title: Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations.
abstract: The NS5A replication complex inhibitor, BMS-790052, inhibits hepatitis C virus (HCV) replication with picomolar potency in preclinical assays. This potency translated in vivo to a substantial antiviral effect in a single-ascending dose study and a 14-day multiple-ascending dose (MAD) monotherapy study. However, HCV RNA remained detectable in genotype 1a-infected patients at the end of the MAD study. In contrast, viral breakthrough was observed less often in patients infected with genotype 1b, and, in several patients, HCV RNA declined and remained below the level of quantitation (<25 IU/mL) through the duration of treatment. Here, we report on the results of the genotypic and phenotypic analyses of resistant variants in 24 genotype 1-infected patients who received BMS-790052 (1, 10, 30, 60, and 100 mg, once-daily or 30 mg twice-daily) in the 14-day MAD study. Sequence analysis was performed on viral complementary DNA isolated from serum specimens collected at baseline and days 1 (4, 8, and 12 hours), 2, 4, 7, and 14 postdosing. Analyses of the sequence variants (1) established a correlation between resistant variants emerging in vivo with BMS-790052 treatment and those observed in the in vitro replicon system (major substitutions at residues 28, 30, 31, and 93 for genotype 1a and residues 31 and 93 for genotype 1b); (2) determined the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (3) revealed the resistance profile and replicative ability (i.e., fitness) of the variants.
  
  
  CONCLUSIONS
  Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination therapy.
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle
authors.forename: Peter
authors.initials: P
authors.lastname: Nower
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valera
authors.forename: Dike
authors.initials: D
authors.lastname: Qiu
authors.forename: Susan
authors.initials: S
authors.lastname: Roberts
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Bernadette
authors.initials: B
authors.lastname: Kienzle
authors.forename: Marc
authors.initials: M
authors.lastname: Bifano
authors.forename: Richard E
authors.initials: RE
authors.lastname: Nettles
authors.forename: Min
authors.initials: M
authors.lastname: Gao
mesh_terms: D002219:Carbamates; D004311:Double-Blind Method; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D010641:Phenotype; D011759:Pyrrolidines; D012367:RNA, Viral / Q000187:drug effects; D012093:Replicon / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000187:drug effects / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012367:RNA, Viral; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir