How much of a problem is resistance in treating hepatitis C?

Abstract

Directly acting antiviral drug (DAA) treatments represent a major advance in hepatitis C management, achieving virological cures in excess of 90%. When treatment failure occurs, it is mostly due to relapse with the emergence of resistance-associated variants. Data from in-vitro studies and clinical trials have enabled characterization of the amino acid substitutions in antiviral drug targets that confer reduced susceptibility to DAAs. These resistance-associated substitutions (RASs) may exist prior to treatment, and are associated with, but do not inevitably result in, treatment failure. The most important RASs with current regimens occur in the NS5A protein of viral variants, which may persist for years after treatment. The optimal strategy is to prevent resistance through administering the best treatment, appropriately matched to patient and virological characteristics, for example the presence of cirrhosis, prior exposure to interferon and so on. International treatment guidelines have been developed to select treatments, which may vary in duration and coadministration with ribavirin. Routine resistance testing prior to treatment of naive patients is not generally recommended. Next-generation DAAs will further reduce the emergence of RASs and, because of activity against RASs to currently used DAAs, will be used as rescue therapies for patients who have failed treatment.