title: Resistance to direct-acting antiviral agents: clinical utility and significance.
abstract: OBJECTIVE
  This article examines the dynamics and factors underlying hepatitis C virus (HCV) resistance, along with their impact on daily clinical management of HCV-infected patients.
  
  
  RESULTS
  Across available treatment-regimens, GT-3 is the most difficult-to-cure genotype, but also genotype-1a may show lower success-rates compared with genotype-1b. Natural resistance to NS3, NS5A and NS5B inhibitors may contribute to treatment failures. The Q80K NS3-protease mutation affects sensibility to simeprevir + peg-interferon/ribavirin combinations. It reaches up to 48% prevalence in genotype-1a in some studies (but it is lower in other). Resistant variants (particularly in NS5A) developed at failure can persist, in a substantial proportion of patients, even 3 years after treatment-discontinuation, potentially affecting readministration of the same direct-acting antiviral agent (DAA)-class. This will become an issue for those patients failing all-oral regimens with multiple-resistant viruses.
  
  
  CONCLUSIONS
  Recent data support the importance of an accurate genotype and genotype-1 subtype (1a/1b) assignment prior therapy. Resistance testing at baseline has no clear indication so far in clinical practice for all-DAA regimens selection, while it remains a valuable option at the retreatment of patients who failed DAA-containing regimens, provided that data are generated to inform treatment decisions based on the results of resistance testing. In this context, long-term RAVs persistence after failure should be taken into account.
authors.affiliation: aDepartment of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy bNational Reference Center for Viral Hepatitis B, C and delta, Department of Virology and INSERM U955, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cento
authors.forename: Stephane
authors.initials: S
authors.lastname: Chevaliez
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005838:Genotype; D060005:Genotyping Techniques; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; 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; 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