Failure to achieve sustained virological response (SVR) with hepatitis C virus (HCV) direct-acting antiviral-based regimens is commonly associated with emergence of resistance-associated variants (RAVs). To avoid cross-resistance, recent guidelines recommend that patients who have failed on nonstructural protein 5A (NS5A) inhibitors should be retreated with sofosbuvir (SOF; NS5B inhibitor) combined with simeprevir (SIM; protease inhibitor [PI]); however, supporting evidence is lacking. This "real-world" study comprised patients who had failed to achieve SVR on previous NS5A-based therapy with daclatasvir (DCV) plus pegylated interferon (Peg-IFN) and ribavirin (RBV), with (n 5 3) or without (n 5 13) asunaprevir (ASV; PI). All 16 patients were retreated for 12 weeks with SOF plus SIM, without RBV. Antiviral efficacy was evaluated using the primary endpoint of SVR12 (SVR 12 weeks post-treatment); on-treatment response was also assessed. Patients (N 5 16; 13 male; mean age: 54 years [range, 43-73]) were chronically infected with HCV genotype (GT) 1 (1a, n 5 11; 1b, n 5 3) or 4 (n 5 2); they had advanced fibrosis or compensated cirrhosis (FibroScan, 9.6-70 kPa; cirrhosis, n 5 9); median baseline HCV-RNA level was 1.38 3 10 6 IU/mL. No patient discontinued treatment because of adverse events or virological failure. All patients achieved HCV RNA below lower limit of quantification (<12 IU/mL) by end of treatment (EOT) and 10 of 16 had a rapid response (week 4). SVR12 was achieved by 14 of 16 patients; the remaining 2 relapsed by 4 weeks post-EOT (both were GT 1a infected with cirrhosis; 1 had previously failed DCV-ASV plus Peg-IFN and RBV). Presence of SIM RAVs/polymorphisms (R155K and Q80K) at study baseline did not predict retreatment failure. Conclusion: Our findings support the concept of retreating NS5A inhibitor failures with SOF combined with SIM. However, the most difficult-to-cure patients may need more than 12 weeks of treatment and/or the addition of RBV. (HEPATOLOGY 2016;63:1809-1816 T reatment of chronic hepatitis C virus (HCV) infection has advanced significantly over the last 5 years, with the introduction of drug combination regimens based on direct-acting antiviral (DAA) agents. Sustained virological response (SVR) rates of the order of 60%-100% have been achieved when one DAA is combined with pegylated interferon (Peg-IFN) alpha and ribavirin (RBV), with SVR rates varying according to HCV genotype, disease severity, the DAA used, and the preexistence at treatment baseline of resistance-associated variants (RAVs). (1)

We assessed the broadly used, off-label combination of sofosbuvir, daclatasvir, simeprevir, and ribavirin in direct-acting antiviral-experienced patients, as recommended in current guidelines despite scarce data. After 24 weeks' treatment, sustained virological response 12 weeks after the end of treatment was achieved in 6 patients (60%). Two cirrhotic patients relapsed and 2 discontinued treatment due to serious adverse events.

This real-world study confirms the excellent results of clinical trials with therapies based on a combination of SOF plus an NS5A inhibitor. It suggests that a personalized approach including baseline NS5A inhibitor resistance testing may inform treatment decisions in cirrhotic patients.

Background In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7–51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24–0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08–0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15–0.54, p < 0.0001), liver-related mortality (HR 0.40, 95% CI 0.17–0.96, p = 0.04), non-liver-related mortality (HR 0.17, 95% CI 0.06–0.49, p = 0.001), liver transplantation (HR 0.17, 95% CI 0.05–0.54, p = 0.003), and hepatocellular carcinoma (HR 0.52, 95% CI 0.29–0.93, p = 0.03). Conclusion Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. Trial registration: ClinicalTrials.gov registry number: NCT01953458.

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Background & Aims Reinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%. Methods French patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs . ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs. Results Among 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective. Conclusions In the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection. Lay summary The early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes.

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