Safety and Efficacy of Sofosbuvir plus Simeprevir in a Spanish Cohort of 622 Cirrhotic Patients Infected with Genotypes 1 or 4

Presentation Poste

Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines. METHODS: HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells. RESULTS: The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation. CONCLUSIONS: The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells

Efficacy of Sofosbuvir and Velpatasvir, With and Without Ribavirin, in Patients With Hepatitis C Virus Genotype 3 Infection and Cirrhosis.

In phase 3 trials and real-world settings, smaller proportions of patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have a sustained virologic response 12 weeks after treatment (SVR12) with the combination of sofosbuvir and velpatasvir than in patients without cirrhosis. It is unclear whether adding ribavirin to this treatment regimen increases SVRs in patients with genotype 3 HCV infection and cirrhosis. We performed a phase 2 trial of 204 patients with genotype 3 HCV infection and compensated cirrhosis (mean age 51 ± 7.4 years) at 29 sites in Spain from August 19, 2016 through April 18, 2017. Patients were assigned to groups given sofosbuvir and velpatasvir for 12 weeks (n = 101) or sofosbuvir and velpatasvir plus ribavirin for 12 weeks (n = 103). The primary efficacy end point was SVR12. The overall rates of SVR12 were 91% (92 of 101; 95% CI 84-96) for the sofosbuvir-velpatasvir group and 96% (99 of 103; 95% CI 90-99) for the sofosbuvir-velpatasvir plus ribavirin group. In the sofosbuvir-velpatasvir group, a smaller proportion of patients with baseline resistance-associated substitutions (RASs) in nonstructural protein 5A (NS5A) achieved an SVR12 (84%) than did patients without (96%). In the sofosbuvir-velpatasvir plus ribavirin group, baseline RASs had less effect on the proportion of patients with an SVR12 (96% for patients with baseline RASs; 99% for patients without). The most common adverse events (which occurred in ≥10% of patients) were asthenia (12%) in the sofosbuvir-velpatasvir group and asthenia (27%), headache (24%), and insomnia (12%) in the sofosbuvir-velpatasvir plus ribavirin group. Consistent with findings from previous studies, a high rate of patients (91% and 96%) with genotype 3 HCV infection and compensated cirrhosis achieved an SVR12 with sofosbuvir and velpatasvir, with or without ribavirin. Of patients treated with sofosbuvir and velpatasvir without ribavirin, fewer patients with baseline NS5A RASs achieved an SVR12 compared with patients without baseline NS5A. ClinicalTrials.govNCT02781558