Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

Compounds targeting nonstructural (NS) proteins of hepatitis C virus (HCV) demonstrate clinical promise, suggesting that NS3/NS4a, NS5A, or NS5B inhibitors are potential components in direct-acting antiviral (DAA) combination therapies. In vitro studies revealed dramatic inhibition of viral replication or alteration in subcellular localization of NS proteins. DAAs bind either to catalytic sites (NS3 and NS5B) or to domain-1 of NS5A. Although >90% of the patients clear HCV RNA from their sera, a significant portion of cirrhotic patients suffer from resistance or virological relapse. Mutations in specific residues (Q80K) in NS3 (M28, A30, L31, and Y93 in genotypes 1a and 1b or L28, L30, M31, and Y93 in genotype 4) in NS5A and A282T in NS5B are associated with resistance to DAA [resistance-associated variants (RAVs)]. Current knowledge on the NS functions, mode of action of DAAs, and impacts of RAVs on treatment response are discussed. Not only mutations affecting the binding of DAAs to target proteins but also substitutions affecting the replication fitness of mutant quasispecies are major determinants of treatment failures. These resistance-associated substitutions (RASs) are now considered the major viral mutants that influence the virological outcome after DAA treatment.