1200 ANTIVIRAL ACTIVITY OF EP-NI266, A POTENT NUCLEOTIDE HCV POLYMERASE INHIBITOR

1198 HCV NS3/4A PROTEASE RESISTANCE-ASSOCIATED VARIANTS (RAVS) IDENTIFIED IN GENOTYPE 1A PATIENTS EXHIBIT DIFFERENCES IN PHENOTYPIC RESISTANCE TO BOCEPREVIR AND TELAPREVIR IN GENOTYPE 1A REPLICON CELLS S. Black, P. McMonagle, R. Chase, S. Curry, R.J.O. Barnard, D.J. Hazuda, A.Y. Howe, J.A. Howe, R.A. Ogert. Merck & Co., Inc., Kenilworth, NJ, USA E-mail: robert.ogert@merck.com Background: The HCV NS3 protease inhibitors boceprevir (BOC) and telaprevir (TPV) in combination with pegylated interferon alpha-2 plus ribavirin (PR) have been approved for treatment of HCV genotype 1 (GT 1) infection. The major RAVs identified in nonsustained virologic response (SVR) GT 1a infected patients were similar for BOC and TPV. These RAVs were analyzed for phenotypic resistance to BOC and TPV using an in-vitro GT 1a replicon assay. Methods: RAVs were detected by population sequencing in samples from SPRINT-2 (treatment naive) and RESPOND-2 (prior nonresponder/relapser) patients. RAVs were engineered into a GT 1a replicon derived from the H77 1a strain. Replicon cell lines were treated with BOC or TPV for 3 days, and HCVRNA was quantified by Taqman real time PCR analysis. Results: For patients treated with BOC, RAVs were detected in 53% of non-SVR patients with NS3 sequences available. In BOC treated, non-SVR HCV GT 1a infected patients; the most common RAVs were V36M, T54S and R155K. T54A and A156S/T were also identified in HCV GT 1a non-SVR treated patients but were observed more frequently in HCV GT 1b. A similar pattern of HCV GT 1a RAVs was identified in TPV treated patients (Bartels DJ, et al. Hepatology. 2011;54(S1):1328). These RAVs were analyzed for resistance to BOC and TPV in a GT 1a replicon assay. T54A and T54S produced similar fold-shifts in EC50 with BOC and TPV. However, V36M, R155K and A156S each produced a larger fold-shift in resistance to TPV than BOC. The fold shift in EC50 for each RAV was 2to 6-fold for BOC and 5to 16-fold for TPV. Also, the V36M + R155K double variant resulted in a >20-fold increase in EC50 for TPV but <10-fold for BOC.