title: Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study).
abstract: The phase 2, FOURward study (NCT02175966) investigated short-duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1.
  
  
  
  Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice-daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks.
  
  
  
  Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 106IU/mL). Most patients had undetectable HCV-RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV-RNA (<2 million IU/mL, 71% [n=5/7]; ≥2 million IU/mL, 33% [n=7/21]). None of the 16 non-SVR12 patients had NS3 or NS5B resistance-associated substitutions (RAS) detected at failure. All 15 patients retreated with DCV-TRIO + RBV for 12 weeks achieved SVR12. All regimens were well tolerated.
  
  
  
  Short-duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype-1 infection and high baseline viraemia. Non-SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV-TRIO + RBV for 12 weeks led to SVR in all patients.
authors.affiliation: Viral Hepatitis Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.affiliation: Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Flamm
authors.affiliation: Inland Empire Liver Foundation, Rialto, CA, USA.
authors.forename: Zeid
authors.initials: Z
authors.lastname: Kayali
authors.affiliation: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.affiliation: Indiana University, Bloomington, IN, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kwo
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Bristol-Myers Squibb, Braine l'Alleud, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Torbeyns
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hughes
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Swenson
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Yin
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Misti
authors.initials: M
authors.lastname: Linaberry
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D007546:Isoquinolines / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D000069474:Sofosbuvir / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D000072230:Sustained Virologic Response; D014481:United States; 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; D000069474:Sofosbuvir
keywords: asunaprevir; beclabuvir; daclatasvir; sofosbuvir