Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study)

Liver Int. 2017 Jun;37(6):836-842. doi: 10.1111/liv.13335. Epub 2017 Feb 2.


Background & aims: 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.

Methods: 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.

Results: Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 106 IU/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.

Conclusions: 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.

Keywords: asunaprevir; beclabuvir; daclatasvir; sofosbuvir.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use*
  • Benzazepines / therapeutic use
  • Drug Therapy, Combination
  • Female
  • Hepacivirus / genetics
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Imidazoles / therapeutic use
  • Indoles / therapeutic use
  • Isoquinolines / therapeutic use
  • Male
  • Middle Aged
  • Sofosbuvir / therapeutic use
  • Sulfonamides / therapeutic use
  • Sustained Virologic Response
  • United States
  • Viral Load
  • Young Adult


  • 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
  • Antiviral Agents
  • Benzazepines
  • Imidazoles
  • Indoles
  • Isoquinolines
  • Sulfonamides
  • daclatasvir
  • asunaprevir
  • Sofosbuvir

Associated data