Immunomonitoring of NFAT-regulated gene expression in liver allograft recipients under telaprevir based hepatitis C therapy reveals significant impact on residual gene activity

K Roos; D Gotthardt; T Giese; P Schnitzler; W Stremmel; D Czock; C Eisenbach

doi:10.1055/s-0033-1361034

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Immunomonitoring of NFAT-regulated gene expression in liver allograft recipients under telaprevir based hepatitis C therapy reveals significant impact on residual gene activity

K Roos ¹, D Gotthardt ¹, T Giese ², P Schnitzler ⁴, W Stremmel ¹, D Czock ³, C Eisenbach ¹

¹University Hospital Heidelberg, Department of Gastroenterology, Heidelberg, Germany
²University of Heidelberg, Department of Immunology, Heidelberg, Germany
³University Hospital Heidelberg, Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg, Germany
⁴University Hospital Heidelberg, Department of Infectious Diseases and Virology, Heidelberg, Germany

Abstract

Protease-inhibitor based antiviral therapy of HCV reinfection after liver transplantation constitutes a difficult task due to drug-drug interactions, reduced tolerance and severe side effects.

The aim of the present study was to retrospectively analyze the clinical course, dose adjustment and blood concentrations of immunosuppressive drugs as well as biomarkers of immunosuppressive effects by immunomonitoring of nuclear factor of activated T cells (NFAT) -regulated gene expression of HCV-positive liver transplant patients during telaprevir containing triple therapy.

All 5 patients were HCV-RNA negative at treatment week 12 and stayed negative until the end of observation. Safety was acceptable with minimal acute rejection and reactivation of cytomegalovirus as the most serious adverse events. Anemia with a hemoglobin level lower than 8.5 g/dL and grade 3 neutropenia were common. Cyclosporine (CsA) dose was reduced to 30.8% and CsA drug-clearance was reduced to 38.5% by telaprevir. Despite correctly adapted target trough levels, we observed a significant decrease in the CsA peak trough level under telaprevir therapy. Immunomonitoring of NFAT regulated genes Il-2, IFN-γ and GM-CSF revealed an inverse correlation with CsA blood levels leading to markedly altered mRNA levels and an increase in residual gene activity. That means that the main immunosuppressive effect is diminished during telaprevir therapy and indicates an overestimation of the immunosuppressive CsA – effect if estimated by blood trough levels during telaprevir therapy.

In conclusion, antiviral therapy with protease inhibitors seems feasible in liver transplant patients under close monitoring. Immunomonitoring of NFAT – regulated genes assesses the biological activity of cyclosporine and therefore helps to prevent over- and under-immunosuppression during triple therapy