Journal article
In Vitro Phenotypic Characterization of Hepatitis C Virus NS3 Protease Variants Observed in Clinical Studies of Telaprevir
Antimicrobial agents and chemotherapy, Vol.57(12), pp.6236-6245
12/01/2013
DOI: 10.1128/AAC.01578-13
PMCID: PMC3837892
PMID: 24100495
Abstract
Telaprevir is a linear, peptidomimetic small molecule that inhibits hepatitis C virus (HCV) replication by specifically inhibiting the NS3.4A protease. In phase 3 clinical studies, telaprevir in combination with peginterferon and ribavirin (PR) significantly improved sustained virologic response (SVR) rates in genotype 1 chronic HCV- infected patients compared with PR alone. In patients who do not achieve SVR after treatment with telaprevir- based regimens, variants with mutations in the NS3.4A protease region have been observed. Such variants can contribute to drug resistance and limit the efficacy of treatment. To gain a better understanding of the viral resistance profile, we conducted phenotypic characterization of the variants using HCV replicons carrying site- directed mutations. The most frequently observed (significantly enriched) telaprevir- resistant variants, V36A/M, T54A/ S, R155K/ T, and A156S, conferred lower- level resistance (3- to 25-fold), whereas A156T and V36M+R155K conferred higher- level resistance (> 25-fold) to telaprevir. Rarely observed (not significantly enriched) variants included V36I/L and I132V, which did not confer resistance to telaprevir; V36C/G, R155G/I/M/S, V36A+T54A, V36L+R155K, T54S+R155K, and R155T+D168N, which conferred lower- level resistance to telaprevir; and A156F/N/V, V36A+R155K/T, V36M+R155T, V36A/M+A156T, T54A+ A156S, T54S+A156S/T, and V36M+ T54S+R155K, which conferred higher- level resistance to telaprevir. All telaprevir- resistant variants remained fully sensitive to alpha interferon, ribavirin, and HCV NS5B nucleoside and nonnucleoside polymerase inhibitors. In general, the replication capacity of telaprevir- resistant variants was lower than that of the wildtype replicon.
Details
- Title: Subtitle
- In Vitro Phenotypic Characterization of Hepatitis C Virus NS3 Protease Variants Observed in Clinical Studies of Telaprevir
- Creators
- Min Jiang - Vertex Pharmaceuticals (United States)Nagraj Mani - Vertex Pharmaceuticals (United States)Chao Lin - Vertex Pharmaceuticals (United States)Andrzej Ardzinski - Vertex Pharmaceuticals (United States)Michelle Nelson - Vertex Pharmaceuticals (United States)Dugan Reagan - Vertex Pharmaceuticals (United States)Doug Bartels - Vertex Pharmaceuticals (United States)Yi Zhou - Vertex Pharmaceuticals (United States)Olivier Nicolas - Vertex Pharmaceuticals (United States)B. Govinda Rao - Vertex Pharmaceuticals (United States)Ute Mueh - Vertex Pharmaceut Inc, Cambridge, MA USABrian Hanzelka - Vertex Pharmaceuticals (United States)Ann Tigges - Vertex Pharmaceuticals (United States)Rene Rijnbrand - Vertex Pharmaceuticals (United States)Tara L. Kieffer - Vertex Pharmaceuticals (United States)
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.57(12), pp.6236-6245
- DOI
- 10.1128/AAC.01578-13
- PMID
- 24100495
- PMCID
- PMC3837892
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Publisher
- Amer Soc Microbiology
- Number of pages
- 10
- Grant note
- Vertex Pharmaceuticals Incorporated; Vertex Pharmaceuticals
- Language
- English
- Date published
- 12/01/2013
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984284342402771
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