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

Table 1

(a) Sirolimus trials (de novo and maintenance dosing) retrieved from PubMed/congress search, (b) sirolimus conversion trials retrieved from PubMed/congress search, (c) everolimus trials (de novo dosing) retrieved from PubMed/congress search, (d) everolimus conversion trials retrieved from PubMed/congress search.

(a)

	Participants	Study design^a	Duration of study	Sirolimus dosing	Strength of study design based on defined criteria^b
De novo dosing
Chinnakotla et al. Liver Transpl. 2009; 15: 1834–42 [55]	𝑁=227 recipients; (i) 𝑛=121 (SRL); (ii) 𝑛=106 (TAC)	R/P	5 years	2 mg orally, once daily. Levels maintained at 5–8 ng/mL for the first 3 months and at 5 ng/mL thereafter	High
Asthana et al. Can J Gastroenterol. 2011; 25: 28–34 [56]	𝑁=141 recipients; (i) 𝑛=88 (de novo SRL); (ii) 𝑛=53 (CNI)	R	12 months	Maintained at 8–12 ng/mL	Medium
McKenna et al. Am J Transpl. 2011; 11: 2379–87 [57]	𝑁=455 recipients (HCV-positive); (i) 𝑛=173 (SRL); (ii) 𝑛=282 (SRL-free)	R/P	2 years	2 mg daily without a loading dose beginning on the first postoperative day	Medium
Wagner et al. Int Immunopharmacol. 2010; 10: 990–3 [58]	𝑁=67 recipients (HCV-positive); (i) 𝑛=39 (SRL); (ii) 𝑛=28 (CNI)	P, C	12 months	Trough levels were maintained between 3 and 8 ng/mL	Medium
Zhou et al. Transplant Proc. 2008; 40: 3548–553 [59]	𝑁=73 recipients (HCC exceeding Milan criteria); (i) 𝑛=27 (SRL); (ii) 𝑛=46 (TAC)	R	2 years	Given 1 month after transplant: initial dose of 3 mg/m^2 adjusted over time to achieve steady-state trough levels of ≈5–8 ng/mL	Medium
Asthana et al. Presented at AASLD 2011 (Abstract 184) [60]	𝑁=100 recipients (recurrent HCV); (i) 𝑛=40 (SRL); (ii) 𝑛=35 (TAC); (iii) 𝑛=24 (cyclosporine); (iv) 𝑛=36 lost to followup	P, C	Median of 77.6 months	Not stated	Low
Campsen et al. J Transplant. 2011; 2011: 913094 [54]	𝑁=672 recipients; (i) 𝑛=328 (CNI + MPS at time of discharge); (ii) 𝑛=135 (CNI + MPS at time of discharge; SRL added within the first 6 months and continued through the first year); (iii) 𝑛=15 (CNI + MPS at time of discharge; SRL was added within the first 6 months and discontinued before the first year); (iv) 𝑛=156 (SRL as primary immunosuppression); (v) 𝑛=38 (SRL as primary immunosuppression and discontinued before the first year)	R	1 year	Not stated	Low
