Michael Manns1, Didier Samuel2, Edward J Gane3, David Mutimer4, Geoff McCaughan5, Maria Buti6, Martín Prieto7, José Luis Calleja8, Markus Peck-Radosavljevic9, Beat Müllhaupt10, Kosh Agarwal11, Peter Angus12, Eric M Yoshida13, Massimo Colombo14, Mario Rizzetto15, Hadas Dvory-Sobol16, Jill Denning16, Sarah Arterburn16, Phillip S Pang16, Diana Brainard16, John G McHutchison16, Jean-François Dufour17, Hans Van Vlierberghe18, Bart van Hoek19, Xavier Forns20. 1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center of Infection Research (DZIF), Hannover-Braunschweig, Germany. Electronic address: manns.michael@mh-hannover.de. 2. Centre Hepatobiliaire, Hôpital Paul Brousse, and Université Paris Sud, Villejuif, France. 3. New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. 4. Queen Elizabeth Hospital and NIHR Liver Biomedical Research Unit, Birmingham, UK. 5. Australian Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia. 6. Internal Medicine and Hepatology, CIBERHED Vall d'Hebron University Hospital, Barcelona, Spain. 7. Digestive Diseases Service, Hospital Universitario y Politécnico La Fe, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Valencia, Spain. 8. Servicio de Gastroenterología y Hepatología Hospital Universitario Puerta de Hierro Universidad Autonoma, Madrid, Spain. 9. Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. 10. Department for Gastroenterology and Hepatology UniversitätsSpital Zürich, Zürich, Switzerland. 11. Institute of Liver Studies, King's College Hospital Foundation Trust, London, UK. 12. Liver Transplant Unit, Austin Hospital, Heidelberg, VIC, Australia. 13. Division of Gastroenterology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada. 14. Department of Gastroenterology, IRCCS Maggiore Hospital University of Milan, Milan, Italy. 15. Azienda Ospedaliero-Universitaria, Torino, Italy. 16. Gilead Sciences, Foster City, CA, USA. 17. Department of Hepatology, University of Bern, Bern, Switzerland. 18. Ghent University Hospital, Ghent, Belgium. 19. Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, Netherlands. 20. Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain.
Abstract
BACKGROUND: Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. METHODS: We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). FINDINGS:Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. INTERPRETATION:Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. FUNDING: Gilead Sciences.
RCT Entities:
BACKGROUND: Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. METHODS: We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). FINDINGS: Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-Apatients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-Apatients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. INTERPRETATION:Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. FUNDING: Gilead Sciences.
Authors: Sumeyye Samur; Brian Kues; Turgay Ayer; Mark S Roberts; Fasiha Kanwal; Chin Hur; Drew Michael S Donnell; Raymond T Chung; Jagpreet Chhatwal Journal: Clin Gastroenterol Hepatol Date: 2017-06-17 Impact factor: 11.382