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

Subject

Study Day

Viral Load (copies/ml)

UL97 mutations

BT2

Day 70

187,000

I244V, A594Va

692

Month 5

68,865

L126Q

09Q

Month 6

111,826

I244V, H469Y

0P6

Month 4

65,332

N68D, S108N, I244V

08S

Month 5

25,310

G395A

DW5

Day 14

24,367

N68D, S108N, I244V

0P5

Day 28

21,428

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

Disclosures:

S. H. James, None

C. Hartline, None

D. W. Kimberlin, None

R. Whitley, None

M. N. Prichard, None

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