Journal article
Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir
Gastroenterology (New York, N.Y. 1943), Vol.132(5), pp.1767-1777
2007
DOI: 10.1053/j.gastro.2007.02.037
PMID: 17484874
Abstract
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.
Details
- Title: Subtitle
- Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir
- Creators
- Christoph Sarrazin - Klinik für Innere Medizin II, Universität des Saarlandes, Homburg/Saar, GermanyTara L. Kieffer - Vertex PharmaceuticalsDoug Bartels - Vertex PharmaceuticalsBrian Hanzelka - Vertex Pharmaceuticals Incorporated, Cambridge, MassachusettsUte Müh - Vertex PharmaceuticalsMartin Welker - Klinik für Innere Medizin II, Universität des Saarlandes, Homburg/Saar, GermanyDennis Wincheringer - Klinik für Innere Medizin II, Universität des Saarlandes, Homburg/Saar, GermanyYi Zhou - Vertex PharmaceuticalsHui–May Chu - Vertex Pharmaceuticals Incorporated, Cambridge, MassachusettsChao Lin - Vertex Pharmaceuticals Incorporated, Cambridge, MassachusettsChristine Weegink - Academic Medical CenterHenk Reesink - Academic Medical CenterStefan Zeuzem - Klinik für Innere Medizin II, Universität des Saarlandes, Homburg/Saar, GermanyAnn D. Kwong - Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts
- Resource Type
- Journal article
- Publication Details
- Gastroenterology (New York, N.Y. 1943), Vol.132(5), pp.1767-1777
- Publisher
- Elsevier Inc
- DOI
- 10.1053/j.gastro.2007.02.037
- PMID
- 17484874
- ISSN
- 0016-5085
- eISSN
- 1528-0012
- Language
- English
- Date published
- 2007
- Academic Unit
- Microbiology and Immunology; Anatomy and Cell Biology
- Record Identifier
- 9984284346602771
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