title: Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS).
abstract: BACKGROUND
  Patients with cirrhosis resulting from chronic hepatitis C virus (HCV) infection are at risk of life-threatening complications, but consistently achieve lower sustained virological response (SVR) than patients without cirrhosis, especially if treatment has previously failed. We assessed the efficacy and safety of the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir, with and without ribavirin.
  
  
  METHODS
  In this multicentre, double-blind trial, between Oct 21, 2013, and Oct 30, 2014, we enrolled patients with HCV genotype 1 and compensated cirrhosis who had not achieved SVR after successive treatments with pegylated interferon and protease-inhibitor regimens at 20 sites in France. With a computer-generated randomisation sequence, patients were assigned in a 1:1 ratio to receive placebo matched in appearance to study drugs for 12 weeks followed by once daily combination fixed-dose tablets of 90 mg ledipasvir and 400 mg sofosbuvir plus weight-based ribavirin for 12 weeks, or ledipasvir-sofosbuvir plus placebo once daily for 24 weeks. The primary endpoint was SVR 12 weeks after the end of treatment (SVR12), for which 95% CIs were calculated with the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, number NCT01965535.
  
  
  RESULTS
  Of 172 patients screened, 155 entered randomisation, 77 were assigned to receive ledipasvir-sofosbuvir plus ribavirin and 78 ledipasvir-sofosbuvir. 114 (74%) were men, 151 (97%), were white, 98 (63%) had HCV genotype 1a, and 145 (94%) had non-CC IL28B alleles. SVR12 rates were 96% (95% CI 89-99) for patients in the ledipasvir-sofosbuvir plus ribavirin group and 97% (91-100) in the ledipasvir-sofosbuvir group. One patient discontinued treatment because of adverse events while receiving only placebo. The most frequent adverse events were asthenia and headache, pruritus, and fatigue.
  
  
  CONCLUSIONS
  Ledipasvir-sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks provided similarly high SVR12 rates in previous non-responders with HCV genotype 1 and compensated cirrhosis. The shorter regimen, when given with ribavirin, might, therefore, be useful to treat treatment-experienced patients with cirrhosis if longer-term treatment is not possible.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: Hépato-Gastroentérologie, Hôpital Saint Joseph, Marseilles, France. Electronic address: mbourliere@hopital-saint-joseph.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.affiliation: Hépato-Gastroentérologie, INSERM, U954, Centre Hosptialier Universitaire de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: Service d'Hépato-Gastro-Entérologie et d'Oncologie Digestive, CHU de Bordeaux, Pessac, France.
authors.forename: Victor
authors.initials: V
authors.lastname: de Ledinghen
authors.affiliation: Hépato-Gastro-Entérologie, Hôpital Henri Mondor, Université Paris-Est, INSERM U 955, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: Hépato-Gastro-Entérologie, Hôpital de La Croix Rousse, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Services des Maladies de l'Appareil Digestif, CHRU Lille, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mathurin
authors.affiliation: Hépatologie, INSERM, U1065 and CHU de Nice, Nice, France.
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.affiliation: Service d'Hépato-Gastroentérologie, Hôpital Saint Eloi, Montpellier, France.
authors.forename: Dominique G
authors.initials: DG
authors.lastname: Larrey
authors.affiliation: Hépato-Gastro-Entérologie, Hôpital de la Pitié Salpétrière, Paris, France.
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.affiliation: Médecine Interne-Pôle Digestif, CHU Purpan, UMR 152 IRD Toulouse 3 University, Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Alric
authors.affiliation: Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Hyland
authors.affiliation: Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: Deyuan
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Doehle
authors.affiliation: Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
authors.affiliation: Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Service d'Hépatologie, Hôpital Beaujon, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: Hôpitaux Universitaires de Strasbourg, Inserm U 1110, LabEx HepSYS, Université de Strasbourg, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Habersetzer
authors.affiliation: Service de Maladies du Foie, Hôpital Pontchaillou, Rennes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guyader
authors.affiliation: Hépato-Gastro-Entérologie, Hôpital Tenon, Paris, France.
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Grangé
authors.affiliation: Recherche Clinique et de l'Innovation, CHU de Limoges and Inserm UMR 1092, Université de Limoges, Limoges, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Loustaud-Ratti
authors.affiliation: Hépatologie, Hôpital Saint Antoine, Paris, France.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Serfaty
authors.affiliation: Service d'Hépato Gastro Entérologie, Hôpital Purpan, Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Metivier
authors.affiliation: Hépato-Gastroentérologie, CHU de Grenoble, Grenoble, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroy
authors.affiliation: Médecine Digestive, CHU Estaing, Clermont-Ferrand, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Abergel
authors.affiliation: Hépatologie, Université Paris Descartes, Inserm UMS20, Institut Pasteur, Hôpital Cochin, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use*; D005602:France; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000821:virology; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000627:therapeutic use*; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D010919:Placebos; D012367:RNA, Viral; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir