Beyond valganciclovir: A meta-analysis of letermovir’s safety and efficacy in cytomegalovirus prophylaxis after solid organ transplantation

Cytomegalovirus (CMV) remains a major infectious cause of morbidity and graft dysfunction after solid organ transplantation (SOT). Valganciclovir (VGC) is effective for CMV prophylaxis but limited by myelotoxicity. Letermovir (LTV), a CMV terminase complex inhibitor, offers a non-myelosuppressive alternative. This meta-analysis evaluated the efficacy and safety of LTV versus VGC for CMV primary prophylaxis in SOT recipients. A systematic search of PubMed, Embase, and the Cochrane Library through October 2025 identified comparative studies of LTV and VGC in adult SOT recipients. Random-effects meta-analyses using the Mantel–Haenszel method estimated relative risks (RRs) with 95% confidence intervals (CIs). Primary endpoints were CMV disease and CMV DNAaemia during prophylaxis; secondary endpoints included post-prophylaxis CMV infection, haematologic toxicity, graft outcomes, and mortality. Six studies involving 1,413 recipients (526 LTV; 887 VGC) were included. LTV significantly reduced CMV DNAaemia during prophylaxis (RR = 0.33, 95% CI 0.18–0.59; I² = 0%), with comparable CMV disease incidence (RR = 0.87, 95% CI 0.41–1.88). Post-prophylaxis CMV infection, graft rejection, graft loss, and mortality were similar between groups. LTV showed numerically lower rates of neutropenia, leukopenia, and G-CSF use, reflecting improved haematologic safety, although between-study heterogeneity was substantial. Letermovir provides comparable antiviral efficacy to valganciclovir for CMV prophylaxis in SOT recipients. While trends toward improved haematologic tolerability were observed, current evidence remains limited and predominantly observational. Larger multicentre randomized trials are warranted to confirm long-term efficacy and safety across organ types. The meta-analysis protocol registered with PROSPERO ID; CRD420251178234.