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)

Marc Bourlière, Jean Pierre Bronowicki, Victor de Ledinghen, Christophe Hézode, Fabien Zoulim, Philippe Mathurin, Albert Tran, Dominique G. Larrey, Vlad Ratziu, Laurent Alric, Robert H. Hyland, Deyuan Jiang, Brian Doehle, Phillip S. Pang, William T. Symonds, G. Mani Subramanian, John G. McHutchison, Patrick Marcellin, François Habersetzer, Dominique GuyaderJean Didier Grangé, Véronique Loustaud-Ratti, Lawrence Serfaty, Sophie Metivier, Vincent Leroy, Armand Abergel, Stanislas Pol

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)397-404
Number of pages8
JournalLancet Infectious Diseases
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

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Ribavirin
Protease Inhibitors
Hepacivirus
Fibrosis
Genotype
Infection
Placebos
Therapeutics
Random Allocation
Asthenia
sofosbuvir drug combination ledipasvir
Chronic Hepatitis C
Virus Diseases
Pruritus
Interferons
Tablets
France
Fatigue
Headache
Nucleotides

ASJC Scopus subject areas

  • Infectious Diseases
  • Medicine(all)

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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). / Bourlière, Marc; Bronowicki, Jean Pierre; de Ledinghen, Victor; Hézode, Christophe; Zoulim, Fabien; Mathurin, Philippe; Tran, Albert; Larrey, Dominique G.; Ratziu, Vlad; Alric, Laurent; Hyland, Robert H.; Jiang, Deyuan; Doehle, Brian; Pang, Phillip S.; Symonds, William T.; Subramanian, G. Mani; McHutchison, John G.; Marcellin, Patrick; Habersetzer, François; Guyader, Dominique; Grangé, Jean Didier; Loustaud-Ratti, Véronique; Serfaty, Lawrence; Metivier, Sophie; Leroy, Vincent; Abergel, Armand; Pol, Stanislas.

In: Lancet Infectious Diseases, Vol. 15, No. 4, 01.04.2015, p. 397-404.

Research output: Contribution to journalArticle

Bourlière, M, Bronowicki, JP, de Ledinghen, V, Hézode, C, Zoulim, F, Mathurin, P, Tran, A, Larrey, DG, Ratziu, V, Alric, L, Hyland, RH, Jiang, D, Doehle, B, Pang, PS, Symonds, WT, Subramanian, GM, McHutchison, JG, Marcellin, P, Habersetzer, F, Guyader, D, Grangé, JD, Loustaud-Ratti, V, Serfaty, L, Metivier, S, Leroy, V, Abergel, A & Pol, S 2015, '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)', Lancet Infectious Diseases, vol. 15, no. 4, pp. 397-404. https://doi.org/10.1016/S1473-3099(15)70050-2
Bourlière, Marc ; Bronowicki, Jean Pierre ; de Ledinghen, Victor ; Hézode, Christophe ; Zoulim, Fabien ; Mathurin, Philippe ; Tran, Albert ; Larrey, Dominique G. ; Ratziu, Vlad ; Alric, Laurent ; Hyland, Robert H. ; Jiang, Deyuan ; Doehle, Brian ; Pang, Phillip S. ; Symonds, William T. ; Subramanian, G. Mani ; McHutchison, John G. ; Marcellin, Patrick ; Habersetzer, François ; Guyader, Dominique ; Grangé, Jean Didier ; Loustaud-Ratti, Véronique ; Serfaty, Lawrence ; Metivier, Sophie ; Leroy, Vincent ; Abergel, Armand ; Pol, Stanislas. / 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). In: Lancet Infectious Diseases. 2015 ; Vol. 15, No. 4. pp. 397-404.
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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.",
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TY - JOUR

T1 - Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy

T2 - A randomised, double-blind, phase 2 trial (SIRIUS)

AU - Bourlière, Marc

AU - Bronowicki, Jean Pierre

AU - de Ledinghen, Victor

AU - Hézode, Christophe

AU - Zoulim, Fabien

AU - Mathurin, Philippe

AU - Tran, Albert

AU - Larrey, Dominique G.

AU - Ratziu, Vlad

AU - Alric, Laurent

AU - Hyland, Robert H.

AU - Jiang, Deyuan

AU - Doehle, Brian

AU - Pang, Phillip S.

AU - Symonds, William T.

AU - Subramanian, G. Mani

AU - McHutchison, John G.

AU - Marcellin, Patrick

AU - Habersetzer, François

AU - Guyader, Dominique

AU - Grangé, Jean Didier

AU - Loustaud-Ratti, Véronique

AU - Serfaty, Lawrence

AU - Metivier, Sophie

AU - Leroy, Vincent

AU - Abergel, Armand

AU - Pol, Stanislas

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

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