476. Genotypic Resistance Testing in Infants with Congenital Cytomegalovirus Disease Receiving Long-Term Oral Valganciclovir Therapy
Session: Poster Abstract Session: Pediatric Viral Infections
Thursday, October 8, 2015
Room: Poster Hall

Background: In a recent Phase 3 randomized, placebo-controlled, double-blind, multinational study of infants with symptomatic congenital cytomegalovirus (CMV) disease, 6 months of oral valganciclovir (VGCV) therapy was found to improve hearing and developmental outcomes beyond that which is seen with 6 weeks of therapy. To assess the potential for developing antiviral resistance during this prolonged treatment course, preliminary genotypic resistance analyses were performed.  

Methods: Resistance analyses were performed by conventional DNA sequencing of the UL97 gene. CMV DNA was extracted from frozen whole blood specimens and the UL97 gene was amplified with a double nested polymerase chain reaction method to look for the presence of mutations conferring ganciclovir resistance.

Results: Seven subjects found to have rising whole blood CMV loads while on VGCV therapy were selected for targeted resistance screening (Table 1). Virus from one of the 7 subjects was found to have a majority population-level A594V mutation in the UL97 DNA sequence, which is known to confer resistance to ganciclovir. Several natural polymorphisms known to have no effect on antiviral susceptibility were also identified, but no other known resistance mutations were identified in this preliminary resistance screen.

Conclusion: The identification of a CMV antiviral drug resistance mutation corroborates our previous studies indicating that infants with congenital CMV disease could be at increased risk of developing antiviral resistance while on therapy. The finding of emerging antiviral resistance in this patient population is concerning and warrants further investigation into its prevalence and potential clinical impact.

Table 1.  CMV mutations in UL97 while on VGCV Therapy


Study Day

Viral Load (copies/ml)

UL97 mutations


Day 70


I244V, A594Va


Month 5




Month 6


I244V, H469Y


Month 4


N68D, S108N, I244V


Month 5




Day 14


N68D, S108N, I244V


Day 28


N68D, S108N, I244V

a.       This mutation has been confirmed to confer resistance to ganciclovir

Scott H. James, MD1, Caroll Hartline, BS2, David W. Kimberlin, MD, FIDSA, FPIDS3, Richard Whitley, MD, FIDSA4 and Mark N. Prichard, PhD2, (1)Pediatrics, University of Alabama at Birmingham, Birmingham, AL, (2)University of Alabama at Birmingham, Birmingham, AL, (3)University of Alabama At Birmingham, Birmingham, AL, (4)Pediatrics, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL


S. H. James, None

C. Hartline, None

D. W. Kimberlin, None

R. Whitley, None

M. N. Prichard, None

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