820 CD81 EXPRESSION ON LYMPHOCYTE SUBTYPES FOR DISCRIMINATION BETWEEN SUSTAINED VIROLOGIC RESPONSE AND RELAPSE IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH PEG-INTERFERON-ALFA AND RIBAVIRIN

Abstract

The search for direct acting antiviral (DAA) compounds that act against targets on the Hepatitis C virus or host proteins that play a crucial role in the replication of this virus is of high importance since the current standard of care does not achieve a sustained virological response (SVR) in many patients even after an extended treatment period. GSK2485852 is an inhibitor of the HCV NS5B polymerase and is highly active with EC50 values in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell-culture system. In an attempt to elucidate potency of GSK2485852 beyond the standard replicon assays, we used chimeric replicon systems with NS5B genes from different genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotype 1a and 1b. The inhibitory activity of GSK2485852 remained unchanged on these intergenotypic and intragenotypic replicon systems. GSK2485852 furthermore displays an excellent resistance profile and shows less than a five-fold potency loss across clinically important NS5B resistance mutations like S282T, P495L, M423T, C316Y or Y448H. A diverse mutant panel tested also revealed a lack of cross resistance against known resistance mutations against other viral proteins. Data from both 454 and population sequencing showed a pattern of mutations arising in the NS5B RNA dependent RNA polymerase. GSK2485852 shows superior viral RNA reductions of up to five logs in genotype 1b replicons.