Belatacept and the Risk of Cytomegalovirus, BK Polyomavirus, and Epstein-Barr Virus Post-transplant Lymphoproliferative Disease After Kidney Transplantation: A Meta-Analysis and Systematic Review.

BACKGROUND

The long-term risk of cytomegalovirus (CMV), Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD), and BK viral infections from belatacept is unclear. This review aimed to evaluate these outcomes.

METHODS

Several databases were reviewed from inception through September 2025 using the keywords "belatacept" and "kidney transplant" or "safety" and "viral infection". We included case reports, randomized controlled trials (RCTs), and nonrandomized trials (NRTs). Outcomes were prespecified according to dose (more-intense or less-intense), type of infection (CMV, EBV-PTLD, or BK), and follow-up period: short term (1-2 years), medium term (3-5 years), and long-term (> 5 years). RCTs and NRTs were analyzed separately, and case reports were summarized. For binary outcomes, results were presented as risk ratios (RR), with 95% confidence intervals (CI). All statistical analyses were performed using Revman 5.2.

RESULTS

Sixty-four studies (23 RCTs, 28 NRTs, and 13 case reports) were included. Of 23 RCTs, 11 were primary studies while the remainder were follow-up reports of original RCTs. Most NRTs (16/28) included a comparator arm. In the meta-analyses of RCTs only, the risks of CMV, EBV-PTLD, and BK virus infection were similar between patients receiving belatacept and those receiving calcineurin inhibitors (CNIs). During medium-term follow-up for RCTs, BK virus infection was twice as likely among those receiving more-intense compared to less-intense belatacept (RR: 2.08 [CI 1.03, 4.20, I 2 = 0]). Among NRTs, the risk of CMV infection was two-fold higher among those receiving belatacept versus CNI, with an RR of 2.15 [CI 1.58, 2.93, I 2 = 66%]; BK DNAemia or viremia was also greater than two-fold higher, with an RR of 2.59 [CI 1.10-6.11].

CONCLUSIONS

The risks of CMV and EBV-PTLD after kidney transplantation were not significantly increased by belatacept based on RCTs, though a higher risk of BK polyomavirus infection was observed among patients receiving a more-intense dose of belatacept beyond the second year. The risk of CMV and BK polyomavirus infections may also be increased with real-world belatacept use. However, these observations should be interpreted with consideration for the inherent limitations of NRTs.