Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection.

Abstract

IMPORTANCE:

The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection.

OBJECTIVE:

To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor).

DESIGN, SETTING, AND PARTICIPANTS:

This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included.

INTERVENTIONS:

Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg.

MAIN OUTCOMES AND MEASURES:

The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort.

RESULTS:

Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea.

CONCLUSIONS AND RELEVANCE:

In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT01979939.

• Authors: Fred Poordad, William Sievert, Lindsay Mollison, Michael Bennett, Edmund Tse, Norbert Bräu, James Levin, Thomas Sepe, Samuel S Lee, Peter Angus, Brian Conway, Stanislas Pol, Nathalie Boyer, Jean-Pierre Bronowicki, Ira Jacobson, Andrew J Muir, K Rajender Reddy, Edward Tam, Grisell Ortiz-Lasanta, Victor de Lédinghen, Mark Sulkowski, Navdeep Boparai, Fiona McPhee, Eric Hughes, E Scott Swenson, Philip D Yin, UNITY-1 Study Group
• Journal: JAMA (JAMA) Vol. 313 Issue 17 Pg. 1728-35 (May 05 2015) ISSN: 1538-3598 [Electronic] United States
• PMID: 25942723 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• 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
• Carbamates
• Imidazoles
• Indoles
• Isoquinolines
• Pyrrolidines
• Sulfonamides
• Alanine Transaminase
• Valine
• daclatasvir
• asunaprevir

Topics

• Adult
• Aged
• Alanine Transaminase (blood)
• Antiviral Agents (administration & dosage, adverse effects)
• Benzazepines (administration & dosage)
• Carbamates
• Drug Therapy, Combination
• Female
• Genotype
• Hepacivirus (genetics)
• Hepatitis C, Chronic (drug therapy, virology)
• Humans
• Imidazoles (administration & dosage)
• Indoles (administration & dosage)
• Isoquinolines (administration & dosage)
• Male
• Middle Aged
• Pyrrolidines
• Sulfonamides (administration & dosage)
• Valine (analogs & derivatives)