Differential Efficacy of Protease Inhibitors against HCV Genotype 2a, 3a, 5a, and 6a NS3/4A Protease Recombinant Viruses

Gastroenterology. 2011 Jun 12. [Epub ahead of print]

Gottwein JM, Scheel TK, Jensen TB, Ghanem L, Bukh J.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre and Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Denmark.

Abstract

BACKGROUND & AIMS: The hepatitis C virus (HCV) genotype influences efficacy of interferon (IFN)-based therapy. HCV protease inhibitors are being licensed for treatment of genotype 1 infection. Since there is limited or no data on efficacy against HCV genotypes 2-7, we aimed at developing recombinant infectious cell culture systems expressing genotype specific NS3 protease (NS3P).

METHODS: Viability of J6/JFH1- based recombinants with genotype 1-7 NS3P/NS4A was evaluated in Huh7.5 cells. Adaptive mutations were identified in reverse genetic studies. Efficacy of lead compound linear protease inhibitors VX-950 (telaprevir) and SCH503034 (boceprevir) and macrocyclic inhibitors TMC435350, ITMN-191 (danoprevir), and MK-7009 (vaniprevir) was determined in high-throughput infection assays.

RESULTS: For genotype(isolate) 2a(J6), 3a(S52), 5a(SA13), and 6a(HK6a) we developed culture systems producing supernatant infectivity titers of 3.5-4.0 log(10) FFU/ml. Against 2a(J6), 5a(SA13) and 6a(HK6a) all inhibitors showed similar efficacy; macrocyclic inhibitors had ~10-fold greater potency than linear inhibitors. However, compared to 2a recombinant J6/JFH1 efficacy against 3a(S52) was 16- to 70-fold lower for macrocyclic inhibitors and 2- to 7-fold lower for linear inhibitors. Testing of additional genotype 2a and 3a isolates showed that these differences were genotype specific. The resistance of 3a isolates was similar to J6/JFH1 with engineered resistance mutations originally observed for genotype 1 patients. In contrast, we found similar efficacy of NS5A inhibitor BMS-790052 and interferon-alfa2.

CONCLUSIONS: Novel HCV culture systems with genotype specific NS3P/NS4A revealed similar efficacy of protease inhibitors against genotype 2a, 5a, and 6a and comparatively low but varying efficacy against genotype 3a isolates. These systems will facilitate genotype specific studies of HCV protease inhibitors and of viral resistance.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

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