Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study.

Direct-acting antiviral agents have not been studied exclusively in patients with inherited blood disorders and hepatitis C virus (HCV) infection. The objective of the randomized, placebo-controlled, phase III C-EDGE IBLD study was to assess the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) in patients with inherited bleeding disorders and HCV infection. One hundred fifty-nine adults with HCV infection and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled at 31 study sites in the United States, Europe, Australia, Canada, Israel, and Thailand. Patients were given an oral, once-daily, fixed-dose combination of EBR/GZR 50 mg/100 mg for 12 weeks and randomized to the immediate-treatment group (ITG) or deferred-treatment group (DTG; placebo followed by active treatment). The primary endpoints were the proportion of patients in the ITG with unquantifiable HCV RNA 12 weeks posttreatment (sustained virological response 12 weeks after completion of study treatment; SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100 of 107 patients (93.5%) achieved SVR12, 6 relapsed, and 1 was lost to follow-up. SVR12 was achieved in 94.7% (18 of 19), 97.6% (40 of 41), and 89.4% (42 of 47) of patients with sickle cell disease, ß-thalassemia, and hemophilia A/B or von Willebrand disease, respectively. Serious adverse events were reported by 2.8% (n = 3) and 11.5% (n = 6) of patients in the ITG and DTG, respectively. Hemoglobin levels and international normalized ratio values were similar in patients receiving EBR/GZR and placebo; among patients with hemoglobinopathies, change in mean hemoglobin levels was similar in those receiving EBR/GZR compared to those receiving placebo. CONCLUSION: These results add to the expanding pool of data available for EBR/GZR, indicating a high level of efficacy and favorable tolerability in patients with HCV infection. (Hepatology 2017;66:736-745).

Liver stiffness quantification in biopsy-proven nonalcoholic fatty liver disease patients using shear wave elastography in comparison with transient elastography.

PURPOSE: This study prospectively assessed the performance of liver stiffness measurements using point shear-wave elastography (p-SWE) in comparison with transient elastography (TE) in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS: Fifty-six consecutive adult patients with a histological diagnosis of NAFLD prospectively underwent TE and p-SWE on the same day. The median of 10 measurements (SWE-10), the first five (SWE-5), and the first three (SWE-3) measurements were analyzed for p-SWE. Liver biopsy was considered as the reference standard for liver fibrosis grade. Receiver operating characteristic (ROC) curves and areas under the ROC curves (AUROCs) were calculated to assess the performance of TE and p-SWE for the diagnosis of significant (F2-F4) and advanced fibrosis (F3-F4). RESULTS: Forty-six patients (27 men, 19 women; mean age, 54.7±9.1 years) had valid p-SWE and TE measurements. Twenty-seven patients (58.7%) had significant fibrosis and 18 (39.1%) had advanced fibrosis. For significant fibrosis, both SWE-10 (AUROC, 0.787; P=0.002) and SWE- 5 (AUROC, 0.809; P=0.001) provided higher diagnostic performance than TE (AUROC, 0.719; P=0.016) and SWE-3 (AUROC, 0.714; P=0.021), albeit without statistical significance (P=0.301). For advanced fibrosis, SWE-5 showed higher diagnostic performance (AUROC, 0.809; P<0.001) than TE (AUROC, 0.799; P<0.001), SWE-10 (AUROC, 0.797; P<0.001), and SWE-3 (AUROC, 0.736; P=0.003), although the differences were not statistically significant (P=0.496). The optimal SWE-10 and SWE-5 cutoff values were ≥8.4 and ≥7.8 for significant fibrosis, and ≥9.1 and ≥8.8 for advanced fibrosis, respectively. CONCLUSION: TE and p-SWE showed similar performance for the diagnosis of significant and advanced fibrosis in NAFLD patients.

Phylodynamic Analysis and Implication of HCV Genotype 4 Variability on Antiviral Drug Response and T-Cell Recognition.

Therapies for HCV care could change the prevalence and the geographic distribution of genotypes due to differences in Sustained Virologic Response (SVR). In this scenario, uncommon genotypes/subtypes, such as genotype 4, could spread from high-risk groups, replacing genotypes eradicated by antiviral drugs. Genotype eradication is also strongly influenced by the CD8+ T cell response. In this study, the genetic variability in HCV genotype 4 strains obtained from a cohort of 67 patients naïve to DAA therapy was evaluated. We found that the presence of resistance-associated substitutions (RAS) was able to affect drug responses. Next, using a prediction tool, viral mutations were identified by their ability, or lack thereof, to reduce the binding affinity with HLA, which affects T cell recognition. The Bayesian coalescent analysis suggested two different circulation clusters, one in risk groups (IDUs and MSM) and the other due to migration flows, dated to 1940 and 1915, respectively. Most of the RAS overlapped with HLA and a lack of binding mutations was observed in 96% of strains. This study describes the introduction of HCV genotype 4 in a region of the Mediterranean basin and evaluates how HCV genotype 4's genetic variability could affect the response of antiviral drugs and CD8+ T cell recognition.