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Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study
  1. Christophe Hézode1,
  2. Gideon M Hirschfield2,
  3. Wayne Ghesquiere3,
  4. William Sievert4,
  5. Maribel Rodriguez-Torres5,
  6. Stephen D Shafran6,
  7. Paul J Thuluvath7,
  8. Harvey A Tatum8,
  9. Imam Waked9,
  10. Gamal Esmat10,
  11. Eric J Lawitz11,
  12. Vinod K Rustgi12,
  13. Stanislas Pol13,
  14. Nina Weis14,
  15. Paul J Pockros15,
  16. Marc Bourlière16,
  17. Lawrence Serfaty17,
  18. John M Vierling18,
  19. Michael W Fried19,
  20. Ola Weiland20,
  21. Maurizia R Brunetto21,
  22. Gregory T Everson22,
  23. Stefan Zeuzem23,
  24. Paul Y Kwo24,
  25. Mark Sulkowski25,
  26. Norbert Bräu26,
  27. Dennis Hernandez27,
  28. Fiona McPhee27,
  29. Megan Wind-Rotolo28,
  30. Zhaohui Liu29,
  31. Stephanie Noviello28,
  32. Eric A Hughes28,
  33. Philip D Yin27,
  34. Steven Schnittman27
  1. 1Hôpital Henri Mondor, AP-HP, Université Paris-Est, Inserm U955, Créteil, France
  2. 2Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
  3. 3Vancouver Island Health Authority & University of British Columbia, Victoria, British Columbia, Canada
  4. 4Monash University and Monash Health, Melbourne, Australia
  5. 5Fundacion De Investigacion, San Juan Bautista School of Medicine, San Juan, Puerto Rico
  6. 6University of Alberta Hospital, Edmonton, Canada
  7. 7Mercy Medical Center, Baltimore, Maryland, USA
  8. 8Options Health Research, LLC, Tulsa, Oklahoma, USA
  9. 9National Liver Institute, Shebin Elkom, Egypt
  10. 10Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
  11. 11Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA
  12. 12Metropolitan Research, Fairfax, Virginia, USA
  13. 13Inserm U1016 and Liver Unit, Université Paris Descartes, Hôpital Cochin, Paris, France
  14. 14Copenhagen University Hospital, Hvidovre, Denmark
  15. 15Scripps Clinic, La Jolla, California, USA
  16. 16Hôpital Saint Joseph, Marseille, France
  17. 17Hôpital Saint-Antoine, Paris, France
  18. 18Baylor College of Medicine, Houston, Texas, USA
  19. 19University of North Carolina, Chapel Hill, North Carolina, USA
  20. 20Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
  21. 21Hepatology Unit, University Hospital of Pisa, Pisa, Italy
  22. 22University of Colorado Denver, Aurora, Colorado, USA
  23. 23Goethe University, Frankfurt, Germany
  24. 24Indiana University, Indianapolis, Indiana, USA
  25. 25Johns Hopkins University, Baltimore, Maryland, USA
  26. 26James J. Peters VA Medical Center, Bronx, New York, USA
  27. 27Bristol-Myers Squibb, Clinical Research and Development, Wallingford, Connecticut, USA
  28. 28Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA
  29. 29Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA
  1. Correspondence to Dr Christophe Hézode, CHU Henri Mondor Service Hépato-Gastroentérologie, Unité C 13ème étage, 51 avenue du Maréchal de Lattre de Tassigny, Creteil Cedex 94010, France; christophe.hezode{at}hmn.aphp.fr

Abstract

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.

Design In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients.

Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups.

Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4.

Trial registration number NCT01125189.

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