title: Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.
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 m2for 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 m2for 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.
authors.affiliation: Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Saliba
authors.affiliation: Service d'Hépato-Gastro-Entérologie, AP-HP Hôpital Henri Mondor, Créteil, France.
authors.forename: C
authors.initials: C
authors.lastname: Duvoux
authors.affiliation: Département de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet, University of Nice Sophia Antipolis, Nice, France.
authors.forename: J
authors.initials: J
authors.lastname: Gugenheim
authors.affiliation: Département de Néphrologie et Transplantation d'Organes, CHU Rangueil, Toulouse, France.
authors.forename: N
authors.initials: N
authors.lastname: Kamar
authors.affiliation: Service d'Hépato-Gastroentérologie, CHRU de Lille, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Dharancy
authors.affiliation: Service de Chirurgie Hépato-Biliaire et Digestive, Hôpital Trousseau, CHU Tours, Tours, France.
authors.forename: E
authors.initials: E
authors.lastname: Salamé
authors.affiliation: Unité de Chirurgie Biliaire et de Transplantation Hépatique, Hôpital Magellan, CHU Bordeaux, Pessac, France.
authors.forename: M
authors.initials: M
authors.lastname: Neau-Cransac
authors.affiliation: Service d'Hépatologie et Transplantation Hépatique, University Paris Diderot, INSERM U1149, Clichy, France.
authors.forename: F
authors.initials: F
authors.lastname: Durand
authors.affiliation: Service de Chirurgie Hépatobiliaire et Digestive, CIC 1414, Hôpital Pontchaillou, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Houssel-Debry
authors.affiliation: Service d'Hépatologie et Soins Intensifs Digestifs, Hôpital Jean Minjoz, Besançon, France.
authors.forename: C
authors.initials: C
authors.lastname: Vanlemmens
authors.affiliation: Service Hépato-Gastroentérologie, Hôpital Saint Eloi, Montpellier, France.
authors.forename: G
authors.initials: G
authors.lastname: Pageaux
authors.affiliation: Service de Chirurgie et Transplantation Hépatique, Hôpital la Timone, Marseille, France.
authors.forename: J
authors.initials: J
authors.lastname: Hardwigsen
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Eyraud
authors.affiliation: Service de Chirurgie Digestive et Hépato-Biliaire, Transplantation Hépatique, AP-HP Hôpital Pitié Salpêtrière, Paris, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Calmus
authors.affiliation: Novartis Pharma SAS, Rueil-Malmaison, France.
authors.forename: F
authors.initials: F
authors.lastname: Di Giambattista
authors.affiliation: Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France.
authors.forename: J
authors.initials: J
authors.lastname: Dumortier
authors.affiliation: Service de Chirurgie Digestive et Hépato-Biliaire, Transplantation Hépatique, AP-HP Hôpital Pitié Salpêtrière, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Conti
mesh_terms: D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000494:pharmacology*; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D016559:Tacrolimus
keywords: calcineurin inhibitor (CNI); clinical research/practice; glomerular filtration rate (GFR); immunosuppressant; immunosuppression/immune modulation; liver transplantation/hepatology; mechanistic target of rapamycin (mTOR)