Incidence and characterization of cytomegalovirus resistance mutations among pediatric solid organ transplant patients who received valganciclovir prophylaxis.
BACKGROUND
Drug-resistant cytomegalovirus (CMV) infections can cause significant morbidity among high-risk transplant recipients.


OBJECTIVE
The aims of this study were to determine the incidence and clinical consequences of CMV mutations conferring ganciclovir resistance in pediatric solid organ transplant (SOT) patients who received valganciclovir oral solution or tablets for prophylaxis of CMV disease. Recombinant CMV mutants were also generated to assess the role of two UL97 mutations of unknown significance.


METHODS
Genotypic resistance mutations and CMV viral load were sought in blood samples from pediatric SOT recipients who received valganciclovir prophylaxis for 100 days. Recombinant viruses containing novel CMV UL97 mutations were generated using a bacterial artificial chromosome containing the CMV genome to assess ganciclovir susceptibility.


RESULTS
Overall, four known resistance UL97 mutations were observed in blood samples from 2 of 46 patients during the study with no development of CMV disease. Two UL97 changes (M615V and V466G) of unknown significance and one UL97 mutation (C603R) associated with ganciclovir resistance, but not yet confirmed by marker transfer, were also detected. Recombinant viruses containing these novel mutations were generated to assess ganciclovir susceptibility. The M615V recombinant virus was susceptible to ganciclovir while the V466G and C603R mutant viruses displayed 3.5-fold and 3.6-fold decreases in susceptibility, respectively.


CONCLUSIONS
The low incidence of ganciclovir resistance-associated mutations and the absence of clinical consequences associated with drug-resistant viruses observed in this pilot study should encourage the design of larger clinical trials aimed at evaluating the efficacy of valganciclovir prophylaxis and treatment in the pediatric setting.
Research Center in Infectious Diseases, Centre Hospitalier Universitaire de Québec and Laval University, 2705 Blvd Laurier, Room RC-709, Quebec City, Quebec G1V 4G2, Canada.
Mélanie
M
Martin
Nathalie
N
Goyette
Jane
J
Ives
Guy
G
Boivin
D000293:Adolescent; D000998:Antiviral Agents / Q000627:therapeutic use*; D001769:Blood / Q000821:virology; D018890:Chemoprevention / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000821:virology; D024882:Drug Resistance, Viral; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D015994:Incidence; D007223:Infant; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D016377:Organ Transplantation / Q000009:adverse effects*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011995:Recombination, Genetic; D000077562:Valganciclovir; D019562:Viral Load
D000998:Antiviral Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D000077562:Valganciclovir; D015774:Ganciclovir