(b)
| Participants | Study designa | Duration of study | Sirolimus dosing | Strength of study design based on criteriab | |
|---|---|---|---|---|---|
| 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 SRL given at 2 mg/day and CNI withdrawn when SRL reached 5–8 ng/mL | Medium |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/m2 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.