Emergence and Persistence of Letermovir-Resistant Cytomegalovirus in a Patient With Primary Immunodeficiency

Stephanie Popping; Virgil A S H Dalm; Nadine Lübke; Veronica di Cristanziano; Rolf Kaiser; Charles A B Boucher; Jeroen J A Van Kampen

doi:10.1093/ofid/ofz375

Emergence and Persistence of Letermovir-Resistant Cytomegalovirus in a Patient With Primary Immunodeficiency

Open Forum Infect Dis. 2019 Aug 23;6(9):ofz375. doi: 10.1093/ofid/ofz375. eCollection 2019 Sep.

Authors

Stephanie Popping¹, Virgil A S H Dalm^{2

3}, Nadine Lübke⁴, Veronica di Cristanziano⁵, Rolf Kaiser⁵, Charles A B Boucher¹, Jeroen J A Van Kampen¹

Affiliations

¹ Department of Viroscience, Rotterdam, The Netherlands.
² Department of Internal Medicine, Division of Clinical Immunology, Rotterdam, The Netherlands.
³ Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁴ Institute of Virology, Heinrich-Heine-University, University Hospital, Düsseldorf, Germany.
⁵ Institute of Virology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.

Abstract

Background: Letermovir is a novel cytomegalovirus antiviral that is approved for prophylaxis in hematopoietic stem cell transplantation recipients.

Methods: After obtaining informed consent, letermovir prophylaxis was started in a patient with a presumed late-onset primary, combined T- and B-cell immunodeficiency. Plasma CMV DNAemia was monitored with real-time polymerase chain reaction, and letermovir resistance analyses were performed using Sanger sequencing and Illumina MiSeq next-generation sequencing.

Results: A letermovir-resistant cytomegalovirus variant (C325Y mutation in UL56) emerged 17 weeks after start of prophylaxis. The letermovir-resistant variant was able to reactivate without drug selective pressure as this variant was again detected in plasma 20.6 weeks after stopping of letermovir.

Conclusions: This case indicates that the C325Y mutation in UL56 does not significantly alter fitness of cytomegalovirus in vivo.

Keywords: letermovir; resistance; viral fitness.