Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals

Introduced in 2013–2014, the second‐ and third‐wave directly acting antivirals (DAAs) have strongly enhanced the efficacy and tolerability of anti‐HCV treatment, with a sustained virological response (SVR) in 90–95% of cases treated. The majority of patients who did not achieve an SVR were found to be infected with HCV strains with a reduced susceptibility to these drugs. Indeed, the high error rate of the viral polymerase and a fast virion production (100‐fold higher than the human immunodeficiency virus) result in a mixture of viral genetic populations (quasi‐species) pre‐existing treatment initiation. These mutants occur frequently in the NS5A region, with a moderate frequency in the NS3/4A region and rarely in the NS5B region. Treatment‐induced resistant mutants to NS5A DAAs persist for years after treatment discontinuation, whereas those resistant to the NS3 DAAs have a shorter duration. This review focuses on the type and prevalence of viral strains with a reduced sensitivity to DAAs, their clinical impact and influence on the response to treatment and, consequently, on treatment choice for DAA‐experienced patients. J. Med. Virol. 88:1659–1671, 2016 . © 2016 Wiley Periodicals, Inc.