Impact of Ganciclovir Treatment of Congenital Cytomegalovirus Infection on Neurodevelopment

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Impact of Ganciclovir Treatment of Congenital
Cytomegalovirus Infection on Neurodevelopment

• Richard Whitley, MD
• International Herpes Management Forum
• October 2007

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Cytomegalovirus Perinatal Transmission

• Intrauterine - 0.2-2.2 (only 7 symptomatic)
• Maternal primary infection - 30-40
• Maternal recurrent infection - 0.9-1.5
• Intrapartum - 2.5
• CMV detected in genital tract - 10-20
• Breast feeding - 5-15
• CMV mother with gt 1 month of breast feeding -
  30-70 transmission

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Electron micrograph of an autopsy specimen of
retina, demonstrating a CMV-infected endothelial
Cell. Note the number of dense bodies (DB)
compared to virus particles (VP)
IHMF Herpes 41 Mar 97
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CMV Infection in Pregnancy
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Sequelae FollowingFetal Disease/Infection

• Sequelae Symptomatic Asymptomatic
• Sensorineural hearing loss 58 (58/100) 7.4
  (22/299)
• Bilateral hearing loss 37 (37/100) 2.7 (
  8/299)
• Speech threshold moderate 27 (27/100) 1.7 (
  5/299)
• to profound (60 to 90 dB)
• Chorioretinitis 20.4 (19/ 93) 2.5 ( 7/281)
• IQ lt 70 55 (33/ 60) 3.7 ( 6/159)
• Microcephaly, seizures, or 51.9 (54/104) 2.7 (
  9/330)
• paresis/paralysis

Infectious Diseases of the Fetus and Newborn
Infant, 5th Edition, 2001
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Congenital CMV InfectionPublic Health Impact in
United States

• Parameter Estimated
  Figure
• No. of live births per year 4,000,000
• Rate of congenital CMV infection
  1
• No. of infected infants 40,000
• No. of infants symptomatic at birth (5-7)
  2,800
• No. with fatal disease ( ? 12)
  336
• No. with sequelae (90 of survivors)
  2,160
• No. of infants asymptomatic at birth (93-95)
  37,200
• No. with late sequelae (15)
  5,580
• Total no. with sequelae or fatal outcome 8,076

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Ganciclovir
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Ganciclovir Evaluation in Congenital CMV Conduct
of Study
Congenital CMV (culture proven) With CNS
Involvement Informed Consent Ganciclovir vs. No
Treatment x 42 days 12 mg/kg/day Monitoring Clin
ical/Virologic Serology Toxicity Escape
Hematologic, Renal, Liver Toxicity Clini
cal Decline Follow-up (Months 6, 12, 24, 36, 48,
and 60)
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Study Endpoints

• Primary Endpoint
• Improved BSER by one gradation (or remains
  normal) between baseline and 6 month follow-up
• Biologic assessment (total ears)
• Functional assessment (best ear)
• Second Endpoint
• Laboratory improvement by 2 weeks
• Clinical improvement

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Change in Hearing Between Birth and 6 Months of
Age
Ganciclovir Recipients
No Treatment Group

gt 36.7 dB
P lt 0.01
J Pediatr 200314316-25
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Change in Hearing Between Birth and 1 Year of
Age
Ganciclovir Recipients
No Treatment Group


gt 30.6 dB
P lt 0.01
25 dB
J Pediatr 200314316-25
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Time to Normalization of ALT
J Pediatr 200314316-25
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Rate of Growth
J Pediatr 200314316-25
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Development of NeutropeniaDuring Therapy

• Treatment Group
• Ganciclovir No Treatment
• (n47) (n50)
• Grade 3-4 Neutropenia 29/46 (63) 9/43 (21)
  P 0.0001
• Grade 3 ANC 18/46 (39) 8/43 (19)
• 2-7 days old 750-1,249/mm3
• 8-56 days old 500-899/mm3
• 57-90 days old 250-399/mm3
• Grade 4 ANC 11/46 (24) 1/43 ( 2)
• 2-7 days old lt 750/mm3
• 8-56 days old lt 500/mm3
• 57-90 days old lt 250/mm3

J Pediatr 200314316-25
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Sample Sizes
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Average Total Delays Per Subject
P 0.007
No Treatment Ganciclovir Treatment
P 0.06
Average Total Delays
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Average Total Delays Without Language
No Treatment Ganciclovir Treatment
P 0.005
Average Total Delays
P 0.08
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Conclusions

• Subjects receiving 6 weeks GCV had fewer delays
  compared with those receiving no therapy
• Antiviral treatment of babies with symptomatic
  congenital CMV disease with CNS involvement
  improves neurodevelopmental outcomes at 12 months
  of age

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Conclusions

• Weakness of study screening aspect of Denver
  Developmental Test
• Ongoing studies involving antiviral therapy in
  congenital CMV utilize Bayley Scale of Infant
  Development Revised

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New Initiatives

• Controlled clinical trial of oral valganciclovir
  for 6 weeks versus 6 months
• Effect of valganciclovir on hearing loss if
  detected after the first month of life

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Recommendations

• Babies with symptomatic congenital CMV infection
  should receive iv ganciclovir therapy for 6
  weeks.
• Valganciclovir should be studied in a controlled
  clinical trial to replace ganciclovir in the
  treatment of symptomatic congenital CMV infection.

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Recommendations (2)

• Goal is to improve outcome for symptomatically
  infected babies with congenital CMV infection
• Identify asymptomatically infected children at
  risk for hearing impairment for pre-emptive
  therapy

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Contributors

• David Kimberlin, Department of Pediatrics
• Seng-jaw Soong and Gretchen Cloud, Department of
  Biostatistics
• Ed Acosta, Department of Pharmacology