title: Impact of a baseline polymorphism on the emergence of resistance to the hepatitis C virus nonstructural protein 5A replication complex inhibitor, BMS-790052.
abstract: The influence of naturally occurring polymorphisms on the potency of the HCV nonstructural protein 5A (NS5A) replication complex inhibitor, BMS-790052, was investigated by evaluating hybrid replicons in which the entire NS5A coding region of genotype (GT) la and 1b laboratory (lab) strains (H77c and Con1) were replaced with the corresponding regions of specimens collected from 10 GT-1a- and 6 GT-1b-infected subjects. For baseline (BL) specimens, with no previously observed resistance variants identified by population sequencing, the median 50% effective concentration (EC(50) ) values for BMS-790052 were similar for the clinically derived and lab strains. A Q30R variant was observed at viral breakthrough (VBT) in one of the GT-1a-infected subjects. Because the lowest plasma exposure of BMS-790052 observed in this subject was 117 nM and the median 50% effective concentration value for a GT-1a H77c replicon containing a Q30R substitution is ~7 nM, a rigorous investigation was initiated to determine the basis for resistance. Three approaches were used: (1) replacement of the entire H77c NS5A or (2) replacement of the N-terminal region of NS5A, with sequence from BL and day 14, and (3) substitution of specific amino acids. A BL polymorphism (E62D) did not contribute resistance to BMS-790052; however, the linked variant, Q30R-E62D, conferred high-level resistance in vitro and is likely responsible for VBT in vivo.
  
  
  CONCLUSIONS
  Our data show that a BL polymorphism with minimal effect on the anti-HCV effect of BMS-790052 can affect the emergence of resistance and significantly affect clinical outcome. This work establishes a clear, systematic approach to monitor resistance to NS5A inhibitors in the clinic.
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA. jinhua.sun@bms.com
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle Ii
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Nower
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valera
authors.forename: Susan
authors.initials: S
authors.lastname: Roberts
authors.forename: Richard E
authors.initials: RE
authors.lastname: Nettles
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
authors.forename: Min
authors.initials: M
authors.lastname: Gao
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002219:Carbamates; D002460:Cell Line; D024882:Drug Resistance, Viral; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D011759:Pyrrolidines; D012367:RNA, Viral / Q000096:biosynthesis; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; 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