title: Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals.
abstract: 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.
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Coppola
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Minichini
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Starace
authors.affiliation: Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Sagnelli
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy.
authors.forename: Evangelista
authors.initials: E
authors.lastname: Sagnelli
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology; D018937:Hepatitis C Antibodies / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D009154:Mutation; D000072230:Sustained Virologic Response; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D018937:Hepatitis C Antibodies; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: DAAs; HCV infection; NS3/4A; NS5A; NS5B; chronic hepatitis C; viral mutations