title: In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome.
abstract: Hepatitis 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.
  
  
  
  Illumina 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.
  
  
  
  Together, 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.
  
  
  
  In 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.
authors.affiliation: Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Todt
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Gisa
authors.affiliation: Division of Highly Pathogenic Viruses, Robert-Koch-Institut, Centre for Biological Threats and Special Pathogens, Berlin, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Radonic
authors.affiliation: Division of Highly Pathogenic Viruses, Robert-Koch-Institut, Centre for Biological Threats and Special Pathogens, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Nitsche
authors.affiliation: Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Behrendt
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Pothakamuri Venkata
authors.initials: PV
authors.lastname: Suneetha
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany First Medical Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Pischke
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Bremer
authors.affiliation: Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Richard J P
authors.initials: RJ
authors.lastname: Brown
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany German Center for Infectious Disease Research (DZIF), Partnersite Hannover-Braunschweig, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany German Center for Infectious Disease Research (DZIF), Partnersite Hannover-Braunschweig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Cornberg
authors.affiliation: Division of Viral Gastroenteritis, Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert-Koch-Institut, Berlin, Germany.
authors.forename: C Thomas
authors.initials: CT
authors.lastname: Bock
authors.affiliation: Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Steinmann
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany German Center for Infectious Disease Research (DZIF), Partnersite Hannover-Braunschweig, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D002908:Chronic Disease; D016903:Drug Monitoring; D005260:Female; D018740:Genetic Heterogeneity / Q000187:drug effects; D016679:Genome, Viral / Q000187:drug effects*; D016751:Hepatitis E / Q000188:drug therapy / Q000503:physiopathology / Q000821:virology; D016752:Hepatitis E virus / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin
keywords: ANTIVIRAL THERAPY; CHRONIC HEPATITIS; HEPATITIS E