PRECLINICAL PROPERTIES OF THE NOVEL HCV NS3 PROTEASE INHIBITOR GS-9451

POSTERSapoptosis in human hepatoma cell line Huh7.5 and promoting insulin resistance in patients infected by genotype 1 (Pazienza et al.Hepatology 2007).The aims were: a. to analyze if the use of rapamycin in patients with recurrent chronic hepatitis C after liver transplantation improved sustained viral response (SVR) when receiving SOC; b. to know the effect of rapamycin in Huh7.5 cells infected with the JFH-1 replicon on mTOR and IRS-1 gene expression.Patients and Methods: A cohort study of 43 patients with recurrent chronic hepatitis C after liver transplantation, genotype 1 were treated with peginterferon 180 mcg/week and ribavirin (1000-1200 mg/d), of whom 29 received tacrolimus (controls) and 14 received rapamycin at its usual schedule of immunosuppression after transplantation.Both groups were were controlled by fibrosis, baseline viral load, age and BMI.Huh7.5 cells were cultured in supplemented DMEM medium and incubated at 37°C, 5% CO 2 .Cells were transfected with the JFH-1 replicon (genotype 2a).Rapamycin was added (10 nM) to cell cultures.Gene expression was analyzed by semi-quantitative PCR in real time.Results: Patients treated with rapamycin showed SVR in 2 out of 14 (14%) versus 8 out of 29 (28%) in patients receiving tacrolimus; p = ns.In Huh7.5 cells culture, rapamycin significantly increased gene expression in comparison with control of mTOR in both uninfected (1.8 fold) and HCV-infected cells (4.5 fold).Rapamycin also induced the expression of PI3K in HCV-infected cells (3 fold).Rapamycin did not alter cell growth rate at the concentration assayed.Conclusion: Rapamycin treated patients with recurrent chronic hepatitis C after liver transplantation did not obtain improvement in SVR compared to the group of patients receiving tacrolimus.In an in vitro system of HCV infection, rapamycin enhanced mTOR and PI3K gene expression, showing an interaction with the insulin signaling pathway.