Use of everolimus in liver transplantation

Table 1 Outcomes of everolimus-based immunosuppressant for de-novo liver transplantation recipients in prospective randomised controlled trial

Ref.	Treatment group	Time (d) from transplant EVR was initiated	Key inclusion and exclusion criteria	n	Follow-up period (mo)	Efficacy	Mean improvement in eGFR (mL/min per 1.73 m2)	Safety
Fischer et al[13] 2012 (PROTECT Study)	EVR + eliminate CNI by month 4 (EVR C0 5-12 ng/mL, if with CsA, EVR C0 8-12 ng/mL)	from day 30 and by day 56	Inclusion: No rejection 2 wk before study, renal function > 50 mL/min	101	12	BPAR, graft loss or death: 20.8% vs 20.4% (P = 1.0)	7.8 (P = 0.021)	No HAT, no increased risk of delayed wound healing. Higher incidence of infections, leukopenia, hyperlipidemia, anemia, proteinuria and arterial hypertension in the EVR group
	Control: FK or CsA		Exclusion: Severe systemic infections, total cholesterol≥ 9 mmo/L, TG > 8.5 mmol/L, significant renal dysfunction (eGFR < 50 mL/min)	102
Sterneck et al[14] 2014 (PROTECT Study, extended to 36 mo)	Same as above	From day 30 and by day 56		41	36	BPAR, graft loss and death: 19.5% vs 2.5% (P = 0.029) at month 11 (baseline)	9.4 (P = 0.053)	Peripheral edema and back pain were significantly higher in EVR group
				40		BPAR, graft loss and death: 4.9% vs 5.0% (P = 1.0) at month 36
Sterneck et al[15] 2016 (PROTECT Study, extended to 59 mo)	Same as above	From day 30 and by day 56		41	59	BPAR, graft loss and death: 9.8% vs 7.5% (P = 1.0) from month 11 to month 59	11.4 (P = 0.021)	Peripheral edema and back pain were significantly higher in EVR group
				40
De Simone et al[16] 2012 (H2304 Study)	EVR + low FK (EVR C0 3-8 ng/mL and FK C0 3-5 ng/mL)	Day 30	Inclusion: eGFR ≥ 30 mL/min, FK trough ≥ 8 ng/mL.	245	12	BPAR, graft loss or death: 6.5% in EVR group vs 9.5% in control group (P < 0.001)	8.5 (P < 0.001)	Higher incidence of proteinuria, acute renal failure, hyperlipidemia, neutropenia, peripheral edema, stomatitis/mouth ulceration, and thrombocytopenia in the EVR group
	FK elimination (EVR C0 3-8 ng/mL till month 4 then 6-10 ng/mL thereafter and FK elimination started at month 4 when EVR C0 6-10 ng/mL achieved		Patent hepatic artery and veins, absence of rejection	231
	Control: FK (C0 8-12 ng/mL until month 4 and C0 6-10 ng/mL thereafter)		Exclusion: HCC not fulfill Milan criteria, receipt of antibody induction therapy proteinuria ≥ 1 g/24 h	243
Saliba et al[17] 2013 (H2304 Study, extended to 24 mo)	EVR + low FK (EVR C0 3-8 ng/mL and FK C0 3-5 ng/mL)	Day 30		245	24	BPAR, graft loss or death: 10.3% in EVR group vs 12.5% in control group (P = 0.452)	6.7 (P = 0.002)	No increased risk of wound healing. Higher incidence of proteinuria, acute renal failure, hyperlipidemia, neutropenia, peripheral edema, stomatitis/mouth ulceration, and thrombocytopenia in the EVR group
				243
Fischer et al[18] 2015 (H2304 Study, extended to 36 mo)	Same as above	Day 30		106	36	BPAR, graft loss and death: 11.5% vs 14.6% (P = 0.334)	8.5 (P = 0.005)	Higher drop-out rate due to ADR and incidence of hyperlipidemia in EVR group
				125

ADR: Adverse drug reaction; BPAR: Biopsy proven acute rejection; C₀: Trough level; CNI: Calcineurin inhibitor; CsA: Cyclosporine; EVR: Everolimus; FK: Tacrolimus; eGFR: Based on Modification of Diet in Renal Disease (MDRD) 4.