Dunkelberg et al. Liver Transpl. 2003; 9: 463–8 [61]	𝑁=350 recipients; (i) 𝑛=170 (SRL); (ii) 𝑛=180 (historic controls)	R	12 months	6 mg on day 0, and 2 mg/day thereafter no target level was specified	Low
Jiménez-Romero et al. Hepatogastroenterology. 2011; 58: 115–21 [62]	𝑁=16 recipients who developed de novo tumors; All switched from CNI/MMF to SRL monotherapy	P, S	Mean of 15.7 months	Loading dose: 4 mg, followed by 2 mg/day until 8–12 days, thereafter dose adjusted to achieve target blood level of 5–10 ng/mL	Low
Kneteman et al. Liver Transpl. 2004; 10: 1301–11 [63]	𝑁=40 recipients (HCC); All given SRL	P, S	4 years	Adjusted to achieve target levels of 12–20 ng/mL	Low
Maramattom and WijdicksNeurology. 2004; 63: 1958–9 [64]	𝑁=202 recipients; All received SRL	R	18 months	Loading dose: 6 mg, thereafter: 1–10 mg/day with target blood level of 8–15 ng/mL	Low
Molinari et al. Transpl Intl. 2010; 23: 155–68 [53]	𝑁=543 recipients; (i) 𝑛=252 (SRL); (ii) 𝑛=291 (CNI)	R	5 years	Oral dose adjusted to keep the blood levels in the range of 10–15 ng/mL during the first 3–6 months and then in the range of 5–10 ng/mL afterwards	Low
Toso et al. Hepatology. 2010; 51: 1237–43 [65]	𝑁=2491 recipients (HCC); (i) 𝑛=109 (SRL); (ii) 𝑛=2382 (SRL-free)	R	5 years	Not stated	Low
Wiesner et al. Am J Transplant. 2002; 2 (s3): 464 (Abstract 1294) [44]	𝑁=163 recipients; (i) 𝑛=111 (SRL + CsA); (ii) 𝑛=52 (concentration-controlled TAC (trough levels 5–15 ng/mL) + corticosteroids)	P, Ra	6 months	Fixed-dose of 5 mg/day	Low
Zimmerman et al. Liver Transpl. 2008; 14: 633–8 [15]	𝑁=97 recipients (cirrhosis + concomitant HCC); (i) 𝑛=45 (SRL); (ii) 𝑛=52 (standard regimen including CNIs, MMF, and corticosteroids)	R	5 years	Bolus dose of 6 mg on day 0 and given on 2 mg/day thereafter	Low
Combination of de novo and maintenance dosing
Kazimi et al. Transplantation. 2010; 90 (2S): 697 (Abstract 1950) [66]	𝑁=114 recipients; (i) 𝑛=65 (SRL); (ii) 𝑛=49 (CNI)	R	1111±800 days	Not stated	Low

(b)

	Participants	Study design^a	Duration of study	Sirolimus dosing	Strength of study design based on criteria^b
Early conversion (≤3 months after transplantation)
Rogers et al. Clin Transplant. 2009; 23: 887–96 [48]	𝑁=82 recipients; (i) 𝑛=42 (SRL); (ii) 𝑛=40 (CNI)	R	12 months	Target SRL levels for the first three months after conversion were 8–10 ng/dL, 6–8 ng/dL for months 3–6, and 5–6 ng/dL after month 12	High
Harper et al. Transplantation. 2011; 91: 128–32 [67]	𝑁=148 recipients; All converted to SRL	R	Median of 1006 days	Conversion from CNI to SRL performed with an overlap. SRL given at 2 mg/day and CNI withdrawn when SRL reached 5–8 ng/mL	Medium
McKenna et al. ILTS. 2011 (Abstract O-17) [68]	𝑁=1078 recipients; (i) 𝑛=202 (SRL); (ii) 𝑛=876 (SRL-free)	R	10 years	Not stated	Medium
Schleicher et al. Transplant Proc. 2010; 42: 2572–5 [49]	𝑁=57 recipients; (i) 𝑛=11 (early conversion, impaired perioperative renal function; SRL = 7, EVL = 4); (ii) 𝑛=7 (early conversion, normal perioperative renal function; SRL = 6, EVL = 1); (iii) 𝑛=23 (late conversion, impaired perioperative renal function, SRL = 15, EVL = 8); (iv) 𝑛=16 (late conversion, normal perioperative renal function; SRL = 12, EVL = 4)	R	12 months	Initial dose of 10 mg/day. Doses were adjusted successively to maintain trough levels of 5–10 ng/mL	Medium
Sanchez et al. Transplant Proc. 2005; 37: 4416–23 [69]	𝑁=64 recipients; (i) 𝑛=29 (denovo SRL); (ii) 𝑛=35 (conversion SRL)	P, C	2 years	In recipients with HCC or autoimmune disorders, SRL doses used were typically either a 5 mg or 3 mg loading dose followed by 2 mg each day; After conversion, SRL levels were maintained at 10–15 ng/mL when used within 3 months of transplantation and at 5–10 ng/mL after 3 months after transplantation	Medium
Forgacs et al. Transplant Proc. 2005; 37: 1912–4 [70]	𝑁=7 recipients; All converted to SRL	R	Up to 425 days	Not stated	Low
Late conversion (>3 months after transplantation)
Campbell et al. Clin Transplant. 2007; 21: 377–84 [71]	𝑁=179 recipients; (i) 𝑛=79 (SRL conversion); (ii) 𝑛=100 (CNI controls)	R	Median of 359 days	2 mg daily, dose adjusted until target levels of 5–8 ng/mL achieved	High
DuBay et al. Liver Transpl. 2008; 14: 651–9 [72]	𝑁=114 recipients (with renal insufficiency); (i) 𝑛=57 (SRL); (ii) 𝑛=47 (low-dose CNIs)	R	12 months	Recipients on CNI monotherapy were started on SRL 1 mg/day and the CNI dose was halved. At 1 week, the CNI was stopped, and the SRL dose was adjusted on the basis of the serum levels. For recipients on combination therapy, the CNI was stopped, and SRL was started on the same day at 2 mg/day while the antimetabolite or steroid doses were maintained at their current levels. In both groups the SRL dose was adjusted to maintain trough levels of 5–15 𝜇g/day	High
Herlenius et al. Transplant Proc. 2010; 42: 4441–8 [73]	𝑁=25 recipients (with chronic kidney disease); (i) 𝑛=12 (SRL); (ii) 𝑛=13 (MMF)	P, Ra	12 months	A single bolus dose of 10 mg SRL followed by three consecutive daily doses of 8 mg. Target trough concentration of 10 ng/mL	Medium
Lam et al. Dig Dis Sci. 2004; 49: 1029–35 [74]	𝑁=28 recipients (with renal insufficiency after transplantation); All converted to SRL	P, S	Mean of 328±57 days	SRL initiated at 2 mg/day. Doses adjusted to achieve target level of 4–10 ng/mL	Medium
