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World J Gastroenterol. Mar 21, 2014; 20(11): 2902-2912
Published online Mar 21, 2014. doi: 10.3748/wjg.v20.i11.2902
Hepatitis C virus NS5A inhibitors and drug resistance mutations
Shingo Nakamoto, Tatsuo Kanda, Shuang Wu, Hiroshi Shirasawa, Osamu Yokosuka
Shingo Nakamoto, Hiroshi Shirasawa, Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan
Shingo Nakamoto, Tatsuo Kanda, Shuang Wu, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan
Author contributions: Nakamoto S, Kanda T, Wu S, Shirasawa H and Yokosuka O contributed to this paper.
Supported by Grants for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to Nakamoto S, Kanda T); and grants from the Ministry of Health, Labour, and Welfare of Japan (to Yokosuka O)
Correspondence to: Tatsuo Kanda, MD, PhD, Associate Professor, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. kandat-cib@umin.ac.jp
Telephone: +81-43-2262086 Fax: +81-43-2262088
Received: September 24, 2013
Revised: October 23, 2013
Accepted: January 14, 2014
Published online: March 21, 2014
Processing time: 175 Days and 9.3 Hours
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.

Keywords: ACH-3102; Direct-acting antiviral agents; Daclatasvir; Hepatitis C virus; Ledipasvir

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.