title: Prevalence of sofosbuvir resistance-associated variants in Brazilian and worldwide NS5B sequences of genotype-1 HCV.
abstract: The prevalence of natural polymorphisms associated with resistance to NS5B nucleoside/nucleotide (NI) sofosbuvir is distinct in different geographical regions. In Brazil, direct-acting anti-HCV therapy has recently changed with the introduction of interferon (IFN)-free regimens with sofosbuvir; however, the presence of resistant variants on clinical outcomes remains unknown. The aim of this study was to assess the natural polymorphisms associated with resistance to the NS5B NI sofosbuvir in Brazilian HCV-1 isolates and to compare it with that from other geographical regions.
  
  
  
  Nucleotide sequencing of the HCV NS5B gene was performed in serum samples of 95 therapy-naive Brazilian patients infected with subtype 1a (n=43) and 1b (n=52). The sequences were analysed along with 1,525 NS5B sequences from North America, Europe and Asia retrieved from public HCV databases.
  
  
  
  In Brazilian HCV-1b patients who have never been exposed to a direct-acting anti-HCV drug, the C316N was detected in 15/52 (28.85%) patients, of these, 2 (3.85%) had single C316N variant, while 13 (25%) presented the double L159F-C316N mutant. A lower rate of L159F-C316N variants was detected in North American (n=9/238; 3.78%, P<0.001), European (n=17/281; 6.05%, P<0.001) and Asian (n=2/173; 1.16%, P<0.001) isolates. No sofosbuvir resistance-associated variants (RAVs) were identified in HCV-1a sequences.
  
  
  
  Resistant variants to sofosbuvir were found at different frequencies in worldwide HCV-1b sequences but not in HCV-1a sequences. The high frequency of double mutation L159F-C316N observed in Brazilian HCV-1b patients contrast with the lower rate observed in the three continents studied. The association of these findings and the clinical implications awaits further analysis.
authors.affiliation: Laboratório de Hepatites Virais, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Allan
authors.initials: A
authors.lastname: Peres-da-Silva
authors.affiliation: Hospital Universitário Gaffrée e Guinle/UNIRIO, Rio de Janeiro, Brazil.
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Brandão-Mello
authors.affiliation: Laboratório de Hepatites Virais, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lampe
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001938:Brazil / Q000453:epidemiology; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy / Q000453:epidemiology* / Q000821:virology*; D006801:Humans; D008297:Male; D009154:Mutation; D015995:Prevalence; D062486:Public Health Surveillance; D000069474:Sofosbuvir / Q000494:pharmacology / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D000069474:Sofosbuvir; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase