Development of new cytomegalovirus UL97 and DNA polymerase mutations conferring drug resistance after valganciclovir therapy in allogeneic stem cell recipients

Background: We report on two allogeneic stem cell transplant recipients who developed cytomegalovirus disease associated with new viral mutations that conferred antiviral drug resistance. Methods: Blood specimens obtained during symptomatic disease were analyzed for mutations in the CMV UL97 and DNA polymerase genes and new mutations were assessed by recombinant phenotyping. Results: Rising cytomegalovirus (CMV) antigenemia occurred after 4-5 months of preemptive valganciclovir therapy, followed by symptomatic CMV disease including fatal pneumonia in one case. In one case, a new viral UL97 mutation (deletion of codons 601-603) was found which conferred 15-fold increased ganciclovir resistance. In the other case, a known UL97 resistance mutation M460V and a new DNA polymerase (pol) mutation D413A were found. D413A conferred ganciclovir and cidofovir resistance. Conclusions: Known and newly discovered drug resistance mutations arising during preemptive therapy may complicate post-transplant CMV disease in stem cell recipients. Improved recombinant phenotyping methods enable the rapid quantitation of the resistance conferred by newly identified UL97 and pol mutations.