb is drop to below 8gm will hold ribavirin permanently .Also we need to check all blood indices TWBCS ,platelet and neutrophil count and if it cause pancytopenia need to hold the Ribavirin
Management
A case of Hepatitis E virus of genotype 3 which can be transmitted through ingestion of infected meat. Also, can be transmitted with the transplanted organ or through blood transfusion.
The patient has positive HEV RNA since 2011; chronic hepatitis E. Immunosuppression reduction is needed with start on ribavirin for three months followed by HEV RNA testing. With viral clearance ,LFTs to be monitored regularly.
Usual dose of ribavirin is 200 mg 8 hourly, with dose adjustment in patients with eGFR of less than 50 ml/min.
Side effects of ribavirin include: fatigue, headaches, hemolysis ;monitoring CBC, fevers, rigors, nausea, vomiting ,and myalgia.
Prevalence of HEV in SOT:
According to data from selective screening program by NHS Blood and Transplant it is 1 in 2500 donations with HEV RNA positive test.
1. Immunosuppression – It is important to reduce the dose of tacrolimus and monitor serum levels of immunosuppressants to avoid organ rejection
2. Monitoring of the HEV viral load to assess its activity
3. Ribavirin is the drug of choice, but requiring frequent adjustments due to its side effects, mainly related to hemolytic anemia. Renal function and CrCl impact drug choice and discontinuation.
The dose will be dependent on weight and side effects arising from the drug.
Pegylated interferon should be avoided due to the high risk of rejection and toxicity.
Sofosbuvir is a promising alternative in new studies.
HEV occurs around 20.2% in SOT and 12.5 % in kidney transplant recipient
treatment include reduction of immunosuppresion for 3month and follow up except there is picture of sever infection for which ribavirin treatment need to be started early with close monitoring of CBC and dose adjusted according to weight and to eGFR
after starting ribavirin HEV PCR needs to be followed 7 days then monthly till clearance is achieved by 2 successive PCR negative one weak in between. after 6months of achieving remission PCR should be repeated for the risk of relapse if remission not achieved after 3months of ribavirin pegylated interferon can be started with caution of the risk of rejection. Reference :
Te, Helen; Doucette, Karen (2019). Viral Hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clinical Transplantation, (), e13514–. doi:10.1111/ctr.13514
This patient has chronic HEV infection as evidence of infection persist longer than 3 month 1-History : including hepatotoxic drugs , alcohol and other potential hepatotoxic risk factors 2-Examination to role out a- Hepatic complications as liver fibrosis , cirrhosis ,decompensated LCF and extrahepatic complications b- Presence of other causes of hepatitis as metabolic diseases. 3- Laboratory investigations a- Liver function test to exclude decompensated LCF b- Metabolic screen for liver diseases as serum iron and ferritin in hemochromatosis, serum ceruloplasmin for Wilson disease . c- Quantitative HEV RNA in plasma and stool. d- CBC, coagulopathy profile. e- Cryoglubulins level. f- Urine analysis and albuminuria level to exclude complicating GN. 4- Treatment : – Ribavirin 600 mg once daily with monitoring of CBC to exclude drug induced hemolysis. Serial monthly test for HEV RNA in stool and blood .Continue ribavirin treatment till get 2 HEV RNA negative stool samples , one month apart. – Monitor graft function and drug levels. -Reducing tacrolimus dose to lower level , while steroid and MMF doses don’t need change.
What is the prevalence of HEV in solid organ transplantation?
Prevalence of HEV infection is 20.3% in solid organ transplant being highest in liver transplant and lowest in lung transplant.
The clinical features of autochthonous genotype 3 HEV infection in solid organ transplant recipients can be asymptomatic but in some cases, severe complications develop such as chronic hepatitis and cirrhosis .
Extrahepatic manifestations include neurological symptoms such as Guillain-Barre syndrome, kidney injury, cryoglobulinemia, membranoproliferative glomerulonephritis, immunoglobulin A nephropathy, and impaired kidney function .
The mechanism of kidney injury is believed to be associated with immune-mediated kidney diseases.
Once a chronic HEV infection is diagnosed, the therapeutic approach first consists of a reduction in the immunosuppression (if possible) and, in case of failure of self-resolution, implementation of therapy. Reduction of daily dose of MPA therapy alone in transplant patients with chronic HEV infection may not be sufficient to control viral replication. Currently, there are no specific drugs approved for HEV infection, but ribavirin (RBV), the drug of choice, is used for off-label treatment.
HEV clearance under ribavirin therapy shows interindividual variability. Therefore, serial viral monitoring may be useful to personalize treatment duration.
clinical guidelines recommend a program therapy duration of 12 weeks using RBV at the initiation with a weight-adjusted dose or a dose adjusted on the basis of the estimated glomerular filtration rate.
RBV was initiated at a dose of 200 mg every 8 h for 12 weeks, following clinical guidelines.
Prevalence
the prevalence of HEV infection in kidney candidates is higher than reported in the general population, and increases with age and during the first posttransplant year. Contrary to previous reports, we found that although reduced immune status may predispose recipients to HEV infection, infections are largely asymptomatic and appeared to resolve spontaneously.
number of studies have tried to estimate the prevalence of HEV in transplant recipients. Studies using sensitive assays (Wantai HEV test) have reported seroprevalence rates between 8.3% and 43% for anti-HEV antibodies in transplant recipients, the spread probably reflecting true geographic differences in prevalence .The prevalence of detectable HEV RNA among transplant recipients in these studies, indicating current viraemia, ranged from 0-3.2% .However, studies reported to date have been conducted in geographically distinct populations using different methodologies and may not be generalisable to all transplant populations. It is also likely that the incidence of infection and prevalence rate of viraemia have changed over the last decade, with a demonstrable recent increase in incidence .A recent study at a single centre in the UK found the point prevalence of HEV viraemia in transplant recipients was 16/2418 (0.7%) (manuscript submitted).
Patient has persistent transaminitis after first episode of HEV infection. What is possible cause?
Is it chronic hepatitis E infection?
Is it a re-infection or reactivation of previous infection
I will address each issue because treatment plan depends on the same.
Persistent transaminitis:
Viral causes: HBV, HCV, HEV, CMV, HSV
Non-viral causes: alcohol ingestion, hepatotoxicity drugs, older age, deceased
donation, high cyclosporine levels
In our case there is no definite cause identified for persistent transaminitis, except deceased donation. But after 2 years of raised levels of liver enzymes they normalised (could it be a evidence of chronic liver dysfunction – CLD)??.
But it raised again when patient was HEV RNA positive
Is it chronic hepatitis E? I think answer is NO. We don’t have any evidence of persistent positive HEV RNA PCR for more than 3 months after first infection in 2011. Nor we have genotype result of first infection.
Is it re-activation or reinfection? IgG antibodies that developed after first infection were not protective, hence, it appears that second infection was re-infection with another genotype
Thus, I will consider this as acute HEV infection with genotype 3, with a possibility of patient having CLD changes in liver. Therefore
I will reduce tacrolimus levels
I will evaluate for chirrotic changes in liver
I will not start any anti viral including Ribavarin until evidence of CLD is confirmed because Ribavarin in indicated in acute infection only if there is significant liver dysfunction or extra hepatic manifestations.
REF:
Einollahi B, Ghadian A, Ghamar-Chehreh E, Alavian SM. Non-viral related liver enzymes elevation after kidney transplantation. Hepat Mon. 2014;14(2):e9036.
Panning, M., Basho, K., Fahrner, A. et al. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infect Dis 19, 675 (2019). https://doi.org/10.1186/s12879-019-4307-6
Kamar, N.; Lhomme, S.; Abravanel, F.; Marion, O.; Peron, J.-M.; Alric, L.; Izopet, J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses2016, 8, 222. https://doi.org/10.3390/v8080222
this case typical description of chronic infection of HEV infection, as a case of an SOT organ infected by genome 3 and symptoms are minimal and persistent elevation of aminotransferase
management of this patient :
reduction of immunosuppression therapy, TAC should be reduced first if possible as HEV infection is associated with TAC
Ribavirin for 12 weeks the dose 600 -1000 daily in two divided doses
recheck HEV RNA at the end of the treatment if absent recheck after 12 weeks
if the virus did not detect any further treatment.
but if after 12 weeks the virus is detected further additional 12 weeks of treatment by ribavirin. If the virus is still present that means treatment failure
no randomized trials have evaluated the use of ribavirin for the treatment of chronic HEV
management of treatment failure includes:
Sofosbuvir
pegylated interferon alpha: limited data to support the use of pegylated interferon -alpha for SOT.
What is the prevalence of HEV in solid organ transplantation?
NHS screening program of blood and transplant showed that one in 2500 donors are HEV RNA positive
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
Treatment of Persistent Hepatitis E Post-transplantation:
Following acute infection with HEV G3, the infection persists in approximately 60% of solid organtransplant recipients leading to persistent HEV infectionThis can cause a chronic hepatitis thatcan progress rapidly (3-5 years) to cirrhosis in approximately 15% of infected solid organ transplantrecipientsTherefore, persistent HEV infection should be actively treated with the aim of clearingHEV from the blood and stool
Chronic HEV infection is conservatively defined as the finding of detectable HEV RNA in the blood and/ or stool for greater than six months, spontaneous clearance of HEV rarely occurs between three and six months of infection .Fatigue is the most common symptom and jaundice is rare . Neurological symptoms can also occur
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. Typically ALT levels are between 200-300 U/L
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 (HEV RNA non detected in plasma and stool six months after completing treatment Modification of immune suppression:
Persistent HEV infection occurs mainly in heavily immune suppressed individuals, particularly those on T cell suppressing drugs. Reduction of immune suppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV
Tacrolimus 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 in these models Interestingly, mycophenolate was shown to inhibit HEV replication
Transplant recipients with acute HEV to date found that patients treated
with ciclosporin were more likely to have spontaneous clearance than those treated with tacrolimus Antiviral therapy 1-Ribavirin
two patients with persistent HEV were treated with ribavirin 12 mg/kg for
12 weeks, and both cleared HEV RNA from blood and stool by four weeks and remained HEV RNA negative during follow up. 2-PEG-interferon:In case of ribavirine failure
What is the prevalence of HEV in solid organ transplantation?
The meta analysis demonstrate the prevalence of HEV infection in SOT recipient is 20.3% (highest in liver transplant recipient and lowest in lung transplant recipients).
Reference :
1-British Transplantation Society Guidelines 2- Komolmit P, Oranrap V, Suksawatamnuay S, Thanapirom K, Sriphoosanaphan S, Srisoonthorn N, Posuwan N, Thongmee T, Treeprasertsuk S, Poovorawan Y. Clinical significance of post-liver transplant hepatitis E seropositivity in high prevalence area of hepatitis E genotype 3: a prospective study. Sci Rep. 2020;10:7352. [PMC free article] [PubMed] [Google Scholar
Unexplained increase in liver enzymes in immunocompromised patient (after renal transplantation) directed toward HEV diagnosis.
In this patient HEV RNA positive.
In addition the infection remained more than 3 months , therefore this is a persistent chronic infection.
The strategy of treatment
– Reducing immunosuppression (tacrolimus)
– ribavirin in persistent HEV infection is recommended 600- 1000 mg a day divided in 2 doses depending on GFR
– Monitoring of HEV RNA plasma at d7, 1m, 2m and 3m
– Monitoring of HEV RNA in stool from 2m onward or after a negative plasma sample (whichever is sooner)
B- Plasma or stool RNA positive – therefore, continue until 2 stools > 1 month apart are both negative or continue for 6m
Monitoring LFT and renal function CBC
(Hemolytic anemia)
Epidemiology Developing World
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.
Recent studies in populations from Nepal and Bangladesh indicate antibody prevalence rates of 47% and 50% respectively with no differences noted by gender
low prevalence in children <10 years.
Developed World
In the developed world, HEV G3 and G4 are zoonotic infections, being transmitted to humans from an animal reservoir. (pork products (particularly processed) and game meat are associated with HEV infection )
Seroprevalence rates vary widely from 1% to 50% (3,18-19)
Estimates of the burden of infection in the general population of England suggest as many as 200,000 infections occur annually and account for around 600-800 cases of hepatitis E. low rates in children
REFERENCES
Guidelines for Hepatitis E & Solid Organ Transplantation (BTS)
1- A case of persistent (chronic) HEV infection
A- im of treatment is to acheive sustained virological response (no HEV RNA in blood or stool six months after completion of treatment)
Treatment:
reduction of immunosuppression to the lowest target level (tacrolimus)
it should be continued till stool is negative for 2 consecutive tests one
month apart.
Side effects:
-Regular hemoglobin monitoring. it is associated with hemolytic anemia.
-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.
Patients with persistent HEV who relapseafter 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.
Refernces:
1- BTS guidelines for hepatitis E and solid organ transplantation 2017
2- Panning M, Basho K, Fahrner A, Neumann-Haefelin C. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infectious Diseases. 2019 Dec;19(1):1-5.
II-Prevalence in SOT:
Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
The prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipient)
👉 The present case has chronic HEV infection which may have spontaneous resolution in 30% of cases. So close follow up of liver function, PCR for HEV RNA in blood and stool is indicated.
👉 Reduction of immunosupression (CNI and steroids ) can help in viral clearance, but attention towards rejection is a must.
👉 Treatment with ribavirin 200_600 mg/day (divided twice or thrice is indicated, and continued for 3_6 months until 2 negative stool PCR (1 month apart).
👉 Follow UP CBC during treatment with ribavirin is essential for fear of hemolytic anemia , that can be manged by dose reduction, packed RBC transfusion or giving ESA.
⭐ Adjustment of the dose according to eGFR as follows:
_More than 50 ml/min …no dose adjustment.
_30-50 ml/min :200 mg in the morning and 400 mg in the evening every other day.
_less than 30 ml/min:200 mg once daily.
_Dialysis patient : 200 mg every other day.
⭐ Prevalence of HEV is up to 25 % in
CASE of liver transplantation, 12% in herat and kidney transplantation. And lowest in lung transplantation 5%.
How would you manage this case? The patient in the index case is severely immunocompromised and prone to viral infections. There is chronic HEV infection. The management options include-
Reduction of immune suppression The first step will be to reduce immune suppression. It can help in treating and reducing risk of recurrence. Patient should be counselled about risk of rejection.
Ribavarin Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed. It can be given as mono therapy for 3 months. The dose is 600-800 mg / day in 1-2 divided doses. Those with relapse post 3 month treatment can be treated for 6-9 months. Side effects include , hemolytic anemia, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection. Sofosbuvir In one study sofosbuvir showed antiviral activity in chronic hepatitis E in an immunocompromised patient.
What is the prevalence of HEV in solid organ transplantation? Recent data demonstrates HEV seroprevalence rates ranging from < 1% up to 52% across Europe. One meta-analysis, demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients).
Hansrivijit P, Trongtorsak A, Puthenpura MM,et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254.
Kar P, Karna R. A Review of the Diagnosis and Management of Hepatitis E. Curr Treat Options Infect Dis. 2020;12(3):310-320.
Management
This patient has Hepatitis E virus, genotype 3 which is transmitted by ingestion of infected meat. It can also be transmitted at the time of SOT, either with the transplanted organ or through blood components from an HEV infected donor
For this patient, he has had a positive HEV RNA since 2011, categorizing him to have chronic hepatitis E. He will need to have his immunosuppression reduced and started on ribavirin for three months and then the HEV RNA rechecked. If he has cleared then LFTs should be regularly monitored
The dose of ribavirin is 200 mg 8 hourly. It is contraindicated in patients with an eGFR of less than 50 mls/min
The side effects of ribavirin include: fatigue, headaches, hemolysis (important to do regular complete blood counts, myalgia, fevers, rigors, nausea, vomiting. What is the prevalence of HEV in SOT?
Data from the selective screening program implemented by NHS Blood and Transplant indicate that 1 in 2500 donations are HEV RNA positive
35 YR old CKD from HUS,DBD KTR 15 yrs ago -PDL/TAC/MMF
1st 1.5 yrs -CMV reactivation, EBV and BK infection,
3rd yr post transplant -Elevated liver enzymes with normal EGFR.
4yrs later -Elevated liver enzymes, HEV PCR +VE,HEV genotype 3 found while retrospective studies found anti HEV IgM +VE, Anti HEV IgG +ve
MANAGEMENT.
BTS guidelines to be considered in decision making; This is chronic Hep E infection.
Monitor HEV RNA and liver enzymes with an expectation of spontaneous clearance in 3/12.
If persistent consider RIS with keen attention on graft function, decrease tac levels and maintain the other immunosuppressive medications or titrate them with graft function.
Start ribavirin to lower VL, Baseline HEV RNA should be taken with ribavirin treatment for accurate tx monitoring, Ribavirin is given for 3-6 months and stopped once we get 2 consecutive neg HEV RNA 1 month apart. Ribavirin is dosed according to eGFR and its common side effect of hemolytic anemia attended to by regular hemoglobin monitoring with dose decrease if HB falls below 100g/l.
Consider PEG interferon in cases of treatment failure with ribavirin and monitor for graft dysfunction while on pegylated interferon.
PREVALENCE OF HEV IN SOT RECIPIENTS;
Liver transplant recipients -27.2%
KTR – 15.3%
Heart transplant recipients – 12.8%
Lung transplant recipients -5.6%
REF;
BTS -Guidelines for Hep E and SOT.
Panupong et al;Hep E in SOT recipients; A systemic review and meta-analysis.World J Gastroenterol.2021
Dear All Thank you very much for your replies. You kindly mentioned ribavirin as one of the treatment options. What are the side effects of ribavirin? What is the dose of this drug in a transplant patient and how would you adjust the dose?
I have noticed some of you have written a standard dose, Is it applicable in CKD and transplant patients?
Thanks so much ;Our Prof. Ribavirin in treatment of Hepatitis E infection: Oral:
-Optimal dosing has not been established:
-typically 600 to 800 mg/day (range: 400 mg to 1 g/day) in 1 to 2 divided doses.
-Optimal duration is unknown, but is typically ≥3 months based on virologic response. Side effects: Hemolytic anemia; -Hemolytic anemia has been reported with ribavirin therapy. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. Teratogenic; –Is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Avoid pregnancy and use effective contraception during therapy and for 9 months after completion of treatment in female patients and for 6 months in female partners of male patients who are taking ribavirin therapy. Other side effects; More Common: -Anxiety –Body aches or Pain -Nausea, Vomiting , Diarrhea -Nervousness -Quick to react or overreact emotionally -Runny nose -Sleeplessness -Fever, Headache ,Sore throat -Mental depression Less Common: -Constipation -Dry skin and hair -Hair loss -Belching -Dizziness or lightheadedness -Heartburn -Indigestion -Weight loss -Skin rash References; -De Winter 2018; Kamar 2020; Protin 2019; Rivero-Juárez 2020; Tavitian 2015. -AST-IDCOP [Te 2019]; EASL 2018; Kamar 2020; Rivero-Juárez 2020; Tavitian 2015.
(Severe) hemolytic anemia, mood disturbances, sleeping disorders, neuropathy, and a decrease in creatinine clearance.
Dose:
For the treatment of chronic HEV, there are currently no recommendations but only weakly supported suggestions. The dose of ribavirin used to treat HEV varies between instances, ranging from 29 to 1800 mg/day.
These dosages are advised and are modified for renal function based mostly on HCV experience.
The course of therapy might last anywhere from one and eighteen months
Therapy should be continued for a further three months if HEV RNA is still present in the serum or plasma.
An alternate approach is to continue treatment for an additional three months once the HEV RNA sample in serum is negative while monitoring HEV RNA in serum every month.
Treatment should continue until HEV is cleared from stools.
Ribavirin dose should be adjusted for renal function in HCV and SOT patients, emphasizing the importance of evidence.
===================== Reference:
De Winter, Brenda C.M.; Hesselink, Dennis A.; Kamar, Nassim (2018). Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacological Research, (), S1043661817315104–.doi:10.1016/j.phrs.2018.02.030
What are the side effects of ribavirin?
Adverse effects of ribavirin are as follows Most important adverse effect is
Dose-dependent anemia (with both hemolysis and bone marrow suppression), especially when the drug is given at doses of ≥ 1.2 g daily for > 10 days and in case of renal impairment when the drug accumulate Other adverse effect
Arrhythmia,
Elevated lactate and
Pyruvate levels,
Hypocalcemia, and
Hypomagnesemia
Chest pain,
Dizziness,
Hyperuricemia,
Hyperbilirubinemia,
Interstitial pneumonitis,
Decreased WBC count, and
Thrombocytopenia.
Reference
Chiou HE, Liu CL, Buttrey MJ, Kuo HP, Liu HW, Kuo HT, Lu YT. Adverse effects of ribavirin and outcome in severe acute respiratory syndrome: experience in two medical centers. Chest. 2005 Jul;128(1):263-72. doi: 10.1378/chest.128.1.263. PMID: 16002945; PMCID: PMC7094379.
What is the dose of this drug in a transplant patient and how would you adjust the dose?
Can titrate the dose starting 200mg twice a day to thrice a day (ie 400-600mg/day) monitoring the adverse effect and tolerance.
Reference
Ribavirin monotherapy for Hepatitis C virus infection in renal transplant recipient Sharma RK, Bansal SB, Gupta A, Gulati S, Prasad N, Kumar A Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
I have noticed some of you have written a standard dose, Is it applicable in CKD and transplant patients?
No, as dose needed to be modified according to GFR
Moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily)
Severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily)
End-stage renal disease (ESRD) (RBV, 200 mg daily)
Normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily).
Reference
Brennan BJ, Wang K, Blotner S, Magnusson MO, Wilkins JJ, Martin P, Solsky J, Nieforth K, Wat C, Grippo JF. Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment. Antimicrob Agents Chemother. 2013 Dec;57(12):6097-105. doi: 10.1128/AAC.00608-13. Epub 2013 Sep 30. PMID: 24080649; PMCID: PMC3837852.
Need to lower dose if serum creatine is >2 mg/dl (200mg-400mg)
Reference
Ribavirin Dose Modification Based on Renal Function Is Necessary to Reduce Hemolysis in Liver Transplant Patients With Hepatitis C Virus Infection Asbok B. Jain, Bijan Eghtesad, Raman Venkataramanan, Pauh A. Fontes, Randeep Kitshyup,Igor vorchik, A. 0baid hakil, Leah Kingery, and John Fung
Hemolytic anaemia is the main side effect reported with the drug (occur in 10-13%), to the extent that it is unsuitable for unstable cardiac patient since it may cause rapid hemoglobin drop
Leuckopenia and neutropenia and thrombocytopenia (occur in < 10%)
Teratogenic if given in pregnancy
General (fever, arthralgia, fatigue, malaise)
Gastrointestinal side effects (abdominal pain, anorexia, vomiting, diarrhea)
Skin manifestations in the form of alopecia, dermatitis, rash, pruritis
Hyperbilirubinemia
What is the standard dose and factors affecting dosing prescription ?
The drug is supplied in a 200 mg capsule, standard dose is 600-1000 mg daily depending on the weight of the patient
Patient < 50 kg: 200 mg in the morning; 400 mg in the evening.
Patient 50-60 kg: 400 mg twice daily.
Patient >60: 400 mg in the morning; 600 mg in the evening.
The dose should be also adjusted according to creatinine clearance, so serum creatinine should be monitored every month till stopping the treatment
If CrCl >50 mL/minute: No dosage adjustments necessary.
If CrCl 30 to 50 mL/minute: give 200 mg alternating with 400 mg every other day.
CrCl <30 mL/minute: 200 mg once daily.
ESRD: 200 mg once daily, but some recommends starting with lower dose (200 mg 3 times weekly) and then if no side effects the dose can be increased to 200 mg daily
Patient on regular hemodialysis : use 200 mg 3 times weekly
After the start of treatment, we have to check for CBC, every month till stopping treatment
In non-cardiac patient, if hemoglobin <10 g/dL after treatment decrease the dose to 600 mg daily, if hemoglobin increase the dose can be increased gradually by 200 mg a day
In cardiac patient with hemoglobin drop of > 2 gm after 1 month of treatment, decrease the dose to 600 mg daily and if hemoglobin is <12 g/dL after reduction of the dose treatment should be temporary stopped, once hemoglobin increase > 12, the dose can be increased gradually by 200 mg a day
If hemoglobin is <8.5 g/dL at any time stop ribavirin permanently.
At any time if WBC <1,000 mm3, neutrophils <500 mm3, platelets <50 x 109/L: stop treatment permanently
The dose of ribavirin is 200 mg 8 hourly. It is contraindicated in patients with an eGFR of less than 50 mls/min
The side effects of ribavirin include: fatigue, headaches, hemolysis (important to do regular complete blood counts, myalgia, fevers, rigors, nausea, vomiting.
The side effects of ribavirin include hemolytic anemia, sleeping disorders, neuropathy, mood disturbances, and reduction in creatinine clearance (1,2).
What is the dose of this drug in a transplant patient and how would you adjust the dose?
There is no consensus on the drug dosage to be used in transplant patient with wide variation (200-1200 mg/day, with median of 600 mg/day). The daily doses which have been proposed on the basis of creatinine clearance (as per Cockcroft Gault equation) are 1000 mg (100 ml/min), 800 mg (80 ml/min), 600-800 mg (60 ml/min), 600 mg (40 ml/min), and 400 mg (20 ml/min) per day (3). The median dose of initiation of ribavirin for HEV treatment has been 8.1 mg/kg/day in a study (4).
Dose of ribavirin needs to be modified if the hemoglobin falls below 10 g/dl (3).
I have noticed some of you have written a standard dose, Is it applicable in CKD and transplant patients?
No. The dose of ribavirin needs to be modified as per the creatinine clearance (3).
References:
Ribavirin, In: Aronson JK (ed.), Meyler’s Side Effects of Drugs (Sixteenth Edition), Elsevier, 2016. p.115-129.
De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res. 2018 Apr;130:308-315. doi: 10.1016/j.phrs.2018.02.030. Epub 2018 Feb 27. PMID: 29499270.
Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant. 2019 Sep;33(9):e13514. doi: 10.1111/ctr.13514. Epub 2019 Apr 14. PMID: 30817047.
CrCl ≥50 mL/minute: No dosage adjustments necessary.
CrCl <50 mL/minute: Use is contraindicated.
Moderiba and Ribasphere tablets:
CrCl >50 mL/minute: No dosage adjustments necessary.
CrCl 30 to 50 mL/minute: Alternate 200 mg and 400 mg every other day.
CrCl <30 mL/minute: 200 mg once daily.
ESRD requiring hemodialysis: 200 mg once daily.
Note: According to the manufacturer, the dose of Moderiba and Ribasphere should not be further modified in patients with renal impairment.
If severe adverse reactions or laboratory abnormalities develop, it should be discontinued.
Some experts recommend a lower starting dose of ribavirin (ie, 200 mg 3 times weekly), along with close monitoring of hemoglobin and hematocrit and use of erythropoietin therapy, in patients with eGFR <30 mL/minute/1.73 m2 or those on dialysis
Median dosage 600mg/ day. Dose adjustment accordingly ( body weight and creatinine clearance)
side effects:
General GIT / non specific such as : acidic gastritis,belching, taste change, diarrhea Skin : dermatitis , irritation, itching.pancytopeniahaemolytic anemiateratogenic effects on pregnancy
Haemolytic anaemia is the main side effect reported with the drug (occurring in 10-13%), to the extent that it is unsuitable for the unstable cardiac patients since it may cause rapid haemoglobin drop
Leukopenia and neutropenia and thrombocytopenia (occur in < 10%)
Teratogenic if given during pregnancy.
General (fever, arthralgia, fatigue, malaise)
Gastrointestinal side effects (abdominal pain, anorexia, vomiting, diarrhoea)
Skin manifestations in the form of alopecia, dermatitis, rash, pruritis
Hyperbilirubinemia
What is the standard dose and factors affecting dosing prescription ? The drug is supplied in a 200 mg capsule, standard dose is 600-1000 mg daily depending on the weight of the patient
Patient < 50 kg: 200 mg in the morning; 400 mg in the evening.
Patient 50-60 kg: 400 mg twice daily.
Patient >60: 400 mg in the morning; 600 mg in the evening.
The dose should be also adjusted according to creatinine clearance, so serum creatinine should be monitored every month till stopping the treatment
If CrCl >50 mL/minute: No dosage adjustments necessary.
If CrCl 30 to 50 mL/minute: give 200 mg alternating with 400 mg every other day.
CrCl <30 mL/minute: 200 mg once daily.
ESRD: 200 mg once daily, but some recommend starting with a lower dose (200 mg 3 times weekly) and then if no side effects the dose can be increased to 200 mg daily
Patient on regular hemodialysis: use 200 mg 3 times weekly
After the start of treatment, we have to check for CBC, every month till stopping treatment
In non-cardiac patients, if haemoglobin <10 g/dL after treatment decrease the dose to 600 mg daily, if haemoglobin increase the dose can be increased gradually by 200 mg a day
In cardiac patients with a haemoglobin drop of > 2 gm after 1 month of treatment, decrease the dose to 600 mg daily and if haemoglobin is <12 g/dL after reduction of the dose treatment should be temporarily stopped, once haemoglobin increase > 12, the dose can be increased gradually by 200 mg a day
If haemoglobin is <8.5 g/dL at any time stop ribavirin permanently.
At any time if WBC <1,000 mm3, neutrophils <500 mm3, platelets <50 x 109/L: stop treatment permanently
Ribavirin dose range from 600-1000mg daily depending on the patient’s weight.
the dose should be adjusted according to creatinine clearance
if crcl>50 ml/min no dose adjustment
crcl30-50 ml/min 200 mg alternative with 400 mg every other day
<30 ml/min 200mg po od
follow up by CBC monthly if Hb <8.5 g/dl stop ribavirin permanent
if WBC<1,000 neutrophils <500 platelets less than 50,000 should stop permanent
S/E
1- haemolytic anaemia.
2- worsening cardiac events
3- teratogenicity in pregnant
4- GIT side effects
5-skin side effects such as pruritis and skin rash
reference
UpToDate
· change in taste or bad, unusual, or unpleasant (after) taste.
· cracked, scaly skin.
· crusting, irritation, itching, or reddening of the skin.
· difficulty with moving.
· The most frequent side effect of ribavirin is a haemolytic anaemia
What is the dose of this drug in a transplant patient and how would you adjust the dose?
Dosage forms: oral capsule (200 mg), oral solution (40 mg/mL), oral tablet (200 mg; 200 mg-400 mg; 400 mg; 400 mg-600 mg; 600 mg) · To date, all the reported studies have used variable dosing ranging from 200 mg to 1200 mg per day with a median dosage of 600 mg/day.
Is it applicable in CKD and transplant patients?
The pharmacokinetics of ribavirin are variable in transplant recipients and clearance depends particularly on renal function
References
1. Peters van Ton AM, Gevers TJ, Drenth JP. Antiviral therapy in chronic hepatitis E: a systematic review. J Viral Hepat 2015; 22: 965-73.
2-Lhomme S, Kamar N, Nicot F, et al. Mutation in the hepatitis E virus polymerase and outcome of ribavirin therapy. Antimicrob Agents Chemother 2016; 60: 1608-14.
3- Pischke S, Hardtke S, Bode U, et al. Ribavirin treatment of acute and chronic hepatitis E: a single-centre experience. Liver Int 2013; 33: 722-6.
Ribavirin, previously combined with IFN-gamma to treat HCV, was reported being successful in the management of HEV. It should be used with caution because of the risk of hemolysis, especially in those with anemia and CKD. It is teratogenic. In CKD patients uptodate.com with suggested doses according to manufacturers but in general may experts suggest using lower dose with caution
Rebetol capsules/solution, Ribasphere capsules:
CrCl ≥50 mL/minute: No dosage adjustments necessary.
CrCl <50 mL/minute: Use is contraindicated.
Moderiba and Ribasphere tablets: CrCl >50 mL/minute: No dosage adjustments necessary. CrCl 30 to 50 mL/minute: Alternate 200 mg and 400 mg every other day. CrCl <30 mL/minute: 200 mg once daily. ESRD requiring hemodialysis: 200 mg once daily.
hemolytic anaemia may result in worsening of cardiac disease leading to myocardial infarction, hence should not be used in patients with significant or unstable cardiac disease otherwise adjust the dose to 200mg twice daily if there is no significant cardiac disease
discontinue ribavirin if Hb <8.5, WBC <1,000, platelets <50 otherwise adjust the dose to 200mg twice daily in case of non-severe hematologic changes
– GI: abdominal pain, anorexia, diarrhoea
– hepatic: hyperbilirubinemia
– infection: viral infection
– dermatologic: alopecia, pruritus, skin rash
– endocrine/ metabolic: hyperuricemia
– contraindicated in pregnancy – associated with teratogenicity
What is the dose of this drug in a transplant patient and how would you adjust the dose? (1-4)
– typical ribavirin dose: 200mg every 8hours for 12 weeks based on virological response
– optimal dosing has not been defined: typically 600-800mg/day
– optimal duration: typically, ≥3months based on virological response
– adjust dose according to kidney function
eGFR >50: no dose adjustment
eGFR 30-50: alternate 200mg and 400mg every other day
eGFR <30 or on HD: 200mg/d
– closely monitor hemoglobin and hematocrit, use erythropoietin in patients with eGFR <30 or those on HD
– discontinue ribavirin if Hb <8.5, WBC <1,000, platelets <50
– once a laboratory abnormality or clinical adverse event has resolved, restart ribavirin at 50% of the full dose
Please substantiate your answer.
