In Vitro Phenotypic Characterization of Hepatitis C Virus NS3 Protease Variants Observed in Clinical Studies of Telaprevir

作者：Min Jiang, Nagraj Mani, Chao Lin, Andrzej Ardzinski, Michelle Nelson, Dugan Reagan, Doug J. Bartels, Yi Zhou, Olivier Nicolas, B. Govinda Rao, Ute Müh, Brian L. Hanzelka, Ann M. Tigges, René Rijnbrand, Tara L. Kieffer · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2013 · DOI：10.1128/aac.01578-13 · 被引用次数：27 · 研究领域：Hepatitis C virus research、Hepatitis B Virus Studies、HIV/AIDS drug development and treatment

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 ...