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Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Villejuif, France. Service d'Hépato-Gastro-Entérologie, AP-HP Hôpital Henri Mondor, Créteil, France. Département de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet, University of Nice Sophia Antipolis, Nice, France. Département de Néphrologie et Transplantation d'Organes, CHU Rangueil, Toulouse, France. Service d'Hépato-Gastroentérologie, CHRU de Lille, Lille, France. Service de Chirurgie Hépato-Biliaire et Digestive, Hôpital Trousseau, CHU Tours, Tours, France. Unité de Chirurgie Biliaire et de Transplantation Hépatique, Hôpital Magellan, CHU Bordeaux, Pessac, France. Service d'Hépatologie et Transplantation Hépatique, University Paris Diderot, INSERM U1149, Clichy, France. Service de Chirurgie Hépatobiliaire et Digestive, CIC 1414, Hôpital Pontchaillou, Rennes, France. Service d'Hépatologie et Soins Intensifs Digestifs, Hôpital Jean Minjoz, Besançon, France. Service Hépato-Gastroentérologie, Hôpital Saint Eloi, Montpellier, France. Service de Chirurgie et Transplantation Hépatique, Hôpital la Timone, Marseille, France. Département d'Anesthésie-Réanimation, Service de Chirurgie Digestive et Hépato-Biliaire et de Transplantation Hépatique, Groupe Hospitalier Pitié Salpêtrière - Charles Foix, Assistance Publique-Hôpitaux de Paris, Paris, France. Service de Chirurgie Digestive et Hépato-Biliaire, Transplantation Hépatique, AP-HP Hôpital Pitié Salpêtrière, Paris, France. Novartis Pharma SAS, Rueil-Malmaison, France. Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017;(7):1843-1852
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Abstract

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

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