Belatacept in renal transplantation in comparison to tacrolimus and molecular understanding of resistance pattern: Meta-analysis and systematic review

Table 1 Criteria for the inclusion of studies

Type
Study design	Prospective cohort design with a well-defined study population
Study group	Post renal transplant
Study size	Any
Length of follow-up	Any
Source	Peer-reviewed journals
Language	English
Outcome measure	Renal function, patient safety, adverse events, and graft functioning and survival

Table 2 Characteristics of included studies

Ref.	Study design	Donor type	Belatacept based (group 1)	Tacrolimus based (group 2)	Belatacept based (group 3)
Ferguson et al[33], 2011	Multicentre, prospective, randomized (93 patients, 1 yr)	Living and deceased	Belatacept 10 mg/kg on day 1 and 5, then once every 2 wk through 3 mo, every 4 wk through 6 mo and 5 mg/kg from 7 mo onwards; MMF: 1 mg twice daily; Induction: Thymoglobulin + Corticosterids	Tac 0.2 mg/kg divided into two doses; Tac 0.2 mg/kg divided into two doses; Induction: Thymoglobulin + Corticosterids	Belatacept 10 mg/kg on day 1 and 5, then once every 2 wk through 3 mo, every 4 wk through 6 mo and 5 mg/kg from 7 mo onwards; SRL initiated on day 1 and dose level 7-12 ng/mL. Induction: Thymoglobulin + Corticosterids
de Graav et al[34], 2017	Single centre, prospective, randomized (40 patients, 1 yr)	Living	Belatacept 10 mg/kg on day 0, 4, 15, 30, 60, 90 d of transplant, following that 5 mg/kg till 12 mo	Tac 0.2 mg/kg divided into two doses. Target concentration 10 to 15 ng/mL (week 1-2); 8 to 12 ng/mL (week 3-4); 5-10 ng/mL (week > 5)	NA
Newell et al[35], 2017	Multicentre, prospective, randomized (19 patients, 1 yr)	Living and deceased	Belatacept 10 mg/kg on day 0 (day of transplant) and then on days 4, 14, 28, 56, and 84. After day 84, participants received a maintenance dose of 5 mg/kg every 4 wk until completion of the trial; MMF: 1 mg twice daily; Induction: Thymoglobulin, rapid methylprednisolone taper	Tac 0.1 mg/kg divided into two doses; Target concentration8 to 12 ng/mL (week 24), then 5 to 8 ng/mL (week > 24); MMF: 1 mg twice daily; Induction: Thymoglobulin, rapid methylprednisolone taper	Belatacept 10 mg/kg on day 0 (day of transplant) and then on days 4, 14, 28, 56, and 84. After day 84, participants received a maintenance dose of 5 mg/kg every 4 wk. Tac 0.1 mg/kg divided into two doses then adjusted to target trough levels: 8-12 ng/mL by Day 29, 5-8 ng/mL by Day 57, 3-5 ng/mL by Day 85 then stopped. MMF: 1 mg twice daily; Tac: 5 to 8 ng/mL (till 24 wk); Induction: Basiliximab + Corticosteroids
Trial 1856257[36], 2017	Multicentre, prospective, randomized (69 patients, 1 yr)	Living and deceased	Belatacept 10 mg/kg on day 1 (24 h of transplant) and then on days 5, 14, 28, 56, and 84. MMF: 1 mg twice daily; Induction: Thymoglobulin + Corticosteroids	Tac started on day 0/1; Target concentration 8 to 12 ng/mL (week 24), then 5 to 8 ng/mL (week > 24); MMF: 1 mg twice daily; Induction: Thymoglobulin + Corticosteroids	Belatacept 10 mg/kg on day 1 (24 h of transplant) and then on days 5, 14, 28, 56, and 84. Tac started on day 0/1; Target concentration 8 to 12 ng/mL (day 1-84) and then decreased by 1/3 at day 84 and by 1/3 at week 16. If trough levels were less than or equal to 3 ng/mL at week 20 then all tac was stopped. Otherwise, the dose was reduced by 1/2 and stopped at week 24. MMF: 1 mg twice daily; Induction: Basiliximab + Corticosteroids + Tac

MMF: Mycofenolate mofetil; NA: Not applicable; SRL: Sirolimus; Tac: Tacrolimus.

