Corticosteroid-free immunosuppression in liver transplantation: An evidence-based review

Table 3 Baseline study characteristics

Ref.	Indication	Recipients	Regimens	Outcomes	Study duration	Rejection treatments protocols
Belli et al[6] 2001	HCV positive	Group A = 13	RATG + AZA + CyA + ST (3 mo)	Acute rejection, chronic rejection, HCV recurrence	November 1997-November 1999	NS
		Group B = 11	/RATG + AZA + CyA
		Group C = 13	/RATG + AZA + CyA + ribavirin
Boillot et al[7] 2005	Adult patients undergoing first OLT	Group A = 351 (103)	TACRO + daclizumab/TACRO + ST (3 mo)	Acute rejection, corticosteroid resistant acute rejection, graft survival	July 2000-February 2002	Increasing TACRO dose and/or steroids
		Group B = 347 (106)
Eason et al[10] 2003	Adult patients undergoing first OLT	Group A = 59 (34)	RATG + TACRO + MMF/ST (3 mo) + TACRO + MMF	Patient survival, graft survival, rejection, adverse events, HCV recurrence	December 1999-August 2002	Increasing TACRO or adding MMF or sirolimus; steroids if no improvement after 48 h
		Group B = 60 (31)
Filipponi et al[11] 2004	HCV positive	Group A = 74	Basiliximab + ST (3 mo) + CyA + AZA/basiliximab + CyA + AZA	HCV recurrence, patient survival, graft survival, treatment failure	October 1998-March 2001	Methylprednisolone bolus for 3 d
		Group B = 66
Kato et al[14] 2007	HCV positive	1st Period Group A = 15	1st Period TACRO + daclizumab/TACRO + ST (3 mo)/2nd Period TACRO + daclizumab + MMF/TACRO + ST (3 mo) + MMF	Fibrosis stage, acute rejection, adverse events, predictors	November 1999-November 2001	Methylprednisolone bolus ± taper; OKT3 for severe or treatment-resistant rejection
		Group B = 16/2nd Period Group A = 16
		Group B = 23
Klintmalm et al[16] 2007 (updated by Klintmalm 2011)	HCV positive	Group A = 80	TACRO + ST (3 mo)/TACRO + ST (3 mo) + MMF/daclizumab + TACRO + MMF	Risk factors, rejection, HCV recurrence, treatment failure	NS	Methylprednisolone bolus ± taper; mild rejection increasing tacrolimus ± antimetabolite (MMF or azathioprine) Antilymphocyte antibody for corticosteroid-resistant rejection
		Group B = 79
		Group C = 153
Langrehr et al[18] 2002	HCV positive	Group A = 27	TACRO + ST (3 mo)/TACRO + MMF	Rejection, HCV recurrence	NS	NS
		Group B = 26
Lerut et al[19] 2004 (updated by Lerut 2008)	Adult patients undergoing first OLT	Group A = 50	TACRO + ST (3 mo)/TACRO	Acute rejection, graft survival, adverse events	NS	NS
		Group B = 50
Lladó et al[22] 2006 (updated by Llado 2008)	Adult patients undergoing first OLT	Group A = 102 (45)	Basiliximab + CyA + ST (3 mo)/basiliximab + CyA	Acute rejection, patient survival, graft survival, infection	April 2001-September 2004	Methylprednisolone bolus for 3 d ± taper ± increase in TACRO
		Group B = 96 (43)
Lupo et al[17] 2005 (updated by Lupo 2008)	Adult patients undergoing first OLT	Group A = 20 (9)	CyA + ST (3 mo)/CyA + Basiliximab	Acute rejection	NS	Methylprednisolone bolus for 3 d
		Group B = 21 (11)
Margarit et al[25] 2005	Adult patients undergoing first OLT	Group A = 28 (20)	TACRO/TACRO + ST (3 mo)	Acute rejection, severe acute rejection, HCV recurrence, 3 yr-graft survival	October 1998-September 2000	Increasing tacrolimus dose; methylprednisolone bolus for 3 d ± taper for severe rejection
		Group B = 32 (15)
Moench et al[26] 2007 (updated by Weiler 2010)	Adult patients undergoing first OLT	Group A = 56 (15)	TACRO/TACRO + ST (6 mo)	Patient survival, graft survival, acute rejection, chronic rejection, adverse events	February 2000-August 2004	Methylprednisolone; tacrolimus adjusted higher level
		Group B = 54 (16)
Nashan et al[27] 2001	Adult patients undergoing first OLT	Group A = 25 (15)	Basiliximab + CyA + ST (3 mo)/Basiliximab + CyA + MMF	Rejection, HCV recurrence	January 1999-December 2000	NS
