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

Table 1 Evidence-based medicine levels of evidence[43]

Level	Therapy/prevention, etiology/harm	Prognosis
1a	SR (with homogeneity1) of RCTs	SR (with homogeneity1) of inception cohort studies; CDR2 validated in different populations
1b	Individual RCT (with narrow Confidence Interval2)	Individual inception cohort study with > 80% follow-up; CDR2 validated in a single population
1c	All or none3	All or none case-series
2a	SR (with homogeneity1) of cohort studies	SR (with homogeneity1) of either retrospective cohort studies or untreated control groups in RCTs
2b	Individual cohort study (including low quality RCT; e.g., < 80% follow-up)	Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR2 or validated on split-sample4 only
2c	"Outcomes" Research; Ecological studies	"Outcomes" research
3a	SR (with homogeneity1) of case-control studies
3b	Individual case-control study

¹A systematic review (SR) that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Studies displaying worrisome heterogeneity should be tagged with a “-” at the end of their designated level;

²Clinical decision rule (CDR) (These are algorithms or scoring systems that lead to a prognostic estimation or a diagnostic category);

³Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but now none die on it;

⁴Split-sample validation is achieved by collecting all the information in a single tranche, and subsequently artificially dividing this into “derivation” and “validation” samples. RCTs: Randomized control trials.

Table 2 Grades of recommendation[43]

A	Consistent level 1 studies
B	Consistent level 2 or 3 studies or extrapolations from level 1 studies
C	Level 4 studies or extrapolations from level 2 or 3 studies
D	Level 5 evidence or troubling inconsistent or inconclusive studies of any level

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.

Table 4 Summary of the strength and quality of the evidence

Intervention	Level of evidence	Degree of recommendation
Studies including adult patients undergoing first OLT for any indication
Steroid replacement results in fewer cases of overall acute rejection in the corticosteroid-free immunosuppression arm	1a-	D
Steroid replacement by daclizumab + MMF results in fewer cases of BPAR at 24 wk in the corticosteroid-free immunosuppression arm	1b	A
Initial steroid administration for two weeks and early tacrolimus monotherapy is a feasible immunosuppression regimen without steroid replacement, although in view of chronic rejections, further investigations are needed	1b	A
Ab initio tacrolimus monotherapy is a viable immunosuppressive approach in liver transplantation and is associated with lower rejection rates compared to microemulsified cyclosporine	2b	B
Renal insufficiency, de novo hypertension, neurological disorders and infectious complications do not differ significantly among steroid and steroid-free groups	1a	B
Diabetes mellitus, cholesterol levels and CMV infection had a higher incidence in the steroid group. The differences in cases of diabetes mellitus and hypercholesterolemia are independent of steroid replacement	1a-	D
Hypertension, thrombocytopenia, renal impairment and overall incidence of infections do not differ significantly among steroid and steroid-free groups (steroids replaced by daclizumab + MMF)	1b	A
Early tapering down of steroids to tacrolimus monotherapy is possible with significantly fewer cases of diabetes and hypercholesterolemia	1b	A
Side-effects related to monotherapy with microemulsified cyclosporine or tacrolimus are comparable	2b	B
Complete corticosteroid avoidance in adult OLT using basiliximab induction with CNI and EC-MPS maintenance is as safe and as effective as standard corticosteroid containing immunosuppression	2b	B
No significant differences were noted between treatment groups in terms of patient and graft survival regardless of steroid replacement	1b	A
Actuarial 5-yr patient and graft survival related to monotherapy with microemulsified cyclosporine or tacrolimus are comparable	2b	B
Steroid withdrawal should be attempted in OLT recipients with underlying autoimmune hepatitis	2b-	D
Which immunosuppression regimen? Both, tacrolimus-based regimens with daclizumab induction or the addition of MMF, allow for avoidance of steroid treatment	1b	A
Studies addressing exclusively transplanted HCV patients
A significant reduction in HCV recurrence independent of steroid replacement may be expected in steroid-free groups	1a-	D
MMF does not appear to have a significant antiviral effect despite early reports	1b	A
Male gender of donors and recipients, living donors, cold ischemia times, acute rejection, and early histological recurrence are related to the development of advanced hepatitis	1b	A
Donor age, grade 2 inflammation at day 90 or one-year liver biopsy and diagnosis of acute hepatitis may be associated with the development of bridging fibrosis or cirrhosis	2b	B

CMV: Cytomegalovirus; MMF: Mycophenolate Mofetil; OLT: Orthotopic liver transplantation; EC-MPS: Enteric-coated mycophenolate sodium; BPAR: Biopsy-proven acute rejection; CNI: Calcineurin inhibitor; HCV: Hepatitis C virus.