Review Article

Hepatitis E—A Concise Review of Virology, Epidemiology, Clinical Presentation and Therapy

M. C. Donnelly; L. Scobie; C. L. Crossan; H. Dalton; P. C. Hayes; K. J. Simpson

Disclosures

Aliment Pharmacol Ther. 2017;46(2):126-141. 

In This Article

Treatment of HEV Infection

Liver Transplantation for Fulminant Hepatitis

It is rare for patients with HEV-induced acute liver failure to require emergency liver transplantation. The United States Acute Liver Failure Study Group reported upon 681 patients with acute liver injury/failure who were tested for anti-HEV IgM and IgG levels;[126] those with detectable IgM levels underwent HEV RNA testing. One patient who was initially found to have a positive anti-HEV IgM proceeded to emergency liver transplantation. However, in this case, the diagnosis of HEV and its potential causative role in acute liver failure was not clear cut; repeat samples for anti-HEV IgM were negative, and although initial anti-HEV IgG was positive, repeat serum samples were negative. HEV RNA was never detected. Following further investigation, it was felt likely that the cause of the acute liver failure and requirement for transplantation was in fact inadvertent paracetamol overdose. There are no other reports of emergency liver transplantation for acute HEV infection in the literature.

Medical Therapy

Following the identification of chronic HEV infection, there were case reports of successful viral clearance following ribavirin and/or pegylated interferon treatment. Both ribavirin and pegylated interferon inhibit HEV replication in vitro. However, pegylated interferon is contraindicated in kidney transplant recipients due to an appreciable risk of acute rejection and ribavirin has subsequently become the first-line medical treatment for both acute (if required) and chronic HEV infection ( Table 3 ).[108,127–132] Gerolami first reported upon the use of ribavirin in the treatment of acute HEV genotype 3 infection in 2011;[133] the patient was immunocompetent and was treated for 3 weeks, with normalisation of alanine aminotransferase and a fall in detectable HEV RNA levels. Treatment is most commonly started if HEV RNA remains detectable at 3 months, however, this remains an off licence use. Ribavirin has also been used to treat acute HEV genotype 1 infection: Pischke described treatment of a patient with acute HEV genotype 1e infection (acquired in Eritrea) with ribavirin for 6 weeks and the patient obtained SVR.[130] The effect of ribavirin treatment on HEV genotype 1 infection has recently been studied using human liver chimeric mice. Ribavirin treatment led to a statistically significant decrease in viraemia after 6 weeks of treatment, together with a sharp decline in ORF2 and ORF3 proteins as detected by immunofluorescence in the livers of treated animals compared with controls.[33]

Worryingly, cases of ribavirin resistance and treatment failure have been reported, often related to a reduction in ribavirin dose because of side effects (eg, anaemia). In one case, series of patients undergoing treatment of HEV infection, ribavirin-induced anaemia necessitated dose reduction in 29%; the use of erythropoietin in 54% and blood transfusions in 12%.[127] The G1634R mutation in the HEV ORF1 protein has also been associated with treatment failure; one study demonstrated that in patients with ribavirin treatment failure, all patients had this mutation.[128] The G1634R mutation increases the replicative capacity of HEV in the human liver, and thereby reduces the efficacy of ribavirin.

Recently, ribavirin has been reported as mutagenic for the HEV genome during treatment of chronic infection, with an increasing number of variants being identified and mutations in all open reading frames of the genome.[134] In addition to the previously identified G1634R mutation, K1838N, D1384G, V1479I and Y1587F mutations are selected in non-responders to ribavirin therapy. In essence, ribavirin exerts mutagenic pressure on the viral genome and while this may result in viral clearance, it may also lead to the selection of resistant variants in those patients who do not respond.

Debing described a patient with chronic HEV infection, who experienced treatment failure with ribavirin, with a resistant phenotype.[135] In this case, although HEV RNA was undetectable after 10 weeks of treatment, 8 weeks after treatment cessation the patient had viral relapse. Ribavirin was subsequently restarted and at 58 weeks post re-introduction of ribavirin, HEV RNA was still detectable. Next generation sequencing was performed to identify mutations associated with ribavirin resistance: resistance was associated with Y1320H, K1383N and G1634R mutations in the viral polymerase, in addition to an insertion in the hypervariable region. Subsequent in vitro studies identified that Y1320H and G1634R mutations have replication-increasing roles, whereas the K1383N mutation suppressed viral replication and in fact increased the in vitro sensitivity to ribavirin. Further deep sequencing of hepatitis E genomes demonstrated that ribavirin is mutagenic to viral replication in vitro and in vivo.

