The role of everolimus in liver transplantation

Abstract

During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.

Keywords: efficacy; everolimus; liver transplantation; mTOR inhibitors; safety.

Figure 1

Incidence of biopsy-proven acute rejection at month 12 in comparative trials of everolimus. Note: *The CNI was cyclosporine in the study by Masetti et al and tacrolimus in the H2304 study. Abbreviations: EVR, everolimus; CNI, calcineurin inhibitor; BPAR, biopsy-proven acute rejections; NR, not reported; NS, not significant.

Figure 2

Mean estimated glomerular filtration rate with everolimus + reduced tacrolimus versus tacrolimus control in the H2304 study. Note: Copyright © 2012 The American Society of Transplantation and the American Society of Transplant Surgeons. De Simone P, Nevens F, De Carlis L, et al; H2304 Study Group. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant. 2012;12(11):3008–3020. Copyright © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons. Saliba F, De Simone P, Nevens F, et al; H2304 Study Group. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013;13(7):1734–1745. Abbreviations: EVR, everolimus; TAC, tacrolimus; eGFR, estimated glomerular filtration rate.

Figure 3

Key adverse events with everolimus + reduced tacrolimus versus tacrolimus control in the H2304 study. Note: Copyright © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons. Saliba F, De Simone P, Nevens F, et al; H2304 Study Group. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013;13(7):1734–1745. Abbreviations: AE, adverse event; CI, confidence interval; CMV, cytomegalovirus; CV, cardiovascular; EVR, everolimus; GI, gastrointestinal; HCC, hepatocellular carcinoma; ILD, interstitial lung disease; NODM, new-onset diabetes mellitus; TAC, tacrolimus.