%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Debing, Y.
%A Ramiere, C.
%A Dallmeier, K.
%A Piorkowski, G.
%A Trabaud, M. A.
%A Lebosse, F.
%A Scholtes, C.
%A Roche, M.
%A Legras-Lachuer, C.
%A de Lamballerie, Xavier
%A Andre, P.
%A Neyts, J.
%T Hepatitis E virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity
%D 2016
%L PAR00015083
%G ENG
%J Journal of Hepatology
%@ 0168-8278
%K Hepatitis E virus ; Chronic hepatitis E ; Ribavirin ; Resistance ; G1634R ; Fidelity ; RNA-dependent RNA polymerase ; Hypervariable region
%M ISI:000382214000009
%N 3
%P 499-508
%U https://www.documentation.ird.fr/hor/PAR00015083
%V 65
%W Horizon (IRD)
%X Background & Aims: Ribavirin monotherapy is the preferred treatment for chronic hepatitis E, although occasional treatment failure occurs. We present a patient with chronic hepatitis E experiencing ribavirin treatment failure with a completely resistant phenotype. We aimed to identify viral mutations associated with treatment failure and explore the underlying mechanisms. Methods: Viral genomes were deep-sequenced at different time points and the role of identified mutations was assessed in vitro using mutant replicons, antiviral assays, cell culture of patientderived virus and deep-sequencing. Results: Ribavirin resistance was associated with Y1320H, K1383N and G1634R mutations in the viral polymerase, but also an insertion in the hypervariable region comprising a duplication and a polymerase-derived fragment. Analysis of these genome alterations in vitro revealed replication-increasing roles for Y1320H and G1634R mutations and the hypervariable region insertion. In contrast, the K1383N mutation in the polymerase F1-motif suppressed viral replication and increased the in vitro sensitivity to ribavirin, contrary to the clinical phenotype. Analy- sis of the replication of mutant full-length virus and in vitro culturing of patient-derived virus confirmed that sensitivity to ribavirin was retained. Finally, deep-sequencing of hepatitis E virus genomes revealed that ribavirin is mutagenic to viral replication in vitro and in vivo. Conclusions: Mutations Y1320H, G1634R and the hypervariable region insertion compensated for K1383N-associated replication defects. The specific role of the K1383N mutation remains enigmatic, but it appears to be of importance for the ribavirin resistant phenotype in this patient. Lay summary: Ribavirin is the most common treatment for chronic hepatitis E and is mostly effective, although some cases of ribavirin treatment failure have been described. Here, we report on a particular case of ribavirin resistance and investigate the underlying causes of treatment failure. Mutations in the viral polymerase, an essential enzyme for viral replication, appear to be responsible.
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