Everolimus and Early Calcineurin Inhibitor Withdrawal: 3-Year Results From a Randomized Trial in Liver Transplantation

Abstract

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 postrandomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 postrandomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] −1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m2 (95% CI −0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m2 (95% CI −1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.The beneficial effect on renal function achieved by early CNI withdrawal and treatment with everolimus after liver transplantation is still evident after three years.

Everolimus in clinical practice after liver transplantation: a single-center experience

“…среднее изменение клиренса креатинина от исходного было одинаковым у пациентов, получавших эверолимус со сниженной дозой или отменой ИКН, и пациентов, получавших ИКН в стандартной дозе [16]. Даль-нейшие рандомизированные клинические исследо-вания подтвердили, что терапия эверолимусом без ИКН возможна после ОТП, при этом функция почек по сравнению с пациентами, получающими ИКН по крайней мере 3 года, достоверно лучше [17,18]. В проспективном рандомизированном многоцент-ровом открытом исследовании, длившемся 24 мес., скорректированное увеличение СКФ от рандоми-зации до 24-го месяца отмечалось на фоне приема эверолимуса с такролимусом в сниженной дозе по сравнению с теми больными, кто принимал только такролимус (p < 0,001).…”

Use of Everolimus in Liver Transplantation

“…In its subsequent study, 81 patients were further followed-up till 3 years. A significant difference in renal function continued to be seen between the EVR with CNI-withdrawal vs the control group at month 35 from randomization, mainly due to the progressive deterioration of renal function in the standard CNI group [14] . Recently, the 5-year followup on these same 81 patients has been published, reporting a continued improved trend in renal function in the EVR-treated group (eGFR improved by 11.4 mL/min, P = 0.021) with comparable treatment failure rates (9.8% in EVR group vs 7.5% in standard CNI group, P = 1.000) in both groups [15] .…”

Is there such a thing as protocol immunosuppression in liver transplantation?

“…A recent RCT and metaanalysis of the available literature did not support conversion from CNI-based to sirolimus-based IS to improve renal function [6,7]. However, a recent RCT comparing sirolimus plus MMF to MMF plus CNI at 4-12 weeks post-transplant did lead to significantly improved renal function at 12 months, although with higher rates of biopsy-proven acute rejection and hyperlipidemia [8] RCTs using early introduction of everolimus at 4 weeks post-transplant with either CNI withdrawal or dose minimization showed significant improvement in renal function at 2 and 3 years [9]. It should be noted, however, that in the larger Phase III study, complete elimination of CNI was associated with more allograft rejection and that arm of the study had to be stopped prematurely [8].…”