The incidence and prevalence of hepatitis E virus (HEV) infection has increased in many developed countries over the last decade, predominantly due to infection with genotype 3 (G3) HEV. Infection with HEV G3 is important in transplant recipients because it can persist in immunosuppressed individuals, leading, if untreated, to the development of chronic hepatitis and significant liver fibrosis. Because there are currently no international guidelines on the management of hepatitis E in transplant recipients, the British Transplantation Society (BTS) has developed guidelines to inform clinical teams and patients about hepatitis E to help increase the recognition of persistent hepatitis E infection and to provide clear guidance on its management. The following includes an overview of hepatitis E and transplantation with key references, and the statements of recommendations contained within the BTS guideline.
OVERVIEW OF HEPATITIS E AND SOLID ORGAN TRANSPLANTATION
Epidemiology of HEV
HEV belongs to the genus Hepevirus in the Hepeviridae family and infects humans and a range of animal hosts.1 Four major HEV genotypes infect humans (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 and accordingly, the HEV genotype.2 G1 and G2 are restricted to the human host and occur primarily in Asia and Africa. G3 has a worldwide distribution and is associated with infection in humans, pigs, and other mammalian species. G4 only infects humans and pigs, principally in Southeast Asia.
HEV G1 and G2 viruses remain major public health concerns in resource poor settings, where HEV is thought to be responsible for more than 50% of cases of viral hepatitis. The virus is transmitted via the fecal-oral route through the consumption of contaminated food and water. Reported mortality rates from endemic areas are significant, ranging from 0.5% to 4%.2 Infection with G1 and G2 is self-limiting and persistent infection does not occur.
HEV G3 and G4 are zoonotic infections, being transmitted to humans from an animal reservoir. Case-control studies have indicated that the consumption of pork products (particularly processed products) and game meat is associated with HEV infection.3,4 Enhanced surveillance data from England collected over 10 years indicate that there has been a recent rise in indigenous G3 infection.5 Seroprevalence rates in the general population of England is high at approximately 13%6 and estimates of burden in the general population suggest as many as 200 000 HEV infections occur per year and that these account for around 600 to 800 cases of hepatitis in England. Persistent HEV infection is increasingly recognized, probably reflecting increased awareness and testing. Public Health England surveillance shows that these infections occur across a broad range of immunosuppressed patient groups (solid organ transplantation, hematopoietic stem cell transplantation, hemato-oncology, and human immunodeficiency virus–infected).
Data from the selective screening programme implemented by NHS Blood and Transplant in March 2016 indicate that 1 in 2500 donations are HEV RNA–positive (data correct in February 2017). An investigation undertaken in England in recipients of HEV-containing blood components showed that 18 (42%) of 43 went on to develop HEV infection, giving an approximate risk of transfusion-related HEV infection of 1 in 5000.7 As a result, universal screening of all blood components for HEV is now recommended by the UK Advisory Committee for the Safety of Blood, Tissues and Organs on the basis of superior cost effectiveness of universal over selective testing for HEV.8
The transplant patient may acquire HEV in 2 ways, either through diet or through the receipt of substances of human origin including organs and blood components.9 Cross-sectional studies assessing the prevalence of HEV infection in cohorts of transplant recipients indicate that detectable HEV RNA (indicating current viremia) ranged from 0% to 3.2%.10 A recent study at a single center in the United Kingdom found the point prevalence of HEV viremia in transplant recipients was 16 (0.7%) of 2418 (manuscript submitted). It has been previously estimated that the annual risk of acquiring HEV in the UK is approximately 1 in 500 to 1000.7
Acute Hepatitis E
The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure. Symptoms, if they occur, include general malaise, abdominal pain, anorexia, nausea, and fever and are followed by the onset of jaundice accompanied by dark urine, pale stools, and pruritis.11 Most infections are self-limiting. Acute hepatitis E in patients with underlying liver disease may lead to decompensation and a poor outcome,12-14 and very rarely fulminant liver failure.15,16 A number of extrahepatic manifestations linked both to acute and to persistent hepatitis E infection have been reported including thrombocytopenia, glomerulonephritis and a range of neuropathologies.17
Persistent HEV Infection
Reported cases of persistent HEV infections are almost always due to G3 HEV (although G4 has been reported18). The clinical features of persistent HEV infection are often unremarkable. Liver transaminases are usually only modestly raised and few patients present with any symptoms.11,19 Once infected, 60% of solid organ transplant recipients fail to clear the virus and are at risk of developing chronic hepatitis.11,19 Liver biopsy shows rapid progression of liver fibrosis with 10% of patients progressing to cirrhosis over a few years.11
Diagnosis of Hepatitis E
Acute hepatitis E cannot be clinically distinguished from other causes of acute hepatitis. Diagnosis of HEV infection can be undertaken using methods for detecting antibody, antigen, and RNA.20-22 Importantly, laboratory diagnosis of acute or persistent HEV in immunosuppressed individuals must be through detection of the virus itself, either through HEV RNA testing or HEV antigen testing, because antibody detection in the immunosuppressed population is not a reliable marker of infection.11 Viral RNA can be detected a few weeks before the onset of clinical symptoms in both blood and stool samples. In an immunocompetent host, viremia lasts on average for 8 weeks, becoming undetectable in blood approximately 3 to 4 weeks after the onset of symptoms. Viral shedding in stool continues beyond plasma viral clearance in both acute and treated persistent infection.23
The clinical diagnosis of persistent hepatitis E infection is challenging, as such infections are largely asymptomatic.11,19 Testing strategies for identifying individuals with persistent infection are not clear and mean that infection can remain undiagnosed for years. Clinicians must have a high index of suspicion for infection and should investigate raised liver enzymes of any degree with reflex HEV RNA testing. Typically, alanine aminotransferase levels are between 100 and 200 U/L in transplant recipients with HEV infection, but patients may also present with minimally raised liver enzymes or enzymes within the upper normal range.11,19 Persistent HEV infection can be misdiagnosed as drug-induced liver injury,24 rejection (in liver transplants),25 or graft versus host disease, so careful assessment is needed of all liver enzyme abnormalities in transplant recipients.
Management of HEV Infection Posttransplant
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. Clearance of infection occurs spontaneously in more than 30% of the cases.11 Where possible, a reduction in immunosuppression should be considered. If HEV RNA clearance from the blood and stool has not been achieved by 3 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) or extrahepatic manifestations, although evidence for this is currently limited.26-29
Persistent HEV G3 infection causes a chronic hepatitis that can progress rapidly (3-5 years) to cirrhosis in approximately 10% of infected solid organ transplant recipients so it is important that it is treated.11 Individuals with persistent HEV infection (documented or estimated duration of infection of greater that 3 months) should be actively managed with the aim of achieving a sustained virological response (HEV RNA nondetected in plasma and stool 6 months after completing treatment).
If not already attempted in the acute phase, first-line management of persistent HEV infection is a strategic reduction in immunosuppression which can lead to clearance of HEV infection in approximately 30% of individuals with persistent HEV.11 Different classes of immunosuppressant drugs have different effects on HEV replication. Overall, current 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 effect on HEV replication in vitro.11,30-34 Therefore, strategic modification of immunosuppression might help with viral clearance. Further studies are awaited to help define the role of modification of immunosuppression in persistent HEV. 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.
The second-line treatment for persistent HEV, after modification of immunosuppression, is ribavirin. Several studies have demonstrated efficacy of ribavirin in the treatment of persistent HEV, with sustained virological response rates (SVR) (HEV RNA negative 6 months posttreatment) ranging from 63% to 78% with 3 to 6 months of ribavirin treatment.31,32,35-38 Initial studies used different doses and duration of ribavirin so the optimum duration remains unknown. More recent studies, using a more standardized protocol of 3 months of ribavirin treatment using creatinine clearance adjusted dosing, showed SVR rates of 63%.31,32 These studies also demonstrated that on-treatment virological response may predict outcome from treatment. Kamar et al31 showed that a fall in HEV RNA at day 7 of treatment with ribavirin predicted SVR after 3 months of ribavirin. In that study, falls of 0.5 log copies/mL or 1 log copies/mL at day 7 of ribavirin treatment had positive predictive values for SVR of 88% and 100%, respectively. Therefore, assessment of day 7 virological response could be incorporated into treatment algorithms to help determine treatment course length (ie, those with a favourable response at day 7 could be treated for 3 months with ribavirin and those with a slower virological response probably require a longer course, such as 6 months). However, this was a small study and requires validation.
