Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment

Abstract

The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC(50)]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC(50)) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

Fig 1

Comparison of early response to T/PR (telaprevir, peginterferon, and ribavirin) in treatment-naive patients with or without predominant telaprevir-resistant variants prior to treatment. The y axis displays the mean HCV RNA decline from baseline through the first 4 weeks of treatment. The results obtained for treatment-naive patients with the lower-level telaprevir-resistant variants V36M (green; n = 6), T54S (blue; n = 50), or R155K (red; n = 10) prior to treatment with telaprevir, peginterferon, and ribavirin (including patients enrolled to receive 8 weeks of telaprevir [19]) are indicated. For comparison, the median HCV RNA decline for patients who received a regimen of 12 weeks of telaprevir with response-guided peginterferon and ribavirin (black) in the phase 3 treatment, i.e., the Naive ADVANCE Study (19), is also shown. Results for all patients in the ADVANCE study receiving peginterferon and ribavirin (gray) and the subpopulation of patients receiving peginterferon and ribavirin that had undetectable HCV RNA at week 4 (RVR) are indicated by a dashed gray line.