Background: Letermovir (LMV), a CMV-specific terminase inhibitor, is recommended for cytomegalovirus (CMV) prophylaxis in CMV-seropositive allogeneic hematopoietic stem cell transplant (alloHSCT) recipients. The association between low-level CMV DNAemia during prophylaxis and the emergence of mutations in CMV terminase complex genes remains unclear. Methods: We retrospectively analyzed 127 alloHSCT recipients at Saint-Louis Hospital, Paris, receiving LMV prophylaxis (108 primary, 24 secondary, 5 both). Weekly CMV DNAemia monitoring was performed, and samples with viral loads ≥3 log IU/mL underwent whole-genome next-generation sequencing to detect mutations in terminase complex genes. Results: During LMV prophylaxis, CMV DNAemia was detected in 31.5% of primary and 62.5% of secondary prophylaxis patients; however, viral loads ≥3 log IU/mL remained low in both groups (8.3%). The frequency of polymorphisms in terminase complex genes increased 2.5-fold during prophylaxis compared with pre-prophylaxis, and then decreased 3.0-fold after prophylaxis withdrawal. Confirmed LMV resistance was found in two patients, representing 1.6% of all patients and 18.2% of those with CMV DNAemia ≥ 3 log IU/mL. Two additional patients harbored mutations at resistance-associated positions in UL56 and UL89, totaling 36% of patients with viral loads ≥3 log IU/mL displaying mutations at known resistance sites. Clinically significant CMV infections were successfully managed with preemptive therapies. Conclusions: This study confirms the efficacy of LMV prophylaxis and demonstrates that LMV exerts selective pressure on the terminase complex, increasing the risk of resistance when CMV DNA levels exceed 3 log IU/mL, underscoring the importance of timely consideration of alternative antiviral therapies when CMV replication persists.

Background: Accurate prediction of SARS-CoV-2 severity remains a challenge. Torque Teno Virus (TTV), recognized as a surrogate marker for cellular immunity in solid organ transplant recipients, holds potential for assessing infection outcomes. Objectives: We investigated whether quantifying TTV in nasopharyngeal samples upon emergency ward (ED) admission could serve as an early predictor of SARS-CoV-2 severity. Study design: Retrospective single-center study in the ED of Saint-Louis Hospital in Paris, France. TTV DNA was quantified in nasopharyngeal swab samples collected for SARS-CoV-2 testing. Results: Among 295 SARS-CoV-2 infected patients, 92 returned home, 160 were admitted to medical wards, and 43 to the intensive care unit. Among 295 SARS-CoV-2 patients, 92 were discharged, 160 hospitalized, and 43 admitted to the intensive care unit (ICU). Elevated TTV loads were observed in ICU patients (Median: 3.02 log copies/mL, interquartile range [IQR]: 2.215-3.825), exceeding those in discharged (2.215, [0; 2.962]) or hospitalized patients (2.24, [0; 3.29]) (p=0.006). Multivariate analysis identified diabetes, obesity, hepatitis, fever, dyspnea, oxygen requirement, and TTV load as predictors of ICU admission. A 2.91 log 10 copies/mL TTV threshold independently predicted ICU admission. Conclusion: Nasopharyngeal TTV quantification in SARS-CoV-2 infected patients is linked to the likelihood of ICU admission and might reflect respiratory immunosuppression.