title: Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients.
abstract: BACKGROUND
  Direct-acting antiviral (DAA) agents target HCV proteins; some of these have already been approved for the treatment of HCV infection, while others are in development. However, selection of DAA-resistant viral variants may hamper treatment. The aim of this study was to illustrate potential natural DAA-resistance mutations in the HCV NS5A and NS5B regions of HCV genotypes 1a and 1b from DAA-naïve patients.
  
  
  METHODS
  Direct sequencing of HCV NS5A and NS5B regions was performed in 32 patients infected with HCV genotype 1a and 30 patients infected with HCV genotype 1b; all subjects were naïve to DAAs.
  
  
  RESULTS
  In genotype 1a strains, resistance mutations in NS5A (M28V, L31M and H58P) were observed in 4/32 (12.5%) patients, and resistance mutations in NS5B (V321I, M426L, Y448H, Y452H) were observed in 4/32 (12.5%) patients. In genotype 1b, resistance mutations in NS5A (L28V, L31M, Q54H, Y93H and I280V) were observed in 16/30 (53.3%) patients, while resistance mutations in NS5B (L159F, V321I, C316N, M426L, Y452H, R465G and V499A) were observed in 27/30 (90%) patients.
  
  
  CONCLUSIONS
  Mutations conferring DAA resistance were detected in NS5A and NS5B of HCV genotypes 1a and 1b from DAA-naïve patients. Although some mutations confer only a low level of resistance, the presence at baseline of mutated HCV variants should be taken into consideration in the context of DAA therapy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolucci
authors.forename: Loretta
authors.initials: L
authors.lastname: Fiorina
authors.forename: Bianca
authors.initials: B
authors.lastname: Mariani
authors.forename: Roberto
authors.initials: R
authors.lastname: Gulminetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Novati
authors.forename: Giorgio
authors.initials: G
authors.lastname: Barbarini
authors.forename: Raffaele
authors.initials: R
authors.lastname: Bruno
authors.affiliation: Molecular Virology Unit, Virology and Microbiology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy. f.baldanti@smatteo.pv.it.
authors.forename: Fausto
authors.initials: F
authors.lastname: Baldanti
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase