Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

• Published in: Virology journal Vol. 14; no. 1; p. 101
• Main Authors: Vijgen, Leen, Thys, Kim, Vandebosch, An, Van Remoortere, Pieter, Verloes, René, De Meyer, Sandra
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.05.2017; BioMed Central; BMC
• Subjects: Amino acids; Analysis; Antiretroviral drugs; Antiviral agents; Antiviral Agents - therapeutic use; Antiviral drugs; Carbamates - therapeutic use; Comparative analysis; Dosage and administration; Drug development; Drug resistance; Drug Resistance, Viral; Drug therapy; Genetic aspects; Genotype; Genotype & phenotype; Genotype 1; Genotyping Techniques; Hepacivirus - classification; Hepacivirus - genetics; Hepacivirus - isolation & purification; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; Heterocyclic Compounds, 4 or More Rings - therapeutic use; Humans; Infections; Interferon; JNJ-56914845; Mutation; Patients; Population studies; Ribavirin; Ribavirin - therapeutic use; Ritonavir; Ritonavir - therapeutic use; Sequence Analysis, DNA; Simeprevir; Simeprevir - therapeutic use; Sulfonamides - therapeutic use; TMC647055/ritonavir; Treatment Failure; Treatment outcome; Valine - analogs & derivatives; Valine - therapeutic use; Virology; United States > US; Genotype 1; Simeprevir; TMC647055/ritonavir; Hepatitis C virus; JNJ-56914845
• ISSN: 1743-422X; 1743-422X
• DOI: 10.1186/s12985-017-0760-2

In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001. HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates. The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients. Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study. NCT01724086 (date of registration: September 26, 2012).