Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis.
OBJECTIVE
Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis.


OBJECTIVE
All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis.


METHODS
The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls.


METHODS
All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo.


METHODS
Sustained virologic response at posttreatment week 12 (SVR12).


RESULTS
One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5% CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.4%-100.0%) for patients in the treatment-naive group and 87% (97.5% CI, 75.3%-98.0%) for those in the treatment-experienced group. Three serious adverse events were considered to be treatment related and there were 4 adverse event-related discontinuations. Treatment-emergent grade 3 or 4 alanine aminotransferase elevations were observed in 4 patients, of which 1 had concomitant total bilirubin elevation.


CONCLUSIONS
In this open-label uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR12.
Duke Clinical Research Institute, Duke University, Durham, North Carolina.
Andrew J
AJ
Muir
Texas Liver Institute-University of Texas Health Science Center, San Antonio.
Fred
F
Poordad
Quest Clinical Research, San Francisco, California.
Jacob
J
Lalezari
University of Colorado School of Medicine, Denver.
Gregory
G
Everson
Kirby Institute, University of New South Wales, Kensington, New South Wales, Australia6St Vincent's Hospital, Sydney, New South Wales, Australia.
Gregory J
GJ
Dore
Quality Medical Research, Nashville, Tennessee.
Robert
R
Herring
Gastrointestinal Specialists Of Georgia, Marietta.
Aasim
A
Sheikh
Indiana University School of Medicine, Indianapolis.
Paul
P
Kwo
Hôpital Henri Mondor, AP-HP, INSERM U955, Université Paris-Est, Créteil, France.
Christophe
C
Hézode
Scripps Clinic, La Jolla, California.
Paul J
PJ
Pockros
INSERM U1065, Team 8, Hepatic Complications in Obesity, Nice, France13Centre Hospitalier Universitaire of Nice, Digestive Center, Nice, France.
Albert
A
Tran
Lehigh Valley Health Network, Allentown, Pennsylvania.
Joseph
J
Yozviak
University of Chicago Medical Center, Chicago, Illinois.
Nancy
N
Reau
University of British Columbia, Vancouver, British Columbia, Canada.
Alnoor
A
Ramji
Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Brisbane, Australia.
Katherine
K
Stuart
St Vincent's Hospital, Melbourne, Victoria, Australia19University of Melbourne, Melbourne, Victoria, Australia.
Alexander J
AJ
Thompson
Baylor College of Medicine, Houston, Texas.
John
J
Vierling
Kansas City Research Institute, Kansas City, Missouri.
Bradley
B
Freilich
Inova Fairfax Hospital, Falls Church, Virginia.
James
J
Cooper
University of British Columbia, Victoria, British Columbia, Canada.
Wayne
W
Ghesquiere
Bristol-Myers Squibb, Princeton, New Jersey.
Rong
R
Yang
Bristol-Myers Squibb, Wallingford, Connecticut.
Fiona
F
McPhee
Bristol-Myers Squibb, Princeton, New Jersey.
Eric A
EA
Hughes
Bristol-Myers Squibb, Wallingford, Connecticut.
E Scott
ES
Swenson
Bristol-Myers Squibb, Wallingford, Connecticut.
Philip D
PD
Yin
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001552:Benzazepines / Q000008:administration & dosage*; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D007546:Isoquinolines / Q000008:administration & dosage*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012254:Ribavirin / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage*; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load
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