Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
GENOTYPIC AND PHENOTYPIC CHARACTERIZATION OF GENOTYPE 2/3 HCV VARIANTS IN PATIENTS TREATED WITH TELAPREVIR ALONE OR IN COMBINATION WITH PEGINTERFERON ALFA-2A/RIBAVIRIN IN STUDY C209
S. De Meyer1*, G.R. Foster2, A. Ghys1, M. Beumont1, B. Van Baelen1, T.-I. Lin1, G. Picchio3
1Tibotec BVBA, Mechelen, Belgium, 2Queen Mary University of London, Institute of Cell and Molecular Science, London, UK, 3Tibotec Inc, Yardley, PA, USA. *firstname.lastname@example.org
Background: C209 is a Phase-2a study of telaprevir, administered alone or with peginterferon-alfa-2a (Peg-IFN) and ribavirin (RBV) in treatment-naïve G2/G3 HCV patients. Interim analyses showed that telaprevir has significant antiviral activity against G2 in monotherapy, but little or no activity against G3 HCV. We report here the first characterization of G2/3 viral variants emerging during telaprevir-based treatment.
Methods: 49 subjects were randomized to receive 15 days of either telaprevir 750mg q8h alone (arm A; G2/3; n=9/8), telaprevir 750mg q8h with Peg-IFN 180µg/week and RBV 800mg/day (arm B; G2/3; n=5/9), or Peg-IFN 180µg/week and RBV 800mg/day plus placebo (arm C; G2/3; n=9/9). All 3 arms received an additional 24 (arm A) or 22 (arms B and C) weeks of Peg-IFN/RBV. Population sequencing of the NS3/4A region was conducted at baseline, and on selected samples obtained during viral breakthrough (vBT) (defined as >1-log increase in HCV-RNA above nadir) and relapse from arms A and B. Selected patient-derived NS3/4A sequences obtained at these timepoints were cloned, expressed, and tested for telaprevir susceptibility using a biochemical assay.
Results: SVR rates (ITT analysis) in G2/3-infected subjects were 56%/50%, 100%/67%, and 89%/44% for arms A, B, and C, respectively. Among G2/G3 subjects receiving telaprevir monotherapy, 6/9 and 3/8 patients, respectively, developed a vBT by day 15; no vBTs were observed in arm B. Variants carrying mutations were detected in 5/5 G2 vBTs with an available genotype; T54A alone (n=2), R155K alone (n=1), T54A+ R155K (n=1), and A156S alone (n=1). In 2/3 G3 patients a R155K mutation was detected. Two G2 and 1 G3 vBTs with emerging mutations in arm A went on to achieve an SVR. 1/5 G3 patients relapsed with a variant carrying a R155K mutation. Susceptibility to telaprevir decreased in all variants carrying mutations by 5-27 fold in vitro.
Conclusions: All vBTs observed were confined to the arm receiving an initial telaprevir monotherapy, highlighting the importance of combination therapy. Most G2/3 variants emerging during vBT carried mutations at amino acid positions previously described in G1 to confer reduced susceptibility to telapevir and some were able to achieve a SVR with additional Peg-IFN/RBV treatment.