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 numberNCT01724086 (date of registration: September 26, 2012)
Highlights
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
In the Phase 2a study TMC647055HPC2001 (NCT01724086), a 12-week 3-direct-acting antivirals (DAAs) regimen of simeprevir (SMV), TMC647055/ritonavir (RTV) and JNJ56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12; 93% for HCV genotype [GT]1a- and 100% for GT1binfected patients in the JNJ-56914845 60 mg group) while SVR12 rates were lower in the 12-week 2-DAA regimens of SMV and TMC647055/RTV with or without ribavirin (RBV) (SVR12 33 − 86% depending on HCV geno/subtype, presence of RBV and TMC647055 dose) [5]
Baseline polymorphisms At baseline, SMV Resistance-associated variant (RAV) were observed in 6/89 GT1infected patients (6.7%) with NS3 sequencing data available
Summary
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. In the Phase 2a study TMC647055HPC2001 (NCT01724086), a 12-week 3-DAA regimen of simeprevir (SMV), TMC647055/ritonavir (RTV) and JNJ56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12; 93% for HCV genotype [GT]1a- and 100% for GT1binfected patients in the JNJ-56914845 60 mg group) while SVR12 rates were lower in the 12-week 2-DAA regimens of SMV and TMC647055/RTV with or without ribavirin (RBV) (SVR12 33 − 86% depending on HCV geno/subtype, presence of RBV and TMC647055 dose) [5]. At the end of study, these mutations could no longer be detected in half of the patients
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