Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein

Abstract

Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons. In a phase 1b 3-day monotherapy study, patients treated with a 150-mg dose of GS-5816 had a mean maximal HCV RNA decline of ≥3.3 log10 IU/ml in GT1a, -1b, -2, -3, and -4. This report characterizes virologic resistance to VEL in these patients. NS5A resistance-associated substitutions (RASs) were detected by deep sequencing (1% cutoff) pretreatment in 22/70 patients, i.e., 10/35 (29%) patients with GT1a, 1/8 (13%) with GT1b, 4/8 (50.0%) with GT2, 5/17 (29.4%) with GT3, and 2/2 (100.0%) with GT4. In GT1a and GT3 patients, pretreatment RASs were associated with a slightly reduced HCV RNA response compared to that of patients without pretreatment RASs; among patients with GT1b, GT2, and GT4, no significant difference in response was observed in those with or without pretreatment RASs. Following treatment, the pattern of emergent RASs was more complex for GT1a than for the other genotypes. In GT1a, substitutions emerged at positions M28, Q30, L31, P32, H58, E92, and Y93, with the most prevalent substitutions at positions Y93, M28, and L31. RASs were observed at two positions in GT1b and GT2 (Y93 and L31), three positions in GT3 (Y93, L31, and E92), and four positions in GT4 (L28, M31, P32L, and Y93). RASs that were present pretreatment persisted through the 48-week follow-up period; however, RASs emerging during treatment were more likely to decline both in prevalence and in frequency within the viral population during follow-up. (This study has been registered at ClinicalTrials.gov under registration no. NCT01740791.).

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Maximum changes from pretreatment HCV RNA loads. The mean ± the standard deviation of the maximum viral load reductions in patients dosed with GS-5816 for 3 days are shown. (A) GT1a patients. (B) GT3 patients. (C) GT1 to GT4 patients dosed with 150 mg of GS-5816. All patients with pretreatment RASs are indicated with the pretreatment percentage of each RAS shown in parentheses, except for one GT1a patient with only population sequencing available (pretreatment RAS L31L/M).

FIG 2

Changes in the frequency of NS5A RASs among patients with or without pretreatment RASs through 48 weeks posttreatment. (A) Changes in frequencies among patients with pretreatment RASs included Y93H (n = 3 [GT1a, n = 2; GT1b, n = 1]), L31M (n = 11 [GT1a, n = 7; GT2b, n = 4]), H58D (GT3a, n = 3), Q30H (GT1a, n = 2), M28T (GT1a, n = 3), and Q30R (GT1a, n = 2). (B) Changes in frequencies among patients without pretreatment RASs included Y93H (n = 38 [GT1a, n = 18; GT1b, n = 6; GT2b, n = 2; GT3, n = 12]), L31M (n = 16 [GT1a, n = 11; GT1b, n = 4; GT2b, n = 1]), L31V (n = 25 [GT1a, n = 18; GT1b, n = 5; GT2b, n = 1; GT3, n = 1]), H58D (GT1a, n = 5), M28T (GT1a, n = 17), Q30H (GT1a, n = 6), Q30R (GT1a, n = 10), Y93N (n = 21 [GT1a, n = 14; GT1b, n = 2; GT3a, n = 5]). Means ± standard deviations of frequencies of NS5A variants in patients with RASs and available samples at each visit are shown.