title: Characterization of hepatitis C virus intergenotypic recombinant strains and associated virological response to sofosbuvir/ribavirin.
abstract: To date, intergenotypic recombinant hepatitis C viruses (HCVs) and their treatment outcomes have not been well characterized. This study characterized 12 novel HCV recombinant strains and their response to sofosbuvir in combination with ribavirin (SOF/RBV) treatment. Across the phase II/III studies of SOF, HCV samples were genotyped using both the Siemens VERSANT HCV Genotype INNO-LiPA 2.0 Assay (Innogenetics, Ghent, Belgium) and nonstructural (NS)5B sequencing. Among these patient samples, genotype assignment discordance between the two methods was found in 0.5% of all cases (12 of 2,363), of which all were identified as genotype 2 by INNO-LiPA (12 of 487; 2.5%). HCV full-genome sequences were obtained for these 12 samples by a sequence-independent amplification method coupled with next-generation sequencing. HCV full-genome sequencing revealed that these viruses were recombinant HCV strains, with the 5' part corresponding to genotype 2 and the 3' part corresponding to genotype 1. The recombination breakpoint between genotypes 2 and 1 was consistently located within 80 amino acids of the NS2/NS3 junction. Interestingly, one of the recombinant viruses had a 34-amino-acid duplication at the location of the recombination breakpoint. Eleven of these twelve patients were treated with a regimen for genotype 2 HCV infection, but responded as if they had genotype 1 infection; 1 patient had received placebo.
  
  
  CONCLUSIONS
  Twelve new HCV intergenotypic recombinant genotype 2/1 viruses have been characterized. The antiviral response to a 12- to 16-week course of SOF/RBV treatment in these patients was more similar to responses among genotype 1 patients than genotype 2 patients, consistent with their genotype 1 NS5B gene.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hedskog
authors.forename: Brian
authors.initials: B
authors.lastname: Doehle
authors.forename: Krishna
authors.initials: K
authors.lastname: Chodavarapu
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gontcharova
authors.forename: Javier
authors.initials: J
authors.lastname: Crespo Garcia
authors.forename: Robert
authors.initials: R
authors.lastname: De Knegt
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Diana
authors.initials: D
authors.lastname: Brainard
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Stamm
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Evguenia
authors.initials: E
authors.lastname: Svarovskaia
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D016679:Genome, Viral; D060005:Genotyping Techniques; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D011995:Recombination, Genetic; D012254:Ribavirin / Q000627:therapeutic use*; D017423:Sequence Analysis, RNA; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase