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.

Table 2 Outcomes of everolimus-based immunosuppressant as maintenance for lt recipients in prospective RCT

Ref.	Treatment group	Time (mo) from transplant surgery EVR was initiated	Key inclusion and exclusion criteria	n	Follow-up period (mo)	Efficacy	Mean improvement in CrCl (mL/min)	Safety
De Simone et al[19] 2009 (RESCUE Study)	EVR with CNI reduction or elimination (EVR C0 3-8 ng/mL, FK C0 3-5 ng/mL or EVR C0 6-12 ng/mL with FK elimination	12 to 60 mo	Inclusion: CrCl ≤ 60 mL/min and ≥ 20 mL/min Exclusion: Renal dysfunction not due to CNI toxicity, proteinuria ≥ 1 g/24 h, acute rejection < 6 mo, hepatitis C infection need active antiviral therapy	72	12	BPAR, graft loss or death: 8.3% in EVR group vs 4.1% in control group	-1.1 (P = 0.463) at month 6	Higher incidence of hyperlipidemia, mouth ulceration, increased hepatitis C virus viral titer, dry skin, eczema, and rash in the EVR group
	Control: Standard exposure of FK or CsA			73

BPAR: Biopsy proven acute rejection; C₀: Trough level; CNI: Calcineurin inhibitor; CrCl: Creatinine clearance (based on Cockcroft-Gault formula); CsA: Cyclosporine; EVR: Everolimus; FK: Tacrolimus.

Table 3 Recommendation for everolimus use in liver transplantation recipients

Indication and regimen	Renoprotective benefit
	EVR in combination with CNI to allow CNI dose reduction
	Management of CNI neurotoxicity
	EVR allows temporary withdrawal of CNI till resolution of neurotoxicity
Patients	LT recipients with renal function > 60 mL/min
	LT recipients proteinuria < 1 g/24 h
Timing	De novo therapy: Initiate EVR at 1 mo from transplant
	Maintenance therapy: Introduce EVR within 1 yr from transplant
	CNI neurotoxicity: Stop CNI and initiate EVR immediately

CNI: Calcineurin inhibitor; EVR: Everolimus; LT: Liver transplantation.