Analysis of Genotype 2 and 3 Hepatitis C Virus Variants in Patients Treated With Telaprevir Demonstrates a Consistent Resistance Profile Across Genotypes

S. De Meyer; A. Ghys; G. R. Foster; M. Beumont; B. Van Baelen; T.-I. Lin; I. Dierynck; H. Ceulemans; G. Picchio

Disclosures

J Viral Hepat. 2013;20(6):395-403. 

In This Article

Abstract and Introduction

Abstract

Study C209 evaluated the activity of telaprevir in treatment-naïve patients with genotypes 2 or 3 (G2, G3) hepatitis C virus (HCV) infection. Telaprevir monotherapy showed potent activity against HCV G2, but limited activity against G3. This analysis was performed to characterize HCV viral variants emerging during telaprevir-based treatment of G2/G3 HCV-infected patients. Patients were randomized to receive 2 weeks of treatment with telaprevir (telaprevir monotherapy), telaprevir plus peginterferon alfa-2a and ribavirin (triple therapy), or placebo plus peginterferon alfa-2a and ribavirin (control), followed by 22–24 weeks of peginterferon/ribavirin alone. Viral breakthrough was defined as an increase >1 log10 in HCV RNA from nadir, or HCV RNA >100 IU/mL in patients previously reaching <25 IU/mL. Twenty-three patients (47%) had G2 and 26 (53%) had G3 HCV. Viral breakthrough occurred during the initial 2-week treatment phase in six G2 patients (66.7%; subtypes 2, 2a and 2b) and three G3 patients (37.5%; all subtype 3a), all in the telaprevir monotherapy arm. Four breakthrough patients (three G2, one G3) subsequently achieved sustained virologic response (SVR). In all patients with breakthrough and available sequence data, mutations associated with reduced susceptibility to telaprevir in genotype 1 (G1) HCV were observed. No novel G2/G3-specific mutations were associated with telaprevir resistance. The telaprevir resistance profile appeared consistent across HCV genotypes 1, 2 and 3. Although viral breakthrough with resistance occurred in patients receiving telaprevir monotherapy, half of these patients achieved an SVR upon addition of peginterferon/ribavirin highlighting the importance of combination therapy.

Introduction

Chronic hepatitis C virus (HCV) infection is a major global healthcare burden.[1] Six HCV genotypes and over 100 subtypes are documented,[2] each with a distinct geographical distribution. Genotype 1 (G1) HCV predominates in Europe, the United States and Japan, G2 predominates in Mediterranean countries and the Far East, and G3 is common in the Indian subcontinent.[3,4] An increase in the proportion of patients with G3 HCV infection was recently observed in Europe.[5]

Two direct-acting antiviral (DAA) agents that target the HCV NS3-4A serine protease, telaprevir[6] and boceprevir,[7] showed substantial efficacy against chronic HCV G1 infection[8–12] and were recently approved in the United States and Europe. Preliminary in vitro data suggested that telaprevir also has activity against G2/G3 HCV.[13] Therefore, the Phase IIa C209 study evaluated the activity of telaprevir, administered for 15 days with or without peginterferon/ribavirin, on G2/G3 HCV infection. When administered as monotherapy, telaprevir had significant and rapid antiviral activity against G2 HCV, but little or no activity against G3.[14]

G1 HCV variants associated with decreased susceptibility to telaprevir were previously identified in patients not achieving an SVR. The single amino acid changes V36A/M, T54A/S, R155K/T and A156S confer lower-level in vitro resistance to telaprevir (3- to 25-fold increase in replicon 50% inhibitory concentration [IC50]), whereas single change A156T/V and double change V36M+R155K confer higher-level resistance (>25-fold increase in replicon IC50).[15] Whether similar variants are associated with lack of response to telaprevir in G2/G3 HCV infection is unknown. Therefore, this subanalysis of the C209 study characterized HCV viral variants emerging with telaprevir-based therapy in G2/G3 HCV-infected patients.

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