In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome

Abstract

ObjectiveHepatitis E virus (HEV) infection can take chronic courses in immunocompromised patients potentially leading to liver cirrhosis and liver failure. Ribavirin (RBV) is currently the only treatment option for many patients, but treatment failure can occur which has been associated with the appearance of a distinct HEV polymerase mutant (G1634R). Here, we performed a detailed analysis of HEV viral intrahost evolution during chronic hepatitis E infections.DesignIllumina deep sequencing was performed for the detection of intrahost variation in the HEV genome of chronically infected patients. Novel polymerase mutants were investigated in vitro using state-of-the-art HEV cell culture models.ResultsTogether, these data revealed that (1) viral diversity differed markedly between patients but did not show major intraindividual short-term variations in untreated patients with chronic hepatitis E, (2) RBV therapy was associated with an increase in viral heterogeneity which was reversible when treatment was stopped, (3) the G1634R mutant was detectable as a minor population prior to therapy in patients who subsequently failed to achieve a sustained virological response to RBV therapy and (4) in addition to G1634R further dominant variants in the polymerase region emerged, impacting HEV replication efficiency in vitro.ConclusionsIn summary, this first investigation of intrahost HEV population evolution indicates that RBV causes HEV mutagenesis in treated patients and that an emergence of distinct mutants within the viral population occurs during RBV therapy. We also suggest that next-generation sequencing could be useful to guide personalised antiviral strategies.

Hepatitis E virus replication and interferon responses in human placental cells

“…Ribavirin (RBV) remains the treatment of choice in chronic infections and can be considered in fulminant cases 11, 12, 13. However, RBV administration should be carefully considered because of possible side effects,11 in particular anemia and treatment failure due to the selection of viral mutants with increased replication fitness 14, 15, 16. Of note, RBV is also contraindicated in pregnant individuals.…”

Review article: hepatitis E—a concise review of virology, epidemiology, clinical presentation and therapy

“…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.…”

Hepatitis E: Diagnostic and Therapeutic Challenges

“…Interestingly, the emergence of K1383N mutations and their association with an overall increase in viral heterogeneity in several patients, is shown reversible upon RBV cessation [24,26].…”

“…Though, RBV effectively inhibits the HEV replication and induce a sustained virological response (SVR) in chronic patients [22], drug-resistance or non-response associated viral mutations lead to therapeutic failure in a proportion of patients [23,24].…”