Author information
1
Texas Liver Institute, University of Texas Health, San Antonio, TX, USA.
2
Gilead Sciences, Inc., Foster City, CA, USA.
Abstract
BACKGROUND:
Voxilaprevir (VOX, GS-9857) is a pangenotypic hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with potent antiviral activity against HCV genotypes (GTs) 1-6 and improved coverage of GT1 NS3 resistance-associated substitutions (RASs) associated with other HCV PIs. In a 3-day phase 1b monotherapy study in patients infected with HCV GT1a, 1b, 2, 3 and 4, VOX was well tolerated and resulted in maximal mean viral load reduction >3 log10 IU/ml at the 100 mg dose across all genotypes evaluated. This report characterizes the HCV NS3 RASs in the study.
METHODS:
The NS3 gene was amplified and successfully deep sequenced using MiSeq for 66 patients at baseline and 61 patients post-baseline using 15% and 1% assay cutoffs.
RESULTS:
With a 15% assay cutoff, pretreatment HCV NS3 RASs were present in the HCV of 38% (9/24) of patients with GT1a and 5% (1/19) with GT3a; there were no pretreatment NS3 RASs present in patients with GT1b (n=6), GT2 (n=7) or GT4 (n=4). In patients with and without pretreatment NS3 RASs, ≥ 3.4 log10 mean maximal viral load reductions over 3 days of VOX administration were observed. The majority of patients did not have detectable treatment-emergent NS3 RASs and only 12% (7/53) and 26% (14/53) had emergent NS3 RASs using 15% and 1% cutoffs, respectively. No NS3 RASs were detected in patients with GT2 or GT4. A156T or A156V were the most prevalent emergent NS3 RASs in patients with GT1a or GT1b infection, but were not observed in patients with GT3 infection.
CONCLUSIONS:
The lack of selection of NS3 RASs in the majority of patients demonstrates a high resistance barrier for VOX.