title: Naturally occurring substitutions conferring resistance to hepatitis C virus polymerase inhibitors in treatment-naive patients infected with genotypes 1-5.
abstract: BACKGROUND
  The hepatitis C virus (HCV) RNA-dependent RNA polymerase, NS5B, is essential for virus RNA replication. It is thus an attractive therapeutic target. Several compound nucleoside analogues, non-nucleoside inhibitors and cyclosporine analogues are being developed to inhibit NS5B activity. However, nucleotide changes in the NS5B gene can confer resistance to them.
  
  
  METHODS
  We investigated the prevalence of known substitutions conferring resistance in HCV polymerase in 124 treatment-naive French patients infected with HCV genotypes 1, 2, 3, 4 or 5 by sequencing the NS5B gene.
  
  
  RESULTS
  None of the 124 HCV NS5B sequences analysed contained substitutions conferring resistance to nucleoside analogues; however, NS5B polymerases containing substitutions conferring resistance to non-nucleoside inhibitors were frequent within genotype 1 strains (17%) and very common in non-genotype 1 strains. Similarly, substitutions conferring resistance to cyclosporine analogues were more prevalent within the various genotypes.
  
  
  CONCLUSIONS
  Naturally occurring substitutions conferring resistance to NS5B inhibitors are common in treatment-naive patients infected with HCV genotype 1, 2, 3, 4 or 5. Their influence on treatment outcome should be assessed.
authors.affiliation: INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Legrand-Abravanel
authors.forename: Cécile
authors.initials: C
authors.lastname: Henquell
authors.forename: Hélène
authors.initials: H
authors.lastname: Le Guillou-Guillemette
authors.forename: Viorica
authors.initials: V
authors.lastname: Balan
authors.forename: Audrey
authors.initials: A
authors.lastname: Mirand
authors.forename: Martine
authors.initials: M
authors.lastname: Dubois
authors.forename: Francoise
authors.initials: F
authors.lastname: Lunel-Fabiani
authors.forename: Christopher
authors.initials: C
authors.lastname: Payan
authors.forename: Jacques
authors.initials: J
authors.lastname: Izopet
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology; D006801:Humans; D015995:Prevalence; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase