*Purpose: Cytomegalovirus (CMV) commonly affects thoracic solid organ transplant (SOT) recipients, and standard antiviral therapies are limited by myelosuppression, renal dysfunction, and emergence of resistance. Letermovir (LTV) is approved for CMV prevention in hematopoietic cell transplantation, but data supporting its use in thoracic SOT are lacking.

*Methods: We analyzed data from all adult thoracic SOT recipients at our transplant center who received LTV for CMV prophylaxis or treatment from 1/2018 through 10/2019. We examined patient characteristics, immunosuppression and rejection episodes, LTV use, and clinical outcomes.

*Results: Forty-six patients received 48 episodes of LTV, including 39 lung transplants, 6 heart transplants, and 1 combined liver-lung SOT recipient. CMV mismatch (27/48, 56%) and rejection within 6 months prior to LTV initiation (22/48, 46%) were common. Basiliximab induction was used most commonly (44/48, 92%), and at time of initiation of LTV, patients were receiving a median of 2 immunosuppressants (range, 2-4), including steroids (n=48), calcineurin inhibitors (n=47, tacrolimus 79%), mycophenolate (n=14) and azathioprine (n=5). In 8 LTV episodes (17%), anti-thymocyte globulin or alemtuzumab were administered within 6-months and 1-year prior to LTV initiation, respectively. LTV was initiated for primary (30/48, 63%) and secondary prophylaxis (12/48, 25%), as well as treatment (6/48, 12%; CMV viremia [n=2] and retinitis [n=4]). The primary rationale for LTV use was cytopenias (35/48, 73%) and viral resistance (12/48, 25%).

LTV was initiated a median of 596 days (IQR, 227-1091 days) post-SOT. Dosing ranged from 240 mg/day to 960 mg/day with a median duration of therapy of 180 days (IQR, 93-277 days), including 28 (58%) LTV episodes which were ongoing at the study conclusion. Transient CMV viremia (range, detectable <137 to 300 IU/mL) occurred in 15/42 (36%) LTV prophylaxis episodes; however, therapy was continued without prophylaxis failure or documented LTV resistance. Conversely, 3/6 (50%) LTV treatment episodes (for CMV retinitis) failed to maintain virologic suppression despite clinical improvement, including 2 episodes of genotypically confirmed LTV resistance (UL56 mutations C325F and C325Y). LTV prophylaxis was discontinued in 5/42 (12%) LTV prophylaxis episodes due to adverse effects, including worsening cytopenias (n=2), fatigue with confusion or lightheadedness (n=2), and nausea (n=1). No adverse effects were documented in LTV treatment episodes.

*Conclusions: In our cohort of thoracic SOT recipients, LTV provided effective primary and secondary prophylaxis against CMV and was well tolerated. However, caution is advised when using LTV for CMV treatment given risk for clinical failure and resistance emergence. Further study is warranted to determine the safety and efficacy of LTV for CMV treatment and prevention in SOT.

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