title: Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Manns
authors.affiliation: Centre Hepatobiliaire, Hôpital Paul Brousse, and Université Paris Sud, Villejuif, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.affiliation: New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: Queen Elizabeth Hospital and NIHR Liver Biomedical Research Unit, Birmingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mutimer
authors.affiliation: Australian Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.
authors.forename: Geoff
authors.initials: G
authors.lastname: McCaughan
authors.affiliation: Internal Medicine and Hepatology, CIBERHED Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: Digestive Diseases Service, Hospital Universitario y Politécnico La Fe, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Valencia, Spain.
authors.forename: Martín
authors.initials: M
authors.lastname: Prieto
authors.affiliation: Servicio de Gastroenterología y Hepatología Hospital Universitario Puerta de Hierro Universidad Autonoma, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Calleja
authors.affiliation: Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.affiliation: Department for Gastroenterology and Hepatology UniversitätsSpital Zürich, Zürich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Institute of Liver Studies, King's College Hospital Foundation Trust, London, UK.
authors.forename: Kosh
authors.initials: K
authors.lastname: Agarwal
authors.affiliation: Liver Transplant Unit, Austin Hospital, Heidelberg, VIC, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Angus
authors.affiliation: Division of Gastroenterology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology, IRCCS Maggiore Hospital University of Milan, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Azienda Ospedaliero-Universitaria, Torino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Rizzetto
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Denning
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Arterburn
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Department of Hepatology, University of Bern, Bern, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Ghent University Hospital, Ghent, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van Hoek
authors.affiliation: Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forns
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use*; D005838:Genotype; D014943:Global Health; D016174:Hepacivirus / Q000145:classification* / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral; D012254:Ribavirin / Q000627:therapeutic use*; D000069474:Sofosbuvir; D013997:Time Factors; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D012367:RNA, Viral; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir