Research ArticleHepatitis C Virus

Rapid Emergence of Protease Inhibitor Resistance in Hepatitis C Virus

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Science Translational Medicine  05 May 2010:
Vol. 2, Issue 30, pp. 30ra32
DOI: 10.1126/scitranslmed.3000544

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Fighting the Resistance in Hepatitis C

Following a few decades behind the infection-fighting miracles wrought by antibiotics was the cloud to the silver lining—drug resistance. Microbes evolved under the selection pressure exerted by antibiotics, and drug-resistant strains began to emerge. The microbes that cause respiratory infections, HIV/AIDS, diarrhea, tuberculosis, and malaria have all developed some resistance to their primary treatment, forcing physicians to turn to secondary, often inferior agents. Hepatitis C virus (HCV), which can cause serious liver damage, is genetically diverse and so may be particularly prone to develop resistance, sometimes within days of treatment onset. One way to combat this would be to administer multiple drugs, each with a different way of inhibiting the pathogen. Rong and colleagues have used a modeling approach to predict how resistance emerges in this disease and suggest that a combination of drugs that can fight three or more mutated viral strains may be needed to cure this disease.

By using experimentally measured mutation rates and knowing the rate of viral production and other parameters, the authors were able to calculate that all possible HCV variants with single and double mutations already exist in infected patients before treatment and that one additional mutation is expected to arise during therapy. Thus, they concluded that a combination of direct antiviral drugs would need to be effective against variants with three or more mutations. The authors also constructed a model to study the development of drug-resistant virus during treatment. They showed that the model predictions match well with the actual data from a clinical trial in which the drug telaprevir was given to patients with HCV.

Because hepatitis C is potentially curable, this modeling tool for designing more effective treatments is especially welcome. It may, however, also prove useful for application to other situations in which the emergence of viral or bacterial resistance renders the primary therapeutic treatment ineffective.


  • 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).

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