Mark S Sulkowski1, Walford J Fessel2, Adriano Lazzarin3, Juan Berenguer4, Natalia Zakharova5, Hugo Cheinquer6, Pierre Côté7, Douglas Dieterich8, Adrian Gadano9, Gail Matthews10, Jean-Michel Molina11, Christophe Moreno12, Juan Antonio Pineda13, Federico Pulido14, Antonio Rivero15, Jurgen Rockstroh16, Dennis Hernandez17, Fiona McPhee17, Timothy Eley18, Zhaohui Liu19, Patricia Mendez18, Eric Hughes20, Stephanie Noviello20, Peter Ackerman21. 1. Divisions of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins Hospital, The Johns Hopkins University School of Medicine , Baltimore, MD, USA. msulkowski@jhmi.edu. 2. Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA. 3. Unit of Infectious Diseases, Clinica Malattie Infettive, Institute of Hospitalisation and Scientific Care, Milan, Italy. 4. Unidad de Enfermedades Infecciosas/VIH (4100), Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 5. St Petersburg AIDS Center, SPT AIDS C 179A OBVODNIY CANAL, Saint Petersburg, Russian Federation. 6. Servico De Gastroentereologia, Hospital De Clinicas De Porto Alegre, Porto Alegre, Rio Grande Do Sul, Brazil. 7. Clinique Medicale Du Quartier Latin, Montreal, QC, Canada. 8. Institute for Liver Disease, Mount Sinai School of Medicine, New York, NY, USA. 9. Hospital Italiano De Buenos Aires, Buenos Aires, Argentina. 10. St Vincent's Hospital (NSW), Darlinghurst, NSW, Australia. 11. Hopital Saint Louis, Paris, France. 12. Hospital Erasme, Brussels, Belgium. 13. Infectious Diseases and Microbiology Unit, Hospital Universitario de Valme, Seville, Spain. 14. Hospital Universitario 12 De Octubre, Madrid, Spain. 15. Hospital Universitario Reina Sofia, Cordoba, Spain. 16. Universitaetsklinikum Bonn, Medizinische Klinik, Bonn, Germany. 17. Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA. 18. Bristol-Myers Squibb, Princeton, NJ, USA. 19. Bristol-Myers Squibb, Hopewell, Pennington, NJ, USA. 20. Bristol-Myers Squibb, Lawrenceville, NJ, USA. 21. Bristol-Myers Squibb, Wallingford, CT, USA.
Abstract
BACKGROUND: Daclatasvir (DCV) is a potent, pangenotypic, hepatitis C virus (HCV) non-structural protein 5A inhibitor with low potential for drug interactions with antiretroviral therapy (ART). We evaluated the safety and efficacy of DCV plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in HIV-1/HCV genotype-1-coinfected patients. METHODS: AI444043 (NCT01471574), an open-label, Phase III, single-arm, response-guided treatment (RGT) study included 301 patients. They received DCV doses of 30, 60 or 90 mg once daily (depending on concomitant ART), plus weight-based RBV (<75 kg, 1000 mg/day; or ≥75 kg, 1200 mg/day), and once-weekly PegIFN 180 μg, for 24 weeks. If required by RGT, PegIFN/RBV without DCV was extended for an additional 24 weeks of therapy. The primary endpoint was the proportion of patients with sustained virologic response at post-treatment Week 12 (SVR12). RESULTS: Overall, 224 (74%) patients achieved SVR12 and the lower bound of the 95% confidence interval was higher than the historic SVR rate with PegIFN/RBV alone (70 vs. 29%). Most common adverse events (AEs) were fatigue, neutropenia, anemia, asthenia and headache. On-treatment serious AEs occurred in 24/301 (8%) patients; 18/301 (6%) discontinued treatment due to AE. CONCLUSIONS: DCV + PegIFN/RBV led to sustained HCV virologic response in the majority of HIV-1-HCV-coinfected patients, regardless of concomitant ART. HIV control was not compromised and no new safety signals were identified. This study supports DCV use in HIV-1-HCV-coinfected patients, while allowing the vast majority of patients to remain on their existing ART regimen.
BACKGROUND:Daclatasvir (DCV) is a potent, pangenotypic, hepatitis C virus (HCV) non-structural protein 5A inhibitor with low potential for drug interactions with antiretroviral therapy (ART). We evaluated the safety and efficacy of DCV plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in HIV-1/HCV genotype-1-coinfectedpatients. METHODS: AI444043 (NCT01471574), an open-label, Phase III, single-arm, response-guided treatment (RGT) study included 301 patients. They received DCV doses of 30, 60 or 90 mg once daily (depending on concomitant ART), plus weight-based RBV (<75 kg, 1000 mg/day; or ≥75 kg, 1200 mg/day), and once-weekly PegIFN 180 μg, for 24 weeks. If required by RGT, PegIFN/RBV without DCV was extended for an additional 24 weeks of therapy. The primary endpoint was the proportion of patients with sustained virologic response at post-treatment Week 12 (SVR12). RESULTS: Overall, 224 (74%) patients achieved SVR12 and the lower bound of the 95% confidence interval was higher than the historic SVR rate with PegIFN/RBV alone (70 vs. 29%). Most common adverse events (AEs) were fatigue, neutropenia, anemia, asthenia and headache. On-treatment serious AEs occurred in 24/301 (8%) patients; 18/301 (6%) discontinued treatment due to AE. CONCLUSIONS:DCV + PegIFN/RBV led to sustained HCV virologic response in the majority of HIV-1-HCV-coinfectedpatients, regardless of concomitant ART. HIV control was not compromised and no new safety signals were identified. This study supports DCV use in HIV-1-HCV-coinfectedpatients, while allowing the vast majority of patients to remain on their existing ART regimen.
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