Resistance development of hepatitis C virus to protease inhibitors Telaprevir (VX-950) and Danoprevir (ITMN-191)

Genotype differences in susceptibility and resistance development of hepatitis C virus to protease inhibitors Telaprevir (VX-950) and Danoprevir (ITMN-191)

Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)

Ingrid Imhof, Peter Simmonds,

DOI: 10.1002/hep.24172
Copyright © 2011 American Association for the Study of Liver Diseases

Author Information

Centre for Infectious Diseases, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK
Email: Peter Simmonds (Peter.Simmonds@ed.ac.uk)

Correspondence: Peter Simmonds, Centre for Infectious Diseases, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK

Keywords: Phenotype;mutation;NS3 protease;antiviral;BILN 2061

Abstract

Protease inhibitors (PIs) have proven to be effective adjuncts to interferon / Ribavirin treatment of hepatitis C virus (HCV) infections. Little clinical or in vitro data exists however, on their effectiveness for non-type 1 genotypes that predominate in Europe, the Middle East, Africa and most of Asia.

NS3 protease and NS4A genes from genotypes 1-6 were inserted into the JFH clone to generate replication competent intergenotype chimaeras. Susceptibility to PIs was determined by replication and infectivity assays. To study resistance development, chimaeras were cultured in sub-inhibitory concentrations of PIs and mutations phenotypically characterised. Marked differences in susceptibility of different genotypes to Danoprevir (ITMN-191) and Telaprevir (VX-950) were observed. Genotypes 1, 4 and 6 showed IC50 values of 2-3 nM, >100-fold lower than genotypes 2/3/5 (250-750 nM). Telaprevir susceptibilities varied over a five-fold range, with genotypes 1 and 2 being most susceptible, and genotype 4 and 5 most resistant. Culture of genotypes 1-6 in PIs induced numerous mutations in the NS3 protease domain, highly variable between genotypes. Introduction of Danoprevir and BILN 2061-induced mutations into the original clones by site-directed mutagenesis (n=29) all conferred resistant phenotypes, with particularly large increases (1-2 log greater IC50 values) in the initially susceptible genotypes 1/4/6. Most introduced mutations, showed little or no effect on replicative fitness.

Major differences were found between genotypes in their susceptibility and resistance development to PIs. However, equal sensitivities of genotypes 1, 4 and 6 to Danoprevir and a broader efficacy range of Telaprevir between genotypes than initially conceptualised provide strong evidence that PIs might be effectively used beyond their genotype 1 target group. (HEPATOLOGY 2011.)
http://onlinelibrary.wiley.com/doi/10.1002/hep.24172/abstract