Lab researchers shed light on rapid drug resistance in hepatitis C treatment

May 26, 2010—About 170 million people worldwide are infected with hepatitis C virus (HCV). The current standard therapy, which includes generic compounds that are not specific for HCV, leads to sustained viral elimination in approximately 50% of the treated patients. New drugs directly acting against HCV virus proteins are in development. For example, telaprevir, an HCV protease inhibitor, has substantial antiviral activity in patients with chronic HCV infection. However, HCV is genetically diverse.  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 telaprevir treatment. The appearance of these HCV variants at high frequencies so soon after the start of therapy is unexpected, because such rapid phenotypic drug resistance has not been seen with monotherapy for HIV, hepatitis B virus, or any other tested pathogen.

Libin Rong, Harel Dahari, Ruy Ribeiro, and Alan Perelson of Theoretical Biology and Biophysics (T-6) used published data from patients treated with the antiviral drug telaprevir to analyze and explain the emergence of drug-resistant HCV variants. They developed probabilistic models of the viral dynamics, in conjunction with experimentally measured mutation rates, to calculate how fast HCV variants with single, double, and more mutations arise.  The scientists conclude that both drug-sensitive and mutant variants resistant to the drug coexist prior to treatment.  As the HCV virus is produced in the patient, there is a small error rate during replication, causing a change in the HCV genome.  Some of these mutations are resistant to the drug.  By calculating the generation rates of HCV variants, the researchers explained how the preexistence and selection of drug-resistant variants occurs.

The researchers showed that their model predictions match well with the data from a clinical trial in which the drug telaprevir was given to patients with HCV.  The scientists developed a model to design future treatment paradigms. They predict that a therapeutic combination of direct antivirals, which has a genetic barrier of four or more mutations, would be needed to avoid treatment failure. Pretreatment using other types of drugs before direct antiviral drug treatment could reduce the frequency of preexisting direct antiviral-resistant variants. The model could be used to make predictions about the possible success of treatment strategies.

The research was published in Science Translational Medicine, a new journal of the Science family of publications. The National Institutes of Health funded the research.

Hepatitis C image: Louis E. Henderson, Frederick Cancer Research Center