Morard et al. Liver Transpl. 2007; 13: 658–64 [75]	𝑁=48 recipients; (i) 𝑛=16 (SRL); (ii) 𝑛=19 (SRL + MMF); (iii) 𝑛=7 (SRL + prednisone); (iv) 𝑛=2 (SRL + CNI); (v) 𝑛=4 (SRL + MMF + prednisone)	R	Median of 22.6±11 months	Loading dose: 6 mg (day 1) followed by 2 mg/day (day 2–7). SRL dose adjusted to maintain trough levels of 5–10 ng/mL	Medium
Shenoy et al.Transplantation. 2007; 83: 1389–92 [76]	𝑁=40 recipients (with renal dysfunction); (i) 𝑛=20 (SRL); (ii) 𝑛=20 (CNI)	P, Ra	12 months	5 mg loading dose, followed by 3 mg SRL once daily. Levels maintained 6–10 ng/mL	Medium
Uhlmann et al. Exp Clin Transplant. 2012; 10: 30–8 [77]	𝑁=25 recipients; All converted to SRL	P, S	75.6 months	SRL started at 1 mg/day, dose adjusted to maintain trough levels at 69 ng/mL	Medium
Watson et al. Liver Transpl. 2007; 13: 1694–702 [78]	𝑁=27 recipients; (i) 𝑛=13 (SRL); (ii) 𝑛=14 (CNI)	P, Ra	12 months	CNI was discontinued the evening before conversion, and recipients were started on 2 mg/day SRL on the following day. Target range of 5–15 ng/mL	Medium
Stein et al. Presented at the American Transplant Congress 2011 (Abstract 817) [79]	𝑁=40 recipients (received transplant for HCV); (i) 𝑛=18 (SRL conversion); (ii) 𝑛=22 (TAC)	R	5 years	Not stated	Low
Vivarelli et al.Transplant Proc. 2010; 42: 2579–84 [80]	𝑁=78 recipients; (i) 𝑛=38 (SRL); (ii) 𝑛=40 (SRL + CNI)	R	510±366 days	5 mg/m^2 for 1st day, then 2 mg/daily, adjusted to trough blood level <10 ng/mL	Low
Di Benedetto et al.Transplant Proc. 2009; 41: 1297–9 [81]	𝑁=31 recipients; All converted to SRL	R	Mean of 27.5 months (range: 2–71.2 months)	SRL at a loading dose of 0.1 mg/kg on day 1 of the switch, then 0.05 mg/kg for the next few days. Dose adjusted to maintain trough levels of 8–10 ng/mL	Low
Abdelmalek et al. Am J Transplant. 2012; 12: 694–705 [45]	𝑁=607 recipients; (i) 𝑛=393 (SRL conversion); (ii) 𝑛=214 (CNI continuation)	P, Ra	Up to 6 years	Loading dose of SRL: 10–15 mg. First dose given ≥4 h after the last CNI dose; second doses given 12 h later. On study days 2–6, SRL doses of 3–5 mg/day were given. Thereafter, SRL doses maintained to achieve blood levels of 6–16 ng/mL (chromatographic) and subsequently to 8–16 ng/mL (chromatographic) or 10–20 ng/mL (immunoassay)	Low
Bäckman et al. Clin Transplant. 2006; 20: 336–9 [82]	𝑁=15 recipients; All converted to SRL	P, S	6 months	Loading dose of 15 mg SRL on days 1 and 2, then 8 mg/day and adjusted to achieve trough levels of 13–22 and 10–22 ng/mL	Low
Fairbanks et al. Liver Transpl. 2003; 9: 1079–85 [83]	𝑁=21 recipients (developed renal dysfunction while on CNI therapy); All converted to SRL	P, S	Mean of 66.8±38.9 weeks	Initially 1-2 mg/day and increased weekly by 1 mg to achieve therapeutic levels (9–12 ng/mL)	Low
Nair et al. Liver Transpl. 2003; 9: 126–9 [84]	𝑁=16 recipients; All converted to SRL	R	6 months	Loading dose of 5 mg on day 1, followed by 2 mg/day. A trough level of 5–10 ng/mL was maintained	Low
Neff et al. Transplant Proc. 2003; 35: 3029–31 [85]	𝑁=14 recipients; All converted to SRL	R	90 days	Mean starting dose of SRL (10 mg/day) adjusted to maintain trough levels of 8–12 ng/mL during first month and subsequently 3–5 ng/mL for recipients on maintenance combination therapy with SRL	Low
Wadei et al. Transplantation. 2012; 93: 1006–12 [86]	𝑁=102 recipients; All converted to SRL	R	Median of 3.1 years	CNI dose reduced by 50% until target SRL level of 8–12 ng/mL achieved	Low

