title: Antiviral response and resistance analysis of treatment-naïve HCV-infected patients receiving single and multiple doses of GS-9190.
abstract: GS-9190 is a NS5B non-nucleoside analogue with demonstrated effectiveness in a Phase 1 monotherapy study and in combination with other DAAs for treatment of chronic HCV infection. Here, the resistance profile of GS-9190 monotherapy in a Phase 1b study was investigated. Resistance analysis was performed by population sequencing and allele-specific PCR (AS-PCR) for Y448H with an assay cut-off of 0.5%. Phenotypic susceptibility analyses were performed on patient isolates as well as site-directed mutagenesis of mutations selected during monotherapy. No resistance-associated variants were observed in patients before or after receiving single doses of GS-9190 by population sequencing. In contrast, in patients who received GS-9190 for 8 days, mutations Y448H and Y452H in NS5B were observed by population sequencing in 21/36 (58%) and 2/36 (5.6%) patients, respectively, at Day 8 or Day 14. Among the remaining 15 patients who had no detectable Y448H at Day 8 or Day 14 by population sequencing, low frequencies of Y448H ranging from 1.3 to 9.7% were detected in 14 of 15 patients by AS-PCR. By AS-PCR, Y448H remained detectable at reduced frequency in the majority of patients analysed through 4-6 months of follow-up. Chimeric HCV replicons constructed with the NS5B sequence from patients with Y448H and Y448H + Y452H/Y demonstrated 27-fold and 78.5-fold reduced susceptibility to GS-9190. In conclusion, Y448H was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Y448H confers reduced susceptibility to GS-9190 and other NNIs and persisted in most patients for months post-treatment.
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Mo
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hedskog
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Svarovskaia
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: S-C
authors.initials: SC
authors.lastname: Sun
authors.affiliation: Mount Sinai Beth Israel Medical Center, New York, NY, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Miller
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000008:administration & dosage*; D011724:Pyridazines / Q000008:administration & dosage*; D011995:Recombination, Genetic; D012641:Selection, Genetic; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D011687:Purines; D011724:Pyridazines; C571890:tegobuvir
keywords: GS-9190; NS5B; hepatitis C virus; non-nucleoside inhibitors; resistance; tegobuvir