Viral Kinetics of the Y448H HCV NS5B Polymerase Mutant in Patients Treated with the HCV Inhibitor Tegobuvir (GS-9190)
Karin S Ku*, Derrick D Goodman, Andrew S Bae, Michael D Miller, Hongmei Mo and Evguenia S Svarovskaia
Gilead Sciences Inc., Foster City, CA USA
- *Corresponding Author:
- Karin S Ku
Gilead Sciences, Inc., 333 Lakeside Drive
Foster City, CA 94404, USA
E-mail: [email protected]
Received Date: July 11, 2013; Accepted Date: September 01, 2013; Published Date: September 03, 2013
Citation: Ku KS, Goodman DD, Bae AS, Miller MD, Mo H, et al. (2013) Viral Kinetics of the Y448H HCV NS5B Polymerase Mutant in Patients Treated with the HCV Inhibitor Tegobuvir (GS-9190). J Antivir Antiretrovir 5:101-107. doi: 10.4172/jaa.1000071
Copyright: © 2013 Ku KS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Tegobuvir (GSÃ¢ÂÂ9190) is a novel hepatitis C virus (HCV) nonÃ¢ÂÂnucleoside NS5B polymerase inhibitor that effectively inhibits HCV replication in HCV-infected genotype (GT) 1 patients. The NS5B Y448H mutation was the most frequent mutation selected in patients receiving tegobuvir. In this study, we employed allele-specific PCR (AS-PCR) to monitor Y448H kinetics and estimate the pre-existing Y448H levels in HCV-infected patients and replicon cells. Y448H ASPCR was developed with a 0.5% assay cut-off to test replicon cells treated with tegobuvir and samples from HCVinfected GT 1 patients who received 8-days of tegobuvir monotherapy. By population sequencing, Y448H was not detected at baseline in serum samples from any of the 65 patients enrolled in the study. Using the more sensitive AS-PCR, Y448H was assessed in 62/65 patients at baseline and detected at >0.5% in 5/62 patients. Longitudinal patient samples were tested to monitor the Y448H replication kinetics during the 8-day tegobuvir monotherapy. The replication kinetics of the mutant virus were used to extrapolate a median baseline Y448H frequency of 0.025% (-3.6 log10). For the in vitro selection of GT 1b tegobuvir-treated replicon cells, pre-existing Y448H levels were similarly estimated at 0.015% (-3.8 log10). Pre-existing levels of the drug-resistant variant Y448H suggest a maximal 3.6 log10 HCV RNA reduction during monotherapy with optimal doses of NS5B non-nucleoside polymerase inhibitors that select for Y448H. These results aid in the prediction of the patient viral response and study designs to best achieve maximal antiviral response.