Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Surgery, Transplantation, Efficacy, everolimus, liver transplantation, reduced, tacrolimus, withdrawal, CHRONIC KIDNEY-DISEASE, GLOMERULAR-FILTRATION-RATE, SIROLIMUS-BASED IMMUNOSUPPRESSION, HEPATOCELLULAR-CARCINOMA, MYCOPHENOLATE-MOFETIL, CALCINEURIN INHIBITOR, DOSE TACROLIMUS, CONVERSION, COMPLICATIONS, METAANALYSIS, Adolescent, Adult, Aged, Confidence Intervals, Cross-Over Studies, Dose-Response Relationship, Drug, Drug Administration Schedule, Everolimus, Follow-Up Studies, Glomerular Filtration Rate, Graft Rejection, Graft Survival, Humans, Immunosuppressive Agents, Kaplan-Meier Estimate, Kidney, Kidney Function Tests, Liver Failure, Liver Transplantation, Male, Middle Aged, Prospective Studies, Risk Assessment, Sirolimus, Survival Analysis, Tacrolimus, Time Factors, Transplantation Immunology, Treatment Outcome, Young Adult, H2304 Study Group, 11 Medical and Health Sciences, 3202 Clinical sciences, 3204 Immunology

Abstract:

    In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.