Department of Clinical Virology.
GS-5885 is a novel hepatitis C virus (HCV) NS5A inhibitor. In a 3-day monotherapy study in treatment-naïve genotype (GT) 1a and 1b HCV-infected subjects, median viral load reductions ranged from 2.3 to 3.3 log10 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. 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 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 susceptibility 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 (DAA), interferon-α, and ribavirin. Importantly, the non-overlapping resistance profile and high potency of GS-5885 supports its further development with other direct acting antivirals for the treatment of chronic HCV.