title: Successful valganciclovir treatment of post-transplant cytomegalovirus infection in the presence of UL97 mutation N597D.
abstract: Mutations in the human cytomegalovirus (CMV) UL97 protein kinase are the most common mechanism of ganciclovir (GCV) resistance in the clinical setting. A CMV strain with a previously unrecognized UL97 mutation N597D was identified in the blood of a heart transplant recipient who experienced a persistent CMV infection with high viral loads accompanying pain and fever while receiving valganciclovir (valGCV) therapy. The N597D mutation was transferred by mutagenesis to an antiviral sensitive CMV strain for analysis of antiviral susceptibility by standardized phenotypic assay. Recombinant phenotyping showed N597D conferred a less than twofold increase in GCV IC(50) compared to the sensitive control strain. Despite the presence of this mutation, valGCV eventually resolved the infection after 6 weeks of therapy. A subsequent CMV reactivation was also responsive to valganciclovir. This case illustrates the diversity of UL97 mutations in the codon segment 590-607 usually associated with GCV resistance, with some mutations producing minimal levels of resistance that do not preclude a therapeutic response to the drug. Accurate interpretation of genotypic test results ultimately requires experimental determination of the level of resistance conferred by newly discovered UL97 mutations.
authors.affiliation: Virology Division, Department of Microbiology, SEALS, POWH & UNSW Research Laboratories, Prince of Wales Hospital, Randwick, NSW, Australia.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Iwasenko
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Scott
authors.forename: William D
authors.initials: WD
authors.lastname: Rawlinson
authors.forename: Anne
authors.initials: A
authors.lastname: Keogh
authors.forename: Daniel
authors.initials: D
authors.lastname: Mitchell
authors.forename: Sunwen
authors.initials: S
authors.lastname: Chou
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D001769:Blood / Q000821:virology; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000821:virology*; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016027:Heart Transplantation / Q000009:adverse effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D016896:Treatment Outcome; D000077562:Valganciclovir; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D000077562:Valganciclovir; D015774:Ganciclovir