De Novo Letermovir for Primary Cytomegalovirus Prophylaxis in Seropositive Kidney Transplant Recipients Improves Tolerance and Maintains Higher Mycophenolate Doses at 12 Months

Background: Letermovir (LTV) is indicated for cytomegalovirus (CMV) prophylaxis in high-risk KT recipients (KTRs), providing an alternative to the standard-of-care valganciclovir (VGC) with static renal dosing, reduced toxicity and comparable efficacy. Use in CMV seropositive (R+) KTRs has not been described. Methods: Adult R+ KTRs transplanted between 6/1/2021-4/30/2024 were evaluated based on de novo antiviral agent utilization (historical VGC vs current LTV). The primary objective was comparable efficacy and tolerability. Results: 391 KTRs met inclusion criteria: 315 received VGC and 76 received LTV. Cohorts were comparable; the majority received a primary transplant (84.8% vs 90.8%, p=0.58) from a deceased donor (69.4% vs 67.1%, p=0.608) with lymphocyte depletion (82.9% vs 90.8%, p=0.21). 61.3% of patients in the VGC cohort required 1+ renal dose modification; 43.5% required two or more. KRTs on LTV were more likely to complete antiviral prophylaxis (63.2% vs 84.2%, p<0.001). The most common reason for prophylaxis termination in the VGC cohort was intolerance (85.3%), which was uncommon in the LTV cohort (3.9%). Mean time to termination in the VGC cohort was 95 days (p=0.009). Prophylaxis failure occurred infrequently in the VGC cohort (0.6%) and did not occur in the LTV cohort. Leukopenia (WBC<3.0x103 cells/mm3) was more common in the VGC cohort (68.9% vs 56.6%, p=0.41) with earlier time to first event (86 vs 129 days, p=0.027). Significantly fewer patients in the LTV cohort had ANC<1000 cells/µL (34.9% vs 11.8%, p<0.001) or required GCSF (17.8% vs 5.3%, p=0.007). At 12 months, more patients in the LTV cohort were on >1000 mg mycophenolate/day (57.5% vs 72.4%, p=0.017). CMV viremia through 12 months occurred at similar rates (15.9% vs 9.2%, p=0.140). No differences in allograft function, rejection or death at 12 months were observed. Conclusion: De novo LTV in R+ KTRs appears to be safe and effective. This study suggests antiviral prophylaxis is more likely to be successfully completed with LTV and is associated with less myelosuppression, permitting higher mycophenolate doses at 12 months and avoiding corrective healthcare resource utilization.