Here we report NS5A deep sequencing analyses of patient HCV samples obtained from a 3-day monotherapy study of GS-5816 in HCV-infected subjects. Methods: Treatment naïve patients with chronic HCV infection were administered GS-581 6 for 3 days at doses ranging from 5mg-150mg. Pretreatment, on-treatment, and post-treatment plasma samples from GT 1,2, and 3 subjects were analyzed for NS5A RAVs by deep sequencing analysis with a 1% assay
cutoff. The presence of NS5A RAVs at amino acids 28, click here 30, 31, 58 and 93 were examined for GT 1a, 2, and 3 samples and NS5A amino
acids 31 and 93 for GT 1 b. Results: The NS5A RAVs M28T, Q30H/R, L31M/V, and Y93C/H/R were detected at baseline in 10/32 (31.3%) sequenced GT 1 a infected subjects. Despite this high rate of detectable FK506 supplier RAVs, similar viral load decreases were observed in subjects with detectable baseline RAVs versus those with no detectable RAVs. One GT 1 b infected subject had Y93H at baseline that did not impact response to GS-5816 150mg. Four of seven GT 2 infected subjects had detectable L31M at baseline. No significant differences in maximum viral load reductions between subjects with L31 or M31 were observed. In GT 3 infected selleck chemicals subjects, the A30K and Y93H RAVs were observed in 1/10 and 2/10 subjects, respectively. One GT 3 infected subject with Y93H (16% of population)
had a 2.7 log 10 reduction in HCV RNA with administration of GS-5816 150 mg. The single GT 3 infected subject with A30K had a 2.9 log10 decrease in HCV RNA. Overall, NS5A RAVs were detected at varying prevalence, with frequencies varying from 1-99% as a proportion of the HCV quasispecies. Fourteen-day post-treatment analyses demonstrated complex mixtures of NS5A RAVs including M28T, Q30R/H, L31M/V, H58D, and Y93H/N/S among GT 1a subjects. In GT 1b and GT 2b subjects, L31V/M and Y93H were commonly observed while Y93H/N was the most common RAV in GT 3 subjects following 3-day GS-5816 treatment. Conclusions: The NS5A inhibitor GS-5816 demonstrated potent antiviral activity in GT 1,2, and 3 HCV-infected subjects despite the presence of NS5A RAVs at baseline. The patterns of NS5A RAVs observed after GS-5816 monotherapy were GT/subtype dependent. Disclosures: Christy Hebner – Employment: Gilead Sciences, Inc. Ramakrishna K.
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