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

Table 4

(a) Studies reporting HAT and pulmonary vein thrombosis (b) adverse events associated with sirolimus (c) adverse events associated with everolimus.

(a)

	mTOR inhibitor	HAT (%)	Portal vein thrombosis (%)
De novo dosing
Levy et al. Liver Transpl. 2006; 12: 1640–8 [52]	EVR	Placebo: 3.3, EVR 1, 2, and 4 mg/day: 0, 3.3, and 3.2, respectively
Chinnakotla et al. Liver Transpl. 2009; 15: 1834–42 [55]	SRL	1.65 versus 0 (SRL versus TAC, 𝑃=NS)	1.65 versus 0.94 (SRL versus TAC, 𝑃=NS)
Molinari et al. Transpl Intl. 2010; 23: 155–68 [53]	SRL	1.2 versus 5.8 (SRL versus CNI, 𝑃=0.004)	0.8 versus 1.8 (SRL versus CNI, 𝑃=NS)
Dunkelberg et al. Liver Transpl. 2003; 9: 463–8 [61]	SRL	Hepatic artery complications: 5.3 versus 8.3 (SRL versus controls, 𝑃=NS)
Wiesner et al. Am J Transplant. 2002; 2 (s3): 464 (Abstract 1294) [44]	SRL	8.1 versus 3.8 and 9.0 versus 3.8 (SRL + CsA + CS versus TAC + CS, 2 and 6 months after transplant, 𝑃=NS for both timepoints)
Zimmerman et al. Liver Transpl. 2008; 14: 633–8 [15]	SRL	2.2 versus 1.9 (SRL versus CNI)	0 versus 0
Early conversion (≤3 months after conversion)
De Simone et al. Am J Transplant. 2012; 12: 3008–20 [87]	EVR	0.4 versus 0.4 compared to 1.9 in all patients during the prerandomization run-in phase (EVR + TAC-RD versus EVR + TAC-WD)
Masetti et al. Am J Transplant. 2010; 10: 2252–62 [89]	EVR	Hepatic artery stenosis/thrombosis: 1.9 versus 15.4 (EVR versus CsA, 𝑃=0.04)
McKenna et al. Am J Transplant. 2011; 11: 2379–87 [57]	SRL	1.2 versus 5.6 (SRL versus SRL-free, 𝑃=0.02)
Rogers et al. Clin Transplant. 2009; 23: 887–96 [48]	SRL	7 versus 11 (SRL versus CNI, 𝑃=NS)	0 versus 8 (𝑃=0.02)
Schleicher et al. Transplant Proc. 2010; 42: 2572–5 [49]	SRL	0
Late conversion (>3 months after conversion)
Abdelmalek et al. Am J Transplant. 2012; 12: 694–705 [45]	SRL	0.25 versus 0 (SRL versus CNI, 𝑃=NS)

𝑃 values are included where available.
CNI: calcineurin inhibitor; CsA: cyclosporine A; EVR: everolimus; HAT: hepatic artery thrombosis; NS: nonsignificant; SRL: sirolimus; TAC: tacrolimus; TAC-RD: reduced-dose tacrolimus (C0: 3–5 ng/mL); TAC-WD: tacrolimus withdrawn.

(b)

