Abstract
This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53–61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis.Trial Registration: ClinicalTrials.gov NCT01830127.
Highlights
Chronic infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality worldwide [1,2,3]
Improvements in the understanding of the HCV lifecycle have led to the development of numerous oral direct-acting antiviral agents (DAAs) that act on several different viral targets, including NS3/4A serine protease, NS5B RNA polymerase and the multifunctional NS5A protein [2]
A total of 6 patients had at least one important protocol violation: 3 patients did not receive the additional faldaprevir loading dose on Day 1; a further 3 patients were assigned to the wrong dose of deleobuvir and were excluded from the pharmacokinetic analysis population
Summary
Chronic infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality worldwide [1,2,3]. Treatment regimens using DAAs continued to rely on combination with PegIFN [6, 7]. Recognising the limitations of PegIFN and the substantial improvements in simplicity, tolerability and efficacy of DAA treatment, attention is increasingly focusing on combining DAAs in IFN-free treatment strategies [8]. This field continues to rapidly evolve, with many novel agents and combination therapies approved or in advanced stages of development [6, 7, 8]
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