Hepatitis C resistance to NS5A inhibitors: Is it going to be a problem?

Treatment of hepatitis C virus (HCV) infection has evolved greatly through the recent decade. The availability of direct-acting antiviral agents (DAAs) targeting the functional proteins of HCV has resulted in the introduction of DAA-based combination therapies, providing an optimal rate of treatment success. Among the DAAs, NS5A inhibitors are used in most of the introduced and approved HCV antiviral regimens. Resistance-associated substitutions (RASs) are amino acid substitutions in HCV protein sequences that result in decreased antiviral efficacy of the HCV DAAs. Among the HCV RASs, the NS5A RASs were found to effectively modify and decrease treatment response to NS5A inhibitor-containing regimens. As a baseline predictor of treatment response, NS5A RAS draws attention for pretreatment testing in targeted patient groups. Given NS5A RASs are either naturally-occurring or DAA-selected, the application of NS5A RAS testing can be considered in two settings of NS5A inhibitor-naïve patients and NS5A inhibitor-experienced patients. Less than 5% of NS5A inhibitor-naïve patients harbor naturally-occurring NS5A RAS with high resistance level (> 100X resistance fold-change). In NS5A inhibitor-naïve patients, NS5A RAS testing accompanied by treatment optimization cannot increase treatment response more than 2%-3%, while in NS5A inhibitor-experienced patients, > 75% are found to have NS5A RASs > 100X and NS5A RAS testing in this group of patients seems to be reasonable. This editorial will address the debate on the application of NS5A RAS testing and will discuss if the NS5A RAS testing has any role in clinical management of hepatitis C.