Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Sep 27, 2018; 10(9): 543-548
Published online Sep 27, 2018. doi: 10.4254/wjh.v10.i9.543
Hepatitis C resistance to NS5A inhibitors: Is it going to be a problem?
Heidar Sharafi, Seyed Moayed Alavian
Heidar Sharafi, Seyed Moayed Alavian, Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran 1435915371, Iran
Heidar Sharafi, Seyed Moayed Alavian, Middle East Liver Diseases Center, Tehran 1415513651, Iran
Author contributions: Sharafi H and Alavian SM contributed to the development of the idea and drafting of the paper; both authors read and approved the final version of the manuscript.
Conflict-of-interest statement: Both authors declare no potential conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Heidar Sharafi, BSc, MA, MPhil, MSc, PhD, Research Scientist, Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran 1415513651, Iran. h.sharafi@meldcenter.com
Telephone: +98-21-88945186 Fax: +98-21-88945188
Received: June 7, 2018
Peer-review started: June 7, 2018
First decision: July 11, 2018
Revised: July 19, 2018
Accepted: August 4, 2018
Article in press: August 4, 2018
Published online: September 27, 2018

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.

Keywords: Direct-acting antiviral agent, Hepatitis C, NS5A, Resistance, Treatment

Core tip: Hepatitis C virus resistance to NS5A inhibitors is one of the main problems of treatment with NS5A inhibitors. While the treatment of NS5A inhibitor-naïve patients is feasible and efficient, retreatment of NS5A inhibitor-experienced patients is challenging. In the context of failure following treatment with NS5A inhibitor-containing regimens, NS5A resistance-associated substitution testing can help in clinical decision-making, while the usefulness of baseline NS5A resistance-associated substitution testing in NS5A inhibitor-naïve patients is in question.