A new locus of foscarnet resistance in the cytomegalovirus UL54 DNA polymerase gene among uncharacterized mutations in recent clinical trials.

In two recent Phase 3 clinical trials of maribavir that also involved existing standard therapies, many uncharacterized cytomegalovirus UL54 DNA polymerase genetic variants were encountered. Six UL54 mutations were selected for phenotyping, based on proximity to published resistance loci and quality of sequencing information. UL54 amino acid substitutions E949K and E949Q conferred foscarnet resistance with slightly decreased ganciclovir and cidofovir susceptibility, representing a novel palm domain resistance locus. UL54 N498S and P598S mutants had slight decreases in ganciclovir and cidofovir susceptibility, with N498S also having a slightly decreased foscarnet susceptibility. No drug resistance was attributed to A786V and A928V. Retesting published phenotypes for UL54 mutants D515E, D542E, A543V and A928T revealed some discordant findings, including ganciclovir resistance for D542E and A543V, and no drug resistance for D515E and A928T. These genotype-phenotype correlations add to the evidence base for clinical diagnostic testing of cytomegalovirus drug resistance.