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Telaprevir and pegylated interferon–alpha‐2a inhibit wild‐type and resistant genotype 1 hepatitis C virus replication in patients
Author(s) -
Kieffer Tara L.,
Sarrazin Christoph,
Miller Janice S.,
Welker Martin W.,
Forestier Nicole,
Reesink Hendrik W.,
Kwong Ann D.,
Zeuzem Stefan
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21781
Subject(s) - telaprevir , pegylated interferon , virology , hepatitis c virus , genotype , alpha interferon , ribavirin , virus , biology , medicine , interferon , genetics , gene
Abstract Telaprevir (VX‐950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants (≥5%), mutations were identified that conferred low‐level (V36M/A, T54A, or R155K/T) or high‐level (A156V/T and 36/155) resistance to telaprevir in vitro . We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon–alpha‐2a (PEG‐IFN–alpha‐2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG‐IFN–alpha‐2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. Conclusion: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild‐type virus, which uncovers pre‐existing telaprevir‐resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG‐IFN–alpha‐2a inhibited both wild‐type and resistant variants. In the present study, every patient who began PEG‐IFN–alpha‐2a and ribavirin after the 14‐day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir‐resistant variants are sensitive to PEG‐IFN–alpha‐2a and ribavirin. (H EPATOLOGY 2007.)