P. de Ruiter, Y. Gadjradj, J. de Jonge, J. Kwekkeboom, R.W.F. de Bruin, H.J. Metselaar, J.N.M Ijzermans, L.J.W. van der Laan
Chair(s): prof. dr. Carla C. Baan, Erasmus MC Rotterdam
Thursday 10 march 2016
12:30 - 13:00h at Foyer
Parallel session: Postersessies XI - Opgesplitst in 3 tijdblokken en 3 categoriëen (klinisch, basaal, donatie)
Liver disease caused by chronic hepatitis C (HCV) infection is currently the major indication for liver transplantation. Recently, new direct acting antivirals (DAAs) have been developed for the treatment of patients with chronic HCV, including patients who underwent liver transplantation. Although a few reports have investigated the efficacy of DAAs after liver transplantation, the exact effects of specific immunosuppressive medication on the antiviral efficacy is largely unknown. The aim of this study is to investigate the antiviral activity of the NS5A inhibitor daclatasvir (DAC) and the NS3 inhibitor asunaprevir (ASU) combined with immunosuppressants in a cell culture model for HCV.
As a model for HCV replication we used Huh7 cells, stably transfected with the non-structural coding sequence of HCV coupled to luciferase (Huh7-ET). Cells were treated with three different doses of DAAs, in combination with cyclosporin A (CSA), tacrolimus (TAC), mycophenolic acid (MPA) or rapamycin (RAPA). Huh7 cells stably transfected with a luciferase gene controlled by an Interferon-Stimulated Response Element (ISRE-luc cells) were used to investigate effects on interferon-stimulated gene expression.
TAC and RAPA had no effect on antiviral activity of DAC or ASU. Also CSA did not significantly inhibit the antiviral action of DAAs. MPA, a potent inhibitor of the nucleotide synthesizing enzyme IMPDH, has antiviral effect itself, but also further enhanced the antiviral action of both DAC and ASU. Previously we have shown that the antiviral action of MPA is related to the induction of antiviral effector genes, the so called interferon-stimulated genes. In Huh7-ISRE-luc cells, DAAs did not induce gene expression and no additional effect of DAAs on the MPA stimulated gene expression was found. This suggests that the combined antiviral effect of MPA and DAAs is mediated via independent mechanisms.
The immune suppressants TAC, RAPA and CSA did not affect the antiviral activity of DAAs. MPA enhanced the antiviral activity of both DAC and ASU. This implies that there is no contra-indication to combine antiviral therapies with these immunosuppressants in the post-transplantation management of HCV recurrence.