title: L159F and V321A Sofosbuvir-Associated Hepatitis C Virus NS5B Substitutions.
abstract: BACKGROUND
  Sofosbuvir (SOF) exhibits a high barrier to resistance, with no S282T NS5B substitution or phenotypic resistance detected in phase 3 registration studies.
  
  
  METHODS
  Here, emergence of the NS5B variants L159F and V321A and possible association with resistance was evaluated in 8 studies of SOF (NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1, PHOTON-2, and P7977-2025) and 5 studies of combination ledipasvir (LDV) and SOF (LDV/SOF; LONESTAR, ELECTRON [LDV/SOF arms], ION1, ION2, and ION3), using deep sequencing.
  
  
  RESULTS
  Deep sequencing detected L159F in 15% (53 of 353) and V321A in 5% (17 of 353) of patients with virologic failure in the SOF studies. Intensification of SOF treatment with LDV reduced the emergence of L159F or V321A to 2% (1 of 50 each) at virologic failure. L159F and V321A did not influence the outcome of retreatment with SOF, ribavirin, and pegylated interferon. At baseline, L159F was detected only in genotype 1-infected patients (1%) and was only associated with increased virologic failure in patients treated for short durations with SOF and ribavirin.
  
  
  CONCLUSIONS
  Deep-sequencing analysis confirmed that NS5B variants L159F and V321A emerged in a subset of patients treated with SOF at virologic failure. These variants had no impact on retreatment outcome with SOF, ribavirin, and pegylated interferon. Baseline L159F in genotype 1 did not affect the treatment outcome with LDV/SOF.
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Evguenia S
authors.initials: ES
authors.lastname: Svarovskaia
authors.affiliation: University of Auckland, New Zealand.
authors.forename: Edward
authors.initials: E
authors.lastname: Gane
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Ross
authors.initials: R
authors.lastname: Martin
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Brian
authors.initials: B
authors.lastname: Doehle
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hedskog
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, University of Texas Health Science Center, San Antonio.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Gilead Sciences, Foster City, California.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017720:Molecular Epidemiology; D017423:Sequence Analysis, RNA; D000069474:Sofosbuvir / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D000069474:Sofosbuvir
keywords: HCV NS5B sofosbuvir resistance–associated variants; L159F; V321A; direct-acting antivirals; resistance; sofosbuvir