The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

Table 2

(a) Efficacy of sirolimus, (b) efficacy of everolimus.

(a)

	Patient survival rate (%)			Graft rejection rate (%)		Acute rejection rate (%)	BPAR (%)	Acute cellular rejection rate
	6 months	1 year	Crude mortality rate/1000 person-months	Crude graft failure rate/1000 person-months	1 year			(%)	ACR/1000 person-months	Steroid-resistant rejection/1000 person-months
De novo dosing
Sanchez et al.  Transplant Proc. 2005; 37: 4416–23 [69]								17.2
Molinari et al.  Transpl Intl. 2010; 23: 155–68 [53]	95 versus 94 (SRL versus CNI)	92 versus 91 (SRL versus CNI)			0 versus 0 (SRL versus CNI)		32.5 versus 44.1 (SRL versus CNI, 𝑃=0.03)	46.7 versus 58.9 (SRL versus CNI, 𝑃=0.003)
Campsen et al.  J Transplant. 2011; 2011: 913094 [54]; *See footnote for groups			2.39 (group 1), 1.96 and 3.88 (SRL conversion groups 2 and 3), 1.82 and 2.13 (SRL de novo groups 4 and 5). All NS	2.68 (group 1), 2.15 and 3.88 (SRL conversion groups 2 and 3), 1.82 and 2.13 (SRL de novo groups 4 and 5). All NS					12.5 (group 1), 13.4, 12.9 (SRL conversion groups 2, 3, 𝑃=NS versus control), 6.5, 5.2 (SRL de novo groups 4,5; 𝑃≤0.0001, 𝑃=0.0007 versus controls)	3.48 (group 1), 4.29, 3.88 (SRL conversion groups 2, 3,; 𝑃=0.03, 𝑃=NS versus controls), 1.58, 1.54 (SRL de novo groups 4, 5; 𝑃<0.001,𝑃=0.04 versus controls)
Late conversion (>3 months after transplantation)
DuBay et al. Liver Transpl. 2008; 14: 651–9 [72]						5 versus 4 (SRL versus control)
Shenoy et al. Transplantation. 2007; 83: 1389–92 [76]						5 versus 5 (SRL versus control)
Watson et al. Liver Transpl. 2007; 13: 1694–702 [78]						7.7 versus 0 (SRL versus CNI)
Abdelmalek et al. Am J Transplant. 2012; 12: 694–705 [45] (Low)		93.4 versus 94.4 (SRL versus CNI)			0 versus 0 (SRL versus CNI)	6.4 versus 1.9 (SRL versus CNI)	11.7 versus 6.1 (SRL versus CNI, 𝑃=0.02)
Bäckman et al. Clin Transplant. 2006; 20: 336–9 [82]						6.7
Di Benedetto et al. Transplant Proc. 2009; 41: 1297–9 [81]							12.9
Fairbanks et al. Liver Transpl. 2003; 9: 1079–85 [83]						4.8
Nair et al. Liver Transpl. 2003; 9: 126–9 [84]								0
Conversion times compared
Rogers et al.Clin Transplant. 2009; 23: 887–96 [48]							35, 38, 43 (early, late conversion SRL and CNI)
Variable conversion times
Harper et al. Transplantation. 2011; 15; 91: 128–32 [67]							3.4
Sanchez et al.; Transplant Proc. 2005; 37: 4416–23 [69]								2.8

𝑃values are included where available.
ACR: acute cellular rejection; BPAR: biopsy-proven acute rejection; CNI: calcineurin inhibitor; NS: nonsignificant; SRL: sirolimus.
∗Key to groups:
(1) CNI + MPS at time of discharge.
(2) CNI + MPS at time of discharge; SRL added within the first 6 months and continued through the first year.
(3) CNI + MPS at time of discharge; SRL was added within the first 6 months and discontinued before the first year.
(4) SRL as primary immunosuppression.
(5) SRL as primary immunosuppression and discontinued before the first year.

(b)

	Patient survival rate (%)			Graft rejection rate (%)			Acute rejection rate   (%)	BPAR (%)
	6 months	1 year	Other time points	6 months	1 year	3 years		6 months	1 year	Other time points
De novo/maintenance dosing
De Simone et al. Am J Transplant. 2012; 12: 3008–20 [87]		96.3 versus 97.5 (EVR + TAC-RD versus TAC-SD, 𝑃=NS)			2.4 versus 1.2 (EVR + TAC-RD versus TAC-SD, 𝑃=NS)				4.1 versus 10.7 (EVR + TAC-RD versus TAC-SD, 𝑃=0.005)
Grazi et al. Presented at ILTS; 2011 (Abstract P-256) [88]
Levy et al. Liver Transpl. 2006; 12: 1640–8 [52] (Low) + CNI		82.1, 96.7, 87.1 for EVR 1, 2 and 4 mg/day^*†			0, 13.3 and 3.2 for EVR 1, 2 and 4 mg/day^*†	39.3, 30.0 and 29.0 for EVR 1, 2 and 4 mg/day^*†			32.1, 26.7, and 25.8 for EVR 1, 2 and, 4 mg/day^*†	39.3, 30.0, and 29.0 for EVR 1, 2, and 4 mg/day^*† at 3 years
Early conversion (≤3 months after transplantation)
Fischer et al. Am J Transplant. 2012; 12: 1855–1865 [50]		95.8 versus 95.9 (EVR versus CNI control at 11 months, 𝑃=NS)			2.1 versus 2.0 (EVR versus CNI control at 11 months)					17.7 versus 15.3 (EVR versus CNI control at 11 months)
Schlitt et al. AASLD 2012 [91]			95.7 versus 90.0 (EVR versus CNI control at 35 months, 𝑃=NS)							24.4 versus 15.8 (EVR versus CNI control at 35 months, 𝑃=NS)
Masetti et al. Am J Transplant. 2010; 10: 2252–62 [89]	92.3 versus 92.3 (EVR versus CsA, 𝑃=NS)	90.4 versus 88.5 (EVR versus CsA, 𝑃=NS)								5.7 at 40–87 days after transplant versus 7.7 at days 41–240 after transplant CsA (𝑃=NS)
De Simone et al. Am J Transplant. 2012; 12: 3008–3020 [87]		96.5 versus 96.3 versus 97.5 (TAC elim versus EVR + TAC-RD versus TAC-SD)			2.2 versus 2.4 versus 1.2 (TAC elim versus EVR + TAC-RD versus TAC-SD)				19.9 versus 4.1 versus 10.7 (TAC elim versus EVR + TAC-RD versus TAC-SD)
Saliba et al. AASLD 2012 [90]										6.1 versus 13.3; delta risk: −7.2% (95% CI: −13.5%, −0.9%; 𝑃=0.010. EVR+TAC-RD versus TAC-SD at 24 months)
Late conversion (>3 months after transplantation)
Casanovas et al. Transplant Proc. 2011; 43: 2216–9 [93]		94.3
Castroagudín et al.  Liver Transpl. 2009; 15: 1792–7 [94]							0
De Simone et al. Transpl Int. 2009; 22: 279–86 [95]		100			0				15
De Simone et al. Liver Transpl. 2009; 15: 1262–9 [96]	98.6 versus 100 (EVR versus CNI)	95.8 versus 95.9 (EVR versus CNI)		0 versus 0 (EVR versus CNI)				1.4 versus 1.4 (EVR versus CNI)	4.2 versus 4.1 (EVR versus CNI)
Saliba et al. Liver Transpl. 2011; 17: 905–13 [98]									1.6
Vallin et al. Clin Transplant. 2011; 25: 660–9 [99]									9

𝑃 values are included where available;^∗𝑃: not significant for all efficacy-related events versus placebo; otherwise, where not stated.
†Timepoint refers to time after immunosuppression was initiated.
AASLD: The Liver Meeting 62nd Annual Meeting of the American Association for the Study of Liver Diseases; BPAR: biopsy-proven acute rejection; CsA: cyclosporin A; CNI: calcineurin inhibitor; EVR: everolimus; NS: nonsignificant; TAC elim; tacrolimus elimination; TAC-RD: reduced dose tacrolimus (C0: 3–5 ng/mL); TAC-SD: standard-dose tacrolimus (C0: 6–10 ng/mL).