title: Daclatasvir + asunaprevir + beclabuvir ± ribavirin for chronic HCV genotype 1-infected treatment-naive patients.
abstract: OBJECTIVE
  This phase-2b study examined the safety and efficacy of an all-oral, interferon-free combination of the NS5A replication complex inhibitor daclatasvir (DCV), the NS3 protease inhibitor asunaprevir (ASV), and the nonnucleoside NS5B polymerase inhibitor beclabuvir (BCV) with or without ribavirin in patients with HCV genotype (GT) 1 infection.
  
  
  METHODS
  A total of 187 patients received 12 weeks of DCV 30 mg BID plus ASV 200 mg BID and BCV 150 mg BID (n = 86) or 75 mg BID with (n = 21) or without (n = 80) weight-based ribavirin BID. The primary endpoint was HCV RNA <25 IU/ml at post-treatment week 12 (SVR12).
  
  
  RESULTS
  Overall, 90% of patients (169/187) in the combined treatment groups achieved SVR on or after post-treatment week 12. SVR rates were similar across subgroups (by mITT analysis), i.e. patients with cirrhosis (88%, 14/16), HCV GT-1a (90%, 137/155), and IL28B non-CC genotype (90%, 115/128). There were no drug-related serious AEs or grade 4 AEs. The most frequently reported AEs were headache, diarrhoea, fatigue and nausea. Addition of ribavirin to DCV+ASV+BCV was associated with decreased haemoglobin, compared with DCV+ASV+BCV alone. There were six grade 3/4 laboratory abnormalities noted, all unrelated to the study drugs. Viral breakthrough occurred in 2.5-4.8% of patients across groups and appeared unrelated to BCV dose or ribavirin inclusion.
  
  
  CONCLUSIONS
  Results support phase 3 evaluation of a twice-daily, fixed-dose formulation of this DCV+ASV+BCV regimen with or without ribavirin in HCV GT-1-infected patients.
authors.affiliation: University of Colorado Denver, Aurora, CO, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Everson
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Sims
authors.affiliation: Mercy Medical Center, Baltimore, MD, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thuluvath
authors.affiliation: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Southern California GI and Liver Centers, Coronado, CA, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.affiliation: Fundación de Investigación, San Juan, PR, USA.
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.affiliation: Precision Research Institute, San Diego, CA, USA.
authors.forename: Tadesse
authors.initials: T
authors.lastname: Desta
authors.affiliation: Southwest CARE Center, Santa Fe, NM, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hawkins
authors.affiliation: Dean Foundation for Health, Research and Education Inc, Madison, WI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Levin
authors.affiliation: Orlando Immunology Center, Orlando, FL, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Hinestrosa
authors.affiliation: The Thomas Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Rustgi
authors.affiliation: Miami Research Associates, South Miami, FL, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Schwartz
authors.affiliation: Inova Fairfax Hospital, Center for Liver Diseases, Falls Church, VA, USA.
authors.forename: Zobair
authors.initials: Z
authors.lastname: Younossi
authors.affiliation: PRA Health Sciences, Raleigh, NC, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
authors.affiliation: Atlanta Gastroenterology Associates' Liver Center, Atlanta, GA, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Gitlin
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Gardiner
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects; D002219:Carbamates; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load / Q000187:drug effects
chemical_list: C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; D000998:Antiviral Agents; D001552:Benzazepines; D002219:Carbamates; D007093:Imidazoles; D007211:Indoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
keywords: direct-acting antiviral; drug combination; liver disease; therapy