Gastroenterology

Gastroenterology

Volume 132, Issue 5, May 2007, Pages 1767-1777
Gastroenterology

Clinical–liver, pancreas, and biliary tract
Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir

https://doi.org/10.1053/j.gastro.2007.02.037Get rights and content

Background & Aims: Telaprevir (VX-950), a hepatitis C virus (HCV) NS3·4A protease inhibitor, has shown strong antiviral activity in phase 1 clinical studies. Because of high levels of HCV replication and the low fidelity of HCV polymerase, selection of resistant isolates during therapy may occur. Methods: A highly sensitive sequencing method was developed in which approximately 80 clones/sample were analyzed to identify mutations in the NS3 protease catalytic domain in HCV genotype-1–infected patients dosed with 450 mg every 8 hours, 750 mg every 8 hours, or 1250 mg every 12 hours of telaprevir for 14 days. Results: Mutations that confer low-level resistance (V36A/M, T54A, R155K/T, and A156S) and high-level resistance (A156V/T, 36+155, 36+156) to telaprevir were detected and correlated with telaprevir exposure and virologic response. Changes in the frequency of mutations after the end of dosing showed an inverse relationship between in vivo viral fitness and resistance. In the absence of telaprevir selective pressure the majority of resistant variants were replaced by wild-type virus within 3–7 months. Conclusions: Resistant HCV isolates are selected rapidly during therapy with the highly active protease inhibitor telaprevir. Combination therapy with pegylated interferon-alfa or other direct antiviral drugs seem mandatory to avoid developing resistance.

Section snippets

Patient Population and Study Design

Thirty-four patients were enrolled into a randomized, double-blind, placebo-controlled, 14-day, multiple-dose, phase 1b trial and received one of the following doses of telaprevir: 450 mg every 8 hours (10 patients), 750 mg every 8 hours (8 patients), 1250 mg every 12 hours (10 patients), or placebo (6 patients). The clinical results of the trial have been reported in detail elsewhere.21 All patients had a chronic infection with HCV subtype 1a/b with plasma HCV-RNA levels of 105 IU/mL or

Viral Response Pattern to Telaprevir

The samples analyzed in this study were obtained from 34 patients infected with HCV genotype 1 who were dosed for 14 days with placebo or telaprevir in a randomized, double-blind, phase 1b study.21 Of the 34 patients, 27 (79%) had failed prior treatment. As expected, patients who received placebo showed no significant change in their plasma HCV-RNA levels. All patients who received telaprevir had a sharp initial decline of approximately 3-log10 in plasma HCV-RNA concentration during the first 2

Discussion

The development of drug resistance has been a challenge for treatment strategies in many viral infections such as human immunodeficiency virus, hepatitis B virus, herpes simplex virus, and influenza.32 The high replication rate and the error-prone nature of viral RNA polymerases generate a viral quasispecies from which variants resistant to viral inhibitors can be selected. Minor populations of pre-existing, resistant variants have a fitness advantage over wild-type virus in the presence of a

References (39)

  • D.D. Richman

    Antiviral drug resistance

    Antiviral Res

    (2006)
  • X. Tong et al.

    Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034

    Antiviral Res

    (2006)
  • E. Lawitz et al.

    28 Days of the hepatitis C protease inhibitor VX-950, in combination with peg-interferon-alfa-2a (Pegasys) and ribavirin, is well-tolerated and demonstrates robust antiviral effects

    Gastroenterology

    (2006)
  • T. Swan

    The hepatitis C virus (HCV) treatment pipeline

  • L.B. Seeff

    Natural history of chronic hepatitis C

    Hepatology

    (2002)
  • M.P. Curry

    Hepatitis B and hepatitis C viruses in liver transplantation

    Transplantation

    (2004)
  • R.H. Purcell

    Hepatitis C virus: historical perspective and current concepts

    FEMS Microbiol Rev

    (1994)
  • D.B. Strader et al.

    Diagnosis, management, and treatment of hepatitis C

    Hepatology

    (2004)
  • M.W. Fried et al.

    Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection

    N Engl J Med

    (2002)
  • Cited by (0)

    Supported in part by a grant from the Deutsche Forschungsgemeinschaft (KFO 129; Teilprojekt 2, to C.S. and S.Z.). T.L.K., D.B., B.H., U.M., Y.Z., H–M.C., C.L., and A.D.K. are employees of Vertex Pharmaceuticals. C.S. and S.Z. have financial arrangements with Vertex Pharmaceuticals and Schering-Plough Research Institute (Kenilworth, NJ) (consultancies, research support).

    1

    C.S. and T.L.K. contributed equally to this work.

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