Hepatitis C virus (HCV) drug resistance in patients treated with a new protease inhibitor
by
Libin Rong
Los Alamos National Laboratory
Coauthors: Harel Dahari (UIC), Ruy M. Ribeiro (LANL) and Alan S. Perelson (LANL)

Telaprevir, a novel HCV protease inhibitor, has demonstrated substantial antiviral activity in patients infected with HCV genotype 1. However, drug resistance variants appear very rapidly after treatment initiation. The exact mechanism underlying the rapid emergence of drug resistance during dosing is not fully understood. We develop a mathematical model to address this issue, and then extend the simple model to a general model with multiple strains. We examine the effects of backward mutation and liver cell proliferation on the pre-existence of the mutant virus and the competition between wild-type and drug resistant virus during therapy. Mutations during therapy do not play a significant role in the dynamics of various viral strains, although they are capable of generating low levels of HCV variants that would otherwise be completely suppressed because of fitness disadvantages. Liver cell proliferation may not affect the pretreatment frequency of mutant variants, but is able to influence the quasi-species dynamics during therapy. It is the relative fitness of each mutant strain compared with wild-type that determines which strain(s) will dominate the virus population. Our study provides a theoretical framework for exploring the prevalence of pre-existing mutant variants and the evolution of drug resistance during treatment with other HCV protease or polymerase inhibitors.

Date received: February 16, 2009