Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis

Andrew J. Muir, Fred Poordad, Jacob Lalezari, Gregory Everson, Gregory J. Dore, Robert Herring, Aasim Sheikh, Paul Kwo, Christophe Hézode, Paul J. Pockros, Albert Tran, Joseph Yozviak, Nancy Reau, Alnoor Ramji, Katherine Stuart, Alexander J. Thompson, John Vierling, Bradley Freilich, James Cooper, Wayne GhesquiereRong Yang, Fiona McPhee, Eric A. Hughes, E. Scott Swenson, Philip D. Yin

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: Sustained virologic response at posttreatment week 12 (SVR<inf>12</inf>). 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. SVR<inf>12</inf> 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 AND RELEVANCE: 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 SVR<inf>12</inf>.

Original languageEnglish
Pages (from-to)1736-1744
Number of pages9
JournalJournal of the American Medical Association
Volume313
Issue number17
DOIs
StatePublished - May 5 2015

Fingerprint

Hepacivirus
Fibrosis
Genotype
Infection
Ribavirin
Therapeutics
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
asunaprevir
BMS-790052
Chronic Hepatitis C
Virus Diseases
Protease Inhibitors
Alanine Transaminase
Bilirubin
Interferons
France
Canada
Outpatients

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis. / Muir, Andrew J.; Poordad, Fred; Lalezari, Jacob; Everson, Gregory; Dore, Gregory J.; Herring, Robert; Sheikh, Aasim; Kwo, Paul; Hézode, Christophe; Pockros, Paul J.; Tran, Albert; Yozviak, Joseph; Reau, Nancy; Ramji, Alnoor; Stuart, Katherine; Thompson, Alexander J.; Vierling, John; Freilich, Bradley; Cooper, James; Ghesquiere, Wayne; Yang, Rong; McPhee, Fiona; Hughes, Eric A.; Swenson, E. Scott; Yin, Philip D.

In: Journal of the American Medical Association, Vol. 313, No. 17, 05.05.2015, p. 1736-1744.

Research output: Contribution to journalArticle

Muir, AJ, Poordad, F, Lalezari, J, Everson, G, Dore, GJ, Herring, R, Sheikh, A, Kwo, P, Hézode, C, Pockros, PJ, Tran, A, Yozviak, J, Reau, N, Ramji, A, Stuart, K, Thompson, AJ, Vierling, J, Freilich, B, Cooper, J, Ghesquiere, W, Yang, R, McPhee, F, Hughes, EA, Swenson, ES & Yin, PD 2015, 'Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis', Journal of the American Medical Association, vol. 313, no. 17, pp. 1736-1744. https://doi.org/10.1001/jama.2015.3868
Muir, Andrew J. ; Poordad, Fred ; Lalezari, Jacob ; Everson, Gregory ; Dore, Gregory J. ; Herring, Robert ; Sheikh, Aasim ; Kwo, Paul ; Hézode, Christophe ; Pockros, Paul J. ; Tran, Albert ; Yozviak, Joseph ; Reau, Nancy ; Ramji, Alnoor ; Stuart, Katherine ; Thompson, Alexander J. ; Vierling, John ; Freilich, Bradley ; Cooper, James ; Ghesquiere, Wayne ; Yang, Rong ; McPhee, Fiona ; Hughes, Eric A. ; Swenson, E. Scott ; Yin, Philip D. / Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis. In: Journal of the American Medical Association. 2015 ; Vol. 313, No. 17. pp. 1736-1744.
@article{9ca39d1082b542869d6da8a467cccd11,
title = "Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis",
abstract = "IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.",
author = "Muir, {Andrew J.} and Fred Poordad and Jacob Lalezari and Gregory Everson and Dore, {Gregory J.} and Robert Herring and Aasim Sheikh and Paul Kwo and Christophe H{\'e}zode and Pockros, {Paul J.} and Albert Tran and Joseph Yozviak and Nancy Reau and Alnoor Ramji and Katherine Stuart and Thompson, {Alexander J.} and John Vierling and Bradley Freilich and James Cooper and Wayne Ghesquiere and Rong Yang and Fiona McPhee and Hughes, {Eric A.} and Swenson, {E. Scott} and Yin, {Philip D.}",
year = "2015",
month = "5",
day = "5",
doi = "10.1001/jama.2015.3868",
language = "English",
volume = "313",
pages = "1736--1744",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "17",

}

TY - JOUR

T1 - Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis

AU - Muir, Andrew J.

AU - Poordad, Fred

AU - Lalezari, Jacob

AU - Everson, Gregory

AU - Dore, Gregory J.

AU - Herring, Robert

AU - Sheikh, Aasim

AU - Kwo, Paul

AU - Hézode, Christophe

AU - Pockros, Paul J.

AU - Tran, Albert

AU - Yozviak, Joseph

AU - Reau, Nancy

AU - Ramji, Alnoor

AU - Stuart, Katherine

AU - Thompson, Alexander J.

AU - Vierling, John

AU - Freilich, Bradley

AU - Cooper, James

AU - Ghesquiere, Wayne

AU - Yang, Rong

AU - McPhee, Fiona

AU - Hughes, Eric A.

AU - Swenson, E. Scott

AU - Yin, Philip D.

PY - 2015/5/5

Y1 - 2015/5/5

N2 - IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

AB - IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

UR - http://www.scopus.com/inward/record.url?scp=84929208843&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929208843&partnerID=8YFLogxK

U2 - 10.1001/jama.2015.3868

DO - 10.1001/jama.2015.3868

M3 - Article

C2 - 25942724

AN - SCOPUS:84929208843

VL - 313

SP - 1736

EP - 1744

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 17

ER -