Table 3 Summary of outcomes in clinical trials

Ref.	Renal function (Gp 1 vs Gp 2)	BPAR (Gp 1 vs Gp 2)	Adverse event (Gp1 or vs Gp 2)	Remarks
Ferguson et al[33], 2011	12 mo; Sr. Cr: NA; eGFR: 63.6 ± 27.27 vs 54.0 ± 14.95 mL/min; (P = 0.14)	15.2% (5/33) vs 3.3% (1/30) (P = 0.24)	SAE/Infection: 57.5% (19/33) vs 53.3% (16/30); (P = 0.007); CMV infection: 3.0% (1/33) vs 3.3% (1/30) (P = 0.96); BK infection: 6.0% (2/33) vs 3.3% (1/30) (P = 0.59); NODAT: 0% (0/33) vs 3.3% (1/30) (P = 0.47)	Graft survival: 93.93% (31/33) vs 100% (30/30) (P = 0.51); Patient survival 93.93% (31/33) vs 100% (30/30) (P = 0.51)
de Graav et al[34], 2017	12 mo; Sr. Cr: 133.5 ± 39.26 vs 127.5 ± 28.87 μmol/L (P = 0.80); eGFR: 56.25 ± 17.61 vs 54.25 ± 14.73 mL/min (P = 0.57)	55% (11/20) vs 10% (2/20) (P = 0.006)	SAE/Infection: 10.25 ± 4.18 vs 11.90 ± 5.43 (P = 0.41); CMV infection: 10% (2/20) vs 5% (1/20) (P = 0.96); BK infection: 5% (1/20) vs 3.3% (2/20) (P = 0.54); NODAT: 5% (1/20) vs 35% (7/20) (P = 0.04)	Graft survival: 85% (17/20) vs 100% (20/20) (P = 0.22); Patient Survival 100% (20/20) vs 95% (19/20) (P = 0.31)
Newell et al[35], 2017	12 mo; Sr Cr: NA; eGFR: 51.6 ± 23.5 vs 55.9 ± 8.9 mL/min (P = 0.74)	33.3% (2/6) vs 50% (3/6) (P = 0.55)	SAE/Infection: 33.3% (2/6) vs 33.3% (2/6) (P = 1.0); CMV infection: 0% (0/6) vs 16.6% (1/6) (P = 0.29); BK infection: 0% (0/6) vs 0% (0/6) (P = 1.00); NODAT: 0% (0/6) vs 0% (0/6) (P = 1.00)	Graft survival: 50% (3/6) vs 83.33% (5/6) (P = 0.85); Patient survival 100% (6/6) vs 83.33% (5/6) (P = 0.29)
Clinicaltrial.gov 1856257[36], 2017	12 mo, Sr. Cr: NA, eGFR: 61.5 ± 23.3 vs 59.2 ± 19.9 mL/min (P = 0.70)	37.9% (11/29) vs 6.8% (2/29) (P = 0.009)	SAE/Infection: 72.41% (21/29) vs 65.5% (19/29) (P = 0.77); CMV infection: 20.6% (6/29) vs 3.4% (1/29) (P = 1.0); BK infection: 13.7% (4/29) vs 0% (0/29) (P = 0.11); NODAT: 3.4% (1/29) vs 3.4% (1/29) (P = 1.0)	Graft survival: 93.1% (27/29) vs 100% (29/29) (P = 0.49); Patient survival: 93.1% (27/29) vs 100% (29/29) (P = 0.49)

CMV: Cytomegalovirus; eGFR: Estimated glomerular filtration rate; Gp: Group; SAE: Serious adverse experiences; Sr Cr: Serum creatinine; NODAT: New onset diabetes mellitus after transplantation.

Table 4 Summary of biopsy proven acute rejection in clinical trials

Ref.	IA		IB		IIA		IIB		III		Mixed
	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)
Ferguson et al[33], 2011	0	0	0	0	3	0	2	1	0	0
de Graav et al[34], 2017	0	0	1	1	2	1	6	0	1	0	1	0
Newell et al[35], 2017	1	0	0	0	0	0	1	0	0	0			1	0
Clinicaltrial.gov 1856257[36], 2017	3	0	1	1	4	0	0	0	2	0			1	1

BPAR: Biopsy proven acute rejection; Gp: Group; AMR: Antibody mediated rejection.

Table 5 Summary of metabolic outcomes in clinical trials

Parameters	Ferguson et al[33], 2011 (25)		de Graav et al[34], 2017		Newell et al[35], 2017 (27)		Clinicaltrial.gov 1856257, 2017 (28)
	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)	Gp1 (Belatacept)	Gp2 (Tacrolimus)
Total CH, Mean (SD) (mg/dL)	NA	NA	193.34 ± 42.43	187.41 ± 42.28	187.0	156.0 ± 30.4	163.7 ± 38.8	177.1 ± 25.6
Total TG, Mean (SD) (mg/dL)	NA	NA	194.86 ± 51.14	221 ± 127.87	187.0	319.3 ± 294.0	170.0 ± 118.6	125.8 ± 93.0
LDL, Mean (SD) (mg/dL)	NA	NA	64.78 ± 30.20	96.67 ± 55.84	114.0	69.5 ± 38.0	86.3 ± 50.6	102.9 ± 17.7
BP mm/Hg (SBP/DBP) (12 mo)	129.3 ± 19.24/73.3 ± 11.96	138.2 ± 19.50/77.6 ± 10.51	141.25 ± 14.75/74 .25 ± 8.75	142.5 ± 17.31/78.0 ± 13.0	146.7 ± 5.1/92.7 ± 9.8	147.5 ± 18.7/80.8 ± 12.8	133.7 ± 14.7/79.1 ± 10.2	135.0 ± 18.9/77.7 ± 10.9

Lipid parameters represented in mean change from baseline to month 12 post transplantation.