title: Virologic resistance analysis from a phase 2 study of MK-5172 combined with pegylated interferon/ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection.
abstract: BACKGROUND
  Virologic failure following treatment of hepatitis C virus (HCV) genotype 1 with direct-acting antiviral agents is often accompanied by the emergence of resistant variants. MK-5172 is an investigational once-daily protease inhibitor. We analyzed variants in treatment-naive noncirrhotic patients with virologic failure on MK-5172 (100-800 mg/day) plus pegylated interferon alfa/ribavirin (peg-IFN/RBV) during a phase 2 trial.
  
  
  METHODS
  Population and selective clonal sequencing were performed at baseline and at virologic failure in the 4 MK-5172 dosing arms. MK-5172 activity was determined using a mutant replicon assay.
  
  
  RESULTS
  Six of 266 (2.3%) MK-5172 recipients satisfied prespecified criteria for virologic failure, all with genotype 1a infection. Five patients with virologic failure were in the MK-5172 100-mg arm, including 4 patients with low plasma MK-5172 levels documented during triple therapy. Variants associated with >4-fold loss of potency were detected in 3 of the 4 patients with genotype 1a breakthrough while on MK-5172. The fifth patient had undetectable HCV-RNA levels at the end of triple therapy but subsequently broke through during the peg-IFN/RBV tail 16 weeks after completion of MK-5172. Three patients had D168 variants at virologic failure, including 2 with the D168A variant associated with a 95-fold loss of potency. The sole apparent relapse was actually a genotype 3a reinfection in the MK-5172 200-mg group.
  
  
  CONCLUSIONS
  Virologic failure occurred uncommonly (6/266 [2.3%]) in MK-5172/peg-IFN/RBV recipients. The most prevalent treatment-emergent variants were detected at the D168 locus. D168A variants conferring approximately 2-log reduction in MK-5172 susceptibility emerged in 2 of the 4 evaluable patients with genotype 1a breakthrough. Clinical Trials Registration. NCT01353911.
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Anita Y M
authors.initials: AY
authors.lastname: Howe
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Stuart
authors.initials: S
authors.lastname: Black
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Curry
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Ludmerer
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Richard J O
authors.initials: RJ
authors.lastname: Barnard
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: William
authors.initials: W
authors.lastname: Newhard
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Peggy M T
authors.initials: PM
authors.lastname: Hwang
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: David
authors.initials: D
authors.lastname: Nickle
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gilbert
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Luzelena
authors.initials: L
authors.lastname: Caro
authors.affiliation: Office of the Chief Medical Officer, Merck, North Wales, Pennsylvania.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: DiNubile
authors.affiliation: Merck Research Laboratories, West Point.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Mobashery
mesh_terms: D000577:Amides; D002219:Carbamates; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D005838:Genotype; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D012254:Ribavirin / Q000627:therapeutic use*; D013449:Sulfonamides; D047029:Lactams, Macrocyclic
chemical_list: D000577:Amides; D002219:Carbamates; D003521:Cyclopropanes; D007372:Interferons; D011810:Quinoxalines; D012254:Ribavirin; D013449:Sulfonamides; C578009:grazoprevir; D047029:Lactams, Macrocyclic
keywords: MK-5172; hepatitis C genotype 1; resistance-associated variants; treatment-naive