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

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