Rapid Emergence of Protease Inhibitor Resistance in Hepatitis C Virus

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http://stm.sciencemag.org/content/2/30/30ra32.abstract

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@...

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.

Footnotes

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).

, American Association for the Advancement of Science