Steering of Transplant Immunosuppression by Virus-Specific T Cells (IVIST Trial)

Abstract

Background: Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells (Tvis) correlate with virus-specific as well as general cellular immune defense. Additional steering by Tvis levels may optimize dosing of immunosuppressants. Methods: In a multicenter, randomized controlled trial, 64 pediatric kidney recipients were randomized 1:1 to a control group with trough level monitoring of immunosuppressants or to an intervention group with additional steering by Tvis levels, quantified by cytokine flow cytometry. Both groups received immunosuppression with cyclosporine A and everolimus in the same target range of trough levels. Primary endpoint was the estimated glomerular filtration rate (eGFR) two years after transplantation. Findings: We observed an increase of eGFR in the intervention group and no substantial change in the control group. The mean difference (intervention-control) was 7.5±27.6 mL/min/1.73m2. Patients in the intervention group received lower daily doses (mg/m2) of everolimus (0.8±0.3 vs. 1.2±0.5, p=0.004) and cyclosporine A (78.4±20.0 vs. 88.4±26.5, p=0.13) resulting in lower trough levels (µg/L) of everolimus (3.5±0.7 vs. 4.5±0.8, p<0.001) and cyclosporine A (47.4±9.9 vs. 64.1±11.1, p<0.001). Fewer patients in the intervention group received glucocorticoids two years after transplantation (20% vs. 47%, p=0.04). Patients in the control group had a higher risk for rejections (p=0.11) and EBV DNAemia (p=0.09). Numbers of donor-specific antibodies and (serious) adverse events were comparable. Interpretation: Additional steering of immunosuppressive therapy by Tvis levels is safe and personalizes immunosuppressive therapy by lowering exposure to immunosuppressants, resulting in stabilization of eGFR and reduced risk for rejections and EBV DNAemia. Trial Registration: EudraCT No: 2009-012436-32, ISRCTN89806912, 17.06.2009. Funding Statement: Funded by the German Ministry of Education and Research and Novartis. Declaration of Interests: LP reports receiving research support by Novartis and Chiesi and lecture fees by Alexion, Novartis and Chiesi as well as travel grants from Neovii. LTW reports receiving research support by Chiesi, lecture fees by Novartis, advisory fees by Alexion and travel grants by Astellas. JO received research support by Chiesi, lecture fees by Chiesi and Alexion, advisory fees by Alexion, Chiesi, Boehringer Ingelheim, Neovii, Amgen and travel grants by Neovii. TA received travel grants from Novartis, Astellas and Alexion and lecture fees from Novartis. All other authors declare no conflict of interest. Ethics Approval Statement: The trial protocol was approved by the scientific ethics committees of the participating university hospitals. The trial was performed in accordance with the principles of the Declaration of Helsinki.