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Cytomegalovirus breakthrough and resistance during letermovir prophylaxis

Abstract

Letermovir is a relatively new antiviral for prophylaxis against cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT). CMV-seropositive HCT recipients who received letermovir prophylaxis from 2018 to 2020 at our center were evaluated for letermovir resistance and breakthrough CMV reactivation. Two-hundred twenty-six letermovir recipients were identified and 7/15 (47%) with CMV DNAemia ≥200 IU/mL were successfully genotyped for UL56 resistance. A single C325Y resistance mutation was identified in an umbilical cord blood recipient. Ninety-five (42%), 43 (19%), and 15 (7%) patients had breakthrough CMV at any level, ≥150 IU/mL, and ≥500 IU/mL, respectively. Risk factors for breakthrough CMV reactivation at each viral threshold were examined. Cumulative steroid exposure was the strongest risk factor for CMV at all evaluated viral thresholds. Graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide (aHR 2.34, 95% CI 1.28–4.28, p = 0.001) or calcineurin inhibitors plus mycophenolate (aHR 2.24, 95% CI 1.30–3.86, p = 0.004) were also associated with an increased risk of CMV reactivation at any level. De novo letermovir resistance is rare and can be successfully treated using other antivirals. Letermovir effectively prevents clinically significant CMV, however, subclinical CMV reactivation occurs frequently at our center.

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Fig. 1: Cumulative incidence of CMV reactivation during the first 100 days after HCT.
Fig. 2: Weekly proportion of CMV reactivation during the first 15 weeks after HCT by CMV DNAemia level.
Fig. 3: Cumulative incidence of CMV reactivation during the first 100 days after letermovir initation.
Fig. 4: Clinical course in patient with a mutation in CMV UL56 confering letermovir resistance.
Fig. 5: Multivariable Cox regression of clinical risk factors on time to CMV reactivation during letermovir prophylaxis.

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Acknowledgements

The authors thank Dr. Sunwen Chou for providing mutant UL56 plasmids, Meei-Li Huang for her thoughtful discussion, and recognize Melinda Biernacki as an Amy Strelzer Manasevit Research Program Scholar.

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Contributions

GP, DZ, MB, and AG were responsible for the conception and design of the study. Data and sample collection were performed by GP, DZ, LJS, MAB, and MUO. DZ and HX performed statistical analyses. Data interpretation and literature search were performed by GP and DZ. All authors contributed to the writing and revision of the paper and approved the final version.

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Correspondence to Danniel Zamora.

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Competing interests

All authors report grant support from the NIH (CA15704 and CA078902) and Fred Hutchinson Cancer Center (Fred Hutch) during the conduct of the study. DZ reports additional support from The Joel Meyers Endowment Scholarship and from the NIH (1K23AI163343–01A1). PJM has served on advisory boards or consulted for Neovii Biotech GmbH, Genentech, Enlivex Therapeutics, Mesoblast and Pharmacyclics and has received institutional research funding from AltruBio. PJM provided an invited lecture, sponsored by Janssen, to the 2019 meeting of the Israeli Society of Hematology and Transfusion Medicine; Janssen had no input regarding the content of the lecture. Funding was used solely for travel costs and housing directly related to the meeting; all arrangements were made by a third party, and he did not receive an honorarium. KRJ reports contract testing from Abbott. ALG reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen, Hologic, and research support from Gilead and Merck, outside of the described work. MB has received research support from Astellas, Gilead Sciences, Shire Pharmaceutical (now known as Takeda), and Merck & Co Inc; and personal fees from Merck & Co. Inc., Allovir, and SymBio; and personal fees and nonfinancial support from EvrysBio; all outside of the submitted work. The remaining authors have no additional conflicts of interest to disclose.

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Perchetti, G.A., Biernacki, M.A., Xie, H. et al. Cytomegalovirus breakthrough and resistance during letermovir prophylaxis. Bone Marrow Transplant (2023). https://doi.org/10.1038/s41409-023-01920-w

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