References
1. Rivero-Juarez A, Vallejo N, Lopez-Lopez P, Díaz-Mareque AI, Frias M, Vallejo A, et al. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms. 2019 Dec 26;8(1). PubMed PMID: 31888090. Pubmed Central PMCID: PMC7022260. Epub 2020/01/01. eng.
2. Lhomme S, Marion O, Abravanel F, Izopet J, Kamar N. Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections. Journal of clinical medicine. 2020 Jan 24;9(2). PubMed PMID: 31991629. Pubmed Central PMCID: PMC7073673. Epub 2020/01/30. eng.
3. De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacological research. 2018 Apr;130:308-15. PubMed PMID: 29499270. Epub 2018/03/03. eng.
4. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
Q1: side effects include: dermatitis or skin rash. Hyperuricemia, growth retardation, GI side effects such as anorexia, abdominal pain, diarrhea, nausea, hemolytic anemia, lymphocytopenia, neutropenia, and hyperbilirubinemia viral infection. Q2: optimal dose varies between 600 to 800 mg/day in 1 to 2 divided doses for more than three months based on virus PCR response. Ribasphere tablets dose for Cr Cl>50 ml/min doesn’t need adjustments. Cr Cl 30-50 ml/min: alternate every other day 200 mg and 400 mg Cr Cl<30 ml/min and HD patients: 200 mg daily
History and examination to role out chronic hepatitis
Serial Laboratory investigations of liver enzymes and blood count and HEV RNA in plasma and stool
Start ribavirin 600 mg once a day for 12 weeks with monitoring drug level and sign of organ rejection and blood count for hemoglobin level
Reducing immunosuppressive therapy especially tacrolimus to lower level and keep steroid dose and MMF dose with previous same dose.
If persistent infection considering interferon but should be carful regarding organ rejection.
Serial monthly test for HEV antigen in stool and blood, once negative consider stop ribavirin.
What is the prevalence of HEV in solid organ transplantation?
Prevalence of HEV infection is higher in organ transplant reach to 20.3%.
HEV is transmitted by the fecal-oral route, infection is more prevalent in areas with poor water quality and food contamination.
1. A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. He was on prednisolone, MMF, and tacrolimus. During the first 1.5 years after transplantation, he developed CMV reactivation, primary EBV infection, and BK-virus viremia. Almost 3 years after transplantation at a routine check-in 2011, ALT (94 U/L) and AST (55 U/L) were found to be elevated. Kidney function was stable with an eGFR of 80 mL/min. Liver enzymes remained slightly increased in 2012 and 2013. No clear relation could be found with drugs. HCV and HBV PCR were negative. Repeated testing for BK, EBV and CMV DNA was negative. After temporary normalization, liver enzymes increased again with an ALT of 117 U/L. At that point, HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analysed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
Issues/ concerns
– 35yo, CKD5, HUS, DBD kidney transplantation in 2008
– Tacrolimus, MMF, prednisone
– developed CMV reactivation, primary EBV infection, BKV viremia during the first 1.5years
– in 2011 noted elevated ALT (94) & AST (55)
– stable kidney function eGFR 80
– liver enzymes remained slightly elevated in 2012 and 2013
– drug history unremarkable to explain the elevated liver enzymes
– HCV PCR, HBV PCR – negative
– repeat BKV DNA, EBV DNA, CMV DNA – negative
– liver enzymes normalized temporarily then increased again ALT (117)
– HEV PCR – positive, genotype3
– archived blood samples anti-HEV IgM positive and IgG negative in the first HEV RNA positive sample in 2011, later anti-HEV IgG became positive
– Hepatitis E virus (HEV) causes a self-limited viral hepatitis
– 4 genotypes are known to infect man
– HEV is transmitted through contaminated food and water, blood transfusions, mother-to-child transmission
– chronic HEV has been described mostly in immunocompromised hosts, it is defined as detection of HEV RNA in serum or stool for more than 6 months
– baseline investigations: – HEV RNA test done to confirm the diagnosis
– HEV RNA assay should be performed in both serum and stool
– for HEV RNA to be regarded as absent both stool and serum assays should be negative however for HEV RNA to be reported as present it should be detectable in either serum or stool
– management of acute HEV infection is usually supportive since the disease is mild and self-limiting in immunocompetent patients
– management of chronic HEV infection in SOT recipients on immunosuppression involves: – (1-3)
1st pathway –
reduce immunosuppressive therapy (tacrolimus),
initiate ribavirin 12 weeks and recheck HEV RNA at the end of treatment,
if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virologic response and no further treatment or monitoring is required however if after the 12 weeks HEV RNA is still present reinitiate ribavirin for 24 weeks then recheck HEV RNA at the end of treatment; if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virologic response and no further treatment or monitoring is required however if after the 12 weeks HEV RNA is present consider this as treatment failure and follow up patient for signs of progressive liver disease
similarly, if HEV RNA is still present after 24 weeks of ribavirin, consider this as treatment failure and monitor the patient for signs of progressive liver disease
2nd pathway –
reduce immunosuppressive therapy (tacrolimus),
initiate ribavirin 12 weeks and recheck HEV RNA at the end of treatment,
if HEV RNA is still present continue with ribavirin for an additional 12 weeks and recheck HEV RNA at the end of treatment
if HEV RNA is present consider this as treatment failure and follow up patient for signs of progressive liver disease
if HEV RNA is absent, stop ribavirin and recheck the HEV RNA in 12 weeks, if still absent this is regarded as sustained virologic response and no further treatment or monitoring is required but if HEV RNA is present, consider this as treatment failure and follow up patient for signs of progressive liver disease
What is the prevalence of HEV in solid organ transplantation? (4, 5)
– among SOT recipients, the pooled estimated prevalence of acute HEV infection was 4.3% (4)
– among kidney transplant recipients, prevalence of HEV RNA increased from 19% (pre-transplant) to 26% (post-transplant) (5)
References
1. Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, et al. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011 May;140(5):1481-9. PubMed PMID: 21354150. Epub 2011/03/01. eng.
2. Khuroo MS, Khuroo MS. Hepatitis E: an emerging global disease – from discovery towards control and cure. Journal of viral hepatitis. 2016 Feb;23(2):68-79. PubMed PMID: 26344932. Epub 2015/09/08. eng.
3. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
4. Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World journal of gastroenterology. 2021 Mar 28;27(12):1240-54. PubMed PMID: 33828397. Pubmed Central PMCID: PMC8006097. Epub 2021/04/09. eng.
5. Lim MA, Kamili S, Cohen JB, Green-Montfort T, Tejada-Strop A, Kohli J, et al. Hepatitis E Virus Infection in Kidney Transplant Patients: A Single-Center Study. Transplantation. 2018;102(4):e126-e7. PubMed PMID: 00007890-201804000-00012.
What are the side effects of ribavirin? (1-4)
– hematologic: –
hemolytic anaemia may result in worsening of cardiac disease leading to myocardial infarction, hence should not be used in patients with significant or unstable cardiac disease otherwise adjust the dose to 200mg twice daily if there is no significant cardiac disease
discontinue ribavirin if Hb <8.5, WBC <1,000, platelets <50 otherwise adjust the dose to 200mg twice daily in case of non-severe hematologic changes
References
1. Rivero-Juarez A, Vallejo N, Lopez-Lopez P, Díaz-Mareque AI, Frias M, Vallejo A, et al. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms. 2019 Dec 26;8(1). PubMed PMID: 31888090. Pubmed Central PMCID: PMC7022260. Epub 2020/01/01. eng.
2. Lhomme S, Marion O, Abravanel F, Izopet J, Kamar N. Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections. Journal of clinical medicine. 2020 Jan 24;9(2). PubMed PMID: 31991629. Pubmed Central PMCID: PMC7073673. Epub 2020/01/30. eng.
3. De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacological research. 2018 Apr;130:308-15. PubMed PMID: 29499270. Epub 2018/03/03. eng.
4. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
· This patient has persistent positive HEV RNA -elevated liver enzyme (Chronic HEV infection )
· Treatment with antiviral ribavirin for at least 3 month
· Monthly HEV RNA testing in plasma and stool until a decision is made to stop treatment.
· the aim of treatment is achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment)
· Regular haemoglobin monitoring during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect.
· Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV tacrolimus mainly
In A systematic review and meta-analysis (n = 4557)
the pooled estimated prevalence of HEV infection in SOT patients was 20.2%
The pooled estimated prevalence of HEV infection for each organ transplant was as follows: liver 27.2%
kidney 12.8%
heart 12.8%
and lung 5.6%
Patient had positive anti HEV IgM first and then anti HEV IgG positive later. Anti HEV IgM remains detectable for unto 6 months from the onset of symptoms, while anti HEV IgG persists for many years after infection. IgM is the serological marker for acute HEV infection.
Increased liver enzymes, and high level of antibodies in immunocompromised patient is indicative of chronic HEV infection. This is partly why clinical workup on noticing increased liver enzymes should include testing for HEV infection irrespective of IgG HEV status because anti HEV IgG presence may not be protective unconditionally.
Treatment can be done using ribavirin for chronic HEV infection. Therapy can be done for 12 weeks with monitoring, but can continue unto 24 weeks if there is detectable level of viral load in plasma, serum or feces at week 12.
Reduction or change in immunosuppressive regimen is to be considered, but the antiviral therapy is the most important in HEV infection resolution. This patient is on tacrolimus. Tacrolimus dose reduction may benefit the patient and help in infection resolution. However, this is to be done carefully, since the time between initiation of dose reduction of immunosuppression and the time of infection resolution may well be upto 1 year. This can increase the chances of graft rejection.
Switching from tacrolimus to cyclosporine can be considered.
Prevalence of HEV in SOT
There is high prevalence of HEV in solid organ transplant, mainly liver and kidney. Antiviral therapy as prophylaxis needs to be given upto 6 months to prevent incidence of infection, which includes drugs such as ganciclovir.
anti HEV IgM is seen in serum first, upon onset of symptoms, followed by HEV IgG which can last from 12 months to several years. The former lasts upto 6 months and indicates acute or current infection. Even if the patient has high detectable levels of HEV IgG, there can be infection reactivation in the patient or reinfection, i.e., de novo infection. Clinical vigilance is needed to identify chronic infection as there can be fluctuation in positivity of tests. Silent or subclinical infections are common, much more than active disease after IgG develops within the first 12 month period. This may become a problem in the future.
Numbers and statistics
In terms of numbers, acute HEV infection can be seen in 10% patients in Middle East. HEV IgG seroprevalence in liver transplant recipients is seen from 3-28%, with a serum RNA detection rate of 0-2%, and incidence of chronic hepatitis E upto 3% in Europe and North America.
Global anti HEV IgG seroprevalence has been found to be 12.5%. Risk factors for anti HEV IgG positivity were found to be raw meat, exposure to soil, blood transfusion, traveling to endemic areas, contacting with infected animals, and rural area habitation.
The pooled estimated prevalence of HEV infection for each solid organ transplant is below :
Liver – 27.2%; 95% CI 20-35.8
kidney – 12.8%; 95% CI:9.3-17.3
heart – 12.8%; 95% CI : 9.3-17.3
lung – 5.6%; 95% CI: 1.6-17.9
References
Panning, M., Basho, K., Fahrner, A. et al. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infect Dis 19, 675 (2019). https://doi.org/10.1186/s12879-019-4307-6
Mayo Clinic laboratories. Microbiology and infectious disease catalog. 2023.
Rivero-Juarez A, Vallejo N, Lopez-Lopez P, Díaz-Mareque AI, Frias M, Vallejo A, Caballero-Gómez J, Rodríguez-Velasco M, Molina E, Aguilera A. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms. 2019 Dec 26;8(1):51. doi: 10.3390/microorganisms8010051. PMID: 31888090; PMCID: PMC7022260.
Komolmit, P., Oranrap, V., Suksawatamnuay, S. et al. Clinical significance of post-liver transplant hepatitis E seropositivity in high prevalence area of hepatitis E genotype 3: a prospective study. Sci Rep 10, 7352 (2020). https://doi.org/10.1038/s41598-020-64551-x
Sayed IM, El-Mokhtar MA, Mahmoud MAR, Elkhawaga AA, Gaber S, Seddek NH, Abdel-Wahid L, Ashmawy AM, Alkareemy EAR. Clinical Outcomes and Prevalence of Hepatitis E Virus (HEV) Among Non-A-C Hepatitis Patients in Egypt. Infect Drug Resist. 2021;14:59-69. https://doi.org/10.2147/IDR.S289766
Pengei Li, et al. The global epidemiology of hepatitis E virus infection : a systemic review and meta analysis. Liver International. 2020; 40 (7) : 1516-1528.
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
This case reflects the importance of HEV as one of the differential diagnoses in patient with elevated liver enzymes without obvious cause. Specially when HBV and HCV screening are negative.
After confirming the diagnosis:
Monitoring of liver enzymes and HEV RNA is important as up to 34% of cases may clear the infection without specific treatment. Another 21% may clear the virus with a reduction of immunosuppression.
So, more than half of the patient cleared the infection without specific anti viral treatment. So initial management should be monitoring HEV RNA and liver enzymes with reduction of immunosuppression. If no improvement within 3months, then consideration for anti viral treatment is needed.
Modifications of immunosuppression can cleat up to 30% of cases in some series.
Steroid and CNI can increase virus replications and MMF, interestingly, was found to inhibit vital replications. So lowering level of CNI and steroid to the minimum possible 2.5mg to 5mg od could help in clearing the virus.
Anti-virus therapy:
Ribavirin is a guanosine analogue and may also act as a nucleoside inhibitor,
inhibiting replicating HEV RNA. A sustained virological response (serum HEV RNA negative six months after treatment) was achieved in 78% of cases in one study. 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
What is the prevalence of HEV in solid organ transplantation?
HEV genotype 1 &2 are common in developing countries, reaching 50% of cases of hepatitis. Where is genotype 3 and 4 are more common in developed countries.Also, prevalence differs between countries and different organs. In one systemic review included more than 4500 cases, it was found that the pooled prevalence in all organs was 20.2% and in individual organ was as follow:
Liver 27.2%.
Kidney 12.8%.
Heart 12.8%.
Lung 5.6%.
References:
1-World J Gastroenterol 2021 March 28; 27(12): 1240-125 Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis.
2-Guidelines for Hepatitis E & Solid Organ Transplantation British Transplantation Society Guidelines 2017.
3-Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation, Immun Inflamm Dis. 2021;1–8.
Thank you well done. Your recommendation of immunosuppression reduction you referred to the preferential reduction of steroids and CNI. You have to be very cautious especially with high immunological risk recipients. The approach is usually to reduce antimetabolite first in case it’s needed.
How would you manage this case?
This patient has HEV infection post kidney transplantation evidenced by deranged liver enzymes that were steadily rising and positive HEV RNA. Retrospectively HEV RNA and IgG and IgM anti-HEV were first positive in 2011, hence this patient has persistent infection.
Persistent HEV infection mainly occurs in individuals who are heavily immunosuppressed mainly with T cell depleting agents.
CNI and MTOR may contribute to the persistence of HEV in hepatocytes hence persistent infection. MMF inhibits HEV replication while steroids have no effect.
1.The CNI should be reduced with close monitoring of UECS due to risk of rejection.
Reduction of immunosuppression may lead to clearance of infection in 30% of individuals.
2.Antivirals- Ribavarin a guanosine analogue which acts as a nucleoside inhibitor can be used.
However its optimal dose and duration is not known.
Should be continued until 2 stool and plasma tests are negative for HEV RNA.
Most common adverse effect of ribavarin is hemolytic anaemia thus regular monitoring of blood counts is required.
3.Other treatment options:
Pegylated interferon not recommended for first line treatment due to risk of rejection in SOT. Thus is indicated for cases that are refractory to ribavarin.
Sofosbuvir has an inhibitory effect on HEV which is additive when combined with ribavarin. Further studies are required on its use.
What is the prevalence of HEV in SOT?
A meta analysis reported a pooled prevalence of 20%, with high prevalence in liver and kidney recipients and low in lung recipients.
However prevalence is mainly determined by the geographical location, with genotype 1 and 2 more prevalent in developing countries while genotype 3 and 4 in developed countries.
References
Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis
Panupong Hansrivijit, Angkawipa Trongtorsak, […], and Wisit Cheungpasitporn
Kamar N, Bendall R, Legrand-Abravanel F, et al. Hepatitis E. Lancet. 2012 Jun 30;379(9835):2477-88.
Guidelines for Hepatitis E & Solid Organ Transplantation First Edition Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report Marcus Panning1*, Kristi Basho1, Andreas Fahrner2 and Christoph Neumann-Haefelin3
Thank you for your answers. I quote from your answer ‘Should be continued until 2 stool and plasma tests are negative for HEV RNA’. Haemolytic anaemia is one of the main side effects of ribavirin. Many of those who are treated may require EPO injections. Therefore you should mention the interval between the two stool samples that is adequate to stop Ribavirin treatment.
Thank you prof.
The interval of the 2 negative plasma and stool should be one month apart.
The ribavirin should be given for at least 3 months with maximum duration of 6 months.
If no response after 6 months should be considered to be ribavirin refractory.
Ribavirin is the first-choice therapy to treat HEV infection.
Further studies are needed to identify novel antiviral therapies for patients that are resistant or partial responders to ribavirin.
Anemia is well-known side effect & can lead to the discontinuation of therapy.
Pegylated interferon-alfa:
Has antiviral activity against HEV, however, it is not recommended for use in patients with stem cell or organ transplants due to a high risk of rejection.
Sofosbuvir (polymerase inhibitor of HCV):
Promising in vitro data; however, only case reports are available.
================================= What is the prevalence of HEV in solid organ transplantation?
Recent data showed that HEV seroprevalence rates are ranging from < 1% up to 52% across Europe.
Prevalence in SOT:
A meta-analysis showed a pooled estimated prevalence of 20.2%. The pooled estimated prevalence for each organ transplant was as follows:
Liver (27.2%)
Kidney (12.8%)
Heart (12.8%)
Lung (5.6%).
The prevalence of HEV infection among SOT recipients was significantly higher in middle-income countries compared to high-income countries.
The pooled estimated prevalence of de novo HEV infection was 5.1% & the pooled estimated prevalence of acute HEV infection was 4.3%.
References
Marcus Panning, Kristi Basho, Andreas Fahrner and Christoph Neumann-Haefelin, Chronic hepatitis E after kidneytransplantation with an antibody responsesuggestive of reinfection: a case report
Hansrivijit P et al., Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis, World J Gastroenterol 2021 March 28; 27(12): 1240-1254, DOI: 10.3748/wjg.v27.i12.1240
How would you manage this case?
Diagnosis -chronic HEV occurring post kidney transplantation. Treatment
Reduction of Immunossupresion treatment
Reduce dose of tacrolimus and steroids and continue MMF in same dose
Close follow up of serum creatinine as liver enzyme.
Monitor the patient for 3 months
See for Serum and stool HEV RNA clearance- if no clearance then start antiviral.
Antiviral Therapies
Ribavirin(600-800 mg/day), the dosage is adjusted according to creatinine clearance.
Liver enzymes (for response) and CBC (for side effects) should be closely monitored.
Duration of treatment of ribavirin should be 3 months
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
If relapse occur after ceasing Ribavirin
Need to give it for 6 months
No response of ribavirin in 6 month or intolerance to ribavirin or relapse after 6 months ribavirin
Then need to give pegylated interferon alpha(no preferable as there is high chance of rejection)
What is the prevalence of HEV in solid organ transplant?
The prevalence of HEV infection is higher in SOT patients (20.1% vs 12.5%) compared to non- transplant.
prevalence of de novo HEV infection in SOT recipients was 5.1%
The HEV seropositivity was significantly higher among transplant-recipients compared with waitlist patients (24% vs. 16.4%,
1)Lecture : May A Hassaballa HEV in kidney transplant
2)Kamar N, Lhomme S, Abravanel F, Marion O, Peron J-M, Alric L, Izopet J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses. 2016; 8(8):222. https://doi.org/10.3390/v8080222
3)Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, Farci P, Ghabril M, Lucey MR, Rangnekar AS, Reddy KR, Ghany MG. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec;29(12):1134-1142. doi: 10.1111/jvh.13739. Epub 2022 Sep 21. PMID: 36036116.
4)Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
Thank you Prof for the question. It look like the De novo infection because retrospectively, archived blood samples were analyzed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.and he had undergone transplant on 2008
The index patient is a 35-year-old cadaveric donor renal transplant recipient (October 2008, basic disease HUS) with history of multiple infections (BK virus, cytomegalovirus, Epstein Barr virus) in first 18 months post-transplant, currently on tacrolimus based triple drug immunosuppression with stable graft function.
In 2011, patient developed elevated liver enzymes, which increased in 2012 after initial normalization. HEV evaluation in 2013 revealed a positive test, with genotype 3. Retrospective analysis revealed HEV RNA and anti-HEV IgM positivity in 2011, with development of anti-HEV IgG later.
The clinical scenario pertains to persistent HEV infection post-transplant (HEV positivity for > 3 months). 60% of genotype 3 HEV infections in SOT lead to persistent HEV infection (1)
The management in this scenario includes (1,2):
Detailed history and examination: Especially to assess any extrahepatic manifestations.
Getting a baseline plasma and stool HEV RNA test.
Reduction in immunosuppression: Assess the tacrolimus trough levels and modify doses to keep at lower level, or can be changed to cyclosporine, as tacrolimus use, when compared to cyclosporine, is more associated with chronic HEV infection (3). Patient should be counselled regarding the risk of rejection associated with immunosuppression reduction.
Antiviral: Ribavirin should be started with dosage of 600 mg/day(in 2 divided doses) for at least 3 months.
Test plasma HEV RNA on day 7. It will provide clues towards the response to treatment (favorable response would require shorter duration of treatment).
Monthly testing of plasma and stool HEV should be done.
Ribavirin treatment should be stopped once 2 consecutive negative plasma and stool results (1 month apart) are obtained at 3 months.
If the plasma and stool HEV is still positive at 3 months, continue treatment till 2 consecutive negative plasma and stool results (1 month apart) are obtained or till 6 months.
Post-treatment completion, test for presence of HEV RNA in plasma and stool at 3 and 6 months.
Monitoring: Ribavirin is associated with hemolytic anemia, hence regular hemoglobin monitoring should be done. Dose should be adjusted as per creatinine clearance. Erythropoietin or blood transfusion might be required for managing anemia.
Ribavirin-refractory scenario: In case the patient does not respond to ribavirin, Pegylated interferon may be used, but would require close monitoring due to moderate risk of rejection.
Relapse post- ribavirin treatment: A course of Ribavirin can be repeated with higher dose and longer duration (6 months), as per creatinine clearance and the tolerability of the patient.
What is the prevalence of HEV in solid organ transplantation?
The pooled prevalence of HEV infection in solid organ transplantation (SOT) in a meta-analysis has been found to be 20.2% (14.9-26.8%). The prevalence in different organs ranged from 27.2% (liver), 12.8% (kidneys and heart) to 5.6% (lung) depending on the organ involved (4). The prevalence is 2 times more in middle-income countries as compared to high-income countries (4,5). The pooled estimated prevalence of de novo HEV infection ranged from 2.6% to 9.6%. The pooled prevalence of acute HEV infection is 4.3% (4). Another study revealed 24% prevalence of HEV in transplant recipients (6). The prevalence was higher in old aged, use of CNI, graft hepatitis history, and renal transplant recipients (6).
Kamar N, Lhomme S, Abravanel F, Marion O, Peron JM, Alric L, Izopet J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses. 2016 Aug 15;8(8):222. doi: 10.3390/v8080222. PMID: 27537905; PMCID: PMC4997584.
Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, Dumortier J, Cannesson A, Cassuto-Viguier E, Thervet E, Conti F, Lebray P, Dalton HR, Santella R, Kanaan N, Essig M, Mousson C, Radenne S, Roque-Afonso AM, Izopet J, Rostaing L. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011 May;140(5):1481-9. doi: 10.1053/j.gastro.2011.02.050. Epub 2011 Feb 24. PMID: 21354150.
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
Li P, Liu J, Li Y, Su J, Ma Z, Bramer WM, Cao W, de Man RA, Peppelenbosch MP, Pan Q. The global epidemiology of hepatitis E virus infection: A systematic review and meta-analysis. Liver Int. 2020 Jul;40(7):1516-1528. doi: 10.1111/liv.14468. Epub 2020 Apr 24. PMID: 32281721; PMCID: PMC7384095.
Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, Farci P, Ghabril M, Lucey MR, Rangnekar AS, Reddy KR, Ghany MG. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec;29(12):1134-1142. doi: 10.1111/jvh.13739. Epub 2022 Sep 21. PMID: 36036116.
Thank you for the detailed discussion and answers. I quote ‘Detailed history and examination: Especially to assess any extrahepatic manifestations. Do you think detailed history taking is especially for extrahepatic manifestations which are extremely rare and will not change much of your management plan, or there are other important points that you need to clarify from history taking?
Detailed history includes dietary history (history of consumption of raw/undercooked meat – pork products) and history of blood transfusion.
The need of looking for extrahepatic manifestations is because their presence would require early treatment with Ribavirin.
Examples include: thrombocytopenia (bleeding), acute pancreatitis (pain abdomen), neurological involvement (vestibular neuritis, peripheral neuropathy), etc.
· 35 – Years who had DBD kidney transplant 2008.
· 2011 he had increased liver enzymes and remained slightly raised during 2012 and 2013.
· Liver enzymes increased again after temporal normalization.
· This time HEV was found positive. It was genotype 3.
· Retrospectively HEV RNA was first positive in 2011 anti HEV IgM was positive and IgG was negative.
· Later on also HEV IgG became positive.
How would you manage this case?
This is a case of chronic HEV occurring post kidney transplantation. Diagnosis
· This patient had raised liver enzymes in 2011, HCV, HBV PCR were negative and no clear relation could be found related to drugs.
· HEV RNA was found to be positive retrospectively in 2011 together with ant HEV IgM. So HEV RNA is estimate to be positive for more than 3 months.
· The patient developed acute infection in 2011and later on developed humoral immunity to the virus. Treatment 1. Reduction of IS treatment: · Reduce dose of tacrolimus and steroids and keep MMF. · All data suggest that patients that are heavily immunosuppressed have a high risk of developing a chronic infection. · That the majority of immunosuppressive drugs increase HEV replication except mycophenolic acid can decrease HEV replication in vitro. · It was observed that HEV clearance occurred in 30% SOT patients with chronic HEV infection after reducing immunosuppressive therapies that principally targeted T-cells. · With reduction of IS therapy, close follow up of serum creatinine as AR is a possibility.
2. Antivral Therapies · He should receive treatment with ribavirin, the dosage is adjusted according to creatinine clearance. · A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment, monthly during treatment. · Liver enzymes (for response) and CBC (for side effects) should be closely monitored. · Duration of treatment with of ribavirin should be 3-6 months. · Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart. · Sustained virological response is achieved when HEV RNA is not detected in plasma and stool for six months after completion of treatment. What is the prevalence of HEV in solid organ transplant? · HEV route of transmission via the fecal-oral route is similar to hepatitis A virus, patients with poor hygiene are predisposed to both hepatitis A and hepatitis E infection. · It can be concluded that the prevalence of HEV infection is higher in SOT patients (20.1% vs 12.5%) compared to non- transplant. · The prevalence of acute HEV infection was also higher in SOT patients compared to non-transplant patients (4.3% vs 1.5%). · HEV has been noted to impact solid organ transplant recipient outcomes. HEV infection has been documented to cause graft cirrhosis and subsequent failure in liver graft recipients secondary to chronic infection. · Renal transplant allografts were found to have similar rejection and two year graft survival between HEV seropositive and negative recipients. · Case reports describing the occurrence of HEV in liver transplant recipients who receive an allograft with latent disease. · Once infected with the virus, transplant recipients are at risk for developing chronic liver disease, especially with HEV genotype. · The seroprevalence of anti-HEV IgG could be affected by the assays used for antibody testing. · It is also found that the prevalence of HEV infection was significantly higher in middle-income countries compared to high-income countries. · The seroprevalence of anti-HEV IgG was at least two-fold higher in Africa and Asia in comparison to Europe and North America.
References: 1. Guidelines for Hepatitis E & Solid Organ Transplantation, BTS, First edition. 2. Nassim Kamar et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis.Viruses 2016, 8, 222. 3. Panupong Hansrivijit, et al, Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis,March 28, 2021 Volume 27 Issue 12.
Thank you Mannoli and well done. Do you think that hyou start with reducing tacrolimus and keep MMF? Can you please quote the reference for this statement?
Because of untoward side effects from Ribavirin most patients do not withstand 6 month of treatment and usually the Ribavirin stopped before you reach the full course
Thank you professor Mohsen El Kossi,
“It was also demonstrated that calcineurin inhibitors (CsA and FK506) promoted HEV infection. In fact the use of FK506 was found to be the main predictive factor for chronic hepatitis E in organ recipients in another study by Kamar et al[16,18]. On the other hand mycophenolic acid/mycophenolate mofetil (MPA/MMF) suppressed viral infection in replica model. The clinical benefit was demonstrated in heart transplant recipients where MMF containing regimens were assumed to play a role in more frequent HEV clearance”. Reference:
Avin Aggarwal, et al, Hepatitis E virus infection in the liver transplant recipients: Clinical presentation and management. January 18, 2016|Volume 8|Issue 2|
This is chronic HEV infections which have been G3 ,it manifested as high liver enzymes three years after transplant and remains high 2years after ,investigated and diagnosed as HEV infection through positive HEV PCR (after exclude HCV and HBV).
After establish the diagnosis by taking history and examination .
Investigation by CBC ,RFT,LFT ,URINE ANALYSIS ,LDH ,and HEV PCR as base line .
CXR and abdominal US. Treatment observation and monitoring of HEV RNA levels and liver enzymes (30% will spontaneously clear the infection within three months).
reduction in immunosuppression.
the risk of rejection should be carefully assessed.
Treatment with ribavirin 600 mg for three to six month till HEV RNA not detected in plasma and stool six months after completion of treatment.
Monthly HEV RNA testing in plasma and stool.
We continue ribavirin till stool test for HEV RNA negative in two occasions .
Monitoring the HB during treatment (haemolytic anemia from RIBAVIRIN.) and GFR . Ribavirin
is an antiviral medication that has been used for many years in combination with pegylated
interferon for the treatment of hepatitis C. The exact mechanism of antiviral activity of
ribavirin is unknown. Ribavirin has been shown to reduce HEV replication in vitro by reducing intracellular pools of GTP.
In persistent HEV who were treated with ribavirin for three months. In that study, the overall SVR(sustained virological response ) rate was 63% . It remains unknown what the optimum dosage of ribavirin is for the treatment of persistent HEV.
Interestingly, one small study found no relationship between ribavirin levels at day seven and
outcomes from treatment in patients with persistent HEV.
The most frequent side effect of ribavirin is a haemolytic anaemia, which required intervention in approximately 40%.
Approximately 40% of transplant recipients with persistent HEV relapse after three months of treatment with ribavirin. PEG-interferon.
treatment in cases of ribavirin refractory HEV.
is well known to increase the risk of rejection in transplant recipients.
PEG-interferon is not recommended as a first line treatment for HEV. Sofosbuvir
One recent study suggested the sofosbuvir inhibited HEV RNA replication in an experimental model of HEV.
What is the prevalence of HEV in solid organ transplantation?
The HEV seropositivity in transplant recipient is around 24%,
which is significantly higher than CKD patients who are waitlisted (16.4%).
HEV infection responsible for more than 50% viral hepatitis world wide.
References
1.Kamar N, Garrouste C, Haagsma EB, et al. Factors associated with chronic hepatitis in patients
with hepatitis E virus infection who have received solid organ transplants. Gastroenterology
2011; 140: 1481-9.
2.Abravanel F, Lhomme S, Rostaing L, Kamar N, Izopet J. Protracted fecal shedding of HEV during ribavirin therapy predicts treatment relapse. Clin Infect Dis 2015; 60: 96-9.
3. Kamar N, Lhomme S, Abravanel F, et al. An early viral response predicts the virological response to ribavirin in hepatitis E virus organ transplant patients. Transplantation 2015; 99: 2124-31.
4.Peters van Ton AM, Gevers TJ, Drenth JP. Antiviral therapy in chronic hepatitis E: a systematic review. J Viral Hepat 2015; 22: 965-73
5.Dao Thi VL, Debing Y, Wu X, Rice CM, Neyts J, Moradpour D, Gouttenoire J. Sofosbuvir Inhibits hepatitis E virus replication in vitro and results in an additive effect when combined with
ribavirin. Gastroenterology 2016; 150: 82-5.
6.
Hartl J, Otto B, Madden RG, Webb G, Woolson KL, Kriston L, et al. Hepatitis E Seroprevalence in Europe: a meta-analysis. Viruses. 2016;8(8)
Thank you. You referred to these investigations and missed a very important one in this case which is stool analysis for HEV PCR. Investigation by CBC ,RFT,LFT ,URINE ANALYSIS ,LDH ,and HEV PCR as base line. CXR and abdominal US.
How would you manage this case?
This patient developed denovo acute HEV in 2011 (3 years after transplantation) through diet (pork, G3). At that time HEV RNA was positive, anti-HEV IgM was positive and liver enzymes were high. No evidence of other viral infections and not drug-related
Acute Hepatitis E:
o Features range from asymptomatic infection to mild hepatitis to fulminant liver failure
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 Incubation period is 2-6 weeks (initial short-lived IgM response followed by IgG antibodies)
o If HEV RNA not cleared from the blood and stool by three months, persistent infection is likely to occur
o Following acute infection with HEV G3, the infection persists in approximately 60% of SOT recipients leading to persistent HEV infection
o Management includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months
o Treatment with ribavirin is indicated in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations
So, this patient developed persistent HEV (Chronic HEV infection) and should be treated
Chronic HEV infection:
o Detectable HEV RNA in the blood and/ or stool for greater than 3-6 months (treat after 3 months)
o The most common symptom
o Neurological symptoms can occur (also in acute HEV)
o Typically ALT levels are between 200-300 U/L (liver enzymes may be minimally raised or within the upper normal range)
Management:
o Modification of immunosuppression (Lead to clearance of HEV infection in 30%)
o Start 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)
o Do baseline quantitative HEV RNA on both plasma and stool at the start of treatment
o Treatment with ribavirin for at least three months (3-6 months for most patients)
o Do monthly HEV RNA testing in plasma and stool during treatment
o Continue ribavirin until stool tests are negative for HEV RNA on two occasions one month apart
o Do plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy (a test of sustained virological response)
o Regular haemoglobin monitoring during ribavirin therapy
o In relapse after a first course of ribavirin, re-treat for at least six months (higher dose)
o Treatmt with PEG-interferon treatment in ribavirin-refractory persistent HEV (close monitoring for rejection)
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
What is the prevalence of HEV in solid organ transplantation? Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis
o The pooled estimated prevalence of HEV infection in SOT recipients was 20.2% The pooled estimated prevalence of HEV infection in each transplanted organ was: Liver (27.2%), kidney (15.3%), heart (12.8%), lung (5.6%), and undifferentiated (29.6%)
o The pooled estimated prevalence of de novo HEV infection in SOT recipients was 5.1%
o The pooled estimated prevalence of acute HEV infection in SOT recipients was 4.3%
References
1. Kamar, N.; Lhomme, S.; Abravanel, F.; Marion, O.; Peron, J.-M.; Alric, L.; Izopet, J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
2. Guidelines for Hepatitis E & Solid Organ Transplantation. British Transplantation Society Guidelines, 2017.
3. Panning, M., Basho, K., Fahrner, A. et al. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infect Dis19, 675 (2019). Song JE, Kim DY. Diagnosis of hepatitis B. Ann Transl Med. 2016 Sep;4(18):338. doi: 10.21037/atm.2016.09.11. PMID: 27761442; PMCID: PMC5066055.
4. Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol 2021; 27(12): 1240-1254.
Thank you very much for such detailed answer. You are absolutely right that nearly all patients on Ribavirin will require dose reduction because of haemolytic anaemia and will need Epo injection. They rarely continue for 6 month treatment because of anaemia. Reducing immunosuppression with Ribavirin are always enough to clear the virus. The only concern in those patients who are high immunological risk who may develop rejection and those who are on dual immunosuppression when any immunosuppression reduction will carry high risk of rejection or sensitisation and development of DSA.
How would you manage this case? This is a case of persistent HEV infection> 3 months detectable RNA. 1- detailed history and clinical examination 2- laboratories for , CBC, KFT, Urinalysis, LDH, liver function (albumin, INR), gamma GT, alkaline phosphatase, and bilirubin, and a quantitative stool HEV PCR(as baseline) 3- ultrasound abdomen, for any organomegaly, and CXR. Treatment: 1- IS modulation :reduce TAC dose to the lowest that required to prevent rejection 2- Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 6 months after stopping the Ribavirin) 3- Adjust dose to GFR monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function. 4- Failure of treatment: repeat the course with high dose Ribavern but observe for side effect as above 5- in cases of ribavirin-refractory persistent HEV infection ,PEG-interferon treatment may be considered. However, it carries a risk of rejection. Prevalence of HEV in SOT The pooled estimated prevalence of HEV infection in SOT patients was 20.2% The pooled estimated prevalence of HEV infection for each organ transplant was as follows: Liver : 27.2% Kidney : 12.8 % Heart : 12.8% Lung 5.6%
This is a case of chronic HEV infection in a heavily immunosuppressed young individual as evident by the viral infection in the first 1.5 year. The corner stone of management in liver, kidney, and heart transplant recipients are ribavirin antiviral therapy and reducing immunosuppression(1) But we need to consider the fact that changes in immunosuppression can precipitate rejection in more immunogenic individuals so the risk of rejection versus the potential benefits of modification of immunosuppression must be carefully balanced. This case of chronic infection with HEV G3 can progress rapidly (3-5 years) to cirrhosis in approximately 15% of infected solid organ transplant recipients. Chronic HEV infection is defined as the finding of detectable HEV RNA in the blood and/ or stool for greater than six months. Aim of treatment is clearing HEV from the blood and stool. persistent HEV infection is defined as documented or estimated duration of infection of greater that three months. Data supporting reduction of immunosuppressants need more controlled trials to support this approach. Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV. The data supporting this approach come from uncontrolled studies and case series. Shifting from Tacrolimus to cyclosporin as high doses of Tacrolimus increased HEV replication in a cell culture model. One large study found that patients treated with ciclosporin were more likely to have spontaneous clearance than those treated with tacrolimus but it has been conducted in acute infection cases. Regarding mycophenolate, it inhibit HEV replication and this was potentiated with the addition of ribavirin. But one small study in established persistent HEV, reported no difference in the rate of HEV clearance in transplant recipients treated with ribavirin whether or not they were on mycophenolate. Corticosteroids had no effect on HEV replication. (2) Ribavirin use was supported by kamar study. Based on that I would use ribavirin dose 600 mg, adjust dose according to creatinine clearance, for three months (range 1-18 months). Kamar study reported a sustained virological response in 78% of cases (serum HEV RNA negative six months after treatment).(3) Follow up of Hb level is mandatory as hemolytic anemia is a well-recognized side effect of ribavirin initially every two weeks until the hemoglobin has reached nadir then monthly thereafter. Dose reduction of ribavirin is recommended when the hemoglobin falls below 100 g/L. A systematic review for use of ribavirin for persistent HEV found an overall sustained virological response rate of 74% with a wide variation in the dosage of ribavirin (200-1200 mg), length of treatment (median three month range 1-18) and duration of infection (median 16 month range 1-84). Follow up is with the HEV RNA after 7 days, 1 month , 2 months and 3 months. The level at 7 days was an independent predictor of sustained virological response to ribavirin treatment. Thus, for a favorable response at day 7 the duration of ribavirin treatment is for three months and a longer course, such as six months can be applied for unfavorable day 7 response. Stopping of ribavirion can be considered at 3 months after 2 negative samples(both plasma and stool) with follow up samples at 3 and 6 months thereafter. If after 3 months there was appositive plasma or stool sample, then continue treatment till 2 stool samples are negative( 1 month apart) or continue for 6 months(2) What is the prevalence of HEV in solid organ transplantation? Southern France incidence of HEV among liver, kidney, or simultaneous kidney-pancreas transplantation was 3.2 cases/100 person-years . In UK, donors has a HEV-IgG seroprevalence rate of 16% but the incidence of HEV infection in transplant recipients is unknown.(4) In Europe and North America, HEV IgG seroprevalence in SOT and LT recipients ranges are from 3–28%, with a serum RNA detection rate of 0–2%.(5) Ref:
1- Maximilian Carter, Kassandra Solsrud, Sirisha Yeddula, Mary Grace Fitzmaurice, Ashina Singh, Shunji Nagai, Syed-Mohammed Jafri, Hepatitis E Diagnosis and Management After Liver, Kidney, or Heart Transplant: A Single-Center Experience, Transplantation Proceedings, Volume 54, Issue 7, 2022, Pages 1737-1741,
2- Guidelines for Hepatitis E & Solid Organ Transplantation Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017 First Edition
3- Kamar N, Mallet V, Izopet J. Ribavirin for chronic hepatitis E virus infection. N Engl J Med 2014; 370: 2447-8 4- Vassallo D, Husain MM, Greer S, McGrath S, Ijaz S, Kanigicherla D. Hepatitis e infection in a renal transplant recipient. Case Rep Nephrol. 2014;2014:865471. doi: 10.1155/2014/865471. Epub 2014 Sep 11. PMID: 25295201; PMCID: PMC4177828.
5- Komolmit, P., Oranrap, V., Suksawatamnuay, S. et al. Clinical significance of post-liver transplant hepatitis E seropositivity in high prevalence area of hepatitis E genotype 3: a prospective study. Sci Rep 10, 7352 (2020)
I appreciate your strategy in relation to Hep E infection and transplant. I make note of your understanding about the need to modify immunosuppression when infected with Hep E, well-supported by literature.
Management
– For this renal transplant recipient it is likely a chronic HEV hepatitis as retrospective serum samples testing at the year 2011 when liver enzymes increased ,it revealed Positive HEV RNA ,positive HEV Ig M and negative HEV Ig G.
Then with re elevation of the liver enzymes ,after temporary normalisation HEV RNA was tested positive
– Reduction of Tac, MMF and prednisolone doses at the same time the graft function needs close follow up due to rejection risk.
– Ribavirin treatment (dose is calculated according to creatinine clearance) for 3-6 months need to be started but with close monitoring of his CBC due to the history of HUS as main cause of ESRD, if anaemia occurred Ribavirin dose can be reduced ,along with HEV RNA testing
– A baseline quantitative HEV RNA level need to be detected in plasma and stool as treatment starts
– HEV RNA stool tests need to be negative on 2 occasions one month apart to achieve sustained virological response and stop Ribavirin therapy .
-The patient have to be counselled regarding avoidance of undercooked meat consumption
–Prevalence of HEV in solid organ transplantation
A metanalytical study, demonstrates the prevalence of HEV infection in SOT recipients was 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients).
The prevalence of HEV infection is 2-fold more common in middle-income countries compared to high-income countries. Reference
-Guidelines for Hepatitis E & Solid OrganTransplantation. BTS guidelines 2018
– Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254.
Management of the case This is the case of HEV reactivation.
There is a defective humoral and cellular response against the immunocompromised patient.
According to BTS guidelines treat new infections by measuring HEV RNA and liver enzymes as more than 30% will spontaneously clear the infection within three months.
Reduce tacrolimus dose cautiously as TAC showed to promote HEV reinfection.
Ribavirin is a novel treatment against HEV infection and should be the first line of therapy, monitoring side effects.
Monitor therapy response via nucleic test and the treatment duration should be continued until HEV RNA -ve in 2 consecutive results 1 month apart, recommended for 3-6 months.
PEG-interferon should only use if persistent HEV infection although ribavirin treatment, monitors graft function as it is associated with the risk of rejection.
Prevalence of HEV in SOT
The estimated prevalence in SOT globally is 20.2%.
The estimated prevalence in liver transplantation is 27.2%.
The estimated prevalence in kidney transplantation is 12.8%.
The estimated prevalence in heart transplantation is 12.8%.
The estimated prevalence in lung transplantation is 5.6%.
Refferences a. BTS guidelines 2018 HEV infection Guidelines for Hepatitis E & Solid Organ Transplantation
a. Webb GW, Dalton HR. Hepatitis E: an underestimated emerging threat. Ther Adv Infect Dis. 2019;6:2049936119837162. – PMC – PubMed
Whitsett M, Feldman DM, Jacobson I. Hepatitis E Virus Infection in the United States: Current Understanding of the Prevalence and Significance in the Liver Transplant Patient Population and Proposed Diagnostic and Treatment Strategies. Liver Transpl. 2020;26:709–717. – PubMed
Patra S, Kumar A, Trivedi SS, Puri M, Sarin SK. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med. 2007;147:28–33. – PubMed
Aggarwal A, Perumpail RB, Tummala S, Ahmed A. Hepatitis E virus infection in the liver transplant recipients: Clinical presentation and management. World J Hepatol. 2016;8:117
Hartl J, Otto B, Madden RG, Webb G, Woolson KL, Kriston L, et al. Hepatitis E Seroprevalence in Europe: a meta-analysis. Viruses. 2016;8(8). 2. Kamar N, Dalton HR, Abravanel F, Izopet J. Hepatitis E virus infection. Clin Microbiol Rev. 2014;27(1):116–38. 3. Schemmerer M, Rauh C, Jilg W, Wenzel JJ. Time course of hepatitis Especific antibodies in adults. J Viral Hepat. 2017;24(1):75–9. 4. Johne R, Plenge-Bonig A, Hess M, Ulrich RG, Reetz J, Schielke A. Detection of a novel hepatitis E-like virus in faeces of wild rats using a nested broad
Hepatitis E virus (HEV) infection is underdiagnosed due to the use of serological assays with low sensitivity. Although most patients with HEV recover completely, HEV infection among patients with pre-existing chronic liver disease and organ-transplant recipients on immunosuppressive therapy can result in decompensated liver disease and death.
How would you manage this case?
The first step is to reduce the immunsupression drug.
If infection persist then antiviral therapy with ribavirin for three months.
IF the infection collapse after stoping antiviral we can continue treatment for additional three months.
we can monitor with liver function an monthly PCR .
What is the prevalence of HEV in solid organ transplantation?
meta-analysis revealed prevelance of HEV in SOT recipients is 20%. De novo HEV infection and acute HEV infection accounted for less than 5% of infections. A recent meta-analysis of 419 studies comprised of 519,872 individuals showed an estimated global seroprevalence of anti-HEV IgG of 12.5% and a pooled estimated anti-HEV IgM seroprevalence of 1.5%.
reference :
1- Li P, Liu J, Li Y, Su J, Ma Z, Bramer WM, Cao W, de Man RA, Peppelenbosch MP, Pan Q. The global epidemiology of hepatitis E virus infection: A systematic review and meta-analysis. Liver Int. 2020;40:1516–1528. 2-McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK Guidelines for Hepatitis E and Solid Organ Transplantation. Transplantation. 2018;102:15–20. [PubMed] [Google Scholar]
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), in the current case we are dealing with chronic HEV infection
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
Treatment of HEV infection 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, it was found that the use of tacrolimus may be associated with high risk of HEV infection, MMF may be associated with lower risk and steroid is neutral, so 1 will keep MMF and steroid dose, keep lower target of tacrolimus
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 till negative result for 2 consecutive samples 1 month apart
If antiviral therapy is given, blood 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 virologic response
So in the current case
I will reduce tacrolimus dose keeping lower trough
I will start ribavirin therapy for 3 months since the patient has chronic HEV infection
I will monitor PCR in blood after 1 week of therapy to predict the duration of therapy, then I will perform PCR in blood and stool monthly
I will continue ribavirin till 2 consecutive PCR in stool are negative 1 month apart
After stopping ribavirin I will monitor viral load every 3 months using blood or stool PCR for 6 months, if negative this means SVR
I will monitor CBC every 2 weeks and adjust the dose of ribavirin according to Hb level
I will monitor liver enzymes every 2 weeks initially then monthly
I will inform the patient to avoid consuming processed undercooked meat especially pork
What is the prevalence of HEV in solid organ transplantation?
The HEV seropositivity in transplant recipient is around 24%, which is significantly higher than CKD patients who are waitlisted (16.4%). (2)
References
1. Guidelines for Hepatitis E & Solid Organ Transplantation
2. Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, et al. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec;29(12):1134-1142.
A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. Maintained on MMF, Tacrolimus and prednisolone. During the first 1.5 years after transplantation, CMV, primary EBV infection, and BK-virus viremia. 3 years later, ALT (94 U/L) and AST (55 U/L) were elevated persistently with negative serology to HCV, HBV,BKV,EBV and CMV PCR and a stable Kidney function eGFR of 80 mL/min. HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analyzed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
How would you manage this case? This is a case of persistent HEV infection> 3 months detectable RNA. First, review of the donor file, and viral serology if available, will check as well the recipient pretransplant viral serology if available. Second, detailed travel history to an endemic area, or consumption of pork, or un cooked meat (as the Genotype 3 detected). Will ask for laboratories for synthetic liver function (albumin, INR), gamma GT, alkaline phosphatase, and bilirubin, CBC, KFT, Urinalysis, LDH, and a quantitative stool HEV PCR(as baseline). Will ask for ultrasound abdomen, for any organomegaly, and CXR. Treatment: It has been noted that tacrolimus and m-TOR inhibitors increase viral replication, but mycophenolate inhibits it, so in indexed case I would decrease the tac level up to the lower safe acceptable level (preventing rejection). The main stay treatment in his case is to start treatment with Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 3 and 6 months after stopping the Ribavirin) the HEV PCR (blood and stool) should be monitored monthly. During treatment close monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function. PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. ? HEV vaccine approved in china, for G1.
What is the prevalence of HEV in solid organ transplantation? HEV infection responsible of > 50% viral hepatitis worldwide, with a prevalence of HEV in solid organ transplant is 4-20%, increased with age, and demographic variables (higher in Africa and Asia and low-middle income).
References: (1) Friebus-Kardash J, Eisenberger U, Ackermann J, Kribben A, Witzke O, Wenzel J, Rohn H, Fiedler M. Prevalence of active hepatitis E virus infection and efficacy of ribavirin treatment in renal allograft recipients. Transpl Infect Dis. 2019 Jun;21(3):e13088. doi: 10.1111/tid.13088. Epub 2019 Apr 16. PMID: 30929308. (2) McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK Guidelines for Hepatitis E and Solid Organ Transplantation. Transplantation. 2018 Jan;102(1):15-20. doi: 10.1097/TP.0000000000001908. PMID: 28795981.
-The index case is KTR had, in the first year post-Tx, frequent viral infections ( CMV, EBV, BKPyV), indicated overt immune suppression.
-He had transient mild transaminitis without clear cause( viral study negative, drug induced ) .
-Patient developed again transaminitis and found to have HEV genotype 3 infection.
-The retrospective analysis of previous sample showed positive serology IgM.
-Patient has persistent HEV infection as he has detectable virus HEV RNA for > 3 months, after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test.
– Chronic HEV infection in SOT recipients have been attributed to genotype 3 and 4, supporting a zoonotic mode of transmission.
– Chronic HEV infection is often asymptomatic, manifesting only with unexplained mild to moderate elevations in serum aminotransferase levels (100‐300 IU/mL).
– Once infected, 60% of SOT 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
-Risk factors for the progression to chronic infection included the use of tacrolimus and the presence of thrombocytopenia at the time of diagnosis.
– The diagnosis in immunocompromised individuals based on HEV RNA detection in the serum or stool.
– HEV serological assay is unreliable in SOT as they may have delayed or absent seroconversion. Would you manage this case?
-Aim of therapy to achieve sustained virological response (SVR), No virus detected in plasma & stool 6 months after completion of treatment) *Baseline work up;
– serum and stool HEV, RNA.
– Liver US ;signs of chronicity.
– CBC, LFT, RFT, CrCL
– Tac level
*Treatment:
– First line: Reduction of immunosuppression RIS to facilitate viral, by reducing Tacrolimus as it potentiate virus replication.
– Ribavirin RBV started if no response to RIS for at least 3 months, or earlier in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations.
– RBV dose adjusted to CrCL
– RBV is continued for at least 3 months until stool tests are negative for HEV RNA on 2 occasions one month apart.
– Relapse after a first course of ribavirin are re-treated for at least 6 months with ribavirin at dosages toward the higher dose range, where tolerated.
– PEG-IFN may be considered in ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection
*Monitoring:
– HEV RNA at day 7 of Ribavirin therapy to predict SVR at 3 months.help determine the likely length of treatment required
– Monthly HEV RNA testing in plasma and stool.
– Monitor Hg during ribavirin therapy as hemolytic anemia is side effect
– Check for SVR by HEV RNA in plasma and stool at 3 & 6 months samples after stopping antiviral therapy
– Monitor rejection during RIS.
*Prevention:
-Advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
– Vaccine against genotypes 1 and 4 HEV (Hecolin) with long‐term efficacy has been shown to be 87% after 4.5 years. No effective against genotype 3
What is the prevalence of HEV in solid organ transplantation?
The prevalence of HEV infection in the SOT population varies from 2% to 44%, depending on the assay used and population studied, while HEV viremia has been found in 1%‐4%.
Meta-analysis showed The pooled estimated prevalence of HEV infection in SOT patients was 20.2%, and in each organ as follow: liver 27.2%, kidney 12.8%, heart 12.8%, and lung 5.6%.
References: Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant. 2019 Sep;33(9):e13514. doi: 10.1111/ctr.13514. Epub 2019 Apr 14. PMID: 30817047.
Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on April 2017 First Edition.
The index case is a KTR with history of CMV reactivation, primary EBV infection, and BK-virus viremia. HEV IgM Positive/HEV IgG negative in the presence of positive HEV RNA, denotes acute HEV infection.
Considering the new HEV infection, these viral infections can be attributed to intense immunosuppression.
The case can be managed as follows(1):
1. 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(1).
2. 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.
3. 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(1).
4. 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).
5. Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
6. 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.
7. To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation.
8. Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
9. 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.
10.PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
What is the prevalence of HEV in solid organ transplantation?
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%(2).HEV infection is common in SOT recipients, particularly in middle-income countries. The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants.
References
1. Guidelines for Hepatitis E & Solid Organ Transplantation; first edition (BTS guidelines) 2. Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
How would you manage this case?
Chronic hepatitis E
The management of chronic infection involves reduction of immunosuppressive therapy and/or antiviral therapy
The goal of treatment is to eradicate HEV RNA, which is predicted by achieving a sustained virologic response (SVR).
An SVR is defined as the absence of HEV RNA by polymerase chain reaction 12 weeks after cessation of treatment.
Patients with an SVR are considered cured since there is no viral reservoir, similar to hepatitis C virus; however, they remain at risk for reinfection.
reduction in immunosuppressive therapy
reduce tacrolimus first, if possible, since there is an association of chronic infection with tacrolimus.
Antiviral therapy is directed against genotype 3, since chronic infection is typically observed in patients with this genotype
a 12-week course of ribavirin monotherapy
The dose of ribavirin is 600 to 1000 mg daily (administered in two divided doses). Monitoring for toxicity (complete blood count, creatinine with estimated glomerular filtration rate calculation, liver enzymes, and bilirubin levels) at week 4 of treatment
then check the complete blood count at weeks 8 and 12 to evaluate for anemia associated with ribavirin. For those who develop anemia, the dose of ribavirin can be adjusted based on the severity and comorbidities. Assessing response to antiviral therapy
check both stool and serum HEV RNA at week 12
●Undetectable HEV RNA after initial treatment – Ribavirin can be stopped if the HEV RNA is negative in the sera and stool at week 12
then repeat HEV RNA testing in blood and stool 12 weeks following the cessation of therapy to determine if the virologic response is sustained.
If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated. Detectable HEV RNA after initial treatment – If HEV is detectable in serum and/or stools at week 12, ribavirin therapy should be extended for an additional 12 weeks. Treatment failure Patients who fail to achieve an SVR should continue to be followed for signs of progression of liver disease. There is no established alternative antiviral therapy with evidence of efficacy in this setting.
Therapies that have been considered for the management of treatment failure include pegylated interferon-alfa and sofosbuvir. However, concerns regarding toxicity and efficacy prevent these agents from being used in routine care. As examples: ●Pegylated interferon-alpha – There are limited data to support the use of pegylated interferon-alpha for liver transplant patients with persistent infection who fail ribavirin . In one series of three liver transplant recipients, viral clearance was observed after three months of treatment with pegylated interferon . However, interferon has an immunostimulatory effect that can increase the risk of acute rejection in all organ transplant settings ● Sofosbuvir appears to control HEV in a cell culture model treatment . However, in contrast with in vitro observations, an HEV/hepatitis C virus coinfected patient who received treatment with a 12-week course of sofosbuvir and daclatasvir failed to clear HEV RNA
What is the prevalence of HEV in solid organ transplantation?
A subset of patients who undergo solid organ transplantation (eg, kidney, liver, and kidney-pancreas) appear to develop chronic HEV infection
In a retrospective multicenter study that included 85 recipients of solid organ transplants, the rate of chronic infection among those who were acutely infected with HEV after transplant was approximately 70 percent
In a prospective cohort of 700 solid organ transplant recipients, 34 (5 percent) acquired HEV infection, of whom 47 percent developed chronic infection
Chronic infection appears to be related to impaired HEV-specific T-cell responses Chronic hepatitis has been associated with lower counts of lymphocytes and of CD2, CD3, and CD4 T cells; use of tacrolimus; a low platelet count at the time of diagnosis with HEV infection; younger age; and liver transplantation
An important risk factor for acute HEV infection in solid organ transplant recipients appears to be consumption of insufficiently cooked game meat or pork products
The natural history of chronic HEV infection in transplant recipients is incompletely understood, but rapid progression of liver disease to cirrhosis has been reported
Chronically infected patients may also be at risk for HEV reactivation . However, studies have been conflicting and the risk, if present, appears to be small
The patient in the provided clinical scenario is severely immunosuppressed, which is clinically manifested as recurrent infections, including CVM, BKPyV, and EBV, and ending with HEV infection.
Because of the following, the aforementioned case has a chronic HEV infection: > 6-month-old HEV RNA.
The initial strategy is to reduce immunosuppression because the patient has potent immunosuppression, which might assist the infection clearance. Reduced immunosuppression may aid in the prevention of further infections. The risk of acute ejection should, however, always be taken into account when reducing or stopping immunosuppressive medication.
If the initial step failed,other treatment options include ribavirin monotherapy (RBV) for 3 months if HEV infection continues despite a reduction in immunosuppression. Patients who relapse after a 3-month course of RBV should be treated for a prolonged length of 6–9 months.
If RBV is not tolerated or a prolonged RBV course is ineffective at eradicating the virus, pegylated interferon alpha may be considered as an alternate treatment for chronic HEV.
The likelihood of graft rejection is one of numerous negative consequences of pegylated interferon alpha.
What is the prevalence of HEV in solid organ transplantation?
According to recent research, HEV seroprevalence rates in Europe ranged from 1% to 52%. HEV infection was thought to be present in 20.2% of SOT patients. For each transplanted organ, the combined estimated prevalence of HEV infection was as follows: liver (27.2%), kidney (12.8%), heart (12.8%), and lung (5.6%). De novo HEV infection was estimated to be present in 5.1% of cases.
HEV infection burden in developed countries have been increased in last few years especially among immunocompromised patients.
Acute HEV infection is self limited in immune competent persons, but among SOT 60% of patients can progressed to chronic infection which is associated with poor patient & graft survival.
Management of chronic HEV infection:(figure)
Baseline plasma & stool HEV RNA.
Careful reduction of immunosuppression (30% of chronic infection cleared by reduction of immunosuppression with 6 months of follow-up). The risk of rejection should be calculated carefully with close monitoring of renal function.
Ribavirin is the drug of choice for HEV infection treatment. The course 3-6 months with monthly measurement of HEV RNA in stool. The clearance of virus range from 72-100% but ribavirin can cause serious adverse effects as anemia leading to treatment discontinuation. Ribavirin dose adjusted according renal function.
In case of ribavirin resistance, PEG-INF can be used as alternative (increased risk of rejection).
No consensus regarding treatment duration, it persist until achieve sustained virological response (negative plasma & stool samples for HEV RNA 3-6 months after treatment discontinuation).
Prevalence of HEV infection:
ranged from 3-28%
Incidence of HEV infection in kidney, liver & simultaneous kidney & pancreas transplantation is 3.2 case/100patient/year.
References:
Affeldt P., Cristanziano V., Grundmann F., Wirtz M., Kaiser R., et al. Monitoring of hepatitis E virus RNA during treatment of chronic hepatitis E virus infection after renal transplantation. Immun Inflamm Disease, 2021;9(2):513-520.
Kamar N., Lhomme S., Abravanel F., Marion O., Person J., et al. Treatment of HEV Infection in Patients with a Solid-Organ Transplantation and Chronic hepatitis. Viruses,2016.
Salma N., Wang R., Auh S., Balla A., Dakhoul L., et al. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat, 2022,29(12):1134-1142.
The indexed case indicates chronic hepatitis E viral infection with genotype 3 which can explain his chronic elevated liver enzymes and can cause liver cirrhosis if not treated
how would you manage this case?
Send for NAAT to detect the HEV RNA in the blood and stool by using Conventional reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and reverse transcription loop-mediated isothermal amplification
Reduction of immunosuppression medication in particular antimetabolites like MMF can reduce the HEV load in 30% of cases and successful viral clearance within 6 months of follow-up, those with no viral clearance may need treatment with ribavirin with 70-100% rate of viral clearance within 3 months after use, ribavirin should be used with caution due to the risk of hemolytic anemia and bone marrow suppression.
Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. But ribavirin is contraindicated in pregnancy while interferon is not preferred in SOT candidates (2).
Ribavirin-resistant HEV infection promising agent like sofosbuvir was also considered as an option in the treatment of ribavirin-resistant HEV infections
Alone or in combination with ribavirin based on limited evidnces What is the prevalence of HEV in solid organ transplantation?
4 genotypes were identified for HEV in humans with 1, and 2 more in developing countries and causing acute hepatitis due to contaminated water supply while genotypes 3, and 4 were more zoonotic from ora fecal contact from contaminated meat or animals in developed countries and cause chronic hepatitis E infection with extra hepatic organ involvement and more in immunocompromised patients like SOT (2). 20%-50% of transplant recipients having exposure to HEV3 develop chronic infection.
Acute hepatitis E viral infection usually self-limiting hepatitis in immunocompetent patients while the chronic development of HEV infection with the (genotype 3) infection was found to cause up to 10% of chronic elevation of liver enzymes and rapid development of liver cirrhosis in immunosuppressed patients like SOT with its negative impact on patient and graft survival.
References
1. Affeldt P, Di Cristanziano V, Grundmann F, Wirtz M, Kaiser R, Benzing T, Stippel D, Kann M, Kurschat C. Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation. Immun Inflamm Dis. 2021 Jun;9(2):513-520. doi: 10.1002/iid3.411. Epub 2021 Feb 8.
2. Aslan AT, Balaban HY. Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World J Gastroenterol. 2020 Oct 7;26(37):5543-5560. doi: 10.3748/wjg.v26.i37.5543. PMID: 33071523; PMCID: PMC7545399.
This is a case of chronic hepatitis E virus infection. Management is as follows.
Get a baseline HEV RNA in serum and stool.
Reduce immunosuppression if possible – reduce prednisolone to 5mg daily and tacrolimus trough target of 4ng/ml.
Wait for about 3 months for response to reduction in immunosuppressive medications.
Monitor serum and stool HEV RNA monthly.
Commence a 3 – month course of ribavirin after 3 months in absence of HEV clearance from stool.
Monitor FBC for anemia and dose ribavirin based on GFR using the serum creatinine levels.
Continue treatment until stool is negative for HEV RNA on 2 occasions one month apart.
In cases of relapse after ceasing ribavirin, restart treatment for a 6-month course.
No other options of treatment in this patient if viremia persists despite ribavirin. However, adherence and proper dosing of medications should be ensured.
Prevalence of HEV in solid organ transplant – The pooled estimated prevalence of HEV infection in solid organ transplant recipients was 20.2% [95% confidence interval (CI): 14.9-26.8]
Reference
European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68(6):1256-1271. doi: 10.1016/j.jhep.2018.03.005. Epub 2018 Mar 31. PMID: 29609832
Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
A 35-year CKD stage 5 due to HUS, with transplant from DBD, on pred, MMF, Tac
in the 1st 1.5 year developed CMV, EBV, BK. Now has elevated liver enzymes.
PCR for HCV, HBV CMV, BK, EBV were all negative. But HEV PCR was positive, genotype 3. with positive IgM, and negative IgG then IgG converted to positive.
How to manage this case?
Chronic HEV infection is usually detected in immunocompromised patient,
in this case as viral detection beyond 6 months, genotype 3 is diagnostic of Chronic HEV with negative other viral infection on PCR.
HEV IgM antibody appears shortly during clinical illness and remain detectible for up to 5 months, but IgG appears later stay for longer times, in one report antibodies were detected as along as 14 years (immunocompetent individuals).
HEV RNA assay can be run on blood and stool, in stool it can be detected one week before clinical illness.[3]
Management
First step would be to reduced immunosuppressant’s particularly CNI as Tacrolimus and mTOR has been shown to increase this infection while MMf seems to have no effect with closed attention to graft rejection.
check HEV RNA if absent than recheck at 12 weeks if not detected leading to SVR. If RNA not improving than will have to start on antiviral therapy.
Ribavirin 600mg to 1000mg in two divided doses for 3 months with close observation for toxicity, anemia and kidney function.
HEV RNA should be check at 12week if there was no response than will have to give for another 3 months.
In case of failed response pegylated interferon alpha can be tried but in SOT it can lead to rejection.
What is the prevalence of HEV in solid organ transplantation?
In retrospective multicenter study with 85 recipients of SOT the rate of chronic HEV after acute infection was 70%. [1] Another study of 700 SOT recipients 5% acquired HEV infection of whom 47% develop chronic infection. [2]
References 1. Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, Dumortier J, Cannesson A, Cassuto-Viguier E, Thervet E, Conti F, Lebray P, Dalton HR, Santella R, Kanaan N, Essig M, Mousson C, Radenne S, Roque-Afonso AM, Izopet J, Rostaing L. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011 May;140(5):1481-9. doi: 10.1053/j.gastro.2011.02.050. Epub 2011 Feb 24. PMID: 21354150. 2. Legrand-Abravanel F, Kamar N, Sandres-Saune K, Lhomme S, Mansuy JM, Muscari F, Sallusto F, Rostaing L, Izopet J. Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis. 2011 Jan;17(1):30-7. doi: 10.3201/eid1701.100527. PMID: 21192851; PMCID: PMC3298369. 3. UpToDate Topic 3677 Vesrsion 33.0
How would you manage this case?
A case of persistent HEV infection with HEV RNA–positive sample, anti-HEV IgG and genotype 3.
1-This patient should receive written advice regarding the risk of HEV from undercooked meat before and after transplantation, especially for HEV G3.
2-We should collect a baseline quantitative HEV RNA on both plasma and stool at the start of treatment.
3-Ribavirin should be started for 3- 6 months and until stool tests are negative for HEV RNA on two occasions one month apart with monthly HEV RNA testing in plasma and stool.
4-Ribavirin dose should be adjusted according to renal function tests.
5-F/U Hemoglobin during Ribavirin course.
6-If infection resistant to Ribavirin, we can use PEG-interferon with close monitoring for rejection. What is the prevalence of HEV in solid organ transplantation?
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%.
The pooled estimated prevalence of HEV infection for each organ transplant was as follows:
1-Liver (27.2%)
2- Kidney (12.8%).
3-Heart (12.8%), and lung (5.6%). References:
1- British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation 2017.
2-Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240.
Its a case of chronic HEV hepatitis.
Persistence of HEV infection detected by serum or stool PCR for more than 6 months is indicative of chronicity. Treatment :includes reduction of immune suppression medication, principally CNi and follow up for 12 then recheck PCR if its negative, then follow up again after 12 months for confirmation, long term follow up is indicated for recurrence of the disease. If there is no improvement after 12 weeks, then anti-viral therapy with ribavirin for 12 weeks must be considered. another approach is to reduce immune suppressants and commence on Ribavirine simultaneously. Incidence of HEV in SOT recipients amount to 20.3% highest in liver transplant recipients and lung transplant recipients. References:
1] Kenneth E Sherman, MD, PhD. Hepatitis E virus infection. http://www.uptode.com. 2] Panupong Hansrivijit et al. Hepatitis E in Solid organ transplant recipients; A systemic review and meta analysis.world journal of gastroenterology:2021 March 28;27 [12]:1240-1254
Due to the fact that the previous sample tested positive for HEV infection, the ultimate diagnosis for this patient is most likely persistent HEV infection, which is defined as HEV infection that has lasted for more than three months. The spread of the disease may also occur via blood or organ donation. The following constitutes the management:
Baseline plasma & stool HEV RNA
Ribavirin for a period ranging from three to six months, or until two consecutive stool tests are taken one month apart comes back negative.
Plasma HEV RNA was measured after seven days for the purpose of determining how long therapy will last
Strive for a sustained response on the virologic front (Negative plasma or stool HEV RNA 6 months after treatment)
HEV RNA on a monthly basis
The antiviral activity of 2-pegylated interferon-alfa against HEV precludes its use in patients who have had organ transplantation owing to the significant risk of rejection associated with this treatment.
Close observation of renal and liver function, CBC, and HEV RNA.
What is the prevalence of HEV in solid organ transplantation?
Recent research has shown that the frequency of HEV antibodies in Europe may range from less than one percent to as high as 52 percent.
HEV-GT3 has been related to the consumption of meat products infected with HEV. In most cases, HEV infection does not cause any symptoms and only manifests as a minor illness that resolves on its own.
The incidence of HEV infection in recipients of solid organ transplants (SOT) varies widely depending on both the country and the organ being donated.
Reference:
British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation.
This patient has suffered many viral infections like EBV, BKV and CMV during first 1.5 years post-transplant.His archived blood sample showed HEV RNA positive as well IgM positive suggestive of acute active HEV infection.His liver enzymes had also increased with HEV genotype 3 positive.Studies have shown that all chronic HEV infections have been G3.He needs to be treated as following acute infection with HEV G3, the infection persists in approximately 60% of solid organ transplant recipients leading to persistent HEV infectionThis can cause a chronic hepatitis that can progress rapidly (3-5 years) to cirrhosis in approximately 15% of infected solid organ transplant recipients Management:
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.He needs to started on early ribavirin treatment.Treatment with ribavirin should continue for at least three monthsMonthly 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 should be conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.Regular haemoglobin monitoring should be 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.What is the prevalence of HEV in solid organ transplantation?
The estimated prevalence of HEV infection in SOT patients was 20.2% The pooled estimated prevalence of HEV infection for each organ transplant was as follows: liver (27.2%)kidney (12.8%)heart (12.8%)lung (5.6%)The pooled estimated prevalence of de novo HEV infection was 5.1%.The pooled estimated prevalence of acute HEV infection was 4.3%Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK guidelines for hepatitis E and solid organ transplantation. Transplantation. 2018 Jan
Hepatitis E virus (HEV) results in approximately 20 million infections each year, particularly in endemic areas in Asia, Africa, and Central America. HEV has been noted to impact solid organ transplant (SOT) recipient outcomes. HEV infection can lead to has been cited to cause liver graft cirrhosis and subsequent failure. In contrast, renal transplant allografts were found to have similar rejection and two-year graft survival between HEV seropositive and negative recipients, thus demonstrating HEV does not always impact non-liver allografts.
As per metanalysis of Hansrivijit P et al, the pooled estimated prevalence of HEV infection in SOT recipients was 20.2%.
To date, the United States has not issued national guidelines for the management of hepatitis E in SOT. However, recent guidelines from the British Transplantation Society (2017) have recommended the following for Rx: · 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) · This patient with persistent infection and liver dysfunction 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) For most individuals 3-6 months of ribavirin treatment will suffice. (1C) · A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C) · 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) · PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Reference: · Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097. · British Transplantation Society Guidelines, 2017.
-It is clearly that this patients suffered a lot of viral infections after the first year informs of CMV, EBV, & BKV.
-At 3 years he had hepatic dysfunction and ultimately diagnoses with HEV infection genotype 3.
-HBV &HCV were excluded by PCR
-The high numbers of these viral infections may points toward over-immune suppression.
-Because the historical sample was positive for HEV infection, the final diagnosis of this patient is likely persistent HEV infection ( HEV infection > 3 month). HEV g3 commonly transmitted by HEV contaminated under cooked meat. Other routes of transmission are blood transmission, or organ transplantation. The management is as follows:
Baseline plasma & stool HEV RNA
Ribavirin for 3 to 6 months until two negative consecutive stool samples one month apart
Plasma HEV RNA after 7 days to predict the duration of treatment
Aim for sustained virologic response (Negative plasma or stool HEV RNA 6 months after treatment)
Monthly HEV RNA
Regular hemoglobin monitoring as ribavirin may induced hemolytic anemia
In an event of relapse, he can be retreated with higher doses of ribavirin for at least 6 months
He must be advised in a written to avoid consumption of under cooked meat (processed pork) due to high risk of HEV contamination
Another point is to consider over all reduction in immune suppression (if not done before) in this patient due significant history of viral opportunistic infections
2.What is the prevalence of HEV in solid organ transplantation?
-Developing world:
> 50% of cases of viral hepatitis
-Developed World:
1% to 50%, the variation is traditionally due to the performance of different assays
Yes, immune competent host is likely to clear the virus without progressing into chronic phase. In pregnancy it can be a bit different because they may have a very severe disease with morality rate increasing up to 25%.
35 years patient CKD stage 5 due to HUS, transplanted from DBD, on pred, MMF, Tac
in the 1st 1.5 year he developed CMV, EBV, BK
has elevated liver enzymes
PCR for HCV, HBV negative, PCR for CMV, BK,EBV were negative
no drug induced elevated liver enzymes
then liver enzymes became slight normal
then increased again
HEV PCR positive, genotype 3
Retrospectively, PCR for HEV was positive, with positive IgM, and negative IgG then IgG converted to positive management of this case:
1- ribavirin should be started in the case of HEV PCR positive for 3 months
2-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
3-reduction of MPA daily dose
RIS may be not enough alone to clear HEV, and should be accompanied by antiviral therapy which is Ribavirin
4-monitoring by CBC, liver function test, graft function, regular monitoring by HEV PCR
prevalence of HEV in solid organ transplantation
Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease.
Rivero-Juarez, A.; Vallejo, N.; Lopez-Lopez, P.; Díaz-Mareque, A.I.; Frias, M.; Vallejo, A.; Caballero-Gómez, J.; Rodríguez-Velasco, M.; Molina, E.; Aguilera, A. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms2020, 8, 51.
1-How would you manage this case? Discussion of current case; –This Case post Deceased KT and after 1.5 year of TX developed CMV reactivation , EBV infection , BKV viremia, showed high immunological risk for recurrent infections and with elevated liver enzymes and with (positive HEV PCR G3) considered of HEV reinfection.
-Abdominal ultrasound should be requested R/O any hepatic lesions or signs of liver cirrhosis. Management of HEV infection; -The goal of Treatment;
-To achieve a sustained virologic response (SVR);which is defined as the absence of HEV RNA by polymerase chain reaction 12 weeks after cessation of treatment. -Strategy of Treatment; A-Reduction of immunosuppression; -RIS is the first step in the treatment of chronic HEV infection. -There are no clear data to guide how immunosuppressive therapy should be reduced; however, Reduce Tacrolimus first, if possible, since there is an association of chronic infection with tacrolimus B-Antiviral therapy; -Ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection. -Because current patient is HEV genotype 3, i suggest a 12-week course of ribavirin with dose (600 to 1000 mg daily) (administered in two divided doses). -Monitoring for toxicity; -Check basic laboratory tests (CBC, sr Cr ,eGFR, LFTs) at week 4 of treatment, then check the complete blood count at weeks 8 and 12 to evaluate for anemia associated with Ribavirin. -Adjustment the dose of ribavirin based on the severity of hemolytic anemia and comorbidities. -Assessing response to antiviral therapy; -To assess the response to antiviral therapy, check both stool and serum HEV RNA at week 12. –Undetectable HEV RNA after initial treatment; -Ribavirin can be stopped if the HEV RNA is negative in the sera and stool at week 12. -Then repeat HEV RNA testing in blood and stool 12 weeks following the cessation of therapy to determine if the virologic response is sustained. -If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated. -HEV RNA testing should be performed at the end of treatment and, if negative, to confirm again 12 weeks later. C-Prevention; –Travelers to regions where HEV is endemic (eg, Asia, Africa, the Middle East, and Central America) should avoid water of unknown purity, food from street vendors, raw or undercooked seafood, meat or pork products, and raw vegetables. -Travelers to Europe should also avoid uncooked and undercooked pork/boar sausage or other wild animal meats (eg, rabbit) that have not been properly heated. 2-What is the prevalence of HEV in solid organ transplantation?
-Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
-To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
-Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
–The prevalence of HEV infection in solid organ transplant (SOT) recipients varies by countries and transplanted organs. -There is meta-analysis, demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients). -The prevalence of HEV infection is two-fold more common in middle-income countries compared to high-income countries. References; – Abravanel F, Lhomme S, Chapuy-Regaud S, Mansuy JM, Muscari F, Sallusto F, et al. Hepatitis E virus reinfections in solid-organ-transplant recipients can evolve into chronic infections. J Infect Dis. 2014;209(12):1900.
-Zhang J, Zhang XF, Huang SJ, Wu T, Hu YM, Wang ZZ, et al. Long-term efficacy of a hepatitis E vaccine. N Engl J Med. 2015;372(10):914–22.
-Choi Y, Zhang X, Skinner B. Analysis of IgG anti-HEV antibody protective levels during hepatitis E virus reinfection in experimentally infected rhesus macaques. J Infect Dis. 2019;219(6):916–24.
-Hartl J, Otto B, Madden RG, Webb G, Woolson KL, Kriston L, et al. Hepatitis E Seroprevalence in Europe: a meta-analysis. Viruses. 2016;8(8).
-Khuroo.MS, Khuroo MS, Hepatitis E: an emerging global disease – from discovery towards control and cure . J Viral Hepat, 2016;23:68.
-Panupong,H., Angkawipa T.,: Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis; World J Gasroenterol. .2021 Mar 28; 27(12): 1240–1254.
How would you manage this case?
Chronic HEV infection is almost exclusively in immunocompromised patient, in this case as viral detection beyond 6 months, genotype 3 and other viral co-infection would clearly pointed towards Chronic HEV.
HEV IgM antibody will appear shortly during clinical illness and remain detectible for upto 5 months. IgG would appears shortly after IgM response and stay for longer times, in one report antibodies were detected as along as 14 years (immunocompetent individuals). HEV RNA assay can be run on blood and stool, in stool it can be detected one week before clinical illness.[3]
Management
First step would be to reduced immunosuppressant’s particularly CNI with closed attention to graft rejection (monitoring could be done by detection of donor derived cell free DNA in recipient blood before clinical rejection) check RNA if absent than recheck at 12 week if not detected leading to SVR. If RNA not improving than will have to start on antiviral therapy. Ribavirin 600mg to 1000mg in two divided doses for 3 months with close observation for toxicity, anemia and kidney function. HEV RNA should be check at 12week if there was no response than will have to give for another 3 months. In case of failed response pegylated interferon alpha can be tried but in SOT it would have implications and sofosbuvir appear to control in a cell culture model treatment but data is lacking.
What is the prevalence of HEV in solid organ transplantation?
In retrospective multicenter study with 85 recipients of SOT the rate of chronic HEV after acute infection was 70%. [1]
Another study of 700 SOT recipients 5% acquired HEV infection of whom 47% develop chronic infection. [2]
References 1. Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, Dumortier J, Cannesson A, Cassuto-Viguier E, Thervet E, Conti F, Lebray P, Dalton HR, Santella R, Kanaan N, Essig M, Mousson C, Radenne S, Roque-Afonso AM, Izopet J, Rostaing L. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011 May;140(5):1481-9. doi: 10.1053/j.gastro.2011.02.050. Epub 2011 Feb 24. PMID: 21354150. 2. Legrand-Abravanel F, Kamar N, Sandres-Saune K, Lhomme S, Mansuy JM, Muscari F, Sallusto F, Rostaing L, Izopet J. Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis. 2011 Jan;17(1):30-7. doi: 10.3201/eid1701.100527. PMID: 21192851; PMCID: PMC3298369. 3. UpToDate Topic 3677 Vesrsion 33.0
In the current case scenario of kidney transplant patient on immunosuppression with history of CMV reactivation, developed EBV and BK viremia post transplantation which means that he is over immunosuppressed. Later on it is noted to have high liver enzymes with negative HBV and HCV screening but positive HEV PCR with HEV genotype 3 positive. In archived blood samples HEV IgM and later on IgG came positive.
That means the patient has chronic HEV infection which defined as detection of HEV RNA in serum or stool for longer than six months(HEV genotype 3 is typically self-limiting in the general population, however, in immunosuppressed or immunocompromised groups, the infection can become chronic).
–IgM anti-HEV appears during the early phase of clinical illness and disappears rapidly over four to five months.
–The IgG response appears shortly after the IgM response, antibodies were detected as long as 14 years after the acute phase of illness.
Management:
The management of chronic infection involves reduction of immunosuppressive therapy and antiviral therapy. -Reduction of immunosuppression: Typically reduce tacrolimus , since there is an association of chronic infection with tacrolimus.
–Antiviral therapy: Suggesteda 12-week course of ribavirin monotherapy. The dose of ribavirin is 600 to 1000 mg daily.
The goal of treatment is to eradicate HEV RNA by achieving a sustained virologic response (SVR)(absence of HEV RNA by PCR 12 weeks after cessation of treatment). Patients with an SVR are considered cured with possibility for reinfection.
What is the prevalence of HEV in solid organ transplantation?
There is a meta-analysis, demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients.
A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. He was on prednisolone, MMF, and tacrolimus. During the first 1.5 years after transplantation, he developed CMV reactivation, primary EBV infection, and BK-virus viremia. Almost 3 years after transplantation at a routine check-in 2011, ALT (94 U/L) and AST (55 U/L) were found to be elevated. Kidney function was stable with an eGFR of 80 mL/min. Liver enzymes remained slightly increased in 2012 and 2013. No clear relation could be found with drugs. HCV and HBV PCR were negative. Repeated testing for BK, EBV and CMV DNA was negative. After temporary normalization, liver enzymes increased again with an ALT of 117 U/L. At that point, HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analysed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
How would you manage this case? THE ABOVE CASE IS CHRONIC HEV INFECTION IN POST KTx. RECIPIENT
Immunocompromised patient ==> HEV RNA +_ Serology ==>+ve ==> HEV-infection ==> HEV RNA +VE >3Month ===> Chronic HEV > 6 month
Persistent infection leading to chronic hepatitis has been reported in immunosuppressed, Genotype 3 ==> infect both animals and human
HEV virus is not uncommon and should be considered in kidney Tx recipients who develop elevated liver transaminases or suggestive symptoms, especially that its course is less benign than in the general population.
Other screening:
CBC , LFT, KFT, CrCL, CNI Level,
Abdominal USS=> looking for signs of liver cirrhosis, Fibro scan is non-invasive and can detect chronic liver disease.
Treatments:
1) IS Reduction e.g Tacrolimus can be reduced
2) Ribavirin tab 600-1000mg in two divided doses according to CeCL for 12 weeks
Early treatment with ribavirin may be considered in specific cases of acute HEV, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra- hepatic manifestations, although evidence for this recommendation is currently limited.
Check LFT ===> Four weeks after commencement of Ribavirin.
Baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
Then 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.
Patients who relapse after a 3 -month course of RBV should be treated for a longer duration of 6 -9 months.
3) Pegylated interferon alpha can be considered as an alternative therapy for chronic HEV if RBV is not tolerated or a prolonged RBV course fails to eradicate the virus .
Pegylated interferon alpha has many adverse effects, including an increased risk of graft rejection.
Prevention:
Avoid undercooked meat of animals, particularly when traveling to endemic regions of the world.
A vaccine has been used in China with efficacy against HEV.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients,
Potential recipients of solid organ transplants do not need routine screening for HEV infection UNLESS SUSPECTED (immunosuppressed individual with raised liver enzymes)
Solid organ transplant recipients with elevated liver transaminases or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay.
Prevalence of HEV in SOT:
A subset of patients who undergo solid organ transplantation (eg, kidney, liver, and kidney-pancreas) appear to develop chronic HEV infection].
In a retrospective multicenter study that included 85 recipients of solid organ transplants, the rate of chronic infection among those who were acutely infected with HEV after transplant was approximately 70%.
In a prospective cohort of 700 solid organ transplant recipients, 34 (5%) acquired HEV infection, of whom 47% developed chronic infection.
Immunization:
Recombinant vaccines developed from genotype 1 HEV have shown efficacy in trials
in China. One of these is licensed for use in China, but not elsewhere in the world.
Its efficacy for the prevention of other HEV genotypes has not been established Reference:
*Kidney Tx in patients with HEV May A. Hassaballa Prof Internal Medicine & Nephrology, Cairo University
*Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
*Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017 First Edition.
*EASL Clinical Practice Guidelines on hepatitis E virus infection (2018)
*Adapted from the British Society of Transplantation Guidelines (2017)
This post kidney transplant patient most likely has chronic HEV infection which is common with the genotype 3 .Management is MDT ( Hepatologist ,nephrologist and clinical pharmacist ) . The approach will be by proper history and good clinical examinations looking for signs of chronic liver disease.Serology and molecular testing already done so other tests include full blood counts,graft function and liver function test .
US abdomen looking for signs of liver cirrhosis , fibroscan is non-invasive and can detect chronic liver disease.
Liver biopsies are invasive and costly .
Treatments :
First step is reduction of immunosuppression for three months which may help to clear the virus .
If HEV infection persists despite reduction in immunosuppression, additional treatment options include ribavirin monotherapy (RBV ) monotherapy for 3 months ,
Patients who relapse after a 3 -month course of RBV should be treated for a longer duration of 6 -9 months.
Pegylated interferon alpha can be considered as an alternative therapy for chronic HEV if RBV is not tolerated or a prolonged RBV course fails to eradicate the virus .
Pegylated interferon alpha has many adverse effects, including an increased risk of graft rejection.
Prevention is always better than cure. All transplant candidates and donors should counselled about mode of transmission of HEV and the protective measures like food hygiene ,proper cooking of meats hand washing and regular cleaning of shared sanitary facilities, should be followed
A recombinant vaccine against genotype 1 and 4 HEV (Hecolin ® ) with an efficacy of 100% has been approved for use in China .However, efficacy of this vaccine against genotype 3, the most common cause of chronic HEV in SOT recipients, has not been demonstrated.
What is the prevalence of HEV in solid organ transplantation?
The prevalence of HEV infection is two-fold more common in middle-income countries compared to high-income countries, in SOT recipients the prevalence of HEV infection is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients).
Reference :
Te, Helen; Doucette, Karen (2019). Viral Hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clinical Transplantation, (), e13514–. doi:10.1111/ctr.13514
The above case is chronic HEV infection because of the following:
Presence of HEV RNA > 6 months
HEV genotype 3 (infect both animals and human)
Chronic HEV has been reported to be more common in Immunosuppressive states
Immunosuppressive individuals may have a delayed or absent seroconversion, hence the reason for recommending HEV RNA of stool or serum as the diagnostic tool for them
Moreso, it has been documented that chronically infected HEV patients may be at risk of HEV reactivation.
Other Investigations during treatments
FBC + differentials
Liver enzymes
kidney function with the calculation of creatinine clearance
Tacrolimus trough level
Abdominal USS
Treatments
The first step in chronic HEV is the reduction of immunosuppression e.g Tacrolimus can be reduced
Tab Ribavirin at 600-1000mg in two divided doses according to kidney function for 12 weeks
Check LFT 4 weeks after commencement of Ribavirin
Check the HEV RNA of stool or serum at 12 weeks, if the virus cleared, stop the drug, but if not cleared continue Ribavirin for another 12 weeks before declaring treatment failure if there is no response.
Prevention
avoid undercooked meat of animals, particularly when traveling to endemic regions of the world
A vaccine has been used in China with efficacy against HEV
Prevalence of HEV in SOT
A subset of patients who undergo solid organ transplantation (eg, kidney, liver, and kidney-pancreas) appear to develop chronic HEV infection].
In a retrospective multicenter study that included 85 recipients of solid organ transplants, the rate of chronic infection among those who were acutely infected with HEV after transplant was approximately 70%.
In a prospective cohort of 700 solid organ transplant recipients, 34 (5%) acquired HEV infection, of whom 47% developed chronic infection
A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. He was on prednisolone, MMF, and tacrolimus. During the first 1.5 years after transplantation, he developed CMV reactivation, primary EBV infection, and BK-virus viremia. Almost 3 years after transplantation at a routine check-in 2011, ALT (94 U/L) and AST (55 U/L) were found to be elevated. Kidney function was stable with an eGFR of 80 mL/min. Liver enzymes remained slightly increased in 2012 and 2013. No clear relation could be found with drugs. HCV and HBV PCR were negative. Repeated testing for BK, EBV and CMV DNA was negative. After temporary normalization, liver enzymes increased again with an ALT of 117 U/L. At that point, HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analysed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
HEV is a virus that infects humans and a range of animal hosts, with four major genotypes (G1 to G4).
The epidemiological picture, transmission routes and reservoirs, as well as clinical features and outcome differ significantly depending on the region of the world.
HEV G1 and G2 are major public health concerns in resource poor settings, with disease mainly reported from young adults and a slight male preponderance. Seroprevalence increases with age and low prevalence in children <10 years.
HEV G3 and G4 are zoonotic infections transmitted to humans from an animal reservoir.
The pig remains the best studied vector and the concept of a zoonosis is supported by the close sequence homology shared between human and swine HEV sequences.
Surveillance of hepatitis E shows a consistent demographic picture with the majority of clinical cases reported in males over the age of 50 years.
Seroprevalence rates vary widely from 1% to 50%, and data from England suggest as many as 200,000 infections occur annually and account for around 600-800 cases of hepatitis E.
What influences the fluctuations in the prevalence of viraemia and disease is unclear.
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, group 1 and group 2.
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.
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.
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.
Early treatment with ribavirin is recommended for acute HEV, with baseline quantitative HEV RNA assessment, monthly HEV RNA testing, and regular haemoglobin monitoring.
Monitoring HEV RNA levels and liver enzymes to help clinical decision-making.
Reduced immunosuppression may help HEV clearance, but risk of rejection should be assessed.
Early treatment with ribavirin is recommended for acute hepatitis E, but evidence is limited.
Persistent HEV infection is diagnosed when HEV RNA is detectable for more than three months and treated with ribavirin to achieve sustained virological response.
Treatment with ribavirin to achieve sustained virological response(HEV RNA not detected in plasma and stool six months after completion of treatment).
Immunization
Recombinant vaccines from genotype 1 HEV have shown efficacy in China, but their efficacy for other HEV genotypes has not been established.
What is the prevalence of HEV in solid organ transplantation?
The meta-analysis revealed that the prevalence of HEV in SOT recipients is 20%, with de novo HEV infection and acute HEV infection accounting for less than 5% of infections.
This suggests a high burden of HEV infection, and whether these infections affect post-transplant clinical outcomes is yet to be investigated.
The seroprevalence of anti-HEV IgG is affected by the type of assay used, and the Wantai assay was found to be significantly higher than other assays.
The prevalence of HEV infection was significantly higher in middle-income countries than high-income countries, with seroprevalence of anti-HEV IgG at least two-fold higher in Africa and Asia.
Poor hygiene, consumption of raw meat, exposure to soil, contact with dogs, residing in rural areas, and an education level less than elementary school are risk factors.
HEV virus is common in kidney Tx recipients and its course is less benign than in the general population.
Kidney Tx in patients with HBV May A. Hassaballa Prof Internal Medicine & Nephrology, Cairo University
Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017 First Edition.
HEV infection in transplant patients must be diagnosed by virus-specific techniques, such as HEV RNA and/or antigen detection, as antibody detection is ineffective in immunosuppressed people.
Although the presence of HEV viraemia in a donor does not necessarily rule out the use of an organ from that donor, it will help guide clinical care choices made after transplant.
Patients who contract HEV through transplantation are treated in accordance with guidelines for other persistently infected patients.
HEV testing should be done on people who have unexplained acute, chronic, or acute liver failure.
Patients with cirrhosis who get hepatitis E while waiting for a liver transplant are given the option of receiving treatment with ribavirin.
Observation and monitoring of HEV RNA levels and liver enzymes are part of the initial care of newly diagnosed or acute HEV infection in solid organ transplant patients because more than 30% of cases will resolve on their own within three months.
Clinical decision-making may be aided by dynamic viral monitoring and antibody profiling.
In patients with acute or persistent HEV, a calculated reduction in immunosuppression may help with viral clearance, but the risk of rejection needs to be carefully evaluated.
Although there is currently insufficient data to support this approach, early therapy with ribavirin may be explored in some cases of acute hepatitis E, such as those who develop severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic symptoms. What is the prevalence of HEV in solid organ transplantation?
In areas with limited resources, where HEV is considered to be responsible for more than 50% of cases of viral hepatitis, HEV G1 and G2 viruses continue to pose serious public health risks.
By consuming tainted food and water, the virus is spread orally via the faecal channel.Spread from person to person is rare.
The meta-analysis found that 20% of SOT recipients have HEV.
Less than 5% of infections were caused by acute and de novo HEV infections.
Thank you for your reply, but you did not answer the question. How would you manage this case? What you have written is just a copy and paste without reflection on the case.
MANAGMENT
The final diagnosis for this patient is most likely chronic HEV infection, which is defined as HEV infection that has lasted for more than three months, because the prior sample tested positive for HEV infection.
Chronic HEV infection is indicated by HEV infection detected by serum or stool PCR for longer than 6 months.
Ribavirin for a duration of three to six months, or until the results of two successive stool tests performed one month apart are negative.
Reduction of immunosupression.
With the course of ribavirin need to monitor toxicity of treatment with complete blood count, liver function and renal function
Treatment algorithm is attached
What is the prevalence of HEV in solid organ transplantation?
In areas with limited resources, where HEV is considered to be responsible for more than 50% of cases of viral hepatitis, HEV G1 and G2 viruses continue to pose serious public health risks.
By consuming tainted food and water, the virus is spread orally via the faecal channel.Spread from person to person is rare.
The meta-analysis found that 20% of SOT recipients have HEV.
Less than 5% of infections were caused by acute and de novo HEV infections.
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.(1)
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. (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.
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
In developing world Nepal and Bangladesh indicate antibody prevalence rates of 47%
and 50%.
Developed World:
from 1% to 50%.
References:
1-BTS Guideline of hepatitis E and solid organ transplantifectio.2017
The diagnosis in chronic HE infection in a post kidney transplant recipient…..I would reduce the immunosuppression of the patient…I will reduce the CNI as there as studies showing that CNI enhances the viral HEV replication….MMF on the other hand has shown to have anti proliferative activities on the virus and hence I would like to continue MMF and low dose steroids…I would closely monitor for graft rejection by serial creatinine monitoring…WE have to monitor for blood HEV clearance and Stool HEV clearance regularly to see for spontaneous remission of the virus if possible…
Antiviral therapy with Ribavirin 600-800mg/day is recommended….the dosage is tiitrated according to the creatinine clearance…
duration of treatment is 3 months..CBC and liver function tests have to be monitored during treatment…the other treatment available is pegylated interferon but it may have immunomodulator effect and it may enhance rejection…
The prevalence of HEV infection is higher in SOT patients as compared to non transplant as high as 20%
The patient is known to be renal transplant recipient diagnosed with HEV infection.
Management would start by reduction of immunosuppressive doses, withholding antimetabolites as MMF, minimizing CNI doses to maintain low levels or even switch to another mTORi would be better.
Using antiviral regimen as ribavirin is the best tolerated by most of patients. The patient has normal renal function profile, hence no need for renal adjustment with optimum dose for 4 weeks at least with regular monitoring of viral load, CBC, liver enzymes mainly.
Special attention to the common side effects as they could be non-specific in the form of fatigue, fever or headache. Moreover severe side effects as hemolytic anaemia or severe GIT manifestations could need dose modification.
The co-administration of statins aids to initiate early response as it minimizes viral load as well.
Prevalence of HEV for organ transplants as liver: 27.2%, kidney 12.8%, and lung 5.6%.
HEV-3 and -4 can cause chronic infection in patients receiving immunosuppressive agents .
● Reducing Immunosuppressive Therapy
** Factors that progress infection to chronicity are :
☆ Low CD4 and CD8 counts at the time of HEV infection
☆ A shorter time since transplantation
☆ A shorter time from an acute rejection
☆ The use of tacrolimus
☆ A lower T-cell response and inflammatory response
☆ Patients that are heavily immunosuppressed
** Immunosuppressive drugs (cyclosporine A, tacrolimus, sirolimus, and everolimus, increase HEV replication but only mycophenolic acid can decrease HEV replication in vitro .
** HEV clearance occurred in 30% SOT patients with chronic HEV infection after reducing immunosuppressive therapies that principally targeted T-cells
** A reduction in immunosuppressive therapy seems to be the first-line therapeutic option
● Two-thirds of patients remain those need an effective antiviral therapy :
☆ Pegylated Interferon
For three months and the sustained virological response (SVR) at six months was 100% but it increases the risk of acute rejection due to its immunostimulatory effect
☆ Ribavirin
** Ribavirin as a monotherapy has become the treatment of choice for chronic HEV infection.
** The recommended dose 600 to 800 mg/day
** In patients with impaired kidney function, ribavirin dose should be adapted to kidney function
** Three months after initiating ribavirin therapy, if HEV RNA is negative in both the sera and stools, ribavirin can be stopped.
** If HEV RNA remains positive in the stools after three months, even if it is negative in the sera, ribavirin therapy should be prolonged for an additional three months.
** If HEV viremia increases after ceasing ribavirin therapy, a longer course of ribavirin 6 months, can be proposed.
** In patients who present with a relapse under ribavirin or who are resistant to ribavirin, there is no alternative, except for liver-transplant patients for whom pegylated interferon can be proposed.
● The main adverse effect is hemolytic anemia ( up to 40 %)
Others:
Insomnia, dyspnea, lack of concentration, emotional lability, and irritability, feeling tired, headache, nausea, fever, muscle pains, and an irritable mood.
Nassim Kamar, Sébastien Lhomme, Florence Abravanel, Olivier Marion, Jean-Marie Peron, Laurent Alric, and Jacques Izopet . Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis . Viruses. 2016 Aug; 8(8): 222.
the use of RBV for the treatment of an HEV infection in organ transplant patients is effective, and the recommendation of 12 weeks of therapy being adequate in terms of efficacy. Nevertheless, there are important issues that urgently need to be assessed, such as the optimal duration of therapy and drug dosage of RBV, as well the development of new drugs with a high safety profile
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022260/
This patient has chronic hepatitis E infection that can be transmitted either by infected meat or by infected organ transplant and blood components.
For management, immunosuppression should be reduced. Ribavirin should be started for at least 3 months until HEV RNA becomes negative.
Regular test for liver eczema is essential as well. The dose of ribavirin depends on Cr Cl. for patients with Cr Cl, more than 50 ml/min 200 mg Q 8h is administered. Ribavirin side effects include hemolytic anemia, GI disorders, dermatological side effects, and general symptoms like fatigue, and fever headache. Hence, regular monitoring for CBC. is important. Prevalence of HEV for each organ transplant liver: 27.2%, kidney 12.8%, and lung 5.6%.
How would you manage this case?
· Hepatitis E virus (HEV) infection is underdiagnosed. Most patients with HEV recover completely but immunosuppressed patients may have a more severe course.
· HEV infection is either acute (< 3 months) or chronic (persist for more than 6 months).
· Diagnosis of HEV infection in SOT depends on detection of HEV PCR in the blood or stool as serology results are altered by immunosuppression
· Management:
· In our case we have chronic HEV infection.
· Immunosuppression management: keep MMF (may be associated with lower risk of HEV infection) and steroids, but I will reduce Tacrolimus being associated with high risk of HEV infection.
· Antiviral treatment: start ribavirin therapy for 3 months since the patient has chronic HEV infection. If relapse occur, the treatment should be restarted with a higher dose and for 6 months. Dose is 600-1000 mg/day, adjusted according to body weight and creatinine clearance
· Blood HEV PCR should be done after 1 week of therapy to predict the duration of the therapy, the ribavirin is continued until 2 consecutive PCR results in the stool are negative one month apart
· During therapy monitor liver enzymes and hemoglobin level every 2 weeks as Ribavirin can cause hemolytic anemia.
· After stopping Ribavirin treatment, ensure sustained viral response (SVR) by repeating the viral load every 3 months using blood or stool PCR for 6 months.
What is the prevalence of HEV in solid organ transplantation?
· In solid organ transplant is 4-20%. This increases with age, and demographic variables being higher in Africa and Asia.
References:
1. Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, et al. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec; 29(12):1134-1142.
2. Aggarwal A, Perumpail RB, Tummala S, Ahmed A. Hepatitis E virus infection in the liver transplant recipients: Clinical presentation and management. World J Hepatol. 2016; 8:117
3. Guidelines for Hepatitis E & Solid Organ Transplantation. BTS guidelines 2018
How would you manage this case? transplant recipient severely immunocompromised with history of multiple viral infection (CMV reactivation, primary EBV infection, and BK-virus viremia) presented with unexplained elevation of liver function, later on diagnosed with chronic HEV infection. management:while managing patients with solid organ transplants, benefits of treatment need to be weighed against risks of rejection.
Reduction of immunosuppression is considered the first-line approach, allowing HEV clearance in about one-third of patients.
Ribavirin, an anti-viral agent, is considered in patients with severe acute or acute on chronic liver failure.
acts by inhibiting HEV viral replication and increases the expression of interferon stimulating genes leading to immune modulation
It can be given as for 3 months, 600 mg / day.
Ribavirin is also used successfully to treat HEV-associated membranoproliferative glomerulonephritis in a solid organ transplant recipient.
In patients with detectable HEV RNA in the serum and/or in the stool, at the end of three months, ribavirin monotherapy can be continued for an additional three months.
the use of IFNα is not recommended among other solid organ transplant recipients due to the risk of graft rejection.
Sofosbuvir was ineffective in achieving sustained virological response.
What is the prevalence of HEV in solid organ transplantation?
HEV genome 3 related infection is associated with solid organ transplant recipients and immunocompromised patients.
Recent data demonstrates HEV seroprevalence rates ranging from < 1% up to 52% in Europe.
Karthik Kovvuru, Nicholas Carbajal, Abhinandan Reddy Pakanati.Renal manifestations of hepatitis E among immunocompetent and solid organ transplant recipients. World J Hepatol. 2022 Mar 27; 14(3): 516–524
How would you manage this case?
This is case of Chronic Hepatis E infection.
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment
Modification of immunosuppression–
Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV. Evidence suggests that calcineurin and mTOR inhibitors may contribute to persistence of HEV replication in hepatocytes and the development of persistent HEV, whereas corticosteroids appear to have no effect on viral replication, and mycophenolate may have an inhibitory HEV replication in vitro. Therefore, strategic modification of immunosuppression might help with viral clearance. It is important to recognise that changes in immunosuppression can precipitate rejection in more immunogenic individuals so the risk of rejection versus the potential benefits of modification of immunosuppression must be carefully balanced.
Antiviral therapy
Ribavirin-
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). Dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation.
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.
What is the prevalence of HEV in solid organ transplantation?
The prevalence of HEV infection in solid organ transplant (SOT) recipients varies by countries and transplanted organs. Meta-analysis demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients
This is a case of chronic HEV infection> 6 months detectable RNA.
1- detailed history and clinical examination
2- laboratories for , CBC, KFT, Urinalysis, LDH, liver function (albumin, INR), gamma GT, alkaline phosphatase, and bilirubin, and a quantitative stool HEV PCR(as baseline)
3- ultrasound abdomen, for any organomegaly, and CXR.
Treatment:
1. Reduction of immunosuppression
2. Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 6 months after stopping the Ribavirin)
3. Adjust dose to GFR monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function.
4. Failure of treatment: repeat the course with high dose Ribavern but observe for side effect as above
5. in cases of ribavirin-refractory persistent HEV infection ,PEG-interferon treatment may be considered. However, it carries a risk of rejection.
Prevalence of HEV in SOT
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%
The pooled estimated prevalence of HEV infection for each organ transplant was as follows:
Liver : 27.2%
Kidney : 12.8 %
Heart : 12.8%
Lung 5.6%
About 30% of patients undergo HEV clearance in the first 3 months, as the patient has already gone through this phase, it is necessary to decrease immunosuppression.
If the patient has progression of liver dysfunction, treatment with Ribavarin will be necessary.
The prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients). The prevalence of HEV infection is two-fold more common in middle-income countries compared to high-income countries.
REFERENCE:
– Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
How would you manage this?
This is a case of chronic HEV in a immunocompromissed recipient.
The main stay of management is reduction of immunosuppression, anti-viral therapy, reduction of immunosuppression may decrease the infection/ viral load by 30%.
To follow the treatment response the sustained viral response.
Which is monitored by PCR test.
Monitor side effect of drugs, treatment can be done using ribavirine (600mg/day for three months) for HEV infection.
If not responding can be given pegylated interferon alpha.
Monitoring and prevention of rejection, as the treatment may take more than six months for clearance of infection.
Drug modification like switching from tacrolimus to cyclosporine can improve outcomes of infection.
Prevalence of HEV in Solid Organ Transplantation.
Usually initially it present with IgM antibodies positivity which shows acute infection, if anti- IgG positive shows chronic infection and persists for years.
Otherwise, HEV infection seen in liver transplantation is around 3-28%,
Pooled estimated prevelance for each solid organ transplant is around
Liver 27.2%,
Kidney 12.8%,
Heart 12.8%, and
Lung 5.6%.
How would you manage this case?
After confirming the presence of HEV RNA in stool or plasma , treatment should start by reduction of immunosuppressant and follow the patient for 3 months unless there’s severe infection, in such case Ribavirin therapy should start.
The dose vary from 600-1000mg /day adjusted according to body weight and GFR.
There’s no consensus about the duration of treatment, but a period of 6months is adopted.
The drug should be monitored after the first week then monthly by CBC and RFT .
The drug is continued till 2 consecutive sample of stool or plasma are negative with one month a part.
The drug SE include hemolytic anemia, skin rash , GIT symptoms,headache.
The prevalence of HEV in solid organ transplantation is 20.2% , with heightest prevalence in liver and lower in lung transplantation, in kidney its 12.2%.
Referece:
BTS guideline 2017.
This DBD recipient in 2008, had intense immunosuppression, indicated by post-transplant CMV, EBV and BKV infection. Repeated deranged LFT, and evaluation detected 5years post-renal transplant infection with HEV genotype3.
As the previous stored sample also detected HEVRNA and IGM antibody, and persistent IgG anti-HEV, it indicates Chronic HEV infection with reactivation due to intense immunosuppression with off and on LFT derangement.
Management:
Reduction of prednisone and tacrolimus to minimum level.
Monitoring Tac levels, RFT for rejection, CBC, LFT and Liver ultrasound.
Tab Ribavirin PO 200mg 3-5times daily – dose adjusted to Creatinine Clearance.
The dose should be adjusted according to creatinine clearance
if CrCl >50 ml/min no dose adjustment needed,
CrCl 30-50 ml/min 200 mg alternative with 400 mg every other day,
CrCl <30 ml/min 200mg OD,
Follow up by CBC monthly if Hb is less than 8.5 g/dl, WBC less than 1,000, platelets less than 50,000 then stop ribavirin.
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 therapy.
· The pooled estimated prevalence of HEV infection in SOT patients was 20.2%, and the prevalence in different organs was as follows:
1. Liver (27.2%)
2. Kidney (12.8%).
3. Heart (12.8%),
4. Lung (5.6%).
Response to ProF Ahmed Halawa’s questions
What are the side effects of ribavirin?
Most important side effect is anaemia – occur in 10-13%
– (haemolysis + bone marrow suppression)
– dose-dependent à when Ribavirin >1.2 g daily for > 10 days given and in case of renal impairment
Other adverse effects:
Leukopenia, Neutropenia, Thrombocytopenia – <10%
Generalised malaise, weakness, nausea, diarrhoea
Hyperbilirubinemia, lactic acidosis, Hyperuricemia
Hypocalcaemia, Hypomagnesemia
Standard dose of Ribavirin and factors affecting dosing
standard dose is 600-1200 mg daily (Available 200 mg capsule)
According to body weight
< 50 kg: 200 mg in the morning; 400 mg in the evening.
50-60 kg: 400 mg twice daily.
>60 Kg: 400 mg in the morning; 600 mg in the evening.
Ribavirin dosage in CKD and transplant patients?
In transplant recipients – start with 200mg twice a day to thrice a day (400-600mg/day)
Can titrate the dose according to adverse effect and tolerance.
serum creatinine should be monitored every month and Ribavirin dose need to be adjusted according to GFR (creatinine clearance (CrCl)
· CrCl >50ml – no dose modification required
· Moderate renal impairment (CrCl) 30 – 50 ml/min à 600 mg daily
– 200 mg alternating with 400 mg every other day (to start with)
· Severe renal impairment (CrCl) <30 ml/min à 200 -400 mg daily
– lower dose if serum creatine is >2 mg/dl à <200mg/day
· End-stage renal disease (ESRD) à 200 mg daily
– starting with lower dose (200 mg 3 times weekly), then increase to 200mg daily, if no side effects
– Patient on regular haemodialysis: use 200 mg 3 times weekly
To check for CBC every month – dose modification needed if severe anaemia develops
In cardiac patient
– with haemoglobin drop of > 2 gm after 1 month of treatment à reduce dose to 600 mg daily
– if hemoglobin is <12 g/dL after reduction of the dose treatment should be temporary stopped
– once haemoglobin increase > 12g à dose increased gradually by 200 mg a day
In non-cardiac patient,
– if haemoglobin <10 g/dL after treatment à reduce dose to 600 mg daily
– if haemoglobin increase the dose can be increased gradually by 200 mg a day
· If hemoglobin is <8.5 g/dL at any time stop ribavirin
· Leukopenia WBC <1,000, neutrophils <500, platelets <50,000 : stop treatment permanently
References
1. Brennan BJ, Wang K, Blotner S, et al. Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment. Antimicrob Agents Chemother. 2013; 57(12): 6097-105. Doi :10.1128/AAC.00608-13
2. Ribavirin, In: Aronson JK (ed.), Meyler’s Side Effects of Drugs (Sixteenth Edition), Elsevier, 2016. p.115-129.
3. De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res 2018 Apr; 130: 308-315. doi: 10.1016/j.phrs. 2018.02.030.
4. British Transplantation Society. Guidelines for Hepatitis E and Solid Organ Transplantation, 1st ed.; British Transplantation Society: Macclesfield, UK, 2017; Available online: https://bts.org.uk/wp-content/uploads/2017/06/BTS_HEV_Guideline-FINAL.pdf
5. Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant. 2019 Sep;33(9):e13514. doi: 10.1111/ctr.13514.
6. Up to date
Above is a case of chronic HEV infection with genotype 3.Firstly,stool and plasma sample for PCR for HEV RNA should be sent, then reduction of immunosuppression i.e., steroids and anti-metabolite should be decreased followed by Tacrolimus .Close monitoring of graft function is must due to increase chances of rejection ,then Ribavirin in renal adjusted dose should be started timely for early virological clearance and that can be checked by doing monthly PCR on stool and plasma sample. Its dose varies from 600-1200 mg/day and no consensus about the duration is being mentioned in the literature , however,it is continued till the two consecutive stool tests are negative for HEV RNA one month apart. Generally duration is 3-6 months and no dosage adjustment required for GFR >50ml/min. But patient should be monitored for the side effects like hemolytic anemia, leucopenia, thrombocytopenia and GI disturbances .In resistant cases, Peg interferon is the option.
What is the prevalence of HEV in solid organ transplantation?
The pooled prevalence of HEV infection in solid organ transplantation is 20.2% , however, varies with different organ transplantation – Liver (27.2%)having highest prevalence followed by kidney (12.8%).and heart(12.8%), and then lung(5.6%).Both acute and chronic HEV infection can occur and according to one study -70% of the patients with acute infection develop chronic infection
REFERENCES:
1-Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254.
2-Guidelines for Hepatitis E & Solid OrganTransplantation. BTS guidelines 2018
. WHO estimates that HEV causes 20 million new infections annually, with more than 3 million cases of acute hepatitis and over 55,000 deaths.
· Genotype 3 is prevalent in Western countries, as well as in Asia and North America.
· patients with solid organ transplantation may develop chronic HEV infection.
Management
· Reduction of immunosuppression. First, reduce Tacrolimus.
· Antiviral therapy: a 12-week course of ribavirin monotherapy with a dose 600 to 1000 mg daily, in two divided doses.
· Monitoring for toxicity: CBC, creatinine with eGFR, liver enzymes, and bilirubin levels at week 4 of treatment. Then CBC at weeks 8 and 12 to evaluate for anemia associated with ribavirin.
· For those who develop anemia, the dose of ribavirin can be adjusted based on the severity and comorbidities.
· If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated.
· If HEV is detectable in serum and/or stools at week 12, ribavirin therapy should be extended for an additional 12 weeks.
What is the prevalence of HEV in solid organ transplantation?
In a prospective cohort of 700 solid organ transplant recipients, 5 % acquired HEV infection, of whom 47 % developed a chronic infection
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022260/#:~:text=Ribavirin%20as%20a%20First%20Treatment%20Approach%20for%20Hepatitis%20E%20Virus%20Infection%20in%20Transplant%20Recipient%20Patients
2. https://www.uptodate.com/contents/hepatitis-e-virus-infection?search=HEV&source=search_result&selectedTitle=1~18&usage_type=default&display_rank=1#:~:text=Back-,Hepatitis%20E%20virus%20infection,-Topic
3. https://pubmed.ncbi.nlm.nih.gov/21192851/#:~:text=Hepatitis%20E%20virus%20infection%20without%20reactivation%20in%20solid%2Dorgan%20transplant%20recipients%2C%20France
Management
The first step is reduction of immunosupression and preferably CNI and glucocorticoids.
This patient would require Ribavirin , as there is active hepatitis and the period of observation for three months usually recommended does not apply to this patient.
It can be given for atleast three months which can be extended to six months depending upon the response. Close monitoring should be done and cure should be considered if two consecutive stool PCR are negative one month apart.
The side effects of Ribavirin should be considered specially hemolytic anemia.
Usual dose is 600 to 1000 mg
we can use 600 mg in Tx patients.
35 year old patient received cadaver transplant with early post transplant infections including BK, CMV, EPV.
Patient experienced elevation in liver enzymes in 2011 and more increase in 2012.
Genotype 3 HEV in 2013 with high HEV RNA and IgG and IgM
Persistent HEV infection more than 3 months
Management :
Full history and examination
Detection of baseline stool and plasma HEV RNA test
Reduction of immunosuppression is starred first especially MMF
Ribavirin 600 mg daily for at least 3 months.
Plasma and stool HEV are monitored every month. With initial 7 days monitor to check initial response.
If persistent HEV test after 3 months continue treatment till 6 months or till 2 tests 1 month apart are negative
If relapse post Ribavirin we shall repeat course of Ribavirin with higher dose and longer duration.
Side effects of Ribavirin may include Hemolytic anemia so check of Complete blood count regularly.
HEV infection is common in SOT recipients and accounts for 20.2%. It is at least two-fold higher in middle-income countries compared to high-income countries. The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants. More studies demonstrating the clinical impacts of HEV infection in SOT recipients, such as graft failure, rejection, and mortality, are warranted.
This renal transplant patient has chronic HEV, as previous samples when the liver enzymes were elevated revealed positive HEV RNA.
Reduction of tacrolimus, MMF and prednisolone. Monitoring Tac levels and monitoring for rejection. Liver ultrasound and monitoring LFTs.
Ribavirin dose ranging from 600-1000mg daily depending on the patient’s weight and CrCl.
The dose should be adjusted according to creatinine clearance
if CrCl >50 ml/min no dose adjustment needed,
CrCl 30-50 ml/min 200 mg alternative with 400 mg every other day,
CrCl <30 ml/min 200mg OD,
Follow up by CBC monthly if Hb is less than 8.5 g/dl, WBC less than 1,000, platelets less than 50,000 then stop ribavirin.
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 therapy.
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%.
The pooled estimated prevalence of HEV infection for each organ transplant was as follows:
1. Liver (27.2%)
2. Kidney (12.8%).
3. Heart (12.8%),
4. Lung (5.6%).
· WHO estimates that HEV causes 20 million new infections annually, with more than 3 million cases of acute hepatitis and over 55,000 deaths.
· Genotype 3 is prevalent in Western countries, as well as in Asia and North America.
· patients with solid organ transplantation may develop chronic HEV infection.
Management
· Reduction of immunosuppression. First, reduce Tacrolimus.
· Antiviral therapy: a 12-week course of ribavirin monotherapy with a dose 600 to 1000 mg daily, in two divided doses.
· Monitoring for toxicity: CBC, creatinine with eGFR, liver enzymes, and bilirubin levels at week 4 of treatment. Then CBC at weeks 8 and 12 to evaluate for anemia associated with ribavirin.
· For those who develop anemia, the dose of ribavirin can be adjusted based on the severity and comorbidities.
· If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated.
· If HEV is detectable in serum and/or stools at week 12, ribavirin therapy should be extended for an additional 12 weeks.
What is the prevalence of HEV in solid organ transplantation?
In a prospective cohort of 700 solid organ transplant recipients, 5 % acquired HEV infection, of whom 47 % developed a chronic infection
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022260/#:~:text=Ribavirin%20as%20a%20First%20Treatment%20Approach%20for%20Hepatitis%20E%20Virus%20Infection%20in%20Transplant%20Recipient%20Patients
2. https://www.uptodate.com/contents/hepatitis-e-virus-infection?search=HEV&source=search_result&selectedTitle=1~18&usage_type=default&display_rank=1#:~:text=Back-,Hepatitis%20E%20virus%20infection,-Topic
3. https://pubmed.ncbi.nlm.nih.gov/21192851/#:~:text=Hepatitis%20E%20virus%20infection%20without%20reactivation%20in%20solid%2Dorgan%20transplant%20recipients%2C%20France
DIAGNOSIS of EBV infection can be established in this case as RNA is positive and ant HEV antibody are present
treatment
RIBAVARIN in GFR depending dosage is advised
200 mg capsule upto 800 mg per day if GFR is normal
Hemolytica anaemia is main adverse effect along with leucopenia , GI upset
Hb need monitoring every month
May need to stop the drug if Hb falls significantly like 2 gm per month
The managment of this case is ribavirin ,this medications need close monitoring for the Hb as one of the main side effect is anemia which is fatal specially in c ardiac patient .
Ribavirin is Exkret through renal for that need dose adjustment in case of renal impairment other wise will lead to ribavirin toxicity .
Because of its teratogenicity and emberiocidal effect of ribavirin it is conntraindicated in pregnency .
The dose of ribavirin is between 600 to 1000mg/day according to the body wt with adjustment according to the eGFR . once we satrted need close follow up for SE and will need monthly assessment of Hb .
If the Hb is drop to below 8gm will hold ribavirin permanently .Also we need to check all blood indices TWBCS ,platelet and neutrophil count and if it cause pancytopenia need to hold the Ribavirin
references
uptodate
Management
A case of Hepatitis E virus of genotype 3 which can be transmitted through ingestion of infected meat. Also, can be transmitted with the transplanted organ or through blood transfusion.
The patient has positive HEV RNA since 2011; chronic hepatitis E. Immunosuppression reduction is needed with start on ribavirin for three months followed by HEV RNA testing. With viral clearance ,LFTs to be monitored regularly.
Usual dose of ribavirin is 200 mg 8 hourly, with dose adjustment in patients with eGFR of less than 50 ml/min.
Side effects of ribavirin include: fatigue, headaches, hemolysis ;monitoring CBC, fevers, rigors, nausea, vomiting ,and myalgia.
According to data from selective screening program by NHS Blood and Transplant it is 1 in 2500 donations with HEV RNA positive test.
Treatment is related to some factors:
1. Immunosuppression – It is important to reduce the dose of tacrolimus and monitor serum levels of immunosuppressants to avoid organ rejection
2. Monitoring of the HEV viral load to assess its activity
3. Ribavirin is the drug of choice, but requiring frequent adjustments due to its side effects, mainly related to hemolytic anemia. Renal function and CrCl impact drug choice and discontinuation.
The dose will be dependent on weight and side effects arising from the drug.
Pegylated interferon should be avoided due to the high risk of rejection and toxicity.
Sofosbuvir is a promising alternative in new studies.
HEV occurs around 20.2% in SOT and 12.5 % in kidney transplant recipient
treatment include reduction of immunosuppresion for 3month and follow up except there is picture of sever infection for which ribavirin treatment need to be started early with close monitoring of CBC and dose adjusted according to weight and to eGFR
after starting ribavirin HEV PCR needs to be followed 7 days then monthly till clearance is achieved by 2 successive PCR negative one weak in between.
after 6months of achieving remission PCR should be repeated for the risk of relapse
if remission not achieved after 3months of ribavirin pegylated interferon can be started with caution of the risk of rejection.
Reference :
This patient has chronic HEV infection as evidence of infection persist longer than 3 month
1-History : including hepatotoxic drugs , alcohol and other potential hepatotoxic risk factors
2-Examination to role out
a- Hepatic complications as liver fibrosis , cirrhosis ,decompensated LCF and extrahepatic complications
b- Presence of other causes of hepatitis as metabolic diseases.
3- Laboratory investigations
a- Liver function test to exclude decompensated LCF
b- Metabolic screen for liver diseases as serum iron and ferritin in hemochromatosis, serum ceruloplasmin for Wilson disease .
c- Quantitative HEV RNA in plasma and stool.
d- CBC, coagulopathy profile.
e- Cryoglubulins level.
f- Urine analysis and albuminuria level to exclude complicating GN.
4- Treatment :
– Ribavirin 600 mg once daily with monitoring of CBC to exclude drug induced hemolysis. Serial monthly test for HEV RNA in stool and blood .Continue ribavirin treatment till get 2 HEV RNA negative stool samples , one month apart.
– Monitor graft function and drug levels.
-Reducing tacrolimus dose to lower level , while steroid and MMF doses don’t need change.
Prevalence of HEV infection is 20.3% in solid organ transplant being highest in liver transplant and lowest in lung transplant.
The clinical features of autochthonous genotype 3 HEV infection in solid organ transplant recipients can be asymptomatic but in some cases, severe complications develop such as chronic hepatitis and cirrhosis .
Extrahepatic manifestations include neurological symptoms such as Guillain-Barre syndrome, kidney injury, cryoglobulinemia, membranoproliferative glomerulonephritis, immunoglobulin A nephropathy, and impaired kidney function .
The mechanism of kidney injury is believed to be associated with immune-mediated kidney diseases.
Once a chronic HEV infection is diagnosed, the therapeutic approach first consists of a reduction in the immunosuppression (if possible) and, in case of failure of self-resolution, implementation of therapy. Reduction of daily dose of MPA therapy alone in transplant patients with chronic HEV infection may not be sufficient to control viral replication. Currently, there are no specific drugs approved for HEV infection, but ribavirin (RBV), the drug of choice, is used for off-label treatment.
HEV clearance under ribavirin therapy shows interindividual variability. Therefore, serial viral monitoring may be useful to personalize treatment duration.
clinical guidelines recommend a program therapy duration of 12 weeks using RBV at the initiation with a weight-adjusted dose or a dose adjusted on the basis of the estimated glomerular filtration rate.
RBV was initiated at a dose of 200 mg every 8 h for 12 weeks, following clinical guidelines.
Prevalence
the prevalence of HEV infection in kidney candidates is higher than reported in the general population, and increases with age and during the first posttransplant year. Contrary to previous reports, we found that although reduced immune status may predispose recipients to HEV infection, infections are largely asymptomatic and appeared to resolve spontaneously.
number of studies have tried to estimate the prevalence of HEV in transplant recipients. Studies using sensitive assays (Wantai HEV test) have reported seroprevalence rates between 8.3% and 43% for anti-HEV antibodies in transplant recipients, the spread probably reflecting true geographic differences in prevalence .The prevalence of detectable HEV RNA among transplant recipients in these studies, indicating current viraemia, ranged from 0-3.2% .However, studies reported to date have been conducted in geographically distinct populations using different methodologies and may not be generalisable to all transplant populations. It is also likely that the incidence of infection and prevalence rate of viraemia have changed over the last decade, with a demonstrable recent increase in incidence .A recent study at a single centre in the UK found the point prevalence of HEV viraemia in transplant recipients was 16/2418 (0.7%) (manuscript submitted).
How to Manage the case?
Important issues
I will address each issue because treatment plan depends on the same.
Viral causes: HBV, HCV, HEV, CMV, HSV
Non-viral causes: alcohol ingestion, hepatotoxicity drugs, older age, deceased
donation, high cyclosporine levels
In our case there is no definite cause identified for persistent transaminitis, except deceased donation. But after 2 years of raised levels of liver enzymes they normalised (could it be a evidence of chronic liver dysfunction – CLD)??.
But it raised again when patient was HEV RNA positive
Thus, I will consider this as acute HEV infection with genotype 3, with a possibility of patient having CLD changes in liver. Therefore
REF:
this case typical description of chronic infection of HEV infection, as a case of an SOT organ infected by genome 3 and symptoms are minimal and persistent elevation of aminotransferase
management of this patient :
reduction of immunosuppression therapy, TAC should be reduced first if possible as HEV infection is associated with TAC
Ribavirin for 12 weeks the dose 600 -1000 daily in two divided doses
recheck HEV RNA at the end of the treatment if absent recheck after 12 weeks
if the virus did not detect any further treatment.
but if after 12 weeks the virus is detected further additional 12 weeks of treatment by ribavirin. If the virus is still present that means treatment failure
no randomized trials have evaluated the use of ribavirin for the treatment of chronic HEV
management of treatment failure includes:
Sofosbuvir
pegylated interferon alpha: limited data to support the use of pegylated interferon -alpha for SOT.
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
Treatment of Persistent Hepatitis E Post-transplantation:
Following 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 in approximately 15% of infected solid organ transplant recipients Therefore, persistent HEV infection should be actively treated with the aim of clearing HEV from the blood and stool
Chronic HEV infection is conservatively defined as the finding of detectable HEV RNA in the blood and/ or stool for greater than six months, spontaneous clearance of HEV rarely occurs between three and six months of infection .Fatigue is the most common symptom and jaundice is rare . Neurological symptoms can also occur
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. Typically ALT levels are between 200-300 U/L
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 (HEV RNA non detected in plasma and stool six months after completing treatment
Modification of immune suppression:
Persistent HEV infection occurs mainly in heavily immune suppressed individuals, particularly those on T cell suppressing drugs. Reduction of immune suppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV
Tacrolimus 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 in these models Interestingly, mycophenolate was shown to inhibit HEV replication
Transplant recipients with acute HEV to date found that patients treated
with ciclosporin were more likely to have spontaneous clearance than those treated with tacrolimus
Antiviral therapy
1-Ribavirin
two patients with persistent HEV were treated with ribavirin 12 mg/kg for
12 weeks, and both cleared HEV RNA from blood and stool by four weeks and remained HEV RNA negative during follow up.
2-PEG-interferon:In case of ribavirine failure
3-Sofosbuvir
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What is the prevalence of HEV in solid organ transplantation?
The meta analysis demonstrate the prevalence of HEV infection in SOT recipient is 20.3% (highest in liver transplant recipient and lowest in lung transplant recipients).
Reference :
1-British Transplantation Society Guidelines
2- Komolmit P, Oranrap V, Suksawatamnuay S, Thanapirom K, Sriphoosanaphan S, Srisoonthorn N, Posuwan N, Thongmee T, Treeprasertsuk S, Poovorawan Y. Clinical significance of post-liver transplant hepatitis E seropositivity in high prevalence area of hepatitis E genotype 3: a prospective study. Sci Rep. 2020;10:7352. [PMC free article] [PubMed] [Google Scholar
Unexplained increase in liver enzymes in immunocompromised patient (after renal transplantation) directed toward HEV diagnosis.
In this patient HEV RNA positive.
In addition the infection remained more than 3 months , therefore this is a persistent chronic infection.
The strategy of treatment
– Reducing immunosuppression (tacrolimus)
– ribavirin in persistent HEV infection is recommended 600- 1000 mg a day divided in 2 doses depending on GFR
– Monitoring of HEV RNA plasma at d7, 1m, 2m and 3m
– Monitoring of HEV RNA in stool from 2m onward or after a negative plasma sample (whichever is sooner)
A- At 3m: Plasma + Stool (x2) negative therefore stop treatment
B- Plasma or stool RNA positive – therefore, continue until 2 stools > 1 month apart are both negative or continue for 6m
Monitoring LFT and renal function CBC
(Hemolytic anemia)
Epidemiology
Developing World
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.
Recent studies in populations from Nepal and Bangladesh indicate antibody prevalence rates of 47% and 50% respectively with no differences noted by gender
low prevalence in children <10 years.
Developed World
In the developed world, HEV G3 and G4 are zoonotic infections, being transmitted to humans from an animal reservoir. (pork products (particularly processed) and game meat are associated with HEV infection )
Seroprevalence rates vary widely from 1% to 50% (3,18-19)
Estimates of the burden of infection in the general population of England suggest as many as 200,000 infections occur annually and account for around 600-800 cases of hepatitis E. low rates in children
REFERENCES
Guidelines for Hepatitis E & Solid Organ Transplantation (BTS)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997573/#!po=56.7308
Thanks, See my answer above
1- A case of persistent (chronic) HEV infection
A- im of treatment is to acheive sustained virological response (no HEV RNA in blood or stool six months after completion of treatment)
Treatment:
Dose: 200-1000 mg /day in 2-5 doses.
Duration: 3-6 months
Monitoring:
it should be continued till stool is negative for 2 consecutive tests one
month apart.
-Regular hemoglobin monitoring. it is associated with hemolytic anemia.
-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.
Refernces:
1- BTS guidelines for hepatitis E and solid organ transplantation 2017
2- Panning M, Basho K, Fahrner A, Neumann-Haefelin C. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infectious Diseases. 2019 Dec;19(1):1-5.
II-Prevalence in SOT:
Thanks, See my answer above
👉 The present case has chronic HEV infection which may have spontaneous resolution in 30% of cases. So close follow up of liver function, PCR for HEV RNA in blood and stool is indicated.
👉 Reduction of immunosupression (CNI and steroids ) can help in viral clearance, but attention towards rejection is a must.
👉 Treatment with ribavirin 200_600 mg/day (divided twice or thrice is indicated, and continued for 3_6 months until 2 negative stool PCR (1 month apart).
👉 Follow UP CBC during treatment with ribavirin is essential for fear of hemolytic anemia , that can be manged by dose reduction, packed RBC transfusion or giving ESA.
⭐ Adjustment of the dose according to eGFR as follows:
_More than 50 ml/min …no dose adjustment.
_30-50 ml/min :200 mg in the morning and 400 mg in the evening every other day.
_less than 30 ml/min:200 mg once daily.
_Dialysis patient : 200 mg every other day.
⭐ Prevalence of HEV is up to 25 % in
CASE of liver transplantation, 12% in herat and kidney transplantation. And lowest in lung transplantation 5%.
Thanks, See my answer above
How would you manage this case?
The patient in the index case is severely immunocompromised and prone to viral infections. There is chronic HEV infection. The management options include-
Reduction of immune suppression
The first step will be to reduce immune suppression. It can help in treating and reducing risk of recurrence. Patient should be counselled about risk of rejection.
Ribavarin
Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed. It can be given as mono therapy for 3 months. The dose is 600-800 mg / day in 1-2 divided doses. Those with relapse post 3 month treatment can be treated for 6-9 months. Side effects include , hemolytic anemia, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability.
Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Sofosbuvir
In one study sofosbuvir showed antiviral activity in
chronic hepatitis E in an immunocompromised patient.
What is the prevalence of HEV in solid organ transplantation?
Recent data demonstrates HEV seroprevalence rates ranging from < 1% up to 52% across Europe. One meta-analysis, demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients).
Hansrivijit P, Trongtorsak A, Puthenpura MM,et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254.
Kar P, Karna R. A Review of the Diagnosis and Management of Hepatitis E. Curr Treat Options Infect Dis. 2020;12(3):310-320.
Thanks
Management
This patient has Hepatitis E virus, genotype 3 which is transmitted by ingestion of infected meat. It can also be transmitted at the time of SOT, either with the transplanted organ or through blood components from an HEV infected donor
For this patient, he has had a positive HEV RNA since 2011, categorizing him to have chronic hepatitis E. He will need to have his immunosuppression reduced and started on ribavirin for three months and then the HEV RNA rechecked. If he has cleared then LFTs should be regularly monitored
The dose of ribavirin is 200 mg 8 hourly. It is contraindicated in patients with an eGFR of less than 50 mls/min
The side effects of ribavirin include: fatigue, headaches, hemolysis (important to do regular complete blood counts, myalgia, fevers, rigors, nausea, vomiting.
What is the prevalence of HEV in SOT?
Data from the selective screening program implemented by NHS Blood and Transplant indicate that 1 in 2500 donations are HEV RNA positive
Short and sweet
OUR CASE;
MANAGEMENT.
BTS guidelines to be considered in decision making; This is chronic Hep E infection.
PREVALENCE OF HEV IN SOT RECIPIENTS;
REF;
That is a comprehensive reply on dosage of ribavarin well-supported by published evidence
Thanks Prof.
Dear All
Thank you very much for your replies.
You kindly mentioned ribavirin as one of the treatment options.
What are the side effects of ribavirin?
What is the dose of this drug in a transplant patient and how would you adjust the dose?
I have noticed some of you have written a standard dose, Is it applicable in CKD and transplant patients?
Please substantiate your answer.
Thanks so much ;Our Prof.
Ribavirin in treatment of Hepatitis E infection:
Oral:
-Optimal dosing has not been established:
-typically 600 to 800 mg/day (range: 400 mg to 1 g/day) in 1 to 2 divided doses.
-Optimal duration is unknown, but is typically ≥3 months based on virologic response.
Side effects:
Hemolytic anemia;
-Hemolytic anemia has been reported with ribavirin therapy. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin.
Teratogenic;
–Is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Avoid pregnancy and use effective contraception during therapy and for 9 months after completion of treatment in female patients and for 6 months in female partners of male patients who are taking ribavirin therapy.
Other side effects;
More Common:
-Anxiety
–Body aches or Pain
-Nausea, Vomiting , Diarrhea
-Nervousness
-Quick to react or overreact emotionally
-Runny nose
-Sleeplessness
-Fever, Headache ,Sore throat
-Mental depression
Less Common:
-Constipation
-Dry skin and hair
-Hair loss
-Belching
-Dizziness or lightheadedness
-Heartburn
-Indigestion
-Weight loss
-Skin rash
References;
-De Winter 2018; Kamar 2020; Protin 2019; Rivero-Juárez 2020; Tavitian 2015.
-AST-IDCOP [Te 2019]; EASL 2018; Kamar 2020; Rivero-Juárez 2020; Tavitian 2015.
There is much variability in ribavarin dose that is being recommended by our fellows: 1-2 doses to 5 doses!
Side effects of Ribavirin:
Dose:
=====================
Reference:
I quote your reply:
The dose of ribavirin used to treat HEV varies between instances, ranging from 29 to 1800 mg/day.
My comment:
29 mg dose is a strange one and too low !
What are the side effects of ribavirin?
Adverse effects of ribavirin are as follows
Most important adverse effect is
Dose-dependent anemia (with both hemolysis and bone marrow suppression), especially when the drug is given at doses of ≥ 1.2 g daily for > 10 days and in case of renal impairment when the drug accumulate
Other adverse effect
Arrhythmia,
Elevated lactate and
Pyruvate levels,
Hypocalcemia, and
Hypomagnesemia
Chest pain,
Dizziness,
Hyperuricemia,
Hyperbilirubinemia,
Interstitial pneumonitis,
Decreased WBC count, and
Thrombocytopenia.
Reference
Chiou HE, Liu CL, Buttrey MJ, Kuo HP, Liu HW, Kuo HT, Lu YT. Adverse effects of ribavirin and outcome in severe acute respiratory syndrome: experience in two medical centers. Chest. 2005 Jul;128(1):263-72. doi: 10.1378/chest.128.1.263. PMID: 16002945; PMCID: PMC7094379.
What is the dose of this drug in a transplant patient and how would you adjust the dose?
Can titrate the dose starting 200mg twice a day to thrice a day (ie 400-600mg/day) monitoring the adverse effect and tolerance.
Reference
Ribavirin monotherapy for Hepatitis C virus infection in renal transplant recipient Sharma RK, Bansal SB, Gupta A, Gulati S, Prasad N, Kumar A Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
I have noticed some of you have written a standard dose, Is it applicable in CKD and transplant patients?
No, as dose needed to be modified according to GFR
Moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily)
Severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily)
End-stage renal disease (ESRD) (RBV, 200 mg daily)
Normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily).
Reference
Brennan BJ, Wang K, Blotner S, Magnusson MO, Wilkins JJ, Martin P, Solsky J, Nieforth K, Wat C, Grippo JF. Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment. Antimicrob Agents Chemother. 2013 Dec;57(12):6097-105. doi: 10.1128/AAC.00608-13. Epub 2013 Sep 30. PMID: 24080649; PMCID: PMC3837852.
Need to lower dose if serum creatine is >2 mg/dl (200mg-400mg)
Reference
Ribavirin Dose Modification Based on Renal Function Is Necessary to Reduce Hemolysis in Liver Transplant Patients With Hepatitis C Virus Infection Asbok B. Jain, Bijan Eghtesad, Raman Venkataramanan, Pauh A. Fontes, Randeep Kitshyup,Igor vorchik, A. 0baid hakil, Leah Kingery, and John Fung
Your reference is incomplete and not in Vancouver style.
thank you prof for the comment, here is the reference in vancouver style,
Jain AB, Eghtesad B, Venkataramanan R, Fontes PA, Kashyap R, Dvorchik I, Shakil AO, Kingery L, Fung JJ. Ribavirin dose modification based on renal function is necessary to reduce hemolysis in liver transplant patients with hepatitis C virus infection. Liver Transpl. 2002 Nov;8(11):1007-13. doi: 10.1053/jlts.2002.36241. PMID: 12424713.
What are the side effects of ribavirin?
What is the standard dose and factors affecting dosing prescription ?
The drug is supplied in a 200 mg capsule, standard dose is 600-1000 mg daily depending on the weight of the patient
The dose should be also adjusted according to creatinine clearance, so serum creatinine should be monitored every month till stopping the treatment
After the start of treatment, we have to check for CBC, every month till stopping treatment
References
1- Uptodate
That is a comprehensive reply on dosage of ribavarin
Thanks, Sherif for the comprehensive answer. I will circulate it.
The dose of ribavirin is 200 mg 8 hourly. It is contraindicated in patients with an eGFR of less than 50 mls/min
The side effects of ribavirin include: fatigue, headaches, hemolysis (important to do regular complete blood counts, myalgia, fevers, rigors, nausea, vomiting.
SHort and sweet
What are the side effects of ribavirin?
The side effects of ribavirin include hemolytic anemia, sleeping disorders, neuropathy, mood disturbances, and reduction in creatinine clearance (1,2).
What is the dose of this drug in a transplant patient and how would you adjust the dose?
There is no consensus on the drug dosage to be used in transplant patient with wide variation (200-1200 mg/day, with median of 600 mg/day). The daily doses which have been proposed on the basis of creatinine clearance (as per Cockcroft Gault equation) are 1000 mg (100 ml/min), 800 mg (80 ml/min), 600-800 mg (60 ml/min), 600 mg (40 ml/min), and 400 mg (20 ml/min) per day (3). The median dose of initiation of ribavirin for HEV treatment has been 8.1 mg/kg/day in a study (4).
Dose of ribavirin needs to be modified if the hemoglobin falls below 10 g/dl (3).
I have noticed some of you have written a standard dose, Is it applicable in CKD and transplant patients?
No. The dose of ribavirin needs to be modified as per the creatinine clearance (3).
References:
That is a comprehensive reply on dosage of ribavarin well-supported by published evidence
Optimal dosing has not been established: typically 600 to 800 mg/day (range: 400 mg to 1 g/day) in 1 to 2 divided doses
(De Winter 2018; Kamar 2020; Protin 2019; Rivero-Juárez 2020; Tavitian 2015).
Optimal duration is unknown, but is typically ≥3 months based on virologic response
(AST-IDCOP [Te 2019]; EASL 2018; Kamar 2020; Rivero-Juárez 2020; Tavitian 2015).
Renal impairment dosage
Rebetol capsules/solution, Ribasphere capsules:
CrCl ≥50 mL/minute: No dosage adjustments necessary.
CrCl <50 mL/minute: Use is contraindicated.
Moderiba and Ribasphere tablets:
CrCl >50 mL/minute: No dosage adjustments necessary.
CrCl 30 to 50 mL/minute: Alternate 200 mg and 400 mg every other day.
CrCl <30 mL/minute: 200 mg once daily.
ESRD requiring hemodialysis: 200 mg once daily.
Note: According to the manufacturer, the dose of Moderiba and Ribasphere should not be further modified in patients with renal impairment.
If severe adverse reactions or laboratory abnormalities develop, it should be discontinued.
Some experts recommend a lower starting dose of ribavirin (ie, 200 mg 3 times weekly), along with close monitoring of hemoglobin and hematocrit and use of erythropoietin therapy, in patients with eGFR <30 mL/minute/1.73 m2 or those on dialysis
(KDIGO 2018; Leise 2019).
——————————————————
Side effects
>10%: common side effects
Dermatologic:
• Alopecia ,
• dermatitis
• diaphoresis
• pruritus
• skin rash
• xeroderma
Endocrine & metabolic:
●Growth retardation (children and adolescents: )
●hyperuricemia
,● weight loss
Gastrointestinal:
●Abdominal pain
●anorexia,
●diarrhea
●dyspepsia
●nausea
●upper abdominal pain
●vomiting
Hematologic & oncologic: Anemia
●hemolytic anemia
● lymphocytopenia
●neutropenia
Hepatic:
●Hyperbilirubinemia
Infection:
●Viral infection
Local:
Erythema at injection site
Nervous system:
●Anxiety
●chills
●depression
●fatigue
●headache ,
●insomnia ,
●irritability
● lack of concentration nervousness
Neuromuscular & skeletal: Arthralgia
●musculoskeletal pain
●myalgia
Respiratory:
●Cough
●dyspnea
●flu-like symptoms
●pharyngitis
●sinusitis,
●upper respiratory tract infection
1% to 10%: less common side effects
Cardiovascular:
●Chest pain,
●flushing
Dermatologic:
●Eczema
Endocrine & metabolic: Hypothyroidism ,
●menstrual disease
Gastrointestinal:
● Constipation
●decompensated liver disease
Hepatic:
Hepatomegaly
●increased serum ALAT
Infection:
●Bacterial infection
●fungal infection
Ophthalmic:
●Blurred vision
● conjunctivitis
.
Thanks, Ghalia
Median dosage 600mg/ day. Dose adjustment accordingly ( body weight and creatinine clearance)
side effects:
General GIT / non specific such as : acidic gastritis,belching, taste change, diarrhea Skin : dermatitis , irritation, itching.pancytopeniahaemolytic anemiateratogenic effects on pregnancy
Thanks, See my answer above. Please expand your answer.
Side effects
Dose
Dose adjustment
Source: BTS guidelines 2017
Thanks, Ben
Thnxs prof
What are the side effects of ribavirin?
What is the standard dose and factors affecting dosing prescription ?
The drug is supplied in a 200 mg capsule, standard dose is 600-1000 mg daily depending on the weight of the patient
The dose should be also adjusted according to creatinine clearance, so serum creatinine should be monitored every month till stopping the treatment
After the start of treatment, we have to check for CBC, every month till stopping treatment
References
1- Uptodate
Curtesy: Dr Sherief Yousef
Ribavirin dose range from 600-1000mg daily depending on the patient’s weight.
the dose should be adjusted according to creatinine clearance
if crcl>50 ml/min no dose adjustment
crcl30-50 ml/min 200 mg alternative with 400 mg every other day
<30 ml/min 200mg po od
follow up by CBC monthly if Hb <8.5 g/dl stop ribavirin permanent
if WBC<1,000 neutrophils <500 platelets less than 50,000 should stop permanent
S/E
1- haemolytic anaemia.
2- worsening cardiac events
3- teratogenicity in pregnant
4- GIT side effects
5-skin side effects such as pruritis and skin rash
reference
UpToDate
What are the side effects of ribavirin?
· Acid or sour stomach.
· being forgetful.
· belching.
· bone pain.
· change in taste or bad, unusual, or unpleasant (after) taste.
· cracked, scaly skin.
· crusting, irritation, itching, or reddening of the skin.
· difficulty with moving.
· The most frequent side effect of ribavirin is a haemolytic anaemia
What is the dose of this drug in a transplant patient and how would you adjust the dose?
Dosage forms: oral capsule (200 mg), oral solution (40 mg/mL), oral tablet (200 mg; 200 mg-400 mg; 400 mg; 400 mg-600 mg; 600 mg)
· To date, all the reported studies have used variable dosing ranging from 200 mg to 1200 mg per day with a median dosage of 600 mg/day.
Is it applicable in CKD and transplant patients?
The pharmacokinetics of ribavirin are variable in transplant recipients and clearance depends particularly on renal function
References
1. Peters van Ton AM, Gevers TJ, Drenth JP. Antiviral therapy in chronic hepatitis E: a systematic review. J Viral Hepat 2015; 22: 965-73.
2-Lhomme S, Kamar N, Nicot F, et al. Mutation in the hepatitis E virus polymerase and outcome of ribavirin therapy. Antimicrob Agents Chemother 2016; 60: 1608-14.
3- Pischke S, Hardtke S, Bode U, et al. Ribavirin treatment of acute and chronic hepatitis E: a single-centre experience. Liver Int 2013; 33: 722-6.
Ribavirin, previously combined with IFN-gamma to treat HCV, was reported being successful in the management of HEV. It should be used with caution because of the risk of hemolysis, especially in those with anemia and CKD. It is teratogenic. In CKD patients uptodate.com with suggested doses according to manufacturers but in general may experts suggest using lower dose with caution
Rebetol capsules/solution, Ribasphere capsules:
CrCl ≥50 mL/minute: No dosage adjustments necessary.
CrCl <50 mL/minute: Use is contraindicated.
Moderiba and Ribasphere tablets:
CrCl >50 mL/minute: No dosage adjustments necessary.
CrCl 30 to 50 mL/minute: Alternate 200 mg and 400 mg every other day.
CrCl <30 mL/minute: 200 mg once daily.
ESRD requiring hemodialysis: 200 mg once daily.
———–
https://www.uptodate.com/contents/ribavirin-systemic-drug-information?search=ribavirin%20renal%20dose&topicRef=9860&source=see_link#F50990451
What are the side effects of ribavirin? (1-4)
– hemotaologic: –
– GI: abdominal pain, anorexia, diarrhoea
– hepatic: hyperbilirubinemia
– infection: viral infection
– dermatologic: alopecia, pruritus, skin rash
– endocrine/ metabolic: hyperuricemia
– contraindicated in pregnancy – associated with teratogenicity
What is the dose of this drug in a transplant patient and how would you adjust the dose? (1-4)
– typical ribavirin dose: 200mg every 8hours for 12 weeks based on virological response
– optimal dosing has not been defined: typically 600-800mg/day
– optimal duration: typically, ≥3months based on virological response
– adjust dose according to kidney function
eGFR >50: no dose adjustment
eGFR 30-50: alternate 200mg and 400mg every other day
eGFR <30 or on HD: 200mg/d
– closely monitor hemoglobin and hematocrit, use erythropoietin in patients with eGFR <30 or those on HD
– discontinue ribavirin if Hb <8.5, WBC <1,000, platelets <50
– once a laboratory abnormality or clinical adverse event has resolved, restart ribavirin at 50% of the full dose
Please substantiate your answer.
References
1. Rivero-Juarez A, Vallejo N, Lopez-Lopez P, Díaz-Mareque AI, Frias M, Vallejo A, et al. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms. 2019 Dec 26;8(1). PubMed PMID: 31888090. Pubmed Central PMCID: PMC7022260. Epub 2020/01/01. eng.
2. Lhomme S, Marion O, Abravanel F, Izopet J, Kamar N. Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections. Journal of clinical medicine. 2020 Jan 24;9(2). PubMed PMID: 31991629. Pubmed Central PMCID: PMC7073673. Epub 2020/01/30. eng.
3. De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacological research. 2018 Apr;130:308-15. PubMed PMID: 29499270. Epub 2018/03/03. eng.
4. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
SE OF RIBAVIRIN;
>10%
1-10%
DOSAGE;
eGFR .>60 – 600-800mg
eGFR 40-60 – 600mg
eGFR 20-40 – 400mg
eGFR <20 – Not indicated.
REF;
BTS Guidelines – 2017.
Side effects
Dose
Dose adjustment
Source: BTS guidelines 2017
Thank you prof.
Side effect of ribavirin: Haemolytic anaemia
Dose of ribavirin according to creatinine clearance:
Ccr(ml/min) Dose(mg/day)
100…………………… 1000
80..,..,…………………..800
60……………………….600 – 800
40………………………..600
20.………………………..400
Q1: side effects include: dermatitis or skin rash. Hyperuricemia, growth retardation, GI side effects such as anorexia, abdominal pain, diarrhea, nausea, hemolytic anemia, lymphocytopenia, neutropenia, and hyperbilirubinemia viral infection.
Q2: optimal dose varies between 600 to 800 mg/day in 1 to 2 divided doses for more than three months based on virus PCR response. Ribasphere tablets dose for Cr Cl>50 ml/min doesn’t need adjustments.
Cr Cl 30-50 ml/min: alternate every other day 200 mg and 400 mg
Cr Cl<30 ml/min and HD patients: 200 mg daily
History and examination to role out chronic hepatitis
Serial Laboratory investigations of liver enzymes and blood count and HEV RNA in plasma and stool
Start ribavirin 600 mg once a day for 12 weeks with monitoring drug level and sign of organ rejection and blood count for hemoglobin level
Reducing immunosuppressive therapy especially tacrolimus to lower level and keep steroid dose and MMF dose with previous same dose.
If persistent infection considering interferon but should be carful regarding organ rejection.
Serial monthly test for HEV antigen in stool and blood, once negative consider stop ribavirin.
Prevalence of HEV infection is higher in organ transplant reach to 20.3%.
HEV is transmitted by the fecal-oral route, infection is more prevalent in areas with poor water quality and food contamination.
Prevalance of Hep E is too high at 20.3%. What is the source of this information?
1. A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. He was on prednisolone, MMF, and tacrolimus. During the first 1.5 years after transplantation, he developed CMV reactivation, primary EBV infection, and BK-virus viremia. Almost 3 years after transplantation at a routine check-in 2011, ALT (94 U/L) and AST (55 U/L) were found to be elevated. Kidney function was stable with an eGFR of 80 mL/min. Liver enzymes remained slightly increased in 2012 and 2013. No clear relation could be found with drugs. HCV and HBV PCR were negative. Repeated testing for BK, EBV and CMV DNA was negative. After temporary normalization, liver enzymes increased again with an ALT of 117 U/L. At that point, HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analysed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
Issues/ concerns
– 35yo, CKD5, HUS, DBD kidney transplantation in 2008
– Tacrolimus, MMF, prednisone
– developed CMV reactivation, primary EBV infection, BKV viremia during the first 1.5years
– in 2011 noted elevated ALT (94) & AST (55)
– stable kidney function eGFR 80
– liver enzymes remained slightly elevated in 2012 and 2013
– drug history unremarkable to explain the elevated liver enzymes
– HCV PCR, HBV PCR – negative
– repeat BKV DNA, EBV DNA, CMV DNA – negative
– liver enzymes normalized temporarily then increased again ALT (117)
– HEV PCR – positive, genotype3
– archived blood samples anti-HEV IgM positive and IgG negative in the first HEV RNA positive sample in 2011, later anti-HEV IgG became positive
– Hepatitis E virus (HEV) causes a self-limited viral hepatitis
– 4 genotypes are known to infect man
– HEV is transmitted through contaminated food and water, blood transfusions, mother-to-child transmission
How would you manage this case?
– multidisciplinary approach – infectious disease specialist, gastroenterologist, virologist
– detailed history – intensity of immunosuppressive therapy, nausea, vomiting, fever, abdominal pain, anorexia, malaise, diarrhoea
– thorough physical examination – hepatomegaly, jaundice, urticarial rash
– most patients spontaneously clear the virus
– chronic HEV has been described mostly in immunocompromised hosts, it is defined as detection of HEV RNA in serum or stool for more than 6 months
– baseline investigations: – HEV RNA test done to confirm the diagnosis
– HEV RNA assay should be performed in both serum and stool
– for HEV RNA to be regarded as absent both stool and serum assays should be negative however for HEV RNA to be reported as present it should be detectable in either serum or stool
– management of acute HEV infection is usually supportive since the disease is mild and self-limiting in immunocompetent patients
– management of chronic HEV infection in SOT recipients on immunosuppression involves: – (1-3)
1st pathway –
2nd pathway –
What is the prevalence of HEV in solid organ transplantation? (4, 5)
– among SOT recipients, the pooled estimated prevalence of acute HEV infection was 4.3% (4)
– among kidney transplant recipients, prevalence of HEV RNA increased from 19% (pre-transplant) to 26% (post-transplant) (5)
References
1. Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, et al. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011 May;140(5):1481-9. PubMed PMID: 21354150. Epub 2011/03/01. eng.
2. Khuroo MS, Khuroo MS. Hepatitis E: an emerging global disease – from discovery towards control and cure. Journal of viral hepatitis. 2016 Feb;23(2):68-79. PubMed PMID: 26344932. Epub 2015/09/08. eng.
3. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
4. Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World journal of gastroenterology. 2021 Mar 28;27(12):1240-54. PubMed PMID: 33828397. Pubmed Central PMCID: PMC8006097. Epub 2021/04/09. eng.
5. Lim MA, Kamili S, Cohen JB, Green-Montfort T, Tejada-Strop A, Kohli J, et al. Hepatitis E Virus Infection in Kidney Transplant Patients: A Single-Center Study. Transplantation. 2018;102(4):e126-e7. PubMed PMID: 00007890-201804000-00012.
Thank you .
what are the follow up for Ribavirin side effects and how to deal with them?
What are the side effects of ribavirin? (1-4)
– hematologic: –
– GI: abdominal pain, anorexia, diarrhoea
– hepatic: hyperbilirubinemia
– infection: viral infection
– dermatologic: alopecia, pruritus, skin rash
– endocrine/ metabolic: hyperuricemia
– contraindicated in pregnancy: associated with teratogenicity
References
1. Rivero-Juarez A, Vallejo N, Lopez-Lopez P, Díaz-Mareque AI, Frias M, Vallejo A, et al. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms. 2019 Dec 26;8(1). PubMed PMID: 31888090. Pubmed Central PMCID: PMC7022260. Epub 2020/01/01. eng.
2. Lhomme S, Marion O, Abravanel F, Izopet J, Kamar N. Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections. Journal of clinical medicine. 2020 Jan 24;9(2). PubMed PMID: 31991629. Pubmed Central PMCID: PMC7073673. Epub 2020/01/30. eng.
3. De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacological research. 2018 Apr;130:308-15. PubMed PMID: 29499270. Epub 2018/03/03. eng.
4. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. The New England journal of medicine. 2014 Mar 20;370(12):1111-20. PubMed PMID: 24645943. Epub 2014/03/22. eng.
· This patient has persistent positive HEV RNA -elevated liver enzyme (Chronic HEV infection )
· Treatment with antiviral ribavirin for at least 3 month
· Monthly HEV RNA testing in plasma and stool until a decision is made to stop treatment.
· the aim of treatment is achieving sustained virological response (HEV RNA not detected in plasma and stool six months after completion of treatment)
· Regular haemoglobin monitoring during ribavirin therapy as haemolytic anaemia is a common treatment-related side effect.
· Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV tacrolimus mainly
In A systematic review and meta-analysis (n = 4557)
the pooled estimated prevalence of HEV infection in SOT patients was 20.2%
The pooled estimated prevalence of HEV infection for each organ transplant was as follows: liver 27.2%
kidney 12.8%
heart 12.8%
and lung 5.6%
Thankyou.
Management
Patient had positive anti HEV IgM first and then anti HEV IgG positive later. Anti HEV IgM remains detectable for unto 6 months from the onset of symptoms, while anti HEV IgG persists for many years after infection. IgM is the serological marker for acute HEV infection.
Increased liver enzymes, and high level of antibodies in immunocompromised patient is indicative of chronic HEV infection. This is partly why clinical workup on noticing increased liver enzymes should include testing for HEV infection irrespective of IgG HEV status because anti HEV IgG presence may not be protective unconditionally.
Treatment can be done using ribavirin for chronic HEV infection. Therapy can be done for 12 weeks with monitoring, but can continue unto 24 weeks if there is detectable level of viral load in plasma, serum or feces at week 12.
Reduction or change in immunosuppressive regimen is to be considered, but the antiviral therapy is the most important in HEV infection resolution. This patient is on tacrolimus. Tacrolimus dose reduction may benefit the patient and help in infection resolution. However, this is to be done carefully, since the time between initiation of dose reduction of immunosuppression and the time of infection resolution may well be upto 1 year. This can increase the chances of graft rejection.
Switching from tacrolimus to cyclosporine can be considered.
Prevalence of HEV in SOT
There is high prevalence of HEV in solid organ transplant, mainly liver and kidney. Antiviral therapy as prophylaxis needs to be given upto 6 months to prevent incidence of infection, which includes drugs such as ganciclovir.
anti HEV IgM is seen in serum first, upon onset of symptoms, followed by HEV IgG which can last from 12 months to several years. The former lasts upto 6 months and indicates acute or current infection. Even if the patient has high detectable levels of HEV IgG, there can be infection reactivation in the patient or reinfection, i.e., de novo infection. Clinical vigilance is needed to identify chronic infection as there can be fluctuation in positivity of tests. Silent or subclinical infections are common, much more than active disease after IgG develops within the first 12 month period. This may become a problem in the future.
Numbers and statistics
In terms of numbers, acute HEV infection can be seen in 10% patients in Middle East. HEV IgG seroprevalence in liver transplant recipients is seen from 3-28%, with a serum RNA detection rate of 0-2%, and incidence of chronic hepatitis E upto 3% in Europe and North America.
Global anti HEV IgG seroprevalence has been found to be 12.5%. Risk factors for anti HEV IgG positivity were found to be raw meat, exposure to soil, blood transfusion, traveling to endemic areas, contacting with infected animals, and rural area habitation.
The pooled estimated prevalence of HEV infection for each solid organ transplant is below :
References
Thankyou, you quoted that antiviral prophylaxis by Gancyclovir!!! can you give a reference for that.
your appreciation of the time lapse between reduction of IS and SVR with risk of rejection is wise.
This case reflects the importance of HEV as one of the differential diagnoses in patient with elevated liver enzymes without obvious cause. Specially when HBV and HCV screening are negative.
After confirming the diagnosis:
Monitoring of liver enzymes and HEV RNA is important as up to 34% of cases may clear the infection without specific treatment. Another 21% may clear the virus with a reduction of immunosuppression.
So, more than half of the patient cleared the infection without specific anti viral treatment. So initial management should be monitoring HEV RNA and liver enzymes with reduction of immunosuppression. If no improvement within 3months, then consideration for anti viral treatment is needed.
Modifications of immunosuppression can cleat up to 30% of cases in some series.
Steroid and CNI can increase virus replications and MMF, interestingly, was found to inhibit vital replications. So lowering level of CNI and steroid to the minimum possible 2.5mg to 5mg od could help in clearing the virus.
Anti-virus therapy:
Ribavirin is a guanosine analogue and may also act as a nucleoside inhibitor,
inhibiting replicating HEV RNA. A sustained virological response (serum HEV RNA negative six months after treatment) was achieved in 78% of cases in one study. 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
HEV genotype 1 &2 are common in developing countries, reaching 50% of cases of hepatitis. Where is genotype 3 and 4 are more common in developed countries.Also, prevalence differs between countries and different organs. In one systemic review included more than 4500 cases, it was found that the pooled prevalence in all organs was 20.2% and in individual organ was as follow:
Liver 27.2%.
Kidney 12.8%.
Heart 12.8%.
Lung 5.6%.
References:
1-World J Gastroenterol 2021 March 28; 27(12): 1240-125 Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis.
2-Guidelines for Hepatitis E & Solid Organ Transplantation British Transplantation Society Guidelines 2017.
3-Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation, Immun Inflamm Dis. 2021;1–8.
Thank you well done. Your recommendation of immunosuppression reduction you referred to the preferential reduction of steroids and CNI. You have to be very cautious especially with high immunological risk recipients. The approach is usually to reduce antimetabolite first in case it’s needed.
How would you manage this case?
This patient has HEV infection post kidney transplantation evidenced by deranged liver enzymes that were steadily rising and positive HEV RNA. Retrospectively HEV RNA and IgG and IgM anti-HEV were first positive in 2011, hence this patient has persistent infection.
Persistent HEV infection mainly occurs in individuals who are heavily immunosuppressed mainly with T cell depleting agents.
CNI and MTOR may contribute to the persistence of HEV in hepatocytes hence persistent infection. MMF inhibits HEV replication while steroids have no effect.
1.The CNI should be reduced with close monitoring of UECS due to risk of rejection.
Reduction of immunosuppression may lead to clearance of infection in 30% of individuals.
2.Antivirals- Ribavarin a guanosine analogue which acts as a nucleoside inhibitor can be used.
However its optimal dose and duration is not known.
Should be continued until 2 stool and plasma tests are negative for HEV RNA.
Most common adverse effect of ribavarin is hemolytic anaemia thus regular monitoring of blood counts is required.
3.Other treatment options:
What is the prevalence of HEV in SOT?
A meta analysis reported a pooled prevalence of 20%, with high prevalence in liver and kidney recipients and low in lung recipients.
However prevalence is mainly determined by the geographical location, with genotype 1 and 2 more prevalent in developing countries while genotype 3 and 4 in developed countries.
References
Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis
Panupong Hansrivijit, Angkawipa Trongtorsak, […], and Wisit Cheungpasitporn
Kamar N, Bendall R, Legrand-Abravanel F, et al. Hepatitis E. Lancet. 2012 Jun 30;379(9835):2477-88.
Guidelines for Hepatitis E & Solid Organ Transplantation First Edition Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report Marcus Panning1*, Kristi Basho1, Andreas Fahrner2 and Christoph Neumann-Haefelin3
Thank you for your answers. I quote from your answer ‘Should be continued until 2 stool and plasma tests are negative for HEV RNA’. Haemolytic anaemia is one of the main side effects of ribavirin. Many of those who are treated may require EPO injections. Therefore you should mention the interval between the two stool samples that is adequate to stop Ribavirin treatment.
Thank you prof.
The interval of the 2 negative plasma and stool should be one month apart.
The ribavirin should be given for at least 3 months with maximum duration of 6 months.
If no response after 6 months should be considered to be ribavirin refractory.
How would you manage this case?
Ribavirin:
Pegylated interferon-alfa:
Sofosbuvir (polymerase inhibitor of HCV):
=================================
What is the prevalence of HEV in solid organ transplantation?
Prevalence in SOT:
References
How would you manage this case?
Diagnosis -chronic HEV occurring post kidney transplantation.
Treatment
Reduction of Immunossupresion treatment
Reduce dose of tacrolimus and steroids and continue MMF in same dose
Close follow up of serum creatinine as liver enzyme.
Monitor the patient for 3 months
See for Serum and stool HEV RNA clearance- if no clearance then start antiviral.
Antiviral Therapies
Ribavirin(600-800 mg/day), the dosage is adjusted according to creatinine clearance.
Liver enzymes (for response) and CBC (for side effects) should be closely monitored.
Duration of treatment of ribavirin should be 3 months
Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
If relapse occur after ceasing Ribavirin
Need to give it for 6 months
No response of ribavirin in 6 month or intolerance to ribavirin or relapse after 6 months ribavirin
Then need to give pegylated interferon alpha(no preferable as there is high chance of rejection)
What is the prevalence of HEV in solid organ transplant?
The prevalence of HEV infection is higher in SOT patients (20.1% vs 12.5%) compared to non- transplant.
prevalence of de novo HEV infection in SOT recipients was 5.1%
The HEV seropositivity was significantly higher among transplant-recipients compared with waitlist patients (24% vs. 16.4%,
1)Lecture : May A Hassaballa HEV in kidney transplant
2)Kamar N, Lhomme S, Abravanel F, Marion O, Peron J-M, Alric L, Izopet J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses. 2016; 8(8):222. https://doi.org/10.3390/v8080222
3)Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, Farci P, Ghabril M, Lucey MR, Rangnekar AS, Reddy KR, Ghany MG. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec;29(12):1134-1142. doi: 10.1111/jvh.13739. Epub 2022 Sep 21. PMID: 36036116.
