title: Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials.
abstract: BACKGROUND
  Sofosbuvir is a chain-terminating nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with HCV genotype 1-6 infection. Sofosbuvir resistance is primarily conferred by the S282T substitution in NS5B.
  
  
  METHODS
  NS5B sequencing and susceptibility testing of HCV from subjects infected with genotypes 1-6 who participated in phase 2 and 3 sofosbuvir clinical trials was performed.
  
  
  RESULTS
  No NS5B variants present at baseline among 1645 sofosbuvir-treated subjects were associated with treatment failure; sofosbuvir susceptibility was within 2-fold of reference. Among 282 subjects who did not achieve sustained virologic response, no novel sofosbuvir resistance-associated variants were identified, and the NS5B changes observed did not confer significant reductions in sofosbuvir susceptibility. In 1 subject with S282T observed at relapse 4 weeks after sofosbuvir monotherapy, the resistant variant (13.5-fold reduced sofosbuvir susceptibility, replication capacity <2% of control) became undetectable by deep sequencing 12 weeks after treatment. L159F and V321A were identified as treatment-emergent variants but did not confer resistance to sofosbuvir in the replicon system.
  
  
  CONCLUSIONS
  These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Evguenia S
authors.initials: ES
authors.lastname: Svarovskaia
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Data First Consulting Inc, Belmont, California.
authors.forename: Neil
authors.initials: N
authors.lastname: Parkin
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Christy
authors.initials: C
authors.lastname: Hebner
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gontcharova
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Ross
authors.initials: R
authors.lastname: Martin
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Wen
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Simin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Karin
authors.initials: K
authors.lastname: Ku
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Sophia
authors.initials: S
authors.lastname: Chiu
authors.affiliation: University of Auckland, Auckland City Hospital, New Zealand.
authors.forename: Edward
authors.initials: E
authors.lastname: Gane
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: University of Florida, Gainesville.
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.affiliation: Texas Liver Institute, San Antonio.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Division of Infectious Diseases, University of California, San Diego.
authors.forename: David L
authors.initials: DL
authors.lastname: Wyles
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Neby
authors.initials: N
authors.lastname: Bekele
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Diana
authors.initials: D
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Gilead Sciences, Foster City.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D016174:Hepacivirus / Q000472:pathogenicity*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D010641:Phenotype; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D014542:Uridine Monophosphate; D000069474:Sofosbuvir
keywords: GS-7977; HCV; NS5B polymerase; antiviral resistance; sofosbuvir