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| Content Provider | PubMed Central |
|---|---|
| Author | Jiang, Min Mani, Nagraj Lin, Chao Ardzinski, Andrzej Nelson, Michelle Reagan, Dugan Bartels, Doug Zhou, Yi Nicolas, Olivier Rao, B. Govinda Müh, Ute Brian, Hanzelka Tigges, Ann Rene, Rijnbrand Kieffer, Tara L. |
| Copyright Year | 2013 |
| 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 wild-type replicon. |
| Related Links | http://dx.doi.org/10.1128/aac.01578-13 |
| Ending Page | 6245 |
| Page Count | 10 |
| Starting Page | 6236 |
| File Format | |
| ISSN | 00664804 |
| e-ISSN | 10986596 |
| Journal | Antimicrobial Agents and Chemotherapy |
| Issue Number | 12 |
| Volume Number | 57 |
| Language | English |
| Publisher | American Society for Microbiology |
| Publisher Date | 2013-12-01 |
| Access Restriction | Open |
| Rights Holder | American Society for Microbiology |
| Subject Keyword | Pharmacology (medical) Pharmacology Infectious Diseases Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Infectious Diseases Pharmacology Pharmacology (medical) |
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