Resistance-Associated Variants in Chronic Hepatitis C Patients Treated with Protease Inhibitors

Abstract

Direct-acting antiviral agents in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) significantly improve sustained virologic response rate and reduce duration of therapy among both treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C. One of the most important considerations with both boceprevir and telaprevir is the potential development of resistant variants with therapy. Patients with poor intrinsic responsiveness to interferon, and those with incomplete virological suppression on protease inhibitor therapy, appear to be at higher risk for resistance. In this article we will define antiviral resistance and review the data on both in vitro and in vivo resistance to protease inhibitors, concentrating on data on boceprevir and telaprevir. We will also explore the significance of resistant variants present at the baseline, as well as the fate of the resistant variants and the ways to minimize the development of resistance to protease inhibitors.

Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE: Table 1.

“…Virologic failure during or after treatment with direct-acting antiviral agents (DAAs) is typically accompanied by the emergence of resistance-associated variants (RAVs) [1,2]. Additional non-cross-resistant drugs are needed for salvage therapy of patients with chronic hepatitis C virus (HCV) infection who do not achieve sustained virologic response (SVR) on DAA regimens [1].…”

“…Additional non-cross-resistant drugs are needed for salvage therapy of patients with chronic hepatitis C virus (HCV) infection who do not achieve sustained virologic response (SVR) on DAA regimens [1]. NS3 variants conferring high-level resistance to the first-generation protease inhibitors (PIs) are well recognized, but the degree of cross-resistance between older and newer drugs in the same class is an active area of investigation [1][2][3][4][5][6][7].…”

Clinical Implications of Detectable Baseline Hepatitis C Virus-Genotype 1 NS3/4A-Protease Variants on the Efficacy of Boceprevir Combined With Peginterferon/Ribavirin

“…The common mutants have been mapped to their positions in the 3-dimensional structure of the NS3-protease active site and correlated with their effects on the enzymatic properties of the NS3/4A-protease and the magnitude of resistance conferred in replicon assays. Although RAVs have been well characterized in vitro, their full therapeutic ramifications are still inadequately understood [ 1 , 3 , 13 – 15 ].…”

Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin

“…The recently licensed nonstructural 3/4A serine protease inhibitors [boceprevir (Victrelis, Merck, Whitehouse Station, NJ) and telaprevir (Incivek, Vertex Pharmaceuticals, Cambridge, MA)] must be given with P/R because of their low barrier to viral resistance when they are used as monotherapy 9, 10. In contrast to conventional P/R therapy, virological failure with protease inhibitor–based combination therapy is often attended by the selection of viral variants with resistance to protease inhibitors.…”

“…In contrast to conventional P/R therapy, virological failure with protease inhibitor–based combination therapy is often attended by the selection of viral variants with resistance to protease inhibitors. This resistance may emerge early during treatment before impending failure becomes apparent by standard monitoring 9‐15…”