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.
Manns M, Samuel D, et al.The Lancet Infectious Diseases 2016; 16(6): 685-697.
Aims
To assess the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with hepatitis C virus (HCV) genotype 1 or 4, and advanced liver disease or liver transplant.
Interventions
Participants were randomized to receive treatment with ledipasvir 90mg and sofosbuvir 400mg in a fixed-dose combination tablet (ledipasvir–sofosbuvir) once daily plus ribavirin for either 12, versus 24 weeks.
Participants
333 patients aged ≥18 years old with either cirrhosis or liver transplant, chronically infected with genotype 1 or 4 HCV.
Outcomes
The primary outcomes measured were sustained virological response 12 weeks after treatment (SVR12), and discontinuation of study treatment because of an adverse event. Secondary outcomes included improvements in Child-Turcotte-Pugh and Model for End-stage Liver Disease scores at 12 weeks after treatment for all patients who achieved SVR12.
Follow-up
24 weeks
CET Conclusions
This phase 2 randomised study investigates the use of the new antiviral agents ledipasvir and sofosbuvir in the management of hepatitis C in two cohorts of patients: those with Childs B or C cirrhosis, and post-transplant patients with recurrent disease. Patients in both cohorts were randomised to 12 or 24 weeks of treatment. All groups of patients demonstrated high rates of sustained virological response (SVR), with only 2% discontinuing treatment due to adverse events. There was no measurable difference in response between 12 and 24 weeks of treatment, but the study was not powered to demonstrate this. Whilst the rates of SVR seen are impressive, there are some limitations to the current study. There is no control cohort treated with current best therapy, and the inclusion criteria limit patients with renal impairment. Use of SVR as a surrogate marker for treatment efficacy has been questioned for interferon-based regimens (Gurusamy et al., PLoS ONE 8(12): e83313), and there is insufficient power to determine effects on transplant or patient survival.
Data analysis
Modified intention-to-treat analysis
Trial registration
EudraCT - 2013-002802-30; ClinicalTrials.gov - NCT02010255