Telaprevir and pegylated interferon–alpha-2a inhibit... : Hepatology (original) (raw)
Viral Hepatitis
Telaprevir and pegylated interferon–alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients
Kieffer, Tara L.1; Sarrazin, Christoph2; Miller, Janice S.1; Welker, Martin W.2; Forestier, Nicole2; Reesink, Hendrik W.3; Kwong, Ann D.1*; Zeuzem, Stefan2
1 Vertex Pharmaceuticals Inc., Cambridge, MA
2 Klinik für Innere Medizin II, Universität des Saarlandes, Homburg/Saar, Germany
3 Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
* Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139
Email:[email protected]
Received 27 February 2007; Accepted 17 April 2007
Published online in Wiley InterScience (www.interscience.wiley.com).
Grant sponsor: Vertex Pharmaceuticals Inc., Cambridge, MA; Grant sponsor: Deutsche Forschungsgemeinschaft; Grant Number: KFO 129; Teilprojekt 2.
Potential conflict of interest: Nothing to report.
See Editorial on Page 615
These authors contributed equally to this study.
Abstract
Telaprevir (VX-950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants (≥5%), mutations were identified that conferred low-level (V36M/A, T54A, or R155K/T) or high-level (A156V/T and 36/155) resistance to telaprevir in vitro . We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon–alpha-2a (PEG-IFN–alpha-2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG-IFN–alpha-2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. Conclusion: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild-type virus, which uncovers pre-existing telaprevir-resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG-IFN–alpha-2a inhibited both wild-type and resistant variants. In the present study, every patient who began PEG-IFN–alpha-2a and ribavirin after the 14-day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir-resistant variants are sensitive to PEG-IFN–alpha-2a and ribavirin. (Hepatology 2007.)
Abbreviations: HCV, hepatitis C virus; PEG-IFN–alpha-2a, pegylated interferon–alpha-2a; RBV, ribavirin.
Copyright © 2007 American Association for the Study of Liver Diseases.