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Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885

Wong, KA and Worth, A and Martin, R and Svarovskaia, E and Brainard, DM and Lawitz, E and Miller, MD and Mo, H (2013) Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885. Antimicrobial Agents and Chemotherapy. pp. 6333-6340.

Abstract

GS-5885 is a novel hepatitis C virus (HCV) NS5A inhibitor. In a 3-day monotherapy study in treatment-naive genotype 1a (GT1a) and GT1b HCV-infected subjects, median viral load reductions ranged from 2.3 to 3.3 log<sub>10</sub> HCV RNA IU/ml across dosing cohorts (1, 3, 10, 30, or 90 mg once daily). Here, we report viral sequencing and phenotypic analysis of clinical isolates from this study. Detection of baseline NS5A amino acid substitutions at positions 28, 30, 31, or 93 in GT1a was associated with a reduced treatment response. In the GT1b cohort, Y93H was detected in 100% of subjects at day 4 or 14. In the Gt1a cohort, population sequencing detected NS5A resistance-associated mutations at day 4 or 14 for 3/10 subjects at the 1-mg dose and for all subjects dosed at > 3 mg. A subset of mutants that confer a low level of reduced susceptibility to GS-5885 was not detected by population sequencing at the 30- and 90-mg doses. Subject-derived M28T, Q30R, L31M, and Y93C mutations all conferred > 30- fold reductions in GS-5885 and daclatasvir susceptibilities in vitro. Site-directed NS5A mutants also showed reduced susceptibility to GS-5885. However, all NS5A mutants tested remained fully susceptible to other classes of direct-acting antivirals (DAAs), interferon alpha, and ribavirin. Importantly, the nonoverlapping resistance profile and high potency of GS-5885 support its further development with other direct-acting antivirals for the treatment of chronic HCV. (This study has been registered at ClinicalTrials. gov under registration number NCT01193478.) Copyright 2013, American Society for Microbiology. All Rights Reserved

Item Type: Article
Additional Information: pubid: 45 nvp_institute: NIBR contributor_address: (Wong, Worth, Martin, Svarovskaia, Miller, Mo) Department of Clinical Virology, Gilead Sciences, Inc., Foster City, CA, United States (Brainard) Department of Clinical Research, Gilead Sciences, Inc., Foster City, CA, United States (Lawitz) Alamo Medical Research, Camden Medical Center, San Antonio, TX, United States (Wong) Novartis Institute for Biomedical Research, Emeryville, CA, United States
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21893

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