title: In vivo emergence of a novel mutant L159F/L320F in the NS5B polymerase confers low-level resistance to the HCV polymerase inhibitors mericitabine and sofosbuvir.
abstract: BACKGROUND
  Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation.
  
  
  METHODS
  Serum HCV RNA from patients who experienced viral breakthrough, partial response, or nonresponse in 2 clinical trials in which patients received mericitabine plus peginterferon alfa-2a (40KD)/ribavirin were analyzed by population and clonal sequence analysis as well as phenotypic assay for assessment of in vivo mericitabine resistance.
  
  
  RESULTS
  Among 405 patients treated with mericitabine plus peginterferon alfa-2a/ribavirin in PROPEL and JUMP-C, virologic breakthrough or nonresponse were not observed; 12 patients experienced a partial response. The NS5B S282T resistance mutation was not observed in any patient. A number of treatment-associated NS5B changes were observed and characterized. A novel double mutant (L159F/L320F) with impaired replication capacity was detected in one HCV genotype 1b-infected patient. Introduction of double mutant L159F/L320F into genotype 1a (H77) and 1b (Con-1) replicons, respectively, increased the EC50 for mericitabine by 3.1- and 5.5-fold and the EC90 by 3.1- and 8.9-fold. The double mutant also decreased susceptibility to sofosbuvir (GS-7977) and GS-938 but not setrobuvir, relative to wild-type.
  
  
  CONCLUSIONS
  A novel and replication-deficient double mutation (L159F/L320F) confers low-level resistance to mericitabine and cross-resistance to both sofosbuvir and GS-938.
  
  
  BACKGROUND
  NCT00869661, NCT01057667.
authors.affiliation: Hoffmann-La Roche Inc, Nutley, New Jersey.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Lewyn
authors.initials: L
authors.lastname: Li
authors.forename: Kristin
authors.initials: K
authors.lastname: Haines
authors.forename: Katherine
authors.initials: K
authors.lastname: Piso
authors.forename: Victoria
authors.initials: V
authors.lastname: Baronas
authors.forename: Jun-Mei
authors.initials: JM
authors.lastname: Yan
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination / Q000379:methods; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D011092:Polyethylene Glycols / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D012093:Replicon / Q000187:drug effects / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use; D000069474:Sofosbuvir; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003841:Deoxycytidine; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C100416:peginterferon alfa-2a
keywords: GS-938; hepatitis C virus; mericitabine; resistance; setrobuvir; sofosbuvir (GS-7977)