Another important study showed that persistent HEV shedding in stool, even after clearance from the plasma, strongly predicted relapse after 3 months of treatment with ribavirin.32 Therefore, assessment of stool HEV RNA to ensure it is negative before stopping ribavirin treatment can significantly reduce the risk of relapse. A suggested algorithm for the treatment of HEV is shown in Figure 1.
The most frequent side effect of ribavirin is hemolytic anemia, which requires intervention in approximately 40% (dose reduction, epoetin, or blood transfusion).35 Therefore, patients require regular monitoring of hemoglobin while on treatment.
Treatment Failure With Ribavirin Treatment
Approximately 40% of transplant recipients with persistent HEV relapse after 3 months of treatment with ribavirin.31,32 Potential reasons for treatment failure include the need for dose reduction, insufficient duration of treatment to ensure HEV is cleared from both blood and stool, and the development of ribavirin-associated mutations (G1634R mutation in the RdRp domain of the ORF1 protein is associated with ribavirin treatment failure).38,39 The majority of patients who relapse will respond to a longer course of treatment with ribavirin, even those harboring the G1634R mutation.37 Therefore, retreatment with a longer course of ribavirin should be considered for patients who relapse, and treatment continued until the HEV RNA is negative in blood and stool on 2 tests at least 1 month apart. Retreatment for 6 months with ribavirin will be sufficient for many patients to achieve a sustained virological response, but some will require longer treatment.36 There are occasional reports of very resistant cases of HEV with multiple mutations that confer resistance to ribavirin who have persisting HEV viremia despite continued treatment.40 This emphasizes the importance of ensuring the patient receives effective treatment on their first course of treatment where possible.
For cases of ribavirin-refractory persistent HEV, treatment with PEG-interferon could be considered because there are case reports of successful clearance of persistent HEV with PEG-interferon in transplant recipients (75% SVR in 8 patients treated for 3-12 months).35 However, PEG-interferon is well known to increase the risk of rejection in transplant recipients, so close monitoring is required.
PROCESS OF WRITING AND METHODOLOGY
The BTS Guidelines for Hepatitis E and Solid organ Transplantation were posted online in June 2017.41 They were written by a team with wide representation from UK clinicians under the auspices of the BTS Standards Committee and were produced in line with the BTS Clinical Practice Guideline Development policy (available at http://www.bts.org.uk/).42 In brief, a systematic review of the relevant literature and synthesis of the available evidence was commissioned from selected clinical experts working to the standards of the above document. Draft chapters were produced by expert authors and reviewed for content, and modified to house style by the editorial committee. This was followed by peer group appraisal and expert review. After revision of the text, appropriate levels of evidence were added to the recommendations by editorial and author consensus. The draft of the document was placed on the BTS website in April 2017 for a period of open consultation, to which clinicians and patient groups were actively encouraged to contribute. After a further round of editorial review, the final document was posted in June 2017.
The last date of formal literature review was December 2016, although additional references were included during the review process.
The guideline used the GRADE system to rate the strength of evidence and the strength of recommendations.43 This approach is consistent with that adopted by previous BTS guidelines. It is recognized that the evidence base in this area of clinical practice is weak, and the grading of the recommendations reflects this. The guidelines are designed to indicate areas of agreement where they exist and to suggest good practice where they do not. As such, it is hoped that they will stimulate debate audit, research, and changes in practice, as well as a providing a reference point to current clinical practice.
The guideline comprises 54 pages and is freely available at https://bts.org.uk/guidelines-standards/. Given the lack of a consistent evidence base the guideline does not attempt to be proscriptive or to define a standard of care. However, to be of value, it must indicate areas where the evidence or consensus of opinion is strong. Therefore, each section of the guideline is prefaced by one or several “statements of recommendation,” which are explained and referenced in the subsequent text.
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