Gregory J Dore1, Eric Lawitz2, Christophe Hézode3, Stephen D Shafran4, Alnoor Ramji5, Harvey A Tatum6, Gloria Taliani7, Albert Tran8, Maurizia R Brunetto9, Serena Zaltron10, Simone I Strasser11, Nina Weis12, Wayne Ghesquiere13, Samuel S Lee14, Dominique Larrey15, Stanislas Pol16, Hugh Harley17, Jacob George18, Scott K Fung19, Victor de Lédinghen20, Peggy Hagens21, Fiona McPhee22, Dennis Hernandez22, David Cohen22, Elizabeth Cooney22, Stephanie Noviello23, Eric A Hughes23. 1. Kirby Institute, University of New South Wales and St Vincent's Hospital, Sydney, Australia. Electronic address: gdore@kirby.unsw.edu.au. 2. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas. 3. Department of Hepatology, Hôpital Henri Mondor, Créteil, France. 4. Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada. 5. Department of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada. 6. Options Health Research, Tulsa, Oklahoma. 7. Department of Clinical Medicine, Sapienza Università di Roma, Rome, Italy. 8. Faculty of Medicine, Hôpital De L'Archet 2, Nice, France. 9. Hepatology Unit, University Hospital, Pisa, Italy. 10. University Division of Infectious and Tropical Diseases, Azienda Ospedaliera Spedali Civili, Brescia, Italy. 11. AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia. 12. Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark. 13. Vancouver Island Health Authority and University of British Columbia, Victoria, British Columbia, Canada. 14. Liver Unit, University of Calgary, Calgary, Alberta, Canada. 15. Département d'Hépato-Gastroentérologie et Transplantation, Hôpital Saint Eloi, Montpellier, France. 16. Université Paris Descartes, Unité d'Hépatologie, Hôpital Cochin, Paris, France. 17. Department of Gastroenterology and Hepatology, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia. 18. Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, Sydney, Australia. 19. Divisions of Gastroenterology and General Internal Medicine, Toronto General Hospital, Toronto, Ontario, Canada. 20. Department of Hepatology and Gastroenterology, Hôpital Haut-Lévêque, Pessac, France. 21. Research and Development, Bristol-Myers Squibb, Braine-l'Alleud, Belgium. 22. Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut. 23. Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
Abstract
BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS:Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.
RCT Entities:
BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS:Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.
Authors: Ira Jacobson; Stefan Zeuzem; Robert Flisiak; Brygida Knysz; Stefan Lueth; Dorota Zarebska-Michaluk; Ewa Janczewska; Peter Ferenci; Moises Diago; Anna Linda Zignego; Rifaat Safadi; Yaacov Baruch; Dzhamal Abdurakhmanov; Stephen Shafran; Dominique Thabut; Rafael Bruck; Adrian Gadano; Alexander James Thompson; Justin Kopit; Fiona McPhee; Tracy Michener; Eric A Hughes; Philip D Yin; Stephanie Noviello Journal: World J Gastroenterol Date: 2016-03-28 Impact factor: 5.742