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

Abstract

BackgroundIn 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.MethodsHCV 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.ResultsThe 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.ConclusionsVirologic 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.Trial registration number NCT01724086 (date of registration: September 26, 2012)Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-017-0760-2) contains supplementary material, which is available to authorized users.

Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors

“…Clinical trials have highlighted its promising antiviral properties against HCV, as well as its good safety and tolerability profiles, with limited toxicity and off-target activities. In combination with the TMC435 protease inhibitor (also known as simeprevir) and ritonavir showed an increased antiviral activity against HCV and was well tolerated by patients (Bourgeois et al, 2017;Vijgen et al, 2017).…”

Sociodemographic and clinical characterization of patients with chronic hepatitis C

“…La Organización Mundial de la Salud (OMS) estima que existen, mundialmente, cerca de 130 a 150 millones de personas infectadas por el HCV, de ellas, 71 millones tienen infección crónica y, aproximadamente, 399.000 mueren al año, por causas derivadas de la hepatitis C, principalmente debido a la cirrosis y al carcinoma hepatocelular. Por tanto, se considera, una enfermedad emergente (1)(2)(3) .…”