title: Clinical and in vitro resistance to GS-9669, a thumb site II nonnucleoside inhibitor of the hepatitis C virus NS5B polymerase.
abstract: Treatment with GS-9669, a novel nonnucleoside inhibitor (site II) of hepatitis C virus (HCV) nonstructural 5B (NS5B) polymerase, resulted in significant antiviral activity in HCV genotype (GT) 1 patients dosed at 50 and 500 mg once daily (QD) and at 50, 100, and 500 mg twice daily (BID) for 3 days. This report characterizes the virologic resistance to GS-9669 in vitro and in GT1 HCV-infected patients from a phase I clinical study. An in vitro resistance selection study with GS-9669 revealed substitutions at several NS5B residues that conferred resistance. The M423 variants were selected at low drug concentrations (5× the 50% effective concentration [EC50]), and the L419, R422, and I482 variants were selected at higher drug concentrations (20× the EC50). During the phase I clinical study, substitutions at NS5B residues 419, 422, and 486 were the predominant changes associated with GS-9669 monotherapy. Substitutions at position 423 were observed only in GT1a patients in the low-dose groups (50 and 100 mg BID). Interestingly, four HCV patients had substitutions at position 423 at baseline. Consistent with the low resistance level at this position, three patients with M423I or M423V at baseline achieved >2-log10 reductions of HCV RNA when treated with 100 mg BID or with 500 mg QD or BID of GS-9669. The fourth patient, who had the M423V substitution at baseline, had a 4.4-log10 reduction of HCV RNA with 500 mg BID of GS-9669. Phenotypic analyses demonstrated that the viral isolates with multiple GS-9669 resistance-associated variants have reduced susceptibility to GS-9669 and lomibuvir (VX-222) but are not cross-resistant to other classes of HCV inhibitors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01431898.).
authors.affiliation: Gilead Sciences, Foster City, California, USA hadas.dvory-sobol@gilead.com.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Voitenleitner
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Mabery
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Skurnac
authors.affiliation: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: McHutchison
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Evguenia S
authors.initials: ES
authors.lastname: Svarovskaia
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: William
authors.initials: W
authors.lastname: Delaney
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D001483:Base Sequence; D001562:Benzimidazoles / Q000627:therapeutic use; D002460:Cell Line; D024882:Drug Resistance, Viral; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D005663:Furans / Q000627:therapeutic use*; D014644:Genetic Variation; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011485:Protein Binding; D011804:Quinolines / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D017423:Sequence Analysis, RNA; D000069474:Sofosbuvir; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D005663:Furans; D011804:Quinolines; D012254:Ribavirin; D000069474:Sofosbuvir; D013876:Thiophenes; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C573362:GS-9451; C582393:GS-9669; C586541:ledipasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase