Low level drug resistance linked to cytomegalovirus UL97 and UL27 mutations detected in maribavir clinical trials.

Cytomegalovirus genetic variants of indeterminate significance reported as supplementary findings in two Phase 3 maribavir clinical trials were evaluated for their effects on antiviral drug susceptibility after transfer into baseline viral strains. Among 8 UL97 kinase variants tested, none were found to confer maribavir resistance, while amino acid substitution G598A conferred borderline ganciclovir resistance (1.9-fold increased 50% effective concentration [EC50]) and K599N did not (1.1-fold). These codons do not appear to be important loci of resistance substitutions as compared with others in the 590-607 range, such as C592G, A594V, L595 S/F and C603W. Among 3 new UL27 variants tested, L317V was found to confer 2-fold increased maribavir EC50, the same increase as a previously published UL27 L193F. Both resistant UL27 mutants were observed in connection with maribavir treatment failure, but L317V differs in being detected as an emergent mutation after 29 days of therapy rather than at baseline. The clinical significance of baseline and emergent UL27 mutations for maribavir therapy requires further surveillance.