Hepatitis C virus NS5A inhibitors and drug resistance mutations

作     者：Shingo Nakamoto Tatsuo Kanda Shuang Wu Hiroshi Shirasawa Osamu Yokosuka 

作者机构：Department of Molecular VirologyGraduate School of MedicineChiba UniversityChiba 260-8677Japan Department of Gastroenterology and NephrologyGraduate School of MedicineChiba UniversityChiba 260-8677Japan 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2014年第20卷第11期

页      面：2902-2912页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 100705[医学-微生物与生化药学] 1001[医学-基础医学(可授医学、理学学位)] 100103[医学-病原生物学] 10[医学] 

基　　金：Supported by Grants for Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology of Japan(to Nakamoto S,Kanda T) grants from the Ministry of Health,Labour,and Welfare of Japan(to Yokosuka O) 

主　　题：ACH-3102 Direct-acting antiviral agents Daclatasvir Hepatitis C virus Ledipasvir 

摘      要：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.