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

Summary

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).

Findings

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.

Interpretation

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.

Funding

Gilead Sciences.

Introduction

Patients with chronic hepatitis C virus (HCV) infection with advanced fibrosis or cirrhosis are at increased risk of hepatocellular carcinoma, liver failure, liver transplantation, and both liver-related and all-cause mortality.¹ For patients who undergo liver transplantation with detectable HCV, recurrent infection is universal. In some transplantation patients, recurrent HCV infection leads to an aggressive course of disease known as fibrosing cholestatic hepatitis, which is characterised by increased risk of cirrhosis, hepatic decompensation, and death.² Despite the serious risks for patients with HCV with advanced liver disease, treatment options for these patients are limited.

The nucleotide analogue sofosbuvir is a direct-acting inhibitor of the HCV NS5B polymerase and was approved in the USA in 2013 and in Europe in early 2014.3, 4 In phase 2 trials, sofosbuvir plus ribavirin was effective in treating patients before and after liver transplantation, including those with compensated cirrhosis.5, 6, 7 The combination of sofosbuvir and ribavirin was given for 24–48 weeks, which might be cumbersome for patients with advanced disease who could have difficulty tolerating the haematological side-effects associated with ribavirin.

Research in context

Evidence before this study

This study was designed in the first half of 2013, before any all-oral regimens for hepatitis C virus (HCV) had been approved. We did PubMed searches for articles using the search terms “HCV treatment”, “decompensated cirrhosis”, and “post-liver transplant” from inception until Feb 20, 2013. There were no language restrictions for this search. We found no reports on the use of direct-acting antivirals in all-oral regimens for HCV in patients with advanced fibrosis or decompensated cirrhosis.

Added value of this study

This study assessed the safety and efficacy of the all-oral regimen of ledipasvir, sofosbuvir, and ribavirin in patients with HCV who have advanced liver disease or have had a liver transplant. The results show that ledipasvir–sofosbuvir plus ribavirin for 12 weeks is an effective treatment for patients with advanced liver disease, including those with decompensated liver function before and after liver transplantation. These patients, who are at substantial risk for mortality, had no effective treatment options until recently. Extending treatment to 24 weeks did not appear to be associated with improved outcomes.

Implications of all the available evidence

Similar results were recorded in the SOLAR-1 study, which also assessed ledipasvir, sofosbuvir, and ribavirin treatment in patients with advanced liver disease before and after liver transplantation, but which enrolled almost exclusively patients with genotype 1 HCV (99%). The recent CORAL-1 study showed that 97% of patients with mild histological recurrent HCV after liver transplantation achieved sustained virological response after treatment with the combination of ombitasvir–paritaprevir–ritonavir and dasabuvir plus ribavirin for 24 weeks. The three studies meet a crucial need of assessing novel therapies in patients who have limited treatment options. Our findings support the efficacy and safety of ledipasvir–sofosbuvir plus ribavirin in patients with decompensated liver disease before and after liver transplantation, and suggest that there is no clinically significant interaction between ledipasvir–sofosbuvir and common immunosuppressive agents used in liver transplant recipients.

In 2014, a fixed-dose combination of sofosbuvir with the HCV NS5A inhibitor ledipasvir was approved in the USA for treating chronic genotype 1 HCV infection and in Europe for treating genotypes 1 or 4 infection.8, 9 In a phase 2 study of HCV genotype 1 patients with compensated cirrhosis, the combination of sofosbuvir and ledipasvir for 24 weeks led to a sustained virological response (SVR) rate of 97%.¹⁰ In the US-based SOLAR-1 study,¹¹ the combination of sofosbuvir, ledipasvir, and ribavirin for 12 or 24 weeks had moderate-to-high SVR rates in HCV patients, predominantly with HCV genotype 1a, who had advanced liver disease, including those who had undergone liver transplantation. Here we present the results of the international SOLAR-2 study, in which we similarly assessed the safety and efficacy of sofosbuvir, ledipasvir, and ribavirin for 12 or 24 weeks in HCV genotype 1a, 1b, or 4 patients with advanced liver disease, including post-transplantation patients with fibrosing cholestatic hepatitis. This phase 2 study was exploratory and not powered to permit comparisons among groups; no statistical hypothesis testing was planned or conducted.