4)Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
Thankyou, is this a de novo infection ?
Thank you Prof for the question. It look like the De novo infection because retrospectively, archived blood samples were analyzed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.and he had undergone transplant on 2008
The index patient is a 35-year-old cadaveric donor renal transplant recipient (October 2008, basic disease HUS) with history of multiple infections (BK virus, cytomegalovirus, Epstein Barr virus) in first 18 months post-transplant, currently on tacrolimus based triple drug immunosuppression with stable graft function.
In 2011, patient developed elevated liver enzymes, which increased in 2012 after initial normalization. HEV evaluation in 2013 revealed a positive test, with genotype 3. Retrospective analysis revealed HEV RNA and anti-HEV IgM positivity in 2011, with development of anti-HEV IgG later.
The clinical scenario pertains to persistent HEV infection post-transplant (HEV positivity for > 3 months). 60% of genotype 3 HEV infections in SOT lead to persistent HEV infection (1)
The management in this scenario includes (1,2):
The pooled prevalence of HEV infection in solid organ transplantation (SOT) in a meta-analysis has been found to be 20.2% (14.9-26.8%). The prevalence in different organs ranged from 27.2% (liver), 12.8% (kidneys and heart) to 5.6% (lung) depending on the organ involved (4). The prevalence is 2 times more in middle-income countries as compared to high-income countries (4,5). The pooled estimated prevalence of de novo HEV infection ranged from 2.6% to 9.6%. The pooled prevalence of acute HEV infection is 4.3% (4). Another study revealed 24% prevalence of HEV in transplant recipients (6). The prevalence was higher in old aged, use of CNI, graft hepatitis history, and renal transplant recipients (6).
References:
Thank you Professor.
Detailed history includes dietary history (history of consumption of raw/undercooked meat – pork products) and history of blood transfusion.
The need of looking for extrahepatic manifestations is because their presence would require early treatment with Ribavirin.
Examples include: thrombocytopenia (bleeding), acute pancreatitis (pain abdomen), neurological involvement (vestibular neuritis, peripheral neuropathy), etc.
· 35 – Years who had DBD kidney transplant 2008.
· 2011 he had increased liver enzymes and remained slightly raised during 2012 and 2013.
· Liver enzymes increased again after temporal normalization.
· This time HEV was found positive. It was genotype 3.
· Retrospectively HEV RNA was first positive in 2011 anti HEV IgM was positive and IgG was negative.
· Later on also HEV IgG became positive.
How would you manage this case?
This is a case of chronic HEV occurring post kidney transplantation.
Diagnosis
· This patient had raised liver enzymes in 2011, HCV, HBV PCR were negative and no clear relation could be found related to drugs.
· HEV RNA was found to be positive retrospectively in 2011 together with ant HEV IgM. So HEV RNA is estimate to be positive for more than 3 months.
· The patient developed acute infection in 2011and later on developed humoral immunity to the virus.
Treatment
1. Reduction of IS treatment:
· Reduce dose of tacrolimus and steroids and keep MMF.
· All data suggest that patients that are heavily immunosuppressed have a high risk of developing a chronic infection.
· That the majority of immunosuppressive drugs increase HEV replication except mycophenolic acid can decrease HEV replication in vitro.
· It was observed that HEV clearance occurred in 30% SOT patients with chronic HEV infection after reducing immunosuppressive therapies that principally targeted T-cells.
· With reduction of IS therapy, close follow up of serum creatinine as AR is a possibility.
2. Antivral Therapies
· He should receive treatment with ribavirin, the dosage is adjusted according to creatinine clearance.
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment, monthly during treatment.
· Liver enzymes (for response) and CBC (for side effects) should be closely monitored.
· Duration of treatment with of ribavirin should be 3-6 months.
· Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
· Sustained virological response is achieved when HEV RNA is not detected in plasma and stool for six months after completion of treatment.
What is the prevalence of HEV in solid organ transplant?
· HEV route of transmission via the fecal-oral route is similar to hepatitis A virus, patients with poor hygiene are predisposed to both hepatitis A and hepatitis E infection.
· It can be concluded that the prevalence of HEV infection is higher in SOT patients (20.1% vs 12.5%) compared to non- transplant.
· The prevalence of acute HEV infection was also higher in SOT patients compared to non-transplant patients (4.3% vs 1.5%).
· HEV has been noted to impact solid organ transplant recipient outcomes. HEV infection has been documented to cause graft cirrhosis and subsequent failure in liver graft recipients secondary to chronic infection.
· Renal transplant allografts were found to have similar rejection and two year graft survival between HEV seropositive and negative recipients.
· Case reports describing the occurrence of HEV in liver transplant recipients who receive an allograft with latent disease.
· Once infected with the virus, transplant recipients are at risk for developing chronic liver disease, especially with HEV genotype.
· The seroprevalence of anti-HEV IgG could be affected by the assays used for antibody testing.
· It is also found that the prevalence of HEV infection was significantly higher in middle-income countries compared to high-income countries.
· The seroprevalence of anti-HEV IgG was at least two-fold higher in Africa and Asia in comparison to Europe and North America.
References:
1. Guidelines for Hepatitis E & Solid Organ Transplantation, BTS, First edition.
2. Nassim Kamar et al, Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
3. Panupong Hansrivijit, et al, Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis, March 28, 2021 Volume 27 Issue 12.
Thank you Mannoli and well done. Do you think that hyou start with reducing tacrolimus and keep MMF? Can you please quote the reference for this statement?
Because of untoward side effects from Ribavirin most patients do not withstand 6 month of treatment and usually the Ribavirin stopped before you reach the full course
Thank you professor Mohsen El Kossi,
“It was also demonstrated that calcineurin inhibitors (CsA and FK506) promoted HEV infection. In fact the use of FK506 was found to be the main predictive factor for chronic hepatitis E in organ recipients in another study by Kamar et al[16,18]. On the other hand mycophenolic acid/mycophenolate mofetil (MPA/MMF) suppressed viral infection in replica model. The clinical benefit was demonstrated in heart transplant recipients where MMF containing regimens were assumed to play a role in more frequent HEV clearance”.
Reference:
Avin Aggarwal, et al, Hepatitis E virus infection in the liver transplant recipients: Clinical presentation and management. January 18, 2016|Volume 8|Issue 2|
How would you manage this case?
This is chronic HEV infections which have been G3 ,it manifested as high liver enzymes three years after transplant and remains high 2years after ,investigated and diagnosed as HEV infection through positive HEV PCR (after exclude HCV and HBV).
After establish the diagnosis by taking history and examination .
Investigation by CBC ,RFT,LFT ,URINE ANALYSIS ,LDH ,and HEV PCR as base line .
CXR and abdominal US.
Treatment observation and monitoring of HEV RNA levels and liver enzymes (30% will spontaneously clear the infection within three months).
reduction in immunosuppression.
the risk of rejection should be carefully assessed.
Treatment with ribavirin 600 mg for three to six month till HEV RNA not detected in plasma and stool six months after completion of treatment.
Monthly HEV RNA testing in plasma and stool.
We continue ribavirin till stool test for HEV RNA negative in two occasions .
Monitoring the HB during treatment (haemolytic anemia from RIBAVIRIN.) and GFR .
Ribavirin
is an antiviral medication that has been used for many years in combination with pegylated
interferon for the treatment of hepatitis C. The exact mechanism of antiviral activity of
ribavirin is unknown. Ribavirin has been shown to reduce HEV replication in vitro by reducing intracellular pools of GTP.
In persistent HEV who were treated with ribavirin for three months. In that study, the overall SVR(sustained virological response ) rate was 63% . It remains unknown what the optimum dosage of ribavirin is for the treatment of persistent HEV.
Interestingly, one small study found no relationship between ribavirin levels at day seven and
outcomes from treatment in patients with persistent HEV.
The most frequent side effect of ribavirin is a haemolytic anaemia, which required intervention in approximately 40%.
Approximately 40% of transplant recipients with persistent HEV relapse after three months of treatment with ribavirin.
PEG-interferon.
treatment in cases of ribavirin refractory HEV.
is well known to increase the risk of rejection in transplant recipients.
PEG-interferon is not recommended as a first line treatment for HEV.
Sofosbuvir
One recent study suggested the sofosbuvir inhibited HEV RNA replication in an experimental model of HEV.
What is the prevalence of HEV in solid organ transplantation?
The HEV seropositivity in transplant recipient is around 24%,
which is significantly higher than CKD patients who are waitlisted (16.4%).
HEV infection responsible for more than 50% viral hepatitis world wide.
References
1.Kamar N, Garrouste C, Haagsma EB, et al. Factors associated with chronic hepatitis in patients
with hepatitis E virus infection who have received solid organ transplants. Gastroenterology
2011; 140: 1481-9.
2.Abravanel F, Lhomme S, Rostaing L, Kamar N, Izopet J. Protracted fecal shedding of HEV during ribavirin therapy predicts treatment relapse. Clin Infect Dis 2015; 60: 96-9.
3. Kamar N, Lhomme S, Abravanel F, et al. An early viral response predicts the virological response to ribavirin in hepatitis E virus organ transplant patients. Transplantation 2015; 99: 2124-31.
4.Peters van Ton AM, Gevers TJ, Drenth JP. Antiviral therapy in chronic hepatitis E: a systematic review. J Viral Hepat 2015; 22: 965-73
5.Dao Thi VL, Debing Y, Wu X, Rice CM, Neyts J, Moradpour D, Gouttenoire J. Sofosbuvir Inhibits hepatitis E virus replication in vitro and results in an additive effect when combined with
ribavirin. Gastroenterology 2016; 150: 82-5.
6.
Hartl J, Otto B, Madden RG, Webb G, Woolson KL, Kriston L, et al. Hepatitis E Seroprevalence in Europe: a meta-analysis. Viruses. 2016;8(8)
Thank you. You referred to these investigations and missed a very important one in this case which is stool analysis for HEV PCR. Investigation by CBC ,RFT,LFT ,URINE ANALYSIS ,LDH ,and HEV PCR as base line. CXR and abdominal US.
How would you manage this case?
This patient developed denovo acute HEV in 2011 (3 years after transplantation) through diet (pork, G3). At that time HEV RNA was positive, anti-HEV IgM was positive and liver enzymes were high. No evidence of other viral infections and not drug-related
Acute Hepatitis E:
o Features range from asymptomatic infection to mild hepatitis to fulminant liver failure
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 Incubation period is 2-6 weeks (initial short-lived IgM response followed by IgG antibodies)
o If HEV RNA not cleared from the blood and stool by three months, persistent infection is likely to occur
o Following acute infection with HEV G3, the infection persists in approximately 60% of SOT recipients leading to persistent HEV infection
o Management includes observation and monitoring of HEV RNA levels and liver enzymes as more than 30% will spontaneously clear the infection within three months
o Treatment with ribavirin is indicated in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations
So, this patient developed persistent HEV (Chronic HEV infection) and should be treated
Chronic HEV infection:
o Detectable HEV RNA in the blood and/ or stool for greater than 3-6 months (treat after 3 months)
o The most common symptom
o Neurological symptoms can occur (also in acute HEV)
o Typically ALT levels are between 200-300 U/L (liver enzymes may be minimally raised or within the upper normal range)
Management:
o Modification of immunosuppression (Lead to clearance of HEV infection in 30%)
o Start 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)
o Do baseline quantitative HEV RNA on both plasma and stool at the start of treatment
o Treatment with ribavirin for at least three months (3-6 months for most patients)
o Do monthly HEV RNA testing in plasma and stool during treatment
o Continue ribavirin until stool tests are negative for HEV RNA on two occasions one month apart
o Do plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy (a test of sustained virological response)
o Regular haemoglobin monitoring during ribavirin therapy
o In relapse after a first course of ribavirin, re-treat for at least six months (higher dose)
o Treatmt with PEG-interferon treatment in ribavirin-refractory persistent HEV (close monitoring for rejection)
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
What is the prevalence of HEV in solid organ transplantation?
Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis
o The pooled estimated prevalence of HEV infection in SOT recipients was 20.2% The pooled estimated prevalence of HEV infection in each transplanted organ was: Liver (27.2%), kidney (15.3%), heart (12.8%), lung (5.6%), and undifferentiated (29.6%)
o The pooled estimated prevalence of de novo HEV infection in SOT recipients was 5.1%
o The pooled estimated prevalence of acute HEV infection in SOT recipients was 4.3%
References
1. Kamar, N.; Lhomme, S.; Abravanel, F.; Marion, O.; Peron, J.-M.; Alric, L.; Izopet, J. Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016, 8, 222.
2. Guidelines for Hepatitis E & Solid Organ Transplantation. British Transplantation Society Guidelines, 2017.
3. Panning, M., Basho, K., Fahrner, A. et al. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infect Dis 19, 675 (2019). Song JE, Kim DY. Diagnosis of hepatitis B. Ann Transl Med. 2016 Sep;4(18):338. doi: 10.21037/atm.2016.09.11. PMID: 27761442; PMCID: PMC5066055.
4. Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol 2021; 27(12): 1240-1254.
Thank you very much for such detailed answer. You are absolutely right that nearly all patients on Ribavirin will require dose reduction because of haemolytic anaemia and will need Epo injection. They rarely continue for 6 month treatment because of anaemia. Reducing immunosuppression with Ribavirin are always enough to clear the virus. The only concern in those patients who are high immunological risk who may develop rejection and those who are on dual immunosuppression when any immunosuppression reduction will carry high risk of rejection or sensitisation and development of DSA.
How would you manage this case?
This is a case of persistent HEV infection> 3 months detectable RNA.
1- detailed history and clinical examination
2- laboratories for , CBC, KFT, Urinalysis, LDH, liver function (albumin, INR), gamma GT, alkaline phosphatase, and bilirubin, and a quantitative stool HEV PCR(as baseline)
3- ultrasound abdomen, for any organomegaly, and CXR.
Treatment:
1- IS modulation :reduce TAC dose to the lowest that required to prevent rejection
2- Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 6 months after stopping the Ribavirin)
3- Adjust dose to GFR monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function.
4- Failure of treatment: repeat the course with high dose Ribavern but observe for side effect as above
5- in cases of ribavirin-refractory persistent HEV infection ,PEG-interferon treatment may be considered. However, it carries a risk of rejection.
Prevalence of HEV in SOT
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%
The pooled estimated prevalence of HEV infection for each organ transplant was as follows:
Liver : 27.2%
Kidney : 12.8 %
Heart : 12.8%
Lung 5.6%
I make note of your understanding about the need to modify immunosuppression when infected with Hep E, well-supported by literature.
This is a case of chronic HEV infection in a heavily immunosuppressed young individual as evident by the viral infection in the first 1.5 year.
The corner stone of management in liver, kidney, and heart transplant recipients are ribavirin antiviral therapy and reducing immunosuppression(1) But we need to consider the fact that changes in immunosuppression can precipitate rejection in more immunogenic individuals so the risk of rejection versus the potential benefits of modification of immunosuppression must be carefully balanced. This case of chronic infection with HEV G3 can progress rapidly (3-5 years) to cirrhosis in approximately 15% of infected solid organ transplant recipients. Chronic HEV infection is defined as the finding of detectable HEV RNA in the blood and/ or stool for greater than six months. Aim of treatment is clearing HEV from the blood and stool. persistent HEV infection is defined as documented or estimated duration of infection of greater that three months.
Data supporting reduction of immunosuppressants need more controlled trials to support this approach. Reduction of immunosuppression can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV. The data supporting this approach come from uncontrolled studies and case series.
Shifting from Tacrolimus to cyclosporin as high doses of Tacrolimus increased HEV replication in a cell culture model. One large study found that patients treated with ciclosporin were more likely to have spontaneous clearance than those treated with tacrolimus but it has been conducted in acute infection cases. Regarding mycophenolate, it inhibit HEV replication and this was potentiated with the addition of ribavirin. But one small study in established persistent HEV, reported no difference in the rate of HEV clearance in transplant recipients treated with ribavirin whether or not they were on mycophenolate. Corticosteroids had no effect on HEV replication. (2)
Ribavirin use was supported by kamar study. Based on that I would use ribavirin dose 600 mg, adjust dose according to creatinine clearance, for three months (range 1-18 months). Kamar study reported a sustained virological response in 78% of cases (serum HEV RNA negative six months after treatment).(3) Follow up of Hb level is mandatory as hemolytic anemia is a well-recognized side effect of ribavirin initially every two weeks until the hemoglobin has reached nadir then monthly thereafter. Dose reduction of ribavirin is recommended when the hemoglobin falls below 100 g/L.
A systematic review for use of ribavirin for persistent HEV found an overall sustained virological response rate of 74% with a wide variation in the dosage of ribavirin (200-1200 mg), length of treatment (median three month range 1-18) and duration of infection (median 16 month range 1-84).
Follow up is with the HEV RNA after 7 days, 1 month , 2 months and 3 months. The level at 7 days was an independent predictor of sustained virological response to ribavirin treatment. Thus, for a favorable response at day 7 the duration of ribavirin treatment is for three months and a longer course, such as six months can be applied for unfavorable day 7 response. Stopping of ribavirion can be considered at 3 months after 2 negative samples(both plasma and stool) with follow up samples at 3 and 6 months thereafter. If after 3 months there was appositive plasma or stool sample, then continue treatment till 2 stool samples are negative( 1 month apart) or continue for 6 months(2)
What is the prevalence of HEV in solid organ transplantation?
Southern France incidence of HEV among liver, kidney, or simultaneous kidney-pancreas transplantation was 3.2 cases/100 person-years . In UK, donors has a HEV-IgG seroprevalence rate of 16% but the incidence of HEV infection in transplant recipients is unknown.(4) In Europe and North America, HEV IgG seroprevalence in SOT and LT recipients ranges are from 3–28%, with a serum RNA detection rate of 0–2%.(5)
Ref:
1- Maximilian Carter, Kassandra Solsrud, Sirisha Yeddula, Mary Grace Fitzmaurice, Ashina Singh, Shunji Nagai, Syed-Mohammed Jafri, Hepatitis E Diagnosis and Management After Liver, Kidney, or Heart Transplant: A Single-Center Experience, Transplantation Proceedings, Volume 54, Issue 7, 2022, Pages 1737-1741,
2- Guidelines for Hepatitis E & Solid Organ Transplantation Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017 First Edition
3- Kamar N, Mallet V, Izopet J. Ribavirin for chronic hepatitis E virus infection. N Engl J Med 2014; 370: 2447-8
4- Vassallo D, Husain MM, Greer S, McGrath S, Ijaz S, Kanigicherla D. Hepatitis e infection in a renal transplant recipient. Case Rep Nephrol. 2014;2014:865471. doi: 10.1155/2014/865471. Epub 2014 Sep 11. PMID: 25295201; PMCID: PMC4177828.
5- Komolmit, P., Oranrap, V., Suksawatamnuay, S. et al. Clinical significance of post-liver transplant hepatitis E seropositivity in high prevalence area of hepatitis E genotype 3: a prospective study. Sci Rep 10, 7352 (2020)
I like your well structured detailed summary.
I appreciate your strategy in relation to Hep E infection and transplant. I make note of your understanding about the need to modify immunosuppression when infected with Hep E, well-supported by literature.
Management
– For this renal transplant recipient it is likely a chronic HEV hepatitis as retrospective serum samples testing at the year 2011 when liver enzymes increased ,it revealed Positive HEV RNA ,positive HEV Ig M and negative HEV Ig G.
Then with re elevation of the liver enzymes ,after temporary normalisation HEV RNA was tested positive
– Reduction of Tac, MMF and prednisolone doses at the same time the graft function needs close follow up due to rejection risk.
– Ribavirin treatment (dose is calculated according to creatinine clearance) for 3-6 months need to be started but with close monitoring of his CBC due to the history of HUS as main cause of ESRD, if anaemia occurred Ribavirin dose can be reduced ,along with HEV RNA testing
– A baseline quantitative HEV RNA level need to be detected in plasma and stool as treatment starts
– HEV RNA stool tests need to be negative on 2 occasions one month apart to achieve sustained virological response and stop Ribavirin therapy .
-The patient have to be counselled regarding avoidance of undercooked meat consumption
–Prevalence of HEV in solid organ transplantation
A metanalytical study, demonstrates the prevalence of HEV infection in SOT recipients was 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients).
The prevalence of HEV infection is 2-fold more common in middle-income countries compared to high-income countries.
Reference
-Guidelines for Hepatitis E & Solid OrganTransplantation. BTS guidelines 2018
– Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254.
I like your well structured detailed summary.
I appreciate your strategy in relation to Hep E infection and transplant.
Management of the case
This is the case of HEV reactivation.
Prevalence of HEV in SOT
Refferences
a. BTS guidelines 2018 HEV infection Guidelines for Hepatitis E & Solid Organ Transplantation
a. Webb GW, Dalton HR. Hepatitis E: an underestimated emerging threat. Ther Adv Infect Dis. 2019;6:2049936119837162. – PMC – PubMed
I appreciate your careful well balanced clinical approach in managing this patient that is well supported by evidence.
I appreciate your clinical approach to patient with Hep E infection in background of immunosuppression. I like your well structured detailed summary.
Hepatitis E virus (HEV) infection is underdiagnosed due to the use of serological assays with low sensitivity. Although most patients with HEV recover completely, HEV infection among patients with pre-existing chronic liver disease and organ-transplant recipients on immunosuppressive therapy can result in decompensated liver disease and death.
The first step is to reduce the immunsupression drug.
If infection persist then antiviral therapy with ribavirin for three months.
IF the infection collapse after stoping antiviral we can continue treatment for additional three months.
we can monitor with liver function an monthly PCR .
meta-analysis revealed prevelance of HEV in SOT recipients is 20%. De novo HEV infection and acute HEV infection accounted for less than 5% of infections. A recent meta-analysis of 419 studies comprised of 519,872 individuals showed an estimated global seroprevalence of anti-HEV IgG of 12.5% and a pooled estimated anti-HEV IgM seroprevalence of 1.5%.
reference :
1- Li P, Liu J, Li Y, Su J, Ma Z, Bramer WM, Cao W, de Man RA, Peppelenbosch MP, Pan Q. The global epidemiology of hepatitis E virus infection: A systematic review and meta-analysis. Liver Int. 2020;40:1516–1528.
2-McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK Guidelines for Hepatitis E and Solid Organ Transplantation. Transplantation. 2018;102:15–20. [PubMed] [Google Scholar]
I appreciate your understanding about the need to modify immunosuppression when infected with Hep E
How would you manage this case? (1)
Treatment of HEV infection after transplantation
Monitoring
So in the current case
What is the prevalence of HEV in solid organ transplantation?
References
1. Guidelines for Hepatitis E & Solid Organ Transplantation
2. Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, et al. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat. 2022 Dec;29(12):1134-1142.
I appreciate your understanding about the need to modify immunosuppression when infected with Hep E.
A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008.
Maintained on MMF, Tacrolimus and prednisolone. During the first 1.5 years after transplantation, CMV, primary EBV infection, and BK-virus viremia.
3 years later, ALT (94 U/L) and AST (55 U/L) were elevated persistently with negative serology to HCV, HBV,BKV,EBV and CMV PCR and a stable Kidney function eGFR of 80 mL/min.
HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analyzed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
How would you manage this case?
This is a case of persistent HEV infection> 3 months detectable RNA.
First, review of the donor file, and viral serology if available, will check as well the recipient pretransplant viral serology if available.
Second, detailed travel history to an endemic area, or consumption of pork, or un cooked meat (as the Genotype 3 detected).
Will ask for laboratories for synthetic liver function (albumin, INR), gamma GT, alkaline phosphatase, and bilirubin, CBC, KFT, Urinalysis, LDH, and a quantitative stool HEV PCR(as baseline).
Will ask for ultrasound abdomen, for any organomegaly, and CXR.
Treatment:
It has been noted that tacrolimus and m-TOR inhibitors increase viral replication, but mycophenolate inhibits it, so in indexed case I would decrease the tac level up to the lower safe acceptable level (preventing rejection).
The main stay treatment in his case is to start treatment with Ribavirin, at least for 3-6 months, till reaching a sustained viral response (not detected virus in blood and stool twice one month apart and at 3 and 6 months after stopping the Ribavirin) the HEV PCR (blood and stool) should be monitored monthly.
During treatment close monitoring of CBC- hemolytic anemia is a common complication of Ribavirin, as well as liver function test and kidney function.
PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
? HEV vaccine approved in china, for G1.
What is the prevalence of HEV in solid organ transplantation?
HEV infection responsible of > 50% viral hepatitis worldwide, with a prevalence of HEV in solid organ transplant is 4-20%, increased with age, and demographic variables (higher in Africa and Asia and low-middle income).
References:
(1) Friebus-Kardash J, Eisenberger U, Ackermann J, Kribben A, Witzke O, Wenzel J, Rohn H, Fiedler M. Prevalence of active hepatitis E virus infection and efficacy of ribavirin treatment in renal allograft recipients. Transpl Infect Dis. 2019 Jun;21(3):e13088. doi: 10.1111/tid.13088. Epub 2019 Apr 16. PMID: 30929308.
(2) McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK Guidelines for Hepatitis E and Solid Organ Transplantation. Transplantation. 2018 Jan;102(1):15-20. doi: 10.1097/TP.0000000000001908. PMID: 28795981.
I appreciate your careful well balanced clinical approach in managing this patient that is well supported by evidence.
-The index case is KTR had, in the first year post-Tx, frequent viral infections ( CMV, EBV, BKPyV), indicated overt immune suppression.
-He had transient mild transaminitis without clear cause( viral study negative, drug induced ) .
-Patient developed again transaminitis and found to have HEV genotype 3 infection.
-The retrospective analysis of previous sample showed positive serology IgM.
-Patient has persistent HEV infection as he has detectable virus HEV RNA for > 3 months, after the onset of symptoms, raised liver enzymes, or from the first positive HEV RNA test.
– Chronic HEV infection in SOT recipients have been attributed to genotype 3 and 4, supporting a zoonotic mode of transmission.
– Chronic HEV infection is often asymptomatic, manifesting only with unexplained mild to moderate elevations in serum aminotransferase levels (100‐300 IU/mL).
– Once infected, 60% of SOT 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
-Risk factors for the progression to chronic infection included the use of tacrolimus and the presence of thrombocytopenia at the time of diagnosis.
– The diagnosis in immunocompromised individuals based on HEV RNA detection in the serum or stool.
– HEV serological assay is unreliable in SOT as they may have delayed or absent seroconversion.
Would you manage this case?
-Aim of therapy to achieve sustained virological response (SVR), No virus detected in plasma & stool 6 months after completion of treatment)
*Baseline work up;
– serum and stool HEV, RNA.
– Liver US ;signs of chronicity.
– CBC, LFT, RFT, CrCL
– Tac level
*Treatment:
– First line: Reduction of immunosuppression RIS to facilitate viral, by reducing Tacrolimus as it potentiate virus replication.
– Ribavirin RBV started if no response to RIS for at least 3 months, or earlier in severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations.
– RBV dose adjusted to CrCL
– RBV is continued for at least 3 months until stool tests are negative for HEV RNA on 2 occasions one month apart.
– Relapse after a first course of ribavirin are re-treated for at least 6 months with ribavirin at dosages toward the higher dose range, where tolerated.
– PEG-IFN may be considered in ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection
*Monitoring:
– HEV RNA at day 7 of Ribavirin therapy to predict SVR at 3 months.help determine the likely length of treatment required
– Monthly HEV RNA testing in plasma and stool.
– Monitor Hg during ribavirin therapy as hemolytic anemia is side effect
– Check for SVR by HEV RNA in plasma and stool at 3 & 6 months samples after stopping antiviral therapy
– Monitor rejection during RIS.
*Prevention:
-Advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation.
– Vaccine against genotypes 1 and 4 HEV (Hecolin) with long‐term efficacy has been shown to be 87% after 4.5 years. No effective against genotype 3
What is the prevalence of HEV in solid organ transplantation?
The prevalence of HEV infection in the SOT population varies from 2% to 44%, depending on the assay used and population studied, while HEV viremia has been found in 1%‐4%.
Meta-analysis showed The pooled estimated prevalence of HEV infection in SOT patients was 20.2%, and in each organ as follow: liver 27.2%, kidney 12.8%, heart 12.8%, and lung 5.6%.
References:
Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant. 2019 Sep;33(9):e13514. doi: 10.1111/ctr.13514. Epub 2019 Apr 14. PMID: 30817047.
Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on April 2017 First Edition.
I appreciate your careful well balanced clinical approach in managing this patient that is well supported by evidence.
How would you manage this case?
The index case is a KTR with history of CMV reactivation, primary EBV infection, and BK-virus viremia. HEV IgM Positive/HEV IgG negative in the presence of positive HEV RNA, denotes acute HEV infection.
Considering the new HEV infection, these viral infections can be attributed to intense immunosuppression.
The case can be managed as follows(1):
1. 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(1).
2. 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.
3. 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(1).
4. 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).
5. Ribavirin is continued until stool tests are negative for HEV RNA on two occasions one month apart.
6. 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.
7. To minimise treatment-related side-effects, the dosage of ribavirin is adapted according to creatinine clearance, estimated using the Cockcroft-Gault equation.
8. Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made to stop treatment.
9. 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.
10.PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection.
What is the prevalence of HEV in solid organ transplantation?
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%(2). HEV infection is common in SOT recipients, particularly in middle-income countries. The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants.
References
1. Guidelines for Hepatitis E & Solid Organ Transplantation; first edition (BTS guidelines)
2. Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
I like your well structured detailed summary.
I appreciate the need for RNA levels to monitor the effectiveness of treatment of Hep E.
How would you manage this case?
Chronic hepatitis E
The management of chronic infection involves reduction of immunosuppressive therapy and/or antiviral therapy
The goal of treatment is to eradicate HEV RNA, which is predicted by achieving a sustained virologic response (SVR).
An SVR is defined as the absence of HEV RNA by polymerase chain reaction 12 weeks after cessation of treatment.
Patients with an SVR are considered cured since there is no viral reservoir, similar to hepatitis C virus; however, they remain at risk for reinfection.
reduction in immunosuppressive therapy
reduce tacrolimus first, if possible, since there is an association of chronic infection with tacrolimus.
Antiviral therapy is directed against genotype 3, since chronic infection is typically observed in patients with this genotype
a 12-week course of ribavirin monotherapy
The dose of ribavirin is 600 to 1000 mg daily (administered in two divided doses).
Monitoring for toxicity (complete blood count, creatinine with estimated glomerular filtration rate calculation, liver enzymes, and bilirubin levels) at week 4 of treatment
then check the complete blood count at weeks 8 and 12 to evaluate for anemia associated with ribavirin. For those who develop anemia, the dose of ribavirin can be adjusted based on the severity and comorbidities.
Assessing response to antiviral therapy
check both stool and serum HEV RNA at week 12
●Undetectable HEV RNA after initial treatment – Ribavirin can be stopped if the HEV RNA is negative in the sera and stool at week 12
then repeat HEV RNA testing in blood and stool 12 weeks following the cessation of therapy to determine if the virologic response is sustained.
If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated.
Detectable HEV RNA after initial treatment – If HEV is detectable in serum and/or stools at week 12, ribavirin therapy should be extended for an additional 12 weeks.
Treatment failure Patients who fail to achieve an SVR should continue to be followed for signs of progression of liver disease. There is no established alternative antiviral therapy with evidence of efficacy in this setting.
Therapies that have been considered for the management of treatment failure include pegylated interferon-alfa and sofosbuvir. However, concerns regarding toxicity and efficacy prevent these agents from being used in routine care. As examples:
●Pegylated interferon-alpha – There are limited data to support the use of pegylated interferon-alpha for liver transplant patients with persistent infection who fail ribavirin . In one series of three liver transplant recipients, viral clearance was observed after three months of treatment with pegylated interferon . However, interferon has an immunostimulatory effect that can increase the risk of acute rejection in all organ transplant settings
● Sofosbuvir appears to control HEV in a cell culture model treatment . However, in contrast with in vitro observations, an HEV/hepatitis C virus coinfected patient who received treatment with a 12-week course of sofosbuvir and daclatasvir failed to clear HEV RNA
What is the prevalence of HEV in solid organ transplantation?
A subset of patients who undergo solid organ transplantation (eg, kidney, liver, and kidney-pancreas) appear to develop chronic HEV infection
In a retrospective multicenter study that included 85 recipients of solid organ transplants, the rate of chronic infection among those who were acutely infected with HEV after transplant was approximately 70 percent
In a prospective cohort of 700 solid organ transplant recipients, 34 (5 percent) acquired HEV infection, of whom 47 percent developed chronic infection
Chronic infection appears to be related to impaired HEV-specific T-cell responses Chronic hepatitis has been associated with lower counts of lymphocytes and of CD2, CD3, and CD4 T cells; use of tacrolimus; a low platelet count at the time of diagnosis with HEV infection; younger age; and liver transplantation
An important risk factor for acute HEV infection in solid organ transplant recipients appears to be consumption of insufficiently cooked game meat or pork products
The natural history of chronic HEV infection in transplant recipients is incompletely understood, but rapid progression of liver disease to cirrhosis has been reported
Chronically infected patients may also be at risk for HEV reactivation . However, studies have been conflicting and the risk, if present, appears to be small
I appreciate your understanding about the need to modify immunosuppression when infected with Hep E, well-supported by level of recommendation.
THANKS .Prof. Ajay Sharma
The patient in the provided clinical scenario is severely immunosuppressed, which is clinically manifested as recurrent infections, including CVM, BKPyV, and EBV, and ending with HEV infection.
Because of the following, the aforementioned case has a chronic HEV infection: > 6-month-old HEV RNA.
The initial strategy is to reduce immunosuppression because the patient has potent immunosuppression, which might assist the infection clearance. Reduced immunosuppression may aid in the prevention of further infections. The risk of acute ejection should, however, always be taken into account when reducing or stopping immunosuppressive medication.
If the initial step failed,other treatment options include ribavirin monotherapy (RBV) for 3 months if HEV infection continues despite a reduction in immunosuppression. Patients who relapse after a 3-month course of RBV should be treated for a prolonged length of 6–9 months.
If RBV is not tolerated or a prolonged RBV course is ineffective at eradicating the virus, pegylated interferon alpha may be considered as an alternate treatment for chronic HEV.
The likelihood of graft rejection is one of numerous negative consequences of pegylated interferon alpha.
According to recent research, HEV seroprevalence rates in Europe ranged from 1% to 52%. HEV infection was thought to be present in 20.2% of SOT patients. For each transplanted organ, the combined estimated prevalence of HEV infection was as follows: liver (27.2%), kidney (12.8%), heart (12.8%), and lung (5.6%). De novo HEV infection was estimated to be present in 5.1% of cases.
I appreciate your clinical approach to patient with Hep E infection in background of immunosuppression.
Management of chronic HEV infection:(figure)
Prevalence of HEV infection:
References:
I like your well structured detailed summary.
I appreciate the need for RNA levels to monitor the effectiveness of treatment of Hep E.
The indexed case indicates chronic hepatitis E viral infection with genotype 3 which can explain his chronic elevated liver enzymes and can cause liver cirrhosis if not treated
how would you manage this case?
Send for NAAT to detect the HEV RNA in the blood and stool by using Conventional reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and reverse transcription loop-mediated isothermal amplification
Reduction of immunosuppression medication in particular antimetabolites like MMF can reduce the HEV load in 30% of cases and successful viral clearance within 6 months of follow-up, those with no viral clearance may need treatment with ribavirin with 70-100% rate of viral clearance within 3 months after use, ribavirin should be used with caution due to the risk of hemolytic anemia and bone marrow suppression.
Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. But ribavirin is contraindicated in pregnancy while interferon is not preferred in SOT candidates (2).
Ribavirin-resistant HEV infection promising agent like sofosbuvir was also considered as an option in the treatment of ribavirin-resistant HEV infections
Alone or in combination with ribavirin based on limited evidnces
What is the prevalence of HEV in solid organ transplantation?
4 genotypes were identified for HEV in humans with 1, and 2 more in developing countries and causing acute hepatitis due to contaminated water supply while genotypes 3, and 4 were more zoonotic from ora fecal contact from contaminated meat or animals in developed countries and cause chronic hepatitis E infection with extra hepatic organ involvement and more in immunocompromised patients like SOT (2). 20%-50% of transplant recipients having exposure to HEV3 develop chronic infection.
Acute hepatitis E viral infection usually self-limiting hepatitis in immunocompetent patients while the chronic development of HEV infection with the (genotype 3) infection was found to cause up to 10% of chronic elevation of liver enzymes and rapid development of liver cirrhosis in immunosuppressed patients like SOT with its negative impact on patient and graft survival.
References
1. Affeldt P, Di Cristanziano V, Grundmann F, Wirtz M, Kaiser R, Benzing T, Stippel D, Kann M, Kurschat C. Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation. Immun Inflamm Dis. 2021 Jun;9(2):513-520. doi: 10.1002/iid3.411. Epub 2021 Feb 8.
2. Aslan AT, Balaban HY. Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World J Gastroenterol. 2020 Oct 7;26(37):5543-5560. doi: 10.3748/wjg.v26.i37.5543. PMID: 33071523; PMCID: PMC7545399.
I appreciate your clinical approach to patient with Hep E infection in background of immunosuppression. I like your well structured detailed summary.
This is a case of chronic hepatitis E virus infection. Management is as follows.
Prevalence of HEV in solid organ transplant – The pooled estimated prevalence of HEV infection in solid organ transplant recipients was 20.2% [95% confidence interval (CI): 14.9-26.8]
Reference
I like your well structured detailed summary.
I appreciate the need for RNA levels to assess the need for treatment by ribavarin.
A 35-year CKD stage 5 due to HUS, with transplant from DBD, on pred, MMF, Tac
in the 1st 1.5 year developed CMV, EBV, BK. Now has elevated liver enzymes.
PCR for HCV, HBV CMV, BK, EBV were all negative. But HEV PCR was positive, genotype 3. with positive IgM, and negative IgG then IgG converted to positive.
How to manage this case?
Management
What is the prevalence of HEV in solid organ transplantation?
In retrospective multicenter study with 85 recipients of SOT the rate of chronic HEV after acute infection was 70%. [1] Another study of 700 SOT recipients 5% acquired HEV infection of whom 47% develop chronic infection. [2]
References
1. Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, Dumortier J, Cannesson A, Cassuto-Viguier E, Thervet E, Conti F, Lebray P, Dalton HR, Santella R, Kanaan N, Essig M, Mousson C, Radenne S, Roque-Afonso AM, Izopet J, Rostaing L. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011 May;140(5):1481-9. doi: 10.1053/j.gastro.2011.02.050. Epub 2011 Feb 24. PMID: 21354150.
2. Legrand-Abravanel F, Kamar N, Sandres-Saune K, Lhomme S, Mansuy JM, Muscari F, Sallusto F, Rostaing L, Izopet J. Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis. 2011 Jan;17(1):30-7. doi: 10.3201/eid1701.100527. PMID: 21192851; PMCID: PMC3298369.
3. UpToDate Topic 3677 Vesrsion 33.0
I like your well structured detailed summary.
I appreciate the need for RNA levels to assess the need for treatment by ribavarin.
How would you manage this case?
A case of persistent HEV infection with HEV RNA–positive sample, anti-HEV IgG and genotype 3.
1-This patient should receive written advice regarding the risk of HEV from undercooked meat before and after transplantation, especially for HEV G3.
2-We should collect a baseline quantitative HEV RNA on both plasma and stool at the start of treatment.
3-Ribavirin should be started for 3- 6 months and until stool tests are negative for HEV RNA on two occasions one month apart with monthly HEV RNA testing in plasma and stool.
4-Ribavirin dose should be adjusted according to renal function tests.
5-F/U Hemoglobin during Ribavirin course.
6-If infection resistant to Ribavirin, we can use PEG-interferon with close monitoring for rejection.
What is the prevalence of HEV in solid organ transplantation?
The pooled estimated prevalence of HEV infection in SOT patients was 20.2%.
The pooled estimated prevalence of HEV infection for each organ transplant was as follows:
1-Liver (27.2%)
2- Kidney (12.8%).
3-Heart (12.8%), and lung (5.6%).
References:
1- British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation 2017.
2- Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240.
I appreciate your clinical approach to patient with Hep E infection in background of transplant.
Its a case of chronic HEV hepatitis.
Persistence of HEV infection detected by serum or stool PCR for more than 6 months is indicative of chronicity.
Treatment :includes reduction of immune suppression medication, principally CNi and follow up for 12 then recheck PCR if its negative, then follow up again after 12 months for confirmation, long term follow up is indicated for recurrence of the disease. If there is no improvement after 12 weeks, then anti-viral therapy with ribavirin for 12 weeks must be considered. another approach is to reduce immune suppressants and commence on Ribavirine simultaneously.
Incidence of HEV in SOT recipients amount to 20.3% highest in liver transplant recipients and lung transplant recipients.
References:
1] Kenneth E Sherman, MD, PhD. Hepatitis E virus infection. http://www.uptode.com.
2] Panupong Hansrivijit et al. Hepatitis E in Solid organ transplant recipients; A systemic review and meta analysis.world journal of gastroenterology:2021 March 28;27 [12]:1240-1254
Thankyou.
Due to the fact that the previous sample tested positive for HEV infection, the ultimate diagnosis for this patient is most likely persistent HEV infection, which is defined as HEV infection that has lasted for more than three months. The spread of the disease may also occur via blood or organ donation. The following constitutes the management:
Baseline plasma & stool HEV RNA
Ribavirin for a period ranging from three to six months, or until two consecutive stool tests are taken one month apart comes back negative.
Plasma HEV RNA was measured after seven days for the purpose of determining how long therapy will last
Strive for a sustained response on the virologic front (Negative plasma or stool HEV RNA 6 months after treatment)
HEV RNA on a monthly basis
The antiviral activity of 2-pegylated interferon-alfa against HEV precludes its use in patients who have had organ transplantation owing to the significant risk of rejection associated with this treatment.
Close observation of renal and liver function, CBC, and HEV RNA.
Recent research has shown that the frequency of HEV antibodies in Europe may range from less than one percent to as high as 52 percent.
HEV-GT3 has been related to the consumption of meat products infected with HEV. In most cases, HEV infection does not cause any symptoms and only manifests as a minor illness that resolves on its own.
The incidence of HEV infection in recipients of solid organ transplants (SOT) varies widely depending on both the country and the organ being donated.
Reference:
British Transplantation Society Guidelines: Guidelines for Hepatitis E & Solid Organ Transplantation.
Was this HEV infection transmitted via the donor or this recipient had it before he was transplanted though management will not differ.!
How would you manage this case?
This patient has suffered many viral infections like EBV, BKV and CMV during first 1.5 years post-transplant.His archived blood sample showed HEV RNA positive as well IgM positive suggestive of acute active HEV infection.His liver enzymes had also increased with HEV genotype 3 positive.Studies have shown that all chronic HEV infections have been G3.He needs to be treated as following acute infection with HEV G3, the infection persists in approximately 60% of solid organ transplant recipients leading to persistent HEV infectionThis can cause a chronic hepatitis that can progress rapidly (3-5 years) to cirrhosis in approximately 15% of infected solid organ transplant recipients Management:
A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.He needs to started on early ribavirin treatment.Treatment with ribavirin should continue for at least three monthsMonthly 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 should be conducted by testing plasma and stool samples for HEV RNA at three and six months after stopping antiviral therapy.Regular haemoglobin monitoring should be 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.What is the prevalence of HEV in solid organ transplantation?
The estimated prevalence of HEV infection in SOT patients was 20.2% The pooled estimated prevalence of HEV infection for each organ transplant was as follows: liver (27.2%)kidney (12.8%)heart (12.8%)lung (5.6%)The pooled estimated prevalence of de novo HEV infection was 5.1%.The pooled estimated prevalence of acute HEV infection was 4.3%Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
McPherson S, Elsharkawy AM, Ankcorn M, Ijaz S, Powell J, Rowe I, Tedder R, Andrews PA. Summary of the British Transplantation Society UK guidelines for hepatitis E and solid organ transplantation. Transplantation. 2018 Jan
Thankyou ,
What is the diff. between PREVALENCE and POOLED PREVALENCE in SOT.
Hepatitis E virus (HEV) results in approximately 20 million infections each year, particularly in endemic areas in Asia, Africa, and Central America.
HEV has been noted to impact solid organ transplant (SOT) recipient outcomes. HEV infection can lead to has been cited to cause liver graft cirrhosis and subsequent failure. In contrast, renal transplant allografts were found to have similar rejection and two-year graft survival between HEV seropositive and negative recipients, thus demonstrating HEV does not always impact non-liver allografts.
As per metanalysis of Hansrivijit P et al, the pooled estimated prevalence of HEV infection in SOT recipients was 20.2%.
To date, the United States has not issued national guidelines for the management of hepatitis E in SOT. However, recent guidelines from the British Transplantation Society (2017) have recommended the following for Rx:
· 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)
· This patient with persistent infection and liver dysfunction 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) For most individuals 3-6 months of ribavirin treatment will suffice. (1C)
· A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment. (1C)
· 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)
· PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent HEV infection. However, patients will require very close monitoring for rejection. (2D)
Reference:
· Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021 Mar 28;27(12):1240-1254. doi: 10.3748/wjg.v27.i12.1240. PMID: 33828397; PMCID: PMC8006097.
· British Transplantation Society Guidelines, 2017.
Well done.
1.How would you manage this case?
-It is clearly that this patients suffered a lot of viral infections after the first year informs of CMV, EBV, & BKV.
-At 3 years he had hepatic dysfunction and ultimately diagnoses with HEV infection genotype 3.
-HBV &HCV were excluded by PCR
-The high numbers of these viral infections may points toward over-immune suppression.
-Because the historical sample was positive for HEV infection, the final diagnosis of this patient is likely persistent HEV infection ( HEV infection > 3 month). HEV g3 commonly transmitted by HEV contaminated under cooked meat. Other routes of transmission are blood transmission, or organ transplantation. The management is as follows:
2.What is the prevalence of HEV in solid organ transplantation?
-Developing world:
-Developed World:
Source; BTS guideline 2017
Thank you Ben would the coarce be diff. if this patient was immunocompetent.
Thank you Prof,
35 years patient CKD stage 5 due to HUS, transplanted from DBD, on pred, MMF, Tac
in the 1st 1.5 year he developed CMV, EBV, BK
has elevated liver enzymes
PCR for HCV, HBV negative, PCR for CMV, BK,EBV were negative
no drug induced elevated liver enzymes
then liver enzymes became slight normal
then increased again
HEV PCR positive, genotype 3
Retrospectively, PCR for HEV was positive, with positive IgM, and negative IgG then IgG converted to positive
management of this case:
1- ribavirin should be started in the case of HEV PCR positive for 3 months
2-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
3-reduction of MPA daily dose
RIS may be not enough alone to clear HEV, and should be accompanied by antiviral therapy which is Ribavirin
4-monitoring by CBC, liver function test, graft function, regular monitoring by HEV PCR
prevalence of HEV in solid organ transplantation
Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease.
Marcus Panning, Kristi Basho, Andreas Fahrner, Christoph Neumann-Haefelin. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. BMC Infectious Diseases volume 19, Article number: 675 (2019).
Rivero-Juarez, A.; Vallejo, N.; Lopez-Lopez, P.; Díaz-Mareque, A.I.; Frias, M.; Vallejo, A.; Caballero-Gómez, J.; Rodríguez-Velasco, M.; Molina, E.; Aguilera, A. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms 2020, 8, 51.
Patrick Affeldt , Veronica Di Cristanziano , Franziska Grundmann , Maike Wirtz , Rolf Kaiser , Thomas Benzing , Dirk Stippel , Martin Kann , Christine Kurschat. Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation. Immun Inflamm Dis. 2021 Jun;9(2):513-520.
Kanter Berga, J, Rodriguez Mendez, G., Crespo Albiach, J., Sancho Calabuig, A., Gavela Martinez, E., Anton Conejero, M. D., Pallardo Mateu, L. Hepatitis E Virus Infection in Renal Transplantation: Report of Four Cases. Transplantation 94(10S):p 886, November 27, 2012.
Diana Vassallo, Mir Mubariz Husain, Shaun Greer, Stephen McGrath, Samreen Ijaz, Durga Kanigicherla. Hepatitis E Infection in a Renal Transplant Recipient.Case Rep Nephrol. 2014; 2014: 865471.
Thankyou wuold you reduce Tac .as well?
yes
1-How would you manage this case?
Discussion of current case;
–This Case post Deceased KT and after 1.5 year of TX developed CMV reactivation , EBV infection , BKV viremia, showed high immunological risk for recurrent infections and with elevated liver enzymes and with (positive HEV PCR G3) considered of HEV reinfection.
-Abdominal ultrasound should be requested R/O any hepatic lesions or signs of liver cirrhosis.
Management of HEV infection;
-The goal of Treatment;
-To achieve a sustained virologic response (SVR);which is defined as the absence of HEV RNA by polymerase chain reaction 12 weeks after cessation of treatment.
-Strategy of Treatment;
A-Reduction of immunosuppression;
-RIS is the first step in the treatment of chronic HEV infection.
-There are no clear data to guide how immunosuppressive therapy should be reduced; however, Reduce Tacrolimus first, if possible, since there is an association of chronic infection with tacrolimus
B-Antiviral therapy;
-Ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
-Because current patient is HEV genotype 3, i suggest a 12-week course of ribavirin with dose (600 to 1000 mg daily) (administered in two divided doses).
-Monitoring for toxicity;
-Check basic laboratory tests (CBC, sr Cr ,eGFR, LFTs) at week 4 of treatment, then check the complete blood count at weeks 8 and 12 to evaluate for anemia associated with Ribavirin.
-Adjustment the dose of ribavirin based on the severity of hemolytic anemia and comorbidities.
-Assessing response to antiviral therapy;
-To assess the response to antiviral therapy, check both stool and serum HEV RNA at week 12.
–Undetectable HEV RNA after initial treatment;
-Ribavirin can be stopped if the HEV RNA is negative in the sera and stool at week 12.
-Then repeat HEV RNA testing in blood and stool 12 weeks following the cessation of therapy to determine if the virologic response is sustained.
-If the patient has detectable HEV RNA in blood or stool after responding to the initial 12-week course of therapy, a 24-week course of ribavirin should be initiated.
-HEV RNA testing should be performed at the end of treatment and, if negative, to confirm again 12 weeks later.
C-Prevention;
–Travelers to regions where HEV is endemic (eg, Asia, Africa, the Middle East, and Central America) should avoid water of unknown purity, food from street vendors, raw or undercooked seafood, meat or pork products, and raw vegetables.
-Travelers to Europe should also avoid uncooked and undercooked pork/boar sausage or other wild animal meats (eg, rabbit) that have not been properly heated.
2-What is the prevalence of HEV in solid organ transplantation?
-Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
-To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
-Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
–The prevalence of HEV infection in solid organ transplant (SOT) recipients varies by countries and transplanted organs.
-There is meta-analysis, demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients).
-The prevalence of HEV infection is two-fold more common in middle-income countries compared to high-income countries.
References;
– Abravanel F, Lhomme S, Chapuy-Regaud S, Mansuy JM, Muscari F, Sallusto F, et al. Hepatitis E virus reinfections in solid-organ-transplant recipients can evolve into chronic infections. J Infect Dis. 2014;209(12):1900.
-Zhang J, Zhang XF, Huang SJ, Wu T, Hu YM, Wang ZZ, et al. Long-term efficacy of a hepatitis E vaccine. N Engl J Med. 2015;372(10):914–22.
-Choi Y, Zhang X, Skinner B. Analysis of IgG anti-HEV antibody protective levels during hepatitis E virus reinfection in experimentally infected rhesus macaques. J Infect Dis. 2019;219(6):916–24.
-Hartl J, Otto B, Madden RG, Webb G, Woolson KL, Kriston L, et al. Hepatitis E Seroprevalence in Europe: a meta-analysis. Viruses. 2016;8(8).
-Khuroo.MS, Khuroo MS, Hepatitis E: an emerging global disease – from discovery towards control and cure . J Viral Hepat, 2016;23:68.
-Panupong,H., Angkawipa T.,: Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis; World J Gasroenterol. .2021 Mar 28; 27(12): 1240–1254.
Thank you for the excellent reply
How would you manage this case?
Chronic HEV infection is almost exclusively in immunocompromised patient, in this case as viral detection beyond 6 months, genotype 3 and other viral co-infection would clearly pointed towards Chronic HEV.
HEV IgM antibody will appear shortly during clinical illness and remain detectible for upto 5 months. IgG would appears shortly after IgM response and stay for longer times, in one report antibodies were detected as along as 14 years (immunocompetent individuals).
HEV RNA assay can be run on blood and stool, in stool it can be detected one week before clinical illness.[3]
Management
First step would be to reduced immunosuppressant’s particularly CNI with closed attention to graft rejection (monitoring could be done by detection of donor derived cell free DNA in recipient blood before clinical rejection) check RNA if absent than recheck at 12 week if not detected leading to SVR. If RNA not improving than will have to start on antiviral therapy.
Ribavirin 600mg to 1000mg in two divided doses for 3 months with close observation for toxicity, anemia and kidney function. HEV RNA should be check at 12week if there was no response than will have to give for another 3 months. In case of failed response pegylated interferon alpha can be tried but in SOT it would have implications and sofosbuvir appear to control in a cell culture model treatment but data is lacking.
What is the prevalence of HEV in solid organ transplantation?
In retrospective multicenter study with 85 recipients of SOT the rate of chronic HEV after acute infection was 70%. [1]
Another study of 700 SOT recipients 5% acquired HEV infection of whom 47% develop chronic infection. [2]
References
1. Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, Dumortier J, Cannesson A, Cassuto-Viguier E, Thervet E, Conti F, Lebray P, Dalton HR, Santella R, Kanaan N, Essig M, Mousson C, Radenne S, Roque-Afonso AM, Izopet J, Rostaing L. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011 May;140(5):1481-9. doi: 10.1053/j.gastro.2011.02.050. Epub 2011 Feb 24. PMID: 21354150.
2. Legrand-Abravanel F, Kamar N, Sandres-Saune K, Lhomme S, Mansuy JM, Muscari F, Sallusto F, Rostaing L, Izopet J. Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis. 2011 Jan;17(1):30-7. doi: 10.3201/eid1701.100527. PMID: 21192851; PMCID: PMC3298369.
3. UpToDate Topic 3677 Vesrsion 33.0
Thank you for the excellent reply
How would you manage this case?
In the current case scenario of kidney transplant patient on immunosuppression with history of CMV reactivation, developed EBV and BK viremia post transplantation which means that he is over immunosuppressed. Later on it is noted to have high liver enzymes with negative HBV and HCV screening but positive HEV PCR with HEV genotype 3 positive. In archived blood samples HEV IgM and later on IgG came positive.
That means the patient has chronic HEV infection which defined as detection of HEV RNA in serum or stool for longer than six months(HEV genotype 3 is typically self-limiting in the general population, however, in immunosuppressed or immunocompromised groups, the infection can become chronic).
–IgM anti-HEV appears during the early phase of clinical illness and disappears rapidly over four to five months.
–The IgG response appears shortly after the IgM response, antibodies were detected as long as 14 years after the acute phase of illness.
Management:
The management of chronic infection involves reduction of immunosuppressive therapy and antiviral therapy.
-Reduction of immunosuppression: Typically reduce tacrolimus , since there is an association of chronic infection with tacrolimus.
–Antiviral therapy: Suggested a 12-week course of ribavirin monotherapy. The dose of ribavirin is 600 to 1000 mg daily.
The goal of treatment is to eradicate HEV RNA by achieving a sustained virologic response (SVR)(absence of HEV RNA by PCR 12 weeks after cessation of treatment). Patients with an SVR are considered cured with possibility for reinfection.
What is the prevalence of HEV in solid organ transplantation?
There is a meta-analysis, demonstrates the prevalence of HEV infection in SOT recipients is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients.
References:
Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants Gastroenterology (2011).
Viral impact on long-term kidney graft function Infect. Dis. Clin. N. Am.
(2010)
Thank you for the excellent reply
A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. He was on prednisolone, MMF, and tacrolimus. During the first 1.5 years after transplantation, he developed CMV reactivation, primary EBV infection, and BK-virus viremia. Almost 3 years after transplantation at a routine check-in 2011, ALT (94 U/L) and AST (55 U/L) were found to be elevated. Kidney function was stable with an eGFR of 80 mL/min. Liver enzymes remained slightly increased in 2012 and 2013. No clear relation could be found with drugs. HCV and HBV PCR were negative. Repeated testing for BK, EBV and CMV DNA was negative. After temporary normalization, liver enzymes increased again with an ALT of 117 U/L. At that point, HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analysed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
How would you manage this case?
THE ABOVE CASE IS CHRONIC HEV INFECTION IN POST KTx. RECIPIENT
Immunocompromised patient ==> HEV RNA +_ Serology ==>+ve ==> HEV-infection ==> HEV RNA +VE >3Month ===> Chronic HEV > 6 month
Persistent infection leading to chronic hepatitis has been reported in immunosuppressed,
Genotype 3 ==> infect both animals and human
HEV virus is not uncommon and should be considered in kidney Tx recipients who develop elevated liver transaminases or suggestive symptoms, especially that its course is less benign than in the general population.
Other screening:
CBC , LFT, KFT, CrCL, CNI Level,
Abdominal USS=> looking for signs of liver cirrhosis, Fibro scan is non-invasive and can detect chronic liver disease.
Treatments:
1) IS Reduction e.g Tacrolimus can be reduced
2) Ribavirin tab 600-1000mg in two divided doses according to CeCL for 12 weeks
Early treatment with ribavirin may be considered in specific cases of acute HEV, such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra- hepatic manifestations, although evidence for this recommendation is currently limited.
Check LFT ===> Four weeks after commencement of Ribavirin.
Baseline quantitative HEV RNA assessment is undertaken on both plasma and stool at the start of treatment.
Then 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.
Patients who relapse after a 3 -month course of RBV should be treated for a longer duration of 6 -9 months.
3) Pegylated interferon alpha can be considered as an alternative therapy for chronic HEV if RBV is not tolerated or a prolonged RBV course fails to eradicate the virus .
Pegylated interferon alpha has many adverse effects, including an increased risk of graft rejection.
Prevention:
Avoid undercooked meat of animals, particularly when traveling to endemic regions of the world.
A vaccine has been used in China with efficacy against HEV.
Surveillance and Screening for HEV in Solid Organ Transplant Recipients,
Potential recipients of solid organ transplants do not need routine screening for HEV infection UNLESS SUSPECTED (immunosuppressed individual with raised liver enzymes)
Solid organ transplant recipients with elevated liver transaminases or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or an antigen assay.
Prevalence of HEV in SOT:
A subset of patients who undergo solid organ transplantation (eg, kidney, liver, and kidney-pancreas) appear to develop chronic HEV infection].
In a retrospective multicenter study that included 85 recipients of solid organ transplants, the rate of chronic infection among those who were acutely infected with HEV after transplant was approximately 70%.
In a prospective cohort of 700 solid organ transplant recipients, 34 (5%) acquired HEV infection, of whom 47% developed chronic infection.
Immunization:
Recombinant vaccines developed from genotype 1 HEV have shown efficacy in trials
in China. One of these is licensed for use in China, but not elsewhere in the world.
Its efficacy for the prevention of other HEV genotypes has not been established
Reference:
*Kidney Tx in patients with HEV May A. Hassaballa Prof Internal Medicine & Nephrology, Cairo University
*Hansrivijit P, Trongtorsak A, Puthenpura MM, et al. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol. 2021;27(12):1240-1254. doi:10.3748/wjg.v27.i12.1240
*Guidelines for Hepatitis E & Solid Organ Transplantation DRAFT Compiled by a Working Party of The British Transplantation Society Draft posted on http://www.bts.org.uk April 2017 First Edition.
*EASL Clinical Practice Guidelines on hepatitis E virus infection (2018)
*Adapted from the British Society of Transplantation Guidelines (2017)
Thank you for the excellent reply
How would you manage this case?
This post kidney transplant patient most likely has chronic HEV infection which is common with the genotype 3 .Management is MDT ( Hepatologist ,nephrologist and clinical pharmacist ) . The approach will be by proper history and good clinical examinations looking for signs of chronic liver disease.Serology and molecular testing already done so other tests include full blood counts,graft function and liver function test .
Treatments :
The prevalence of HEV infection is two-fold more common in middle-income countries compared to high-income countries, in SOT recipients the prevalence of HEV infection is 20.3% (highest in liver transplant recipients and lowest in lung transplant recipients).
Reference :
Thank you for the excellent reply
How do you manage the case?
The above case is chronic HEV infection because of the following:
Immunosuppressive individuals may have a delayed or absent seroconversion, hence the reason for recommending HEV RNA of stool or serum as the diagnostic tool for them
Moreso, it has been documented that chronically infected HEV patients may be at risk of HEV reactivation.
Other Investigations during treatments
Treatments
Prevention
Prevalence of HEV in SOT
References
Thank you for the excellent reply Isaac
A 35-year-old patient with CKD5 due to HUS underwent a DBD kidney transplantation in October 2008. He was on prednisolone, MMF, and tacrolimus. During the first 1.5 years after transplantation, he developed CMV reactivation, primary EBV infection, and BK-virus viremia. Almost 3 years after transplantation at a routine check-in 2011, ALT (94 U/L) and AST (55 U/L) were found to be elevated. Kidney function was stable with an eGFR of 80 mL/min. Liver enzymes remained slightly increased in 2012 and 2013. No clear relation could be found with drugs. HCV and HBV PCR were negative. Repeated testing for BK, EBV and CMV DNA was negative. After temporary normalization, liver enzymes increased again with an ALT of 117 U/L. At that point, HEV PCR was performed, and the result was positive. Genotyping of the virus revealed the presence of HEV genotype 3. Retrospectively, archived blood samples were analysed for the presence of HEV RNA and for anti-HEV IgG and IgM serology. Anti-HEV IgM was positive and IgG negative in the first HEV RNA–positive sample in 2011; later, anti-HEV IgG also became positive.
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How would you manage this case?
History
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Immunization
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What is the prevalence of HEV in solid organ transplantation?
HEV virus is common in kidney Tx recipients and its course is less benign than in the general population.
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Reference
Thank you for the excellent reply Dr Mahmoud
Many thanks Prof.Halawa
HEV infection in transplant patients must be diagnosed by virus-specific techniques, such as HEV RNA and/or antigen detection, as antibody detection is ineffective in immunosuppressed people.
Although the presence of HEV viraemia in a donor does not necessarily rule out the use of an organ from that donor, it will help guide clinical care choices made after transplant.
Patients who contract HEV through transplantation are treated in accordance with guidelines for other persistently infected patients.
HEV testing should be done on people who have unexplained acute, chronic, or acute liver failure.
Patients with cirrhosis who get hepatitis E while waiting for a liver transplant are given the option of receiving treatment with ribavirin.
Observation and monitoring of HEV RNA levels and liver enzymes are part of the initial care of newly diagnosed or acute HEV infection in solid organ transplant patients because more than 30% of cases will resolve on their own within three months.
Clinical decision-making may be aided by dynamic viral monitoring and antibody profiling.
In patients with acute or persistent HEV, a calculated reduction in immunosuppression may help with viral clearance, but the risk of rejection needs to be carefully evaluated.
Although there is currently insufficient data to support this approach, early therapy with ribavirin may be explored in some cases of acute hepatitis E, such as those who develop severe liver dysfunction (jaundice and coagulopathy) or extra-hepatic symptoms.
What is the prevalence of HEV in solid organ transplantation?
In areas with limited resources, where HEV is considered to be responsible for more than 50% of cases of viral hepatitis, HEV G1 and G2 viruses continue to pose serious public health risks.
By consuming tainted food and water, the virus is spread orally via the faecal channel.Spread from person to person is rare.
The meta-analysis found that 20% of SOT recipients have HEV.
Less than 5% of infections were caused by acute and de novo HEV infections.
1- British Transplantation Society Guidelines
Guidelines for Hepatitis E & Solid Organ Transplantation
2- Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis
Panupong Hansrivijit, Angkawipa Trongtorsak, Max M Puthenpura, Boonphiphop Boonpheng, Charat Thongprayoon, Karn Wijarnpreecha, Avishek Choudhury, Wisit Kaewput, Shennen A Mao, Michael A Mao, Caroline C Jadlowiec, and Wisit Cheungpasitporn
Thank you for your reply, but you did not answer the question. How would you manage this case?
What you have written is just a copy and paste without reflection on the case.
MANAGMENT
The final diagnosis for this patient is most likely chronic HEV infection, which is defined as HEV infection that has lasted for more than three months, because the prior sample tested positive for HEV infection.
Chronic HEV infection is indicated by HEV infection detected by serum or stool PCR for longer than 6 months.
Ribavirin for a duration of three to six months, or until the results of two successive stool tests performed one month apart are negative.
Reduction of immunosupression.
With the course of ribavirin need to monitor toxicity of treatment with complete blood count, liver function and renal function
Treatment algorithm is attached
What is the prevalence of HEV in solid organ transplantation?
In areas with limited resources, where HEV is considered to be responsible for more than 50% of cases of viral hepatitis, HEV G1 and G2 viruses continue to pose serious public health risks.
By consuming tainted food and water, the virus is spread orally via the faecal channel.Spread from person to person is rare.
The meta-analysis found that 20% of SOT recipients have HEV.
Less than 5% of infections were caused by acute and de novo HEV infections.
British Transplantation Society Guidelines
Guidelines for Hepatitis E & Solid Organ Transplantation
2- Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis
Panupong Hansrivijit, Angkawipa Trongtorsak, Max M Puthenpura, Boonphiphop Boonpheng, Charat Thongprayoon, Karn Wijarnpreecha, Avishek Choudhury, Wisit Kaewput, Shennen A Mao, Michael A Mao, Caroline C Jadlowiec, and Wisit Cheungpasitporn
3-Khuroo MS, Khuroo MS. Hepatitis E: an emerging global disease – from discovery towards control and cure. J Viral Hepat 2016; 23:68.