HVR-1 heterogeneity during treatment with telaprevir with or without pegylated interferon alfa-2a

Abstract

Background. The extensive heterogeneity of the hypervariable region-1 (HVR-1) of hepatitis C virus (HCV) evidences the high genetic flexibility of HCV and was shown to be associated with virologic response to interferon-α-based therapies. However, the evolution of HVR-1 heterogeneity during treatment with directly acting antivirals has not been studied. Methods. Clonal sequence analysis of HVR-1 quasispecies in the serum of patients who were treated with telaprevir (3 × 750 mg/day) alone, telaprevir plus pegylated interferon-α-2a (pegIFN-α-2a), or pegIFN-α-2a plus placebo for 14 days was performed. HVR-1 heterogeneity, expressed as Shannon complexity and Hamming distance, was analyzed with virologic response and with the emergence of variants associated with resistance to telaprevir. Results. HVR-1 heterogeneity at baseline was not associated with response to telaprevir-based therapy (Shannon complexity 0.34 vs. 0.55, p = 0.38; Hamming distance 0.15 vs. 0.23, p = 0.51; for patients with or without viral breakthrough, respectively). No significant changes in HVR-1 complexity were observed from baseline to day 4 of therapy in patients in whom a continued decline in HCV RNA was observed (Shannon complexity = 0.55 vs. 0.51, p = 0.67; Hamming distance = 0.23 vs. 0.25, p = 0.81, respectively). This was similar in patients with viral breakthrough associated with telaprevir-resistant variants (Shannon complexity = 0.34 vs. 0.42, p = 0.68; Hamming distance = 0.15 vs. 0.2, p = 0.50, at baseline and day 4, respectively). Conclusions. Baseline and on-treatment HVR-1 heterogeneity are not associated with early viral response to telaprevir-based therapy.

Key Words::

• Directly acting antiviral agents
• NS3-4A protease inhibitor
• resistance mutation
• STAT-C
• viral resistance

Acknowledgements

This work was supported by the German Research Foundation Grant (DFG) Klinische Forschergruppe KFO 129/1-2, TP2, TP3 (to CS, EH, and SZ). CML is the recipient of a research fellowship from the Deutsche Forschungsgemeinschaft (LA 2806/1-1). Authors' contributions: The authors have contributed to the manuscript by planning the study (CS, JS, HWR, TLK, ADK), collecting the data (CML, SS, JS, HWR, UK), analysis of data (CML, EH, SZ, CS), and preparation and revision of the manuscript (all authors).

Declaration of interest: CML, SS, EH, UK: none. CS, SZ: Research support from Vertex, TK, ADK: employees and stock owners of Vertex Pharmaceuticals, JS, HWR: Research support from Vertex.