	Edema (% recipients)	Wound complications (% recipients)	Ulcers (% recipients)	Bile duct complications (% recipients)	Infections (% recipients)	Dermatological effects (% recipients)	Hematological effects (% recipients)
De novo dosing
Chinnakotla et al. Liver Transpl. 2009; 15: 1834–1842 [55]		Wound dehiscence: 3.31 versus 1.89 (SRL versus TAC, 𝑃=NS)
McKenna et al. Am J Transplant. 2011; 11: 2379–87 [57]					CMV: 13.3 versus 20.2 (SRL versus controls, 𝑃=0.07)
Sanchez et al. Transplant Proc. 2005; 37 (10): 4416–23 [69]		Wound infection: 13.8; Wound dehiscence: 6.9 (both de novo)			Bacterial infection: 34.5 versus 22.9; CMV: 3.4 versus 14.3 (de novo versus conversion)		Leukopenia: 6.9 versus 25.7 (de novo versus conversion); Thrombocytopenia: 13.7 versus 8.6 (de novo versus conversion)
Molinari et al. Transpl Intl 2010; 23: 155–68 [53]		Wound complications: 15 versus 11.6 (SRL versus CNI, 𝑃=NS); Incisional hernias: 8.7 versus 7.2 (𝑃=NS)		19.4 versus 18.5 (SRL versus CNI, 𝑃=NS)	Opportunistic infections: 18.5 versus 13; CMN: 2.6 versus 2.7; Herpes virus pneumonia: 0 versus 0.9 (SRL versus CNI, 6 months, 𝑃=NS for all)
Dunkelberg et al. Liver Transpl. 2003; 9: 463–8 [61]		Wound complications: 12.4 versus 13.9 (SRL versus controls, 𝑃=NS)
Zimmerman et al. Liver Transpl. 2008; 14: 633–8 [15]		Wound infection: 2.2 versus 3.8 (SRL versus CNI)
Early conversion (≤3 months after transplantation)
Rogers et al. Clin Transplant. 2009; 23: 887–96 [48]		Incisional hernia: 14 versus 15 (SRL versus CNI, 𝑃=NS); Poor wound healing: 6 versus 20 (𝑃=0.017)	Oral ulcers: 15 versus 3 (SRL versus CNI, 𝑃=0.019)		CMV disease: 13 versus 6 (SRL versus CNI, 𝑃=NS)	Facial rash: 8 versus 5 (SRL versus CNI, 𝑃=NS)	Leukopenia: 20 versus 12 (SRL versus CNI, 𝑃=NS); Anemia: 44 versus 11 (SRL versus CNI, 𝑃<0.001)
Harper et al. Transplantation. 2011; 91: 128–32 [67]	Peripheral edema: 21		Mouth ulcer: 15		Pneumonitis: 5	Rash: 7	Anemia: 11
Schleicher et al. Transplant Proc. 2010; 42: 2572–5 [49]		Incisional hernia: 7					Leukopenia: 12; Thrombocytopenia: 10.5; Anemia: 9
Late conversion (>3 months after transplantation)
Campbell et al. Clin Transplant. 2007; 21: 377–84 [71]	Leg edema: 5
DuBay et al. Liver Transpl. 2008; 14: 651–9 [72]	Lower extremity edema: 23 versus 11 (SRL versus CNI, 𝑃=0.08)						Anemia: 16 versus 12 (SRL versus CNI, 𝑃=NS)
Watson et al. Liver Transpl. 2007; 13: 1694–702 [78]	Edema: 30.8 versus 7.1 (SRL versus CNI)	Slow wound healing: 7.7 versus 0 (SRL versus CNI)	Oral ulcers: 38			Rash: 69 versus 0 (SRL versus CNI)	Thrombocytopenia: 23 versus 14.3 (SRL versus CNI)
Herlenius et al. Transplant Proc. 2010; 42: 4441–8 [73]			Oral ulcers: 42 versus 0 (SRL versus MMF, 𝑃=0.01)		Infectious episode: 33.3 versus 38.5 (SRL versus MMF, 𝑃=NS)
Morard et al. Liver Transpl. 2007; 13: 658–64 [75]	Ankle edema: 14		Oral ulcer: 12		Infection: 2	Dermatitis: 14
Shenoy et al. Transplantation. 2007; 83: 1389–92 [76]						Mouth sores: 25 versus 0 (SRL versus CNI); Pruritus: 5 versus 0 (SRL versus CNI)
Uhlmann et al. Exp Clin Transplant. 2012; 10: 30–8 [77]			Oral ulcer: 16
Fairbanks et al. Liver Transpl. 2003; 9: 1079–85 [83] (Low)			Oral ulcer: 9.5			Rash: 9.5; Acne: 9.5	Anemia: 23.8; Leukopenia: 9.5; Thrombocytopenia: 14.3
Di Benedetto et al. Transplant Proc. 2009; 41: 1297–9 [81]							Thrombocytopenia (leading to withdrawal): 12.9
Abdelmalek et al. Am J Transplant. 2012; 12: 694–705 [45]	Peripheral edema: 33 versus 14 (SRL versus CNI, 𝑃<0.001)		Oral ulcer: 11 versus 1 (SRL versus CNI, 𝑃<0.001)		Herpes simpex: 9 versus 1 (SRL versus CNI, 𝑃<0.001); Hepatitis: 2 versus 0 (SRL versus CNI, 𝑃=0.03)	29 versus 8 (SRL versus CNI, 𝑃<0.001)
Vivarelli et al. Transplant Proc. 2010; 42: 2579–84 [80]	Lower limb edema: 23.3		Oral ulcer: 5.8			Rash: 5.8	Anemia: 13.9

𝑃 values are included where available.
CMV: cytomegalovirus; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil; NS: non-significant; SRL: sirolimus; TAC: tacrolimus.

(c)

	Edema (% recipients)	Wound complications (% recipients)	Ulcers (% recipients)	Bile duct complications (% recipients)	Infections (% recipients)	Dermatological effects (% recipients)	Hematological effects (% recipients)
De novo dosing
Levy et al. Liver Transpl. 2006; 12: 1640–8 [52]					CMV disease: 3.3, 3.6, 6.7, and 9.7 (placebo versus EVR 1, 2, and 4 mg/day, respectively, 𝑃=NS for all comparisons)		Thrombocytopenia: 10.0, 14.3, 20.0, and 19.4; Leukopenia: 0, 14.3, 6.7, and 6.5; (placebo, EVR 1, 2, and 4 mg/day, PS = NS for all comparisons)
Early conversion (≤3 months after transplantation)
De Simone et al. Am J Transplant. 2012; 12: 3008–20 [87]	17.6 versus 10.8 (EVR + TAC-RD versus TAC-SD, RR 1.63, 95% CI 1.03, 2.56)	Wound complications: 11.0 versus 7.9 (EVR + TAC-RD versus TAC-SD, RR 1.40, 95% CI 0.80, 2.45); Incisional hernia: 2.9 versus 1.2 (RR 2.30, 95% CI, 0.60, 8.77)					Leukopenia: 11.8 versus 5.0 (EVR + TAC-RD versus TAC-SD, RR 2.38, 95% CI 1.24, 4.55); Thrombocytopenia: 5.3 versus 1.7; Anemia: 7.8 versus 8.3 (EVR + TAC-RD versus TAC-SD, RR 0.93, 95% CI 0.51, 1.71)
Fischer et al. Am J Transplant. 2012; 12: 1855–65 [50]		Wound complications: 2 versus 3.9; Incisional hernia: 11.9 versus 9.8; Wound dehiscence: 0 versus 1; Wound hemorrhage: 1 versus 0 (all EVR versus CNI)			Infections and infestations: 73.3 versus 59.8 (EVR versus CNI)		Anemia: 18.8 versus 10.8; Leukopenia: 20.8 versus 9.8*; Thrombocytopenia: 7.9 versus 6.9 (all EVR versus CNI, 𝑃=NS for anemia and thrombocytopenia)
Masetti et al. Am J Transplant. 2010; 10: 2252–62 [89]	Inferior limb edema: 9.6 versus 0 (EVR versus CsA, 𝑃=NS)	Incisional hernia: 46.1 versus 26.9 (EVR versus CsA, 𝑃=NS)		Biliary complications (stenosis/leak): 21.1 versus 30.8 (EVR versus CsA, 𝑃=NS)	Infections: 46.1 versus 46.1 (EVR versus CsA, 𝑃=NS); CMV: 19.2 versus 23.1 (EVR versus CsA, 𝑃=NS)
Late conversion (>3 months after transplantation)
Bilbao et al. Transplant Proc. 2009; 41: 2172–6 [92]			Mucositis: 4		Sepsis in the context of graft-versus-host disease: 4
Casanovas et al. Transplant Proc. 2011; 43: 2216–9 [93]							Anemia, leukopenia, and thrombocytopenia: 11.4
De Simone et al. Transpl Int. 2009; 22: 279–86 [95]			Oral ulcers/stomatitis: 22.5		Lower urinary tract infection: 5	Pruritis and acne: 7.5
De Simone et al. Liver Transpl. 2009; 15: 1262–9 [96]			Mouth ulcers: 26.4 versus 0.0 (EVR versus SNI, 𝑃<0.01)		Infections: 31.9 versus 21.9, of which 15.3 versus 1.4 were suspected to be drug-related (EVR versus CNI)	Rash/dry skin/eczema: 6.9 versus 0.0 (EVR versus CNI, 𝑃=0.028)	Leukopenia: 12.5 versus 5.5; Thrombocytopenia: 5.6 versus 1.4; Anemia: 9.7 versus 4.1 (all EVR versus CNI)
Saliba et al. Liver Transpl. 2011; 17: 905–13 [98]	Edema: 16.3		Stomatitis/mouth ulcers: 14.2		Bacterial infection: 12.5	Rash: 18.8	Anemia: 12.9; Leukopenia: 9.2; Thrombocytopenia: 6.3
Vallin et al. Clin Transplant. 2011; 25: 660–9 [99]	Edema: 7		Mucositis: 15		Infection: 3	Dermatitis: 19

CMV: cytomegalovirus; CNI: calcineurin inhibitor; CsA: cyclosporine A; EVR: everolimus; NS: nonsignificant; SRL: sirolimus; RR: relative risk; 95% CI: 95% confidence interval; TAC: tacrolimus; TAC-RD: reduced-dose tacrolimus (C0: 3–5 ng/mL); TAC-SD: standard-dose tacrolimus (C0: 6–10 ng/mL).
𝑃 values are included where available ∗Treatment group differences with an exploratory 𝑃 value of 𝑃≤0.05.