Search terms were ‘‘sirolimus liver transplantation’’ OR ‘‘sirolimus liver transplant.’’
CNI: calcineurin inhibitor; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; ILTS: 2011 Joint International Congress of the International Liver Transplantation Society; MMF: mycophenolate mofetil; SRL: sirolimus; TAC: tacrolimus.
aStudy design: C: cohort; P: prospective; R: retrospective; Ra: randomized; S: single-arm.
bSee Section 2 for description of how criteria are defined.

(c)

	Participants	Study design^a	Study duration	Everolimus dosing	Strength of study design based on criteria^b
De Simone et al. Am J Transplant. 2012; 12: 3008–20 [87]	𝑁=719 recipients; (i) 𝑛 = 245 (EVR + TAC-RD); (ii) 𝑛 = 231 (EVR + TAC-WD); (iii) 𝑛=243 (TAC-SD)	P, Ra	12 months	For EVR + TAC-WD, EVR initiated at a dose of 1.0 mg b.i.d. within 24 h of randomization with the dose adjusted from day 5 onward, to maintain C0 3–8 ng/mL until month 4 after transplantation, after which the target range increased to 6–10 ng/mL; In the EVR + TAC-RD arm, EVR initiated and monitored as for EVR + TAC-WD, but the initial target range of 3–8 ng/mL maintained throughout the study	High
Grazi et al. Presented at ILTS; 2011 (Abstract P-256) [88]	𝑁=64 recipients (HCV-related cirrhosis); (i) 𝑛=28 (EVR + Bmab + steroids); (ii) 𝑛=36 (TAC + Bmab + steroids)	P, Ra	1 year	Not stated	Low
Levy et al. Liver Transpl. 2006; 12: 1640–8 [52]	𝑁=119 recipients; (i) 𝑛=28 (EVR 1.0 mg) + CNI; (ii) 𝑛=30 (EVR 2.0 mg) + CNI; (iii) 𝑛=31 (EVR 4.0 mg) + CNI; (iv) 𝑛=30 (placebo) + CNI	P, Ra	36 months	1, 2 or 4 mg/day	Low

Search terms were ‘‘everolimus liver transplantation’’ OR ‘‘everolimus liver transplant.’’
Maintenance therapy refers to immunotherapy for the lifetime of the graft. Conversion therapy is where liver transplant recipients were withdrawn from CNIs and switched to everolimus.
Bmab: basiliximab; CNI: calcineurin inhibitor; EVR: everolimus; HCV: hepatitis C virus; SRL: sirolimus; TAC: tacrolimus.
aStudy design: P: prospective; R: retrospective; Ra: randomized.
bSee Section 2 for description of how criteria are defined.

(d)

	Participants	Study design^a	Study duration	Everolimus dosing	Strength of study design based on criteria^b
Early conversion (≤3 months after transplantation)
De Simone et al. Am J Transplant. 2012; 12: 3008–20 [87]	𝑁=719 recipients; (i) 𝑛= 245 (EVR + TAC-RD); (ii) 𝑛= 231 (EVR + TAC-WD); (iii) 𝑛= 243 (TAC-SD)	P, Ra	12 months	For EVR + TAC-WD, EVR initiated at a dose of 1.0 mg b.i.d. within 24 h of randomization with the dose adjusted from day 5 onward, to maintain C0 3–8 ng/mL until month 4 after transplantation, after which the target range increased to 6–10 ng/mL.; In the EVR + TAC-RD arm, EVR initiated and monitored as for EVR + TAC-WD, but the initial target range of 3–8 ng/mL maintained throughout the study	High
Fischer et al.  Am J Transplant. 2012; 12: 1855–65 [50]	𝑁=203 recipients on CNI with/out corticosteroids; (i) 𝑛=101 (EVR); (ii) 𝑛=102 (CNI continuation)	P, Ra	12 months	EVR started at 1.5 mg b.i.d. and adjusted to achieve a target trough level of 5–12 ng/mL (8–12 ng/mL in patients on treatment with CsA), when CNI was tapered by 70% of the initial CNI dose	High
Masetti et al. Am J Transplant. 2010; 10: 2252–62 [89]	𝑁=78 recipients; (i) 𝑛=52 (EVR); (ii) 𝑛=26 (CsA)	P, Ra	12 months	Initial dose: 2.0 mg/day, trough level of 6–10 ng/mL. When CsA discontinued, trough level: 8–12 ng/mL until end of month 6 and 6–10 ng/mL thereafter	High
Saliba et al. AASLD 2012 [90]	𝑁=719 recipients from De Simone et al. Am J Transplant. 2012 [40]; (i) 𝑛=245 (EVR + TAC-RD); (ii) 𝑛=231 (EVR + TAC-WD); (iii) 𝑛=243 (TAC-SD)	P, Ra	24 months	Same as De Simone et al. Am J Transplant. 2012 [40]	High
Schlitt et al. AASLD 2012 [91]	𝑁=81 recipients from Fischer et al. Am J Transplant. 2012; (i) 𝑛=41 (EVR with/out corticosteroids); (ii) 𝑛=40 (CNI with/out corticosteroids)	P, Ra	35 months	Same as Fischer et al. Am J Transplant. 2012 [43]	High
Late conversion (>3 months after transplantation)
Bilbao et al.  Transplant Proc. 2009; 41: 2172–6 [92]	𝑁=25 recipients; All converted to EVR	R	Mean of 10±9 months	In refractory rejection: initial dose 0.5 mg/12 h. Trough levels 5 ng/mL. For CNI-related adverse events, EVR started at 0.5 mg once or twice a day. For malignancy, EVR introduced at 0.5 mg/day, adjusting trough levels to <3 ng/mL	Medium
Casanovas et al. Transplant Proc. 2011; 43: 2216–9 [93]	𝑁=35 recipients; All converted to EVR	P, S	Mean of 134 months	Initial dose 0.25 mg/12 h for the first 4 days. Target trough 3–5 ng/mL	Medium
Castroagudín et al. Liver Transpl. 2009; 15: 1792–7 [94]	𝑁=21 recipients (chronic renal dysfunction); All converted to EVR	P, S	Median of 19.8 months	0.75 mg b.i.d., with target trough levels of 3–8 ng/mL	Medium
De Simone et al.  Transpl Int. 2009; 22: 279–86 [95]	𝑁=40 recipients	P, S	12 months	EVR 1.5 mg/day. Trough level of 3–8 ng/mL	Medium
De Simone et al.  Liver Transpl. 2009; 15: 1262–9 [96]	𝑁=145 recipients; (i) 𝑛=72 (EVR therapy with CNI reduction or discontinuation); (ii) 𝑛=73 (CNI continuation)	P, Ra	12 months	Initial: 3 mg/day ×2 on day 1. After week 2: EVR trough level maintained at 3–8 ng/mL during concomitant CNI administration and 6–12 ng/mL if CNI eliminated	Medium
Bilbao et al. Presented at ILTS; 2011 (Abstract P-68) [97]	𝑁=62 recipients; All received EVR	R	Median of 12 months	EVR trough level at ~3 ng/mL	Low
Saliba et al. Liver Transpl. 2011; 17: 905–13 [98]	𝑁=240 maintenance recipients; All received EVR	R	12 months	Introduced at mean 2.4 mg/day. The mean trough level = 7.3 ng/mL at month 1 and 8.1 ng/mL at month 12 across total population, with higher values in monotherapy cohort (8.8 ng/mL at month 12)	Low
Vallin et al. Clin Transplant. 2011; 25: 660–9 [99]	𝑁=94 recipients; All received EVR	R	Mean of 12±7 months	Initial dose 0.75–1.5 mg b.i.d. Trough adjusted to 3–8 ng/mL	Low

𝑃 values are included where available.
Search terms were ‘‘everolimus liver transplantation’’ OR ‘‘everolimus liver transplant.’’
AASLD: Annual Meetings of the American Association for the Study of Liver Diseases; b.i.d.: twice daily; CNI: calcineurin inhibitor; CsA: cyclosporin A; EVR: everolimus; ILTS: 2011 Joint International Congress of the International Liver Transplantation Society; TAC: tacrolimus; TAC-RD: reduced-dose tacrolimus; TAC-SD: standard-dose tacrolimus; TAC-WD: tacrolimus withdrawn.
aStudy design: P: prospective; R: retrospective; Ra: randomized; S: single-arm.
bSee Section 2 for description of how criteria are defined.