Cytomegalovirus DNA Doubling Time for Early Identification of Clinically Significant Infection Episodes in Allogeneic Hematopoietic Stem Cell Transplant Recipients Undergoing Primary Letermovir Prophylaxis: A Multicenter Study

Abstract

Background: Letermovir (LMV) prophylaxis currently represents the first-line strategy for preventing clinically significant cytomegalovirus (CMV) infection (CsCMVi) in CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A wide variety of CMV DNA thresholds for LMV interruption and preemptive antiviral therapy (PET) inception are in place across transplantation centers.

Methods: We evaluated the potential of CMV DNA doubling time (dt) in plasma to distinguish between CsCMVi and abortive CMV infection in allo-HSCT recipients on primary LMV prophylaxis. Data from the Spanish Hematopoietic Transplantation and Cell Therapy Group multicenter registry included 296 allo-HSCT patients receiving LMV prophylaxis. Participating centers used a plasma CMV DNA threshold of ≥1000 IU/mL for initiating PET. The CMV DNA dt was calculated from the first two or three positive polymerase chain reaction (PCR) results based on pre-established criteria.

Results: CMV DNAemia developed in 64 recipients (21.6%) with a total of 88 episodes, of which CsCMVi occurred in 9 recipients (3.04%) and included 10 episodes (one patient had confirmed CMV gastrointestinal disease). A non-calculable CMV DNA dt had a negative predictive value of 94% for CsCMVi. For initial episodes with calculable CMV DNA dts (4/7 CsCMVi and 8/57 no-CsCMVi), a threshold of >2.35 days had a specificity of 100% for ruling out CsCMVi.

Conclusion: CMV DNA dt could optimize CMV infection management in allo-HSCT patients under LMV prophylaxis, independent of the PCR platform used.

Keywords: CMV DNA doubling time; PCR; clinically significant CMV infection; cytomegalovirus; letermovir prophylaxis; preemptive antiviral therapy; “abortive” infection.