University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• In infants with symptomatic congenital CMV infection, does treatment with ganciclovir (vs. no treatment) improve neurocognitive outcome?

Clinical Bottom Lines

1. CMV is the most commonly transmitted virus during pregnancy leading to permanent disability in 1 in 750 live births or 8,000 annual cases.
2. 2. Treatment with ganciclovir IV 6 mg/kg BID x 6 weeks prevents deterioration of both function and biological measures of hearing in newborn infants with evidence congenital CMV CNS disease. NNT = 2-2.5. This effect is sustained through at least one year of follow-up
3. 4. Clinically significant neutropenia is the one major adverse event associated with ganciclovir therapy. Number needed to harm (NNH) = 2.38
4. 5. A pharmacologically equivalent dose of oral valganciclovir 15-16 mg/kg BID may be an alternative to IV therapy, avoiding the risks of maintaining an indwelling catheter.

Summary of Key Evidence

1. Randomized, controlled trial conducted in 100 patients with urine-confirmed CMV, evidence of CNS disease, =32 weeks gestations, =1200 g BW, and =1 month at baseline. Exclusion criteria included imminent death, treatment with other antiretrovirals or IVIG, creatinine >1.5 mg/dL, HIV infection, or hydranencephaly. Patients received either IV ganciclovir 6 mg/kg BID x 6 weeks or no-treatment.
2. Both functional and biological assessment of hearing was performed using brainstem auditory evoked response (BAER) were done at baseline, 6 months, 1 year, and 2 years. These were all interpreted by a single audiologist who was blinded to the randomization.
3. No patients treated with ganciclovir had worsening of hearing by both functional and biological assessments versus 41-42% in the no-treatment control at the 6 month follow-up (p<.001). This effect persisted after multivariate analysis; OR 21.11 (p<.01)
4. Only 21% of patients treated with ganciclovir had worsening of hearing by functional or biological assessments versus 61-68% in the no-treatment control after at least 1 year of follow-up (p=.002). This effect also persisted after multivariate analysis; OR 4.38 (p=.03)
5. There was a large proportion (58%) of non-evaluable patients raising the possibility of follow-up bias. These patients were also more likely to be black and premature. Premature infants may be at higher risk of adverse outcome. This represents a selection bias which the multivariate analysis attempted to correct for.
6. Power analysis from the phase II trial calculated n=90 to be sufficient. This was not achieved as the trial was terminated prematurely when the interim analysis showed significant benefit.
7. It is unclear whether functional and biological assessment of hearing via BAER is a sufficient surrogate measure of neurodevelopmental outcome.

Additional Comments

• Further studies are needed (and currently in progress) to more specifically address the effect of this therapy on clinically relevant outcomes (e.g. cerebral palsy, cognitive impairment, developmental delay, seizures).

Citation

1. 1. Kimberlin et al. Effect of ganciclovir therapy of hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003 Jul;143(1):16-25.

CAT Author: Jeffrey H. Yang MD

CAT Appraisers: Kerry Mychaliska, MD

Date appraised: <Kerry Mychaliska, MD