Treatment of Chronic HEV Infection in Transplant Recipients (and Other Immunocompromised Patients)

Solid organ transplant recipients represent a unique therapeutic challenge in the management of HEV infection. Commonly used immunosuppressive agents are now known to affect the in vitro replication of HEV. mTOR (mammalian target of rapamaycin) inhibitors (eg, everolimus) promote in vitro HEV replication via mTOR inhibition.[136] The calcineurin inhibitors (tacrolimus, ciclosporin A) have also been shown to have a pro-proliferative effect, in contrast to mycophenolate mofetil which inhibits HEV replication in vitro.[137]

In transplant recipients, the initial treatment approach should be to reduce immunosuppression if this is feasible. Reduction in immunosuppression by approximately 30% results in clearance of chronic HEV infection in around 30% of this patient cohort.[7] For patients who cannot reduce immunosuppression or who fail to clear the virus despite a reduction in immunosuppression, ribavirin monotherapy is the treatment of choice for the majority of patients ( Table 3 ).[108,127–132] Sustained viral response is the aim of therapy, defined as an undetectable serum HEV RNA level at least 6 months after treatment cessation. There is no definitive guidance as to the ideal treatment duration and dosage; there are reports of treatment courses lasting 1 month to 9 months, with the majority of units who have reported their experience favouring a 3-month course. Initial starting doses of ribavirin range from 600 to 1000 mg. Factors associated with achieving a sustained viral response include a higher lymphocyte count when ribavirin therapy was initiated.[127] Kamar reported that in 59 solid organ transplant recipients who were treated with a median of 9 months of ribavirin for chronic HEV infection, sustained viral response was obtained in 78%. Importantly, in those patients who had recurrence and completed a second, prolonged course of ribavirin, sustained viral response could be achieved in the majority of patients.[127]

Other anti-viral drugs have been investigated in the treatment of HEV in view of potential treatment failure with ribavirin. The role of sofosbuvir, a directly acting antiviral which is the oral prodrug of a nucleotide hepatitis C virus-RNA-dependent polymerase inhibitor, has been studied. Dao Thi demonstrated that sofosbuvir efficiently inhibited HEV genotype 3 replication in vitro.[138] Furthermore, this group was able to demonstrate an additive effect when combined with ribavirin. The authors of this paper did recognise that the anti-HEV property of sofosbuvir is less marked than its anti-hepatitis C property, and clinical studies were required to confirm the efficacy of sofosbuvir in treating human HEV infection, particularly in those who have failed to clear HEV with ribavirin therapy alone. Following this, Donnelly described a patient with chronic hepatitis C and HEV infection post-transplant, who was treated with sofosbuvir and daclatasvir (predominantly for hepatitis C infection and in view of previous ribavirin intolerance) and observed the effects of this treatment on HEV RNA and HEV-specific T-cell responses.[139] Despite the previous report of the inhibition of HEV replication in vitro with sofosbuvir, in this human study, no effect was seen on either HEV RNA levels or HEV-specific T-cell responses. Brown later characterised host T-cell responses against HEV and similarly demonstrated that in organ transplant recipients, anti-HEV T-cell responses were reduced in breadth and magnitude.[140] Another group studied the effect of sofosbuvir combined with ribavirin against HEV genotype 3 infection in a human patient: sofosbuvir at a standard dose had some anti-viral activity against HEV (as evidenced by a decline in HEV RNA levels) but was not potent enough to induce viral clearance.[141] The authors suggest that higher doses of sofosbuvir may be required to completely suppress viral replication; this would be an expensive approach to HEV treatment, and the potential side effects with this dose of therapy are unknown.

An American study analysed the prevalence and clinical consequences of HEV infection in patients who had previously undergone liver transplantation for chronic hepatitis C infection.[142] 42% of patients had detectable anti-HEV IgG at some point from baseline (pre-transplantation) until the end of the 5 year follow-up period; five patients were anti-HEV IgM positive pre-transplant, one patient demonstrated IgM seroconversion post-transplant and eight patients had IgG seroconversion post-transplant. Of those patients seroconverting post-transplant, eight had been treated for hepatitis C recurrence before or at the time of seroconversion. The authors felt that post-transplant treatment of hepatitis C recurrence with ribavirin/PEG-IFN may have afforded a degree of protection against HEV, and warned that with increasing use of new directly acting anti-viral agents, the prevalence of chronic HEV infection in this population may in fact begin to increase.

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