Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial

doi:10.1016/S0022-3476(03)00192-6

The Journal of Pediatrics

Volume 143, Issue 1, July 2003, Pages 16-25

https://doi.org/10.1016/S0022-3476(03)00192-6 Get rights and content

Abstract

Objective To evaluate the efficacy and safety of ganciclovir therapy in neonates with congenital cytomegalovirus (CMV) disease.

Study design Neonates with symptomatic CMV disease involving the central nervous system were randomly assigned to receive 6 weeks of intravenous ganciclovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points).

Results From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 ganciclovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P = .06). None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P<.01). A total of 43 patients had a BSER at both baseline and at 1 year or beyond. Five (21%) of 24 ganciclovir recipients had worsening of hearing between baseline and ≥1 year versus 13 (68%) of 19 control patients (P<.01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P<.01).

Conclusions Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at ≥1 year. Almost two thirds of treated infants have significant neutropenia during therapy.

Section snippets

Study population

Neonates with symptomatic (clinically apparent disease in the newborn period) congenital CMV disease involving the CNS were eligible for enrollment into this trial. All study subjects had confirmed isolation of CMV from a urine specimen obtained before study enrollment and within the first month of life,¹⁵ and all had evidence of CNS disease, such as (1) microcephaly; (2) intracranial calcifications; (3) abnormal cerebrospinal fluid (CSF) for age; (4) chorioretinitis; and/or (5) hearing

Population characteristics

From 1991 through 1999, 100 patients from 18 CASG sites enrolled patients in this clinical trial. These sites and their corresponding enrollment numbers were University of Alabama at Birmingham, 15 subjects; University of Texas Southwestern Medical Center and University of Florida at Gainesville, 13 subjects each; Baylor College of Medicine, 11 subjects; University of Arkansas, 9 subjects; University of California at San Diego, 7 subjects; University of Alberta and Cook Fort Worth Children's

Discussion

Six weeks of intravenous ganciclovir therapy prevents best-ear hearing deterioration at 6 months for patients with symptomatic congenital CMV disease involving the CNS. Ganciclovir therapy also may prevent best-ear hearing deterioration at or beyond 1 year. Although an understanding of the full clinical relevance of this audiologic effect awaits further long-term follow-up of these patients, the ability to prevent a patient from worsening from one level of hearing impairment (eg, mild) to

Acknowledgements

This study is dedicated to Charles A. Alford, Jr, MD, whose vision and leadership were instrumental to this endeavor.

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To assess the efficacy of valganciclovir in infants with hearing loss and clinically inapparent congenital cytomegalovirus infection (cCMV), as there is no consensus on treatment of this group.
A nationwide, nonrandomized controlled trial, comparing 6 weeks of oral valganciclovir to no treatment in infants with cCMV, recruited after newborn hearing screening resulted in referral to an audiologist. The choice whether to treat was left to parents of subjects. Eligible subjects were full term infants aged <13 weeks with sensorineural hearing loss and diagnosed with cCMV through dried blood spot testing. The primary outcome, measured by linear and ordinal logistic regression, was change in best-ear hearing from baseline to follow-up at 18-22 months of age.
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The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus–associated sensorineural hearing loss.
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In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus–associated sensorineural hearing loss.
ClinicalTrials.gov identifier NCT01649869.
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^☆

Supported under contract with the Virology Branch, Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID), NO1-AI-15113 and NO1-AI-62554, and by grants from the General Clinical Research Center Program (RR-032) and the State of Alabama.

Presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Ontario, Canada; 2000; Abstract 1942. Recipient of the ICAAC Program Committee Award in the area of Therapy of Microbial Diseases.

^∗: Committee membership of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group is listed at http://www.casg.uab.edu.

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Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial∗☆

Abstract

Section snippets

Study population

Population characteristics

Discussion

Acknowledgements

Lancet

J Pediatr

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Summary of a workshop on surveillance for congenital cytomegalovirus disease

Rev Infect Dis

Congenital cytomegalovirus infection and sensorineural hearing loss

Ear Hear

Congenital cytomegalic inclusion disease: a longitudinal study of 20 patients

Am J Dis Child

Outcome of symptomatic congenital cytomegalovirus infection: results of long-term longitudinal follow-up

Pediatrics

The cytomegaloviruses: ubiquitous agents with protean clinical manifestations

N Engl J Med

Virologic and clinical observations on cytomegalic inclusion disease

N Engl J Med

Symptomatic congenital cytomegalovirus: disorders of language, learning and hearing

Am J Dis Child

Clinical importance of cytomegalovirus infection: an overview

Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus

J Am Acad Audiol

Congenital cytomegalovirus disease: 20 years is long enough

N Engl J Med

Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial^∗☆