Rapid Emergence of Protease Inhibitor Resistance in Hepatitis C Virus

Computational modeling suggests that the rapid emergence of resistance to drugs against hepatitis C virus is a result of preexisting resistant virus and potent suppression of wild-type virus. 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. 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.