Abstract
There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained viral response (SVR) rates of more than 90% in phase 2 and phase 3 clinical trials; however, this is slightly lower in real-life cohorts. Hepatitis C virus resistant variants are seen in most patients who do not achieve SVR due to selection and outgrowth of resistant hepatitis C virus variants within a given host. These resistance associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes. The understanding of these mutations has a clear clinical implication in terms of choice and combination of drugs used. In this review, we describe mechanism of action of currently available drugs and summarize clinically relevant resistance data.
Highlights
Hepatitis C virus (HCV) infection is a major global health problem and a leading cause of morbidity and mortality
The first approved interferon-free regimens for treating genotype 2 and 3 infection included a combination of sofosbuvir and ribavirin for 12 to 24 weeks
In genotype 1a patients, lower sustained viral response (SVR) 12 rate was observed in patients with pretreatment NS5A resistant associated variants conferring high level (>1000 fold) resistance to NS5A inhibitors when treated for 24 weeks
Summary
Hepatitis C virus (HCV) infection is a major global health problem and a leading cause of morbidity and mortality. The first approved interferon-free regimens for treating genotype 2 and 3 infection included a combination of sofosbuvir (an NS5B inhibitor) and ribavirin for 12 to 24 weeks. This resulted in an SVR of 68%–90% [7,8,9,10]. DAA combinations currently recommended to treat genotype 3 infection include NS5B polymerase inhibitor sofosbuvir and NS5A inhibitor daclatasvir with or without ribavirin while a combination of sofosbuvir and ribavirin is recommended for treatment of HCV genotype 2 infection, with possible addition of pegylated interferon alpha in patients with previous treatment failure. We discuss DAAs according to their mechanism of action, drug resistance profiles, and discuss clinical applications where relevant
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