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Lancet Infect Dis. 2015 Apr;15(4):397-404. doi: 10.1016/S1473-3099(15)70050-2. Epub 2015 Mar 13.

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).

Author information

  • 1Hépato-Gastroentérologie, Hôpital Saint Joseph, Marseilles, France. Electronic address: mbourliere@hopital-saint-joseph.fr.
  • 2Hépato-Gastroentérologie, INSERM, U954, Centre Hosptialier Universitaire de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France.
  • 3Service d'Hépato-Gastro-Entérologie et d'Oncologie Digestive, CHU de Bordeaux, Pessac, France.
  • 4Hépato-Gastro-Entérologie, Hôpital Henri Mondor, Université Paris-Est, INSERM U 955, Créteil, France.
  • 5Hépato-Gastro-Entérologie, Hôpital de La Croix Rousse, Lyon, France.
  • 6Services des Maladies de l'Appareil Digestif, CHRU Lille, Lille, France.
  • 7Hépatologie, INSERM, U1065 and CHU de Nice, Nice, France.
  • 8Service d'Hépato-Gastroentérologie, Hôpital Saint Eloi, Montpellier, France.
  • 9Hépato-Gastro-Entérologie, Hôpital de la Pitié Salpétrière, Paris, France.
  • 10Médecine Interne-Pôle Digestif, CHU Purpan, UMR 152 IRD Toulouse 3 University, Toulouse, France.
  • 11Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
  • 12Service d'Hépatologie, Hôpital Beaujon, Clichy, France.
  • 13Hôpitaux Universitaires de Strasbourg, Inserm U 1110, LabEx HepSYS, Université de Strasbourg, Strasbourg, France.
  • 14Service de Maladies du Foie, Hôpital Pontchaillou, Rennes, France.
  • 15Hépato-Gastro-Entérologie, Hôpital Tenon, Paris, France.
  • 16Recherche Clinique et de l'Innovation, CHU de Limoges and Inserm UMR 1092, Université de Limoges, Limoges, France.
  • 17Hépatologie, Hôpital Saint Antoine, Paris, France.
  • 18Service d'Hépato Gastro Entérologie, Hôpital Purpan, Toulouse, France.
  • 19Hépato-Gastroentérologie, CHU de Grenoble, Grenoble, France.
  • 20Médecine Digestive, CHU Estaing, Clermont-Ferrand, France.
  • 21Hépatologie, Université Paris Descartes, Inserm UMS20, Institut Pasteur, Hôpital Cochin, Paris, France.

Erratum in

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.

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

Gilead Sciences.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID:
25773757
[PubMed - indexed for MEDLINE]
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