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Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients.

ABSTRACT: GS-9451, a novel hepatitis C virus (HCV) nonstructural 3/4a (NS3/4a) protease inhibitor, is highly active in patients infected with HCV genotype 1 (GT 1). The aim of this study is to characterize the clinical resistance profile of GS-9451 in GT 1 HCV-infected patients in a phase 1, 3-day monotherapy study. The full-length NS3/4A gene was population sequenced at baseline, on the final treatment day, and at follow-up time points. NS3 protease domains from patient isolates with emerging mutations were cloned into an NS3 shuttle vector, and their susceptibilities to GS-9451 and other HCV inhibitors were determined using a transient replication assay. No resistance mutations at NS3 position 155, 156, or 168 were detected in any of the baseline samples or in viruses from patients treated with 60 mg of GS-9451 once daily. Among patients who received 200 mg and 400 mg of GS-9451, viruses with mutations at position D168 (D168E/G/V) and R155 (R155K), which confer high-level resistance to GS-9451, were detected in those with GT 1b and GT 1a virus, respectively. Viruses with D168 mutations were no longer detected in any GT 1b patient at day 14 and subsequent time points. In GT 1a patients, R155K mutants were replaced by the wild type in 57% of patients at week 24. These NS3 clinical mutants were sensitive to NS5B and NS5A inhibitors, as well as alpha interferon (IFN-?) and ribavirin. The lack of cross-resistance between GS-9451 and other classes of HCV inhibitors supports the utility of combination therapy.

SUBMITTER: Dvory-Sobol H

PROVIDER: S-EPMC3457362 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients.

Dvory-Sobol Hadas H Wong Kelly A KA Ku Karin S KS Bae Andrew A Lawitz Eric J EJ Pang Phillip S PS Harris Jeanette J Miller Michael D MD Mo Hongmei H

Antimicrobial agents and chemotherapy 20120806 10

GS-9451, a novel hepatitis C virus (HCV) nonstructural 3/4a (NS3/4a) protease inhibitor, is highly active in patients infected with HCV genotype 1 (GT 1). The aim of this study is to characterize the clinical resistance profile of GS-9451 in GT 1 HCV-infected patients in a phase 1, 3-day monotherapy study. The full-length NS3/4A gene was population sequenced at baseline, on the final treatment day, and at follow-up time points. NS3 protease domains from patient isolates with emerging mutations w ...[more]

PMID: 22869562

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Project description:Asunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensive in vitro genotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

Dataset Information

Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients.

Publications

Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients.

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