Published online Mar 21, 2014. doi: 10.3748/wjg.v20.i11.2902
Revised: October 23, 2013
Accepted: January 14, 2014
Published online: March 21, 2014
Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for “difficult-to-treat” HCV-infected patients. “First generation” HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. “Second generation” NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.
Core tip: Hepatitis C virus (HCV) NS5A inhibitors such as daclatasvir and ledipasvir in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin are becoming available for daily clinical practice. These inhibitors can induce resistance mutations more easily in HCV genotype 1a patients than in HCV genotype 1b patients. HCV NS5A inhibitors should be used in combination regimens potent enough to prevent the emergence of resistant mutants and attention should be paid to these mutants’ potential emergence.