title: Hepatitis C virus NS5A inhibitors and drug resistance mutations.
abstract: 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.
authors.affiliation: Shingo Nakamoto, Hiroshi Shirasawa, Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakamoto
authors.affiliation: Shingo Nakamoto, Hiroshi Shirasawa, Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Shingo Nakamoto, Hiroshi Shirasawa, Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Shingo Nakamoto, Hiroshi Shirasawa, Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shirasawa
authors.affiliation: Shingo Nakamoto, Hiroshi Shirasawa, Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase; D001562:Benzimidazoles; D001578:Benzopyrans
chemical_list: D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C000604171:velpatasvir; D001562:Benzimidazoles; D001578:Benzopyrans; C549273:daclatasvir
keywords: ACH-3102; Daclatasvir; Direct-acting antiviral agents; Hepatitis C virus; Ledipasvir