		Group B = 26 (15)
Pageaux et al[30] 2004	Adult patients undergoing first OLT	Group A = 90	Basiliximab + CyA + ST (6 mo)/basiliximab + CyA + placebo	Acute rejection, 6-mo graft and patient survival, treatment failure, recurrent HCV, adverse events	December 1999-August 2001	NS
		Group B = 84
Pelletier et al[31] 2005	Adult patients undergoing first OLT	Group A = 36	TACRO + MMF + ST (3-6 mo)	Rejection, HCV recurrence, graft survival patient survival	June 2002-	Pulse steroids
		Group B = 36	/TACRO + MMF		May 2004
Reggiani et al[33] 2005	Adult patients undergoing first OLT	Group A = 18	TACRO + MMF + ST (3 mo)/TACRO + MMF	Acute rejection, adverse events, pharmacokinetics of MPA	NS	NS/increasing tacrolimus for mild rejection; methylprednisolone bolus 3 d ± taper for moderate rejection; OKT3 for steroid-resistant rejection
		Group B = 12
Samonakis et al[34] 2006	HCV positive	Group A = 27	TACRO/TACRO + ST (3-4 mo) + AZA	Acute rejection, survival, re-transplantation, adverse events	January 2000-January 2004	Methylprednisolone bolus for 3 d
		Group B = 29
Studenik et al[35] 2005	Adult patients undergoing first OLT	Group A = 19	TACRO + daclizumab + ST (3 mo) + MMF/TACRO + daclizumab + MMF	Acute rejection	February 2003-November 2004	NS
		Group B = 20
Tisone et al[37] 1999	Adult patients undergoing first OLT	Group A = 22	CyA + AZA + ST (3 mo)/CyA + AZA	Graft survival, adverse events, HCV recurrence	NS	Methylprednisolone bolus for 3 d only for severe rejection duct damage
		Group B = 23
Varo et al[38] 2005 (updated by Otero 2009)	Adult patients undergoing first OLT	Group A = 79	TACRO + ST (3 mo)/TACRO + daclizumab + MMF	Acute rejection	NS	Up to 3 full courses of high dose steroids
		Group B = 78
Washburn et al[39] 2001	Adult patients undergoing first OLT	Group A = 15	TACRO + MMF + ST (15 mo)/daclizumab + TACRO + MMF	Adverse events, rejection	April 1999-October 1999	Increasing tacrolimus dose; steroid bolus for moderate rejection
		Group B = 15
Manousou et al[24] 2009	HCV positive	Group A = 54	TACRO/TACRO + AZA + ST (3 mo)	Progression to Ishak S4, graft failure resulting in retransplantation or patient death, immunological failure, patient survival, acute rejection, chronic rejection, steroid-resistant rejection, recurrent HCV	January 2000-June 2007	Pulse steroids
		Group B = 49
Ramirez et al[32] 2013	Adult patients undergoing first OLT	Group A = 20	Basiliximab + TACRO + EC-MPS + ST (6 mo)/basiliximab + TACRO + EC-MPS	Patient survival, graft survival, rejection, adverse events	February 2006-November 2007	NS
		Group B = 19
Neumann et al[28] 2012	HCV positive	Group A = 67	TACRO + ST (3 mo)/TACRO + DAC	Viral load of HCV at 12 mo, the incidence of BPAR, patient and graft survival at 12 mo, renal function, adverse events	June 2005- Jun 2008	Increasing tacrolimus dose to trough levels of 15 ng/mL ± pulses of corticosteroids up to 1000 mg/d for 3 consecutive days
		Group B = 68
Takada et al[36] 2013	Living donor liver transplantation HCV positive	Group A = 35	TACRO + ST (3 mo) /TACRO + MMF	Event-free survival: histological recurrence of hepatitis C, BPAR resistant to 2 sets of steroid pulse therapy, hepatocellular carcinoma recurrence, Re-transplantation, Patient death	NS	Pulse steroids
		Group B = 40
Lerut et al[19] 2008	Adult patients undergoing first OLT	Group A = 78	TACRO + ST (64 d)/TACRO	Graft and patient survival, incidences of TAC monotherapy and of low-dosage TAC monotherapy, renal insufficiency, diabetes mellitus, hypercholesterolemia, hyperuricemia, arterial hypertension, infectious, tumor complications, and performance status	February 2000-September 2004	Corticosteroid-sensitive rejection was treated with 3 to 5 oral or IV boluses of 200-mg Methylprednisolone. CRC was treated with a 10-d IV course of muromonab orthoclone OKT3
