Cytomegalovirus Antiviral Resistance Among Kidney Transplant Recipients in a Phase 3 Trial of Letermovir vs Valganciclovir Prophylaxis

In a phase 3 trial, letermovir was noninferior to valganciclovir for cytomegalovirus (CMV) disease prophylaxis in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive. Genotypic antiviral resistance and CMV glycoprotein B (gB) genotype are reported. Plasma samples with detectable CMV DNA were sequenced for the presence of known letermovir and valganciclovir resistance-associated amino acid substitutions (RASs) encoded by CMV gene regions (UL51, UL54, UL56, UL89, UL97) and prevalence of gB (UL55) genotypes (gB1-gB5). Among participants, 84 of 292 (letermovir) and 93 of 297 (valganciclovir) had evaluable data for ≥1 gene target. Letermovir RASs were not detected in participants who received letermovir prophylaxis; however, 3 had valganciclovir RASs (pUL97). Twelve participants who received valganciclovir prophylaxis had valganciclovir RASs (pUL54, pUL97), and 1 who did not receive letermovir during the trial had letermovir RASs (pUL56). All but 1 participant responded to valganciclovir treatment irrespective of breakthrough CMV DNAemia or frequency of RASs. gB1 was the most frequent genotype across all participants and subgroups. Letermovir RASs were not detected with letermovir prophylaxis, supporting a low risk for development of resistance in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive. ClinicalTrials.gov, NCT03443869; EudraCT, 2017-001055-30.