title: Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection.
abstract: OBJECTIVE
  The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection.
  
  
  METHODS
  We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]).
  
  
  RESULTS
  In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms.
  
  
  CONCLUSIONS
  In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.
authors.affiliation: University of Colorado Denver, Aurora, Colorado. Electronic address: greg.everson@ucdenver.edu.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Everson
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Sims
authors.affiliation: Fundación de Investigación, San Juan, Puerto Rico.
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.affiliation: Service d'Hépato-Gastroentérologie, CHU Henri Mondor, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Service d'Hépato-Gastroentérologie, Hôpital Saint Joseph, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.affiliation: University Hospital of Limoges, Limoges, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Loustaud-Ratti
authors.affiliation: Metropolitan Research, Arlington, Virginia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Rustgi
authors.affiliation: Miami Research Associates, South Miami, Florida.
authors.forename: Howard
authors.initials: H
authors.lastname: Schwartz
authors.affiliation: Options Health Research, Tulsa, Oklahoma.
authors.forename: Harvey
authors.initials: H
authors.lastname: Tatum
authors.affiliation: Hôpital Beaujon, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: Université Paris Descartes, INSERM U1610 and Liver Unit, Hôpital Cochin, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Mercy Medical Center, Baltimore, Maryland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thuluvath
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Megan
authors.initials: M
authors.lastname: Wind-Rotolo
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Ellen
authors.initials: E
authors.lastname: Chung
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pasquinelli
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: David F
authors.initials: DF
authors.lastname: Gardiner
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D002219:Carbamates; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011759:Pyrrolidines; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load; D055815:Young Adult
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; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
keywords: DAA; Drug Combination; EC(50); GT; HCV; IL; Liver Disease; SVR; SVR(24); Therapy; genotype; hepatitis C virus; interleukin; median effective concentration; sustained virologic response; sustained virologic response at 12 weeks