		Group B = 78
Becker et al[5] 2008	Adult patients undergoing first OLT or split liver allograft transplantation	Group A = 305	TACRO + daclizumab/TACRO + MMF	Rejection, overall survival and allograft survival, renal function	March 2005-June 2007	NS
		Group B = 297
Cholongitas et al[9] 2011	Chronic liver disease	Group A = 36	CyA/TACRO	Death	January 1996-January 1997	Acute rejection was treated with three 1 g/d methylprednisolone
		Group B = 30
		Gerhardt et al[12] 2009					Adult patients undergoing first OLT	Group A = 8	CNI/MMF vs a MMF/prednisone	Renal function	May 2003- May 2005	‘‘mild’’ rejection episodes were treated with steroid boluses Steroid pulse therapy
Group B = 13
Klintmalm et al[15] 2011	HCV positive	Group A = 77	TACRO + ST (3 mo)/TACRO + ST (3 mo) + MMF/daclizumab + TACRO + MMF	Acute rejection, HCV recurrence, survival	NS	ACR was treated with an increase in TACRO to 15 ng/mL without a corticosteroid bolus and recycle. Moderate to severe ACR 4) was treated with a 1.0-g bolus of methylprednisolone, followed by a 6-d steroid taper of intravenous methylprednisolone or oral prednisone
		Group B = 72
		Group C = 146
Lladó et al[21] 2008	HCV positive	Group A = 46	Basiliximab + CyA + ST (3 mo)/basiliximab + CyA	Acute rejection, patient and graft survival, adverse events (infections and metabolic decompensations), HCV recurrence	April 2001-September 2004	Methylprednisolone bolus for 3 d ± taper ± increase in TACRO
		Group B = 43
Lupo et al[23] 2008	Adult patients undergoing first OLT	Group A = 21	CyA + ST (3 mo)/CyA + Basiliximab	Acute rejection, patient and graft survival, HCV recurrence, medical and surgical complications, infections	November 2002-November 2005	Methylprednisolone bolus for 3 d
		Group B = 26
Otero et al[29] 2009	Adult patients undergoing first OLT	Group A = 79	TACRO + ST (3 mo)/TACRO + Daclizumab + MMF	Acute rejection, time to rejection, patient and graft survival, HCV status, hepatic and renal function	May 2002-December 2003	Up to 2 courses of high dose steroids for 3 d Corticosteroid-resistant rejection episode was treated with anti-lymphocyte therapy
		Group B = 78
Weiler et al[40] 2010	Adult patients undergoing first OLT	Group A = 56	All patients TACRO + steroids for the first 2 wk TACRO/TACRO + ST (6 mo)	Patient survival, organ survival, steroid side-effects, acute rejection, chronic rejection, HCV recurrence	February 2000-August 2004	Methylprednisolone; tacrolimus adjusted higher level
		Group B = 54
Junge et al[13] 2005	Recipients with autoimmune hepatitis	Group A = 14	TACRO + steroids/TACRO + MMF	Graft and patient survival, acute rejection, liver functions, glucose metabolism, bone density, blood pressure, renal function, drug-related side-effects, infections	NS	Mild or moderate rejection: methylprednisolone pulse therapy severe rejection: high-dose steroids + monoclonal antibody
		Group B = 16
Bonaccorsi-Riani et al[8] 2012	HCV positive	Group A = 14	TACRO + steroids (2 mo)/TACRO + placebo	1 and 5 yr survival; HCV recurrence, retransplantation, death	NS	NS
		Group B = 21

Numbers within brackets in the third column show the number of hepatitis C virus (HCV) transplanted patients; CyA: Cyclosporine; TACRO: Tacrolimus; ST: Steroids; RATG: Rabbit antithymocyte globulin; AZA: Azathioprine; MMF: Mycophenolate mofetil; OKT3: Murine monoclonal IgG2a antibody; EC-MPS: Enteric-coated mycophenolate sodium; BPAR: Biopsy-proven acute rejection; S4: Stage 4; CRC: Corticosteroid-resistant rejection; OLT: Orthotopic liver transplantation; BPAR: Biopsy proven acute rejection; NS: Non-significance.