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)

Summary

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.

Introduction

Patients with cirrhosis resulting from chronic infection with the hepatitis C virus (HCV) are at risk of developing life-threatening complications, such as decompensated liver disease and hepatocellular carcinoma.1, 2 Treatment improves long-term outcomes for patients with cirrhosis, and sustained virological response (SVR) is associated with histological improvement and reduced risk of hepatocellular carcinoma, decompensation, and liver-related mortality.3, 4, 5, 6 In clinical trials and real-world settings, however, patients with cirrhosis, especially those for whom previous therapy has failed, achieve consistently lower rates of SVR than patients without cirrhosis.7, 8, 9, 10 Moreover, interferon-based regimens for the treatment of HCV genotype 1 are poorly tolerated by patients with cirrhosis and cause high rates of severe and serious adverse events, leading many patients to discontinue treatment.¹¹ Therefore, interferon-free regimens for patients with cirrhosis are needed.¹²

Ledipasvir is a novel HCV NS5A inhibitor. Sofosbuvir is a nucleotide analogue inhibitor of the HCV NS5B polymerase approved for the treatment of HCV genotype 1–4 infections.¹³ 90 mg ledipasvir and 400 mg sofosbuvir in a fixed-dose combination tablet was assessed in two clinical trials in patients with HCV genotype 1 and cirrhosis who had not previously achieved SVR with protease-inhibitor treatments. The LONESTAR trial¹⁴ involved 22 patients who received ledipasvir-sofosbuvir for 12 weeks or ledipasvir-sofosbuvir plus ribavirin for 12 weeks. Of 11 in each group, ten (91%) and 11 (100%), respectively, achieved SVR 12 weeks after the end of treatment (SVR12). The phase 3 ION-2 trial¹⁵ assessed 54 patients with cirrhosis in whom previous treatment with protease-inhibitor regimens had failed. SVR12 in those receiving 12 weeks of ledipasvir-sofosbuvir with and without ribavirin was seen in 12 (85%) of 14 and 11 (86%) of 13 patients, respectively. In patients who received 24 weeks of ledipasvir-sofosbuvir with and without ribavirin, SVR12 was achieved in 100% of patients.¹⁵

We assessed the efficacy and safety of ledipasvir-sofosbuvir with and without ribavirin in patients with HCV genotype 1 and cirrhosis who had not achieved SVR after successive treatments with pegylated interferon (peginterferon) and protease inhibitors.