Resistance Analyses of HCV NS3/4A Protease and NS5B Polymerase from Clinical Studies of Deleobuvir and Faldaprevir

• Published in: PloS one 2016-08, Vol.11 (8), p.e0160668
• Main Authors: Berger, Kristi L, Sarrazin, Christoph, Nelson, David R, Scherer, Joseph, Sha, Nanshi, Marquis, Martin, Côté-Martin, Alexandra, Vinisko, Richard, Stern, Jerry O, Mensa, Federico J, Kukolj, George
• Format: Article
• Language: English
• Subjects: Acids; Acrylates - therapeutic use; Alanine; Amino Acid Substitution; Amino acids; Antiviral agents; Antiviral Agents - therapeutic use; Benzimidazoles - therapeutic use; Binding sites; Biology and life sciences; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Clinical trials; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Complications and side effects; Consolidation; Disease resistance; Dosage and administration; Drug Resistance, Viral - drug effects; Drug therapy; Gastroenterology; Genetic aspects; Genotype & phenotype; Genotypes; Hepacivirus - drug effects; Hepacivirus - genetics; Hepacivirus - metabolism; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - virology; Humans; Infections; Interferon; Intracellular Signaling Peptides and Proteins; Medicine and health sciences; Microbial drug resistance; Mutation - genetics; Oligopeptides - therapeutic use; Patients; Pharmaceuticals; Physical Sciences; Physiological aspects; Polymorphism; Polymorphism, Genetic - drug effects; Polymorphism, Genetic - genetics; Protease; Protease inhibitors; Protease Inhibitors - therapeutic use; Proteases; Research and analysis methods; Ribavirin; RNA polymerase; RNA-directed RNA polymerase; Studies; Thiazoles - therapeutic use; Treatment Outcome; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0160668

The resistance profile of anti-hepatitis C virus (HCV) agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B amino-acid variants among HCV genotype (GT)-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor), deleobuvir (HCV polymerase non-nucleoside inhibitor), and ribavirin in multiple clinical studies. HCV NS3/4A and NS5B population sequencing (Sanger method) was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B) and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b). Persistence and time to loss of resistance-associated variants (RAVs) was estimated using Kaplan-Meier analysis. Faldaprevir RAVs (NS3 R155 and D168) and deleobuvir RAVs (NS5B 495 and 496) were rare (90%). Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b); some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b). Median time to loss of GT-1b NS5B P495 RAVs post-treatment (5 months) was less than that of GT-1b NS3 D168 (8.5 months) and GT-1a R155 RAVs (11.5 months). Faldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b) may reduce response to this deleobuvir-based regimen.