Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir
Open Access
- 1 November 2015
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 59 (11), 6922-6929
- https://doi.org/10.1128/aac.01390-15
Abstract
Elbasvir is an investigational NS5A inhibitor with in vitro activity against multiple HCV genotypes. Antiviral activity of elbasvir was measured in replicons derived from wild-type or resistant variants of genotypes 1a, 1b, and 3. The barrier to resistance was assessed by the number of resistant colonies selected by exposure to various elbasvir concentrations. In a phase 1b dose-escalating study, virologic responses were determined in 48 noncirrhotic adult men with chronic genotype 1 or 3 infections randomized to placebo or elbasvir from 5 to 50 mg (genotype 1) or 10 to 100 mg (genotype 3) once daily for 5 days. The NS5A gene was sequenced from plasma specimens obtained before, during, and after treatment. Elbasvir suppressed the emergence of resistance-associated variants (RAVs) in vitro in a dose-dependent manner. Variants selected by exposure to high elbasvir concentrations typically encoded multiple amino acid substitutions (most commonly involving loci 30, 31, and 93), conferring high-level elbasvir resistance. In the monotherapy study, patients with genotype 1b had greater reductions in HCV RNA levels than patients with genotype 1a at all elbasvir doses; responses in patients with genotype 3 were generally less pronounced than for genotype 1, particularly at lower elbasvir doses. M28T, Q30R, L31V, and Y93H in genotype 1a, L31V and Y93H in genotype 1b, and A30K, L31F, and Y93H in genotype 3 were the predominant RAVs selected by elbasvir monotherapy. Virologic findings in patients were consistent with the preclinical observations. NS5A-RAVs emerged most often at amino acid positions 28, 30, 31, and 93 in both the laboratory and clinical trial. (The MK-8742 P002 trial has been registered at ClinicalTrials.gov under identifier NCT01532973.)Keywords
This publication has 23 references indexed in Scilit:
- Antiviral activity and resistance of HCV NS5A replication complex inhibitorsCurrent Opinion in Virology, 2013
- Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studiesVirology, 2013
- Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitorsJournal of Clinical Virology, 2013
- Amplification and Sequencing of the Hepatitis C Virus NS3/4A Protease and the NS5B Polymerase Regions for Genotypic Resistance Detection of Clinical Isolates of Subtypes 1a and 1bPublished by Springer Science and Business Media LLC ,2013
- Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical TrialsClinical Infectious Diseases, 2013
- Clinical relevance of HCV antiviral drug resistanceCurrent Opinion in Virology, 2012
- Quantifying the Diversification of Hepatitis C Virus (HCV) during Primary Infection: Estimates of the In Vivo Mutation RatePLoS Pathogens, 2012
- HCV Genotypes Are Differently Prone to the Development of Resistance to Linear and Macrocyclic Protease InhibitorsPLOS ONE, 2012
- Regulation of the Production of Infectious Genotype 1a Hepatitis C Virus by NS5A Domain IIIJournal of Virology, 2011
- In vitro antiviral activity of SCH446211 (SCH6), a novel inhibitor of the hepatitis C virus NS3 serine proteaseJournal of Antimicrobial Chemotherapy, 2006