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Background & Aims: Detailed hepatitis C virus (HCV) kinetics modelling is scarce in patients with advanced liver disease receiving direct-acting antivirals (DAAs). Due to budget restrictions, patients and health systems would benefit from the shortest possible treatment course. We investigated whether modelling very early HCV kinetics in cirrhotic patients under DAAs therapy could be used to individualize care and reduce treatment duration to achieve cure., Methods: We included 74 patients with HCV-related cirrhosis who received interferon-free treatments for 12-24 weeks. HCV genotype, liver disease stage and treatment regimen were recorded. Viral load was determined prospectively at very frequent intervals until target not detected (TND, <15 IU/mL). A viral kinetic model was used to predict time to cure based on HCV clearance in extracellular body fluid (CL-EF)., Results: Sixty-eight patients (92%) achieved cure. Thirteen (18%) had MELD ≥15, 35 (47%) were Child-Pugh (CTP) ≥7. Median time to reach TND was 2 weeks (IQR: 1-4 weeks). Modelling indicated an average DAAs efficacy in blocking viral production of ε = 99.1%. HCV half-life (t 1/2 ) was significantly shorter in patients with CTP <7, LSM <21 kPa or MELD <15 (1.5 vs 2.5 hours; P = 0.0057). The overall median CL-EF was 5.6 weeks (4.1-7.8). A CTP >7 and a LSM ≥21 kPa were significantly (P = 0.016) associated with longer CL-EF., Conclusions: The study provides insights into HCV dynamics during DAAs therapy in patients with compensated and decompensated cirrhosis. Viral kinetics modelling suggests that treatment duration may be optimized in patients with compensated cirrhosis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment-limiting side effects and its additive toxicity with interferon, the search for interferon- and ribavirin-free regimens has been underway. The recent approvals of all-oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co-administered with all-oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all-oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups., (© 2016 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Background & Aims: Setrobuvir is a direct-acting antiviral (DAA) non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study examined interferon-free combinations containing setrobuvir, a ritonavir-boosted protease inhibitor (danoprevir/r) and ribavirin, with/without the nucleoside inhibitor mericitabine in HCV genotype (G)1 patients., Methods: Non-cirrhotic treatment-naïve patients (N = 110) were randomized to five groups. Three groups received a 14-day mericitabine/ribavirin lead-in followed by treatment with 3 DAAs (setrobuvir, danoprevir/r, mericitabine) plus ribavirin for 12 weeks (Group A: G1a; D: G1b) or 24 weeks (B: G1a), and two groups received 2 DAAs (setrobuvir, danoprevir/r) plus ribavirin for 12 weeks (E: G1b) or 24 weeks (C: G1a). Efficacy was defined as sustained virological response (HCV RNA <25 IU/ml after 12 weeks' follow-up, SVR12)., Results: Two groups met predefined futility criteria for breakthrough (C) or relapse (A) and were discontinued. SVR12 rates were 42.9% (3/7) and 74.1% (20/27) in G1a patients in Groups A and B, respectively, and 95.7% (22/23) and 68.2% (15/22) in G1b patients in Groups D and E respectively. All G1a patients assigned to 24 weeks of treatment who experienced a decrease in HCV RNA of ≥2.3 log10 IU by the end of the lead-in period (n = 28) achieved SVR12. Overall, treatment was well tolerated and most adverse events were mild to moderate. No major safety signals were identified., Conclusions: An interferon-free setrobuvir-based regimen (3 DAAs plus ribavirin) is safe and effective in treatment-naïve G1 patients., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: The safety and efficacy of the interferon-free combination of faldaprevir (NS3/A4 protease inhibitor), deleobuvir (BI 207127, non-nucleoside polymerase inhibitor), and ribavirin in treatment-naïve patients chronically infected with HCV genotype-1 was explored., Methods: SOUND-C3 was a multicenter, open-label Phase 2b study. Treatment-naïve patients chronically infected with HCV genotype-1a (IL28B CC genotype only; n = 12) and genotype-1b (n = 20) were assigned to 16 weeks of treatment with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and weight-based ribavirin. Patients with compensated liver disease, including cirrhosis, were eligible for inclusion in this study. The primary endpoint was sustained virological response 12 weeks after completion of therapy., Results: Sustained virological response rates 12 weeks after completion of therapy were 17% and 95% in patients infected with HCV genotype-1a and genotype-1b respectively. All four patients with cirrhosis achieved sustained virological response 12 weeks after completion of therapy. The most frequently reported adverse events of at least moderate intensity were anaemia (16%), nausea, vomiting and fatigue (9% each). Three (9%) patients discontinued because of adverse events., Conclusions: The interferon-free regimen of faldaprevir, deleobuvir and ribavirin was efficacious in patients infected with genotype-1b and generally well tolerated., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Safety and tolerability of peginterferon-based hepatitis C virus (HCV) infection therapy remains suboptimal, even when direct-acting antiviral agents are added. This study assessed the efficacy, safety and tolerability of mericitabine combined with ritonavir-boosted danoprevir (danoprevir/r) ± ribavirin for up to 24 weeks in treatment-naïve HCV genotype (G)1 infected patients., Methods: Patients received twice daily mericitabine (1000 mg) and danoprevir/r (100 mg/100 mg) plus either ribavirin (1000/1200 mg/day; Arm A) or placebo (Arm B) for 12 or 24 weeks. Patients with HCV RNA <43 IU/ml between Weeks 2 and 8 and HCV RNA <15 IU/ml at Week 10 were rerandomized (1:1) at Week 12 to discontinue/continue assigned regimens until Week 24. Because of unacceptable relapse rates in both 12-week arms and in ribavirin-free Arm B, treatment was extended to 24 weeks and patients in Arm B received peginterferon alfa-2a/ribavirin. The primary outcome was sustained virological response 24 weeks after end of treatment (SVR24)., Results: In Arm A, the SVR24 rate in patients receiving 24 weeks of therapy was 37.9% (25/66); 63.6% (14/22) in G1b and 25.0% (11/44) in G1a patients. Virologic breakthrough and relapse were associated with danoprevir-resistant virus in most cases. The mericitabine-resistance mutation (NS5BS282T) was detected in two patients bearing dual resistant virus NS3 R155K/NS5B S282T and dual resistance mutation L159F/L320F in one patient. Treatment was safe and well tolerated., Conclusions: Mericitabine, danoprevir/r plus ribavirin for 24 weeks were safe and well tolerated. However, SVR rates were poor, achieving rates of only 25.0% in G1a and 63.6% in G1b patients., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)