Letermovir in Refractory and Resistant CMV After Lung Transplantation: Therapeutic Potential and Emergence of Resistance

ABSTRACT Background Cytomegalovirus (CMV) infection remains a major challenge in lung transplant (LTx) recipients, particularly in antiviral‐resistant or refractory (R/R) cases. Letermovir, effective for prophylaxis, has been used off‐label as salvage therapy for R/R CMV infection; however, data on treatment‐emergent resistance in LTx recipients remain limited. Methods We retrospectively analyzed 61 consecutive LTx recipients treated with letermovir for R/R CMV infection between March 2018 and August 2024. Results Overall, 21 patients (35%) developed R/R CMV under therapy and were genotypically tested; in 19 (31.1%), UL56 mutations conferring letermovir resistance were detected after a median of 96 [51–395] days. In contrast, 40 patients (65.6%) showed a > 1 log decline in viral load within 14.5 [5–31] days and viral clearance after 34 [6–126] days. Patients who developed resistance had significantly higher viral loads at initiation (35.100 [13.900–228.000] vs. 7.805 [1.173–30.350] IU/mL; p = 0.018) and less frequent positive CMV‐specific immune responses (7.1% vs. 38.7%; p = 0.038). Time to 1 log decline was shorter in patients without resistance (16 [5–31] vs. 34 [17–58] days; p < 0.001). Multivariable regression identified slow viral load decline (OR 0.721; p < 0.001) and higher baseline viral load (OR 1.110; p = 0.044) as independent risk factors. Conclusion Letermovir use for active R/R CMV infection was associated with treatment‐emergent resistance in approximately one‐third of patients, particularly in those with high baseline viral loads and delayed virological response. These findings support cautious use of letermovir for treatment, preferably in selected patients with low viral loads or limited alternative therapeutic options, with close virological monitoring and early resistance testing. image