1. Screening for congenital CMV Nicholas Bennett MBBChir, PhD FAAP Medical director of infectious diseases and immunology Connecticut Childrens Medical Center

2. Disclosures Dr Bennett has no relevant conflicts of interest to disclose Dr Bennett will be discussing off-label use of valganciclovir.

3. Background 1% of all births 90% asymptomatic Most common cause of non- genetic sensorineural hearing loss Effects are progressive in some

4. Prior research IV ganciclovir effective against CMV Approved for retinitis in AIDS Approved for prevention and treatment of transplant complications

5. CASG 102 6 weeks of intravenous ganciclovir for neonate with symptomatic congenital CMV Compared to placebo had improved hearing and developmental outcomes at 1 and 2 years Neutropenia noted in about two thirds of patients

6. Outcomes from CASG102 Remember this was a 6 week treatment with effects seen 1 year later…

7. CASG 112 Pharmacokinetics - 16mg/kg BID of oral valganciclovir equivalent to 6mg/kg BID of IV ganciclovir 6 weeks versus 6 months of oral valganciclovir 6 months of therapy had improved outcomes at 1 and 2 years of age with hearing and development Neutropenia similar to placebo group in historical study cohort (20% or so)

8. Outcomes from CASG112 6mo therapy resulted in approx 8 point higher Bayley Composite scores for language, motor skills, at 12 and 24 months than 6 weeks of therapy No apparently difference in hearing outcomes between 6 months and 6 weeks of therapy But remember that 6 weeks was a huge improvement over no treatment at all

9. Summary of findings Treatment of symptomatic congenital CMV for 6 weeks dramatically reduces hearing loss PO valganciclovir is as effective as IV ganciclovir but with much less neutropenia 6 months of therapy has improved developmental outcomes over 6 weeks of therapy - similar hearing outcomes

10. 2015 Red Book

11. Prior situation Child would fail hearing screens Referral to ENT/Audiology CMV testing Diagnosis aged 6+ weeks ?Treatment?

12. Preferred situation Child fails hearing screens CMV testing Diagnosis aged 3-4 weeks Referral to ENT/Audiology/ID as needed ?Treatment?

13. Why still a question? Hearing-loss only WAS eligible for enrollment in CASG112 No child in CASG112 had only hearing loss Ongoing studies addressing precisely this question No guidance yet from international CMV group

14. Smaller Studies Lackner et al J Laryngol Otol. 2009 Apr;123(4):391-6 3 weeks of ganciclovir, 23 children, 18 followed for 4-11 years 2 untreated children with CMV (out of 9) developed hearing loss years later 0 of 9 treated children had hearing loss

15. Smaller Studies Amir, Wolff and Levy European Journal of Pediatrics, September 2010, Volume 169, Issue 9, pp 1061-1067 (1 year of valganciclovir after IV)European Journal of Pediatrics Issue 9,

16. Advantages Potential improved hearing and neurodevelopment if treated Therapy is oral, can be done at home Side effects appear minimal in the short term

17. Disadvantages Prolonged (6 month) course Need for monitoring for drug toxicity Potential for carcinogenic/mutagenic activity according to animal studies Ongoing research to investigate this in children from prior studies

18. When to test Test for CMV after SECOND failed screen in either ear. Typically still done in the hospital prior to discharge (i.e. not a PCP responsibility!) 80% of first screen failures pass the second screen Do NOT wait for formal audiology referral

19. Limitations Won't pick up late-onset hearing loss But universal CMV screening may be overkill No data in this specific population Will miss home-births, hospitals where hearing screening isn't complete prior to discharge

20. Proposal Early identification by testing neonates who fail hearing screens (at-risk population) Early referral to ID for discussion with the family regarding options May include additional workup Cranial US, hematology, biochemistries Treatment offered if indicated

21. Testing Performed at birth hospitals prior to discharge Saliva can be tested at Yale labs by PCR DO NOT send to State labs! Collect at least 30 minutes after breastfeeding Positives need confirmation by urine PCR/Shell vial culture Can start with CMV urine testing - performed by many commercial labs PCR or shell vial results take a few days

22. Referrals Both Yale and CT Children's ID divisions will see patients and families for evaluation Make sure consult request CLEARLY states reason for referral, may prefer to call ahead Goal is early identification of children who should be treated - routine "next available" appointment may be too late

23. Impact of CMV screening Approx 2500 children fail their hearing tests Approx 2000 of those pass on the repeat test Approx 500 will require CMV testing Estimate ~50 a year will be CMV-positive Cost approx $100 per child Will probably reduce the need for genetic testing Reduced hearing loss - significant savings to society If hearing impairment cut by ⅔, number needed to screen is 25

24. Prevention No vaccine CMV very common (over 50% of adults may be infected) At-risk women - pregnant, CMV-negative Daycare setting (high titers shed in urine) No proven role for treatment of pregnant women Remember that ganciclovir teratogenic/oncogenic in animal models Cytogam (hyperimmune globulin), reduced congenital CMV by more than 90% in several small open-label studies in Europe

25. Prevention Avoiding high-risk activities if you’re an at-risk person Hand-washing! Diaper changing, feeding, wiping noses Do not share food, drinks, or pacifiers! Do not share toothbrushes with a young child. Try to avoid saliva from a young child.

26. Summary Good data exists to support treatment of symptomatic congenital CMV to reduce hearing loss and improve neurodevelopmental outcomes. Some data to support the use of antiviral therapy in less-affected neonates New State law mandates screening for CMV in infants with two failed hearing screens Goal is early identification for referral to ID specialists for possible treatment Send testing to Yale (saliva or urine PCR) or commercial lab (urine PCR/shell vial culture) Request urgent appointment with ID at Yale or Connecticut Children’s Education of pregnant women to help with prevention important