Rapid Emergence of Protease Inhibitor Resistance in Hepatitis C Virus

Sci Transl Med 5 May 2010:
Vol. 2, Issue 30, p. 30ra32
DOI: 10.1126/scitranslmed.3000544
RESEARCH ARTICLE
Rapid Emergence of Protease Inhibitor Resistance in Hepatitis C Virus
Libin Rong1,2, Harel Dahari3, Ruy M. Ribeiro1 and Alan S. Perelson1,*
+ Author Affiliations

1Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
2Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, MI 48309, USA.
3Department of Medicine, University of Illinois, Chicago, IL 60612, USA.
*To whom correspondence should be addressed. E-mail: asp@lanl.gov


ABSTRACT

About 170 million people worldwide are infected with hepatitis C virus (HCV). The current standard therapy leads to sustained viral elimination in only ~50% of the treated patients. Telaprevir, an HCV protease inhibitor, has substantial antiviral activity in patients with chronic HCV infection. However, in clinical trials, drug-resistant variants emerge at frequencies of 5 to 20% of the total virus population as early as the second day after the beginning of treatment. Here, using probabilistic and viral dynamic models, we show that such rapid emergence of drug resistance is expected. We calculate that all possible single- and double-mutant viruses preexist before treatment and that one additional mutation is expected to arise during therapy. Examining data from a clinical trial of telaprevir therapy for HCV infection in detail, we show that our model fits the observed dynamics of both drug-sensitive and drug-resistant viruses and argue that therapy with only direct antivirals will require drug combinations that have a genetic barrier of four or more mutations.

Citation: L. Rong, H. Dahari, R. M. Ribeiro, A. S. Perelson, Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci. Transl. Med. 2, 30ra32 (2010).
Copyright © 2010, American Association for the Advancement of Science
http://stm.sciencemag.org/content/2/30/30ra32.abstract