Stefan Zeuzem1, Christophe Hézode2, Jean-Pierre Bronowicki3, Veronique Loustaud-Ratti4, Francisco Gea5, Maria Buti6, Antonio Olveira5, Tivadar Banyai7, M Tarek Al-Assi8, Joerg Petersen9, Dominique Thabut10, Adrian Gadano11, Ronald Pruitt12, Mihály Makara13, Marc Bourlière14, Stanislas Pol15, Maria Beumont-Mauviel16, Sivi Ouwerkerk-Mahadevan17, Gaston Picchio18, Marc Bifano19, Fiona McPhee20, Navdeep Boparai19, Kin Cheung20, Eric A Hughes19, Stephanie Noviello19. 1. Klinikum der Goethe Universität, Frankfurt, Germany. Electronic address: zeuzem@em.uni-frankfurt.de. 2. Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France. 3. INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France. 4. U850 INSERM, Univ. Limoges, CHU Limoges, F-87000 Limoges, France. 5. Hospital Universitario La Paz, Madrid, Spain. 6. Hospital Vall Hebron, Barcelona and CIBEREHD del Instituto Carlos III, Spain. 7. Pándy Kálmán Hospital, Gyula, Hungary. 8. Texas Digestive Disease Consultants, Arlington, TX, USA. 9. IFI Institut für Interdisziplinäre Medizin, Hamburg, Germany. 10. Hôpital Pitié-Salpêtrière, Paris, France. 11. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. 12. Nashville Medical Research Institute, Nashville, TN, USA. 13. Saint Laszlo Hospital, Budapest, Hungary. 14. Hôpital Saint Joseph, Marseilles, France. 15. Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM UMS-20, Institut Pasteur, Paris, France. 16. Janssen Infectious Disease BVBA, Beerse, Belgium. 17. Janssen Research and Development, Beerse, Belgium. 18. Janssen Research and Development, Titusville, NJ, USA. 19. Bristol-Myers Squibb Research and Development, Princeton, NJ, USA. 20. Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
Abstract
BACKGROUND & AIMS: We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients. METHODS: This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12). RESULTS: For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation. CONCLUSIONS:Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.
RCT Entities:
BACKGROUND & AIMS: We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infectedpatients. METHODS: This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infectedpatients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infectedpatients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12). RESULTS: For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation. CONCLUSIONS:Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infectedpatients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.
Authors: Nadezhda T Doncheva; Francisco S Domingues; David R McGivern; Tetsuro Shimakami; Stefan Zeuzem; Thomas Lengauer; Christian M Lange; Mario Albrecht; Christoph Welsch Journal: J Mol Biol Date: 2019-04-30 Impact factor: 5.469
Authors: Karin S Ku; Ramakrishna K Chodavarapu; Ross Martin; Michael D Miller; Hongmei Mo; Evguenia S Svarovskaia Journal: J Clin Microbiol Date: 2016-05-04 Impact factor: 5.948