Cytomegalovirus Antiviral Resistance Among Kidney Transplant Recipients in a Phase 3 Trial of Letermovir vs Valganciclovir Prophylaxis.
Strizki, J. M., et al.Journal of Infectious Diseases 2024; 230(6): e1287-e1298.
Aims
The aim of this analysis of a phase-3 randomised controlled trial was to characterise antiviral resistance and cytomegalovirus (CMV) glycoprotein B (gB) genotype from plasma samples with detectable CMV DNA.
Interventions
Participants in the original trial were randomised to receive either letermovir or valganciclovir.
Participants
589 kidney transplant recipients that are CMV-seronegative (R−) and receive kidneys from donors who are CMV-seropositive (D+).
Outcomes
Genotyping for antiviral resistance and CMV gB.
Follow-up
52 weeks posttransplant
CET Conclusions
Letermovir is an FDA-approved agent for CMV prophylaxis in kidney transplant recipients (KTR) and is an alternative to valganciclovir as it is less prone to cause leukopaenia. Letermovir has a target of action distinct from other CMV antivirals. Resistance-associated amino acid substitutions (RAS) occur with valganciclovir use and although not routinely assessed, are well characterised. This study sought to characterise the RAS’s associated with Letermovir and compare to those that occur with valganciclovir therapy. 589 KTRs (recipient negative, donor positive) were randomised to either valganciclovir or letermovir prophylaxis for 52 weeks. RAS were assessed at multiple timepoints. 15 patients had valganciclovir RASs (12 in the valganciclovir group, 3 in the letermovir group) and no letermovir associated RASs. The authors suggest that this data support a strategy where using letermovir as prophylaxis would prevent the development of valganciclovir RASs, allowing valganciclovir to be used for treatment, should CMV infection occur. However, in this study, most of the patients who were found to have valganciclovir RASs had a complete response to treatment-dose valganciclovir. The clinical utility of these findings is thus not clear, and likely determined by more complex interactions than is evaluated in this study.
Trial registration
ClinicalTrials.gov - NCT03443869; EudraCT - 2017-001055-30.