*Purpose: Cytomegalovirus (CMV) poses a significant concern in the post-operative management of lung transplant (LT) recipients. Current recommended prophylactic strategies with ganciclovir (GCV) or valganciclovir (VGC) can be complicated by myelosuppressive adverse effects. Letermovir may be utilized as an alternative agent for CMV prophylaxis, although clinical data is limited in LT. The purpose of this study is to compare the incidence of breakthrough CMV viremia between letermovir and VGC/GCV at our institution.

*Methods: This single-center, retrospective study included all recipients of LT at our institution from January 1, 2016 to September 30, 2021. The primary outcome was incidence of breakthrough CMV viremia defined as any detectable viral load while on universal prophylaxis. Secondary outcomes included adjustments to maintenance immunosuppression, development of donor-specific antibodies (DSA), and biopsy proven acute rejection (BPAR).

*Results: A total of 34 LT recipients were included and received CMV prophylaxis with letermovir (n=8) or VGC/GCV (n=26). Standard immunosuppressive therapy included basiliximab induction and triple maintenance immunosuppression. The primary indication for transitioning prophylaxis to letermovir was leukopenia or thrombocytopenia. Median time from LT to letermovir initiation was 100.5 days (range: 82-499 days). A detectable viral load developed in four (50%) letermovir patients and five (19%) VGC/GCV patients. No patient required treatment for CMV disease after transitioning to letermovir. Eight patients receiving letermovir previously required suspension of their antimetabolite; four of these patients were successfully re-challenged. Development of DSA occurred in three (38%) letermovir patients and four (15%) VGC/GCV patients. Incidence of BPAR was similar between groups. Data collection and statistical analysis are ongoing.

*Conclusions: At our institution, universal prophylaxis with letermovir was associated with a higher incidence of low-level viremia compared to standard prophylaxis, however, no letermovir patients required escalation for CMV treatment. An antimetabolite was successfully reinitiated in a proportion of patients previously requiring antimetabolite cessation prior to letermovir initiation. Preliminary results indicate a comparable incidence of rejection at 6 months post-transplant.

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