Diagnosis and Treatment of Neonates with Congenital Cytomegalovirus Infection

Transcription

1 Diagnosis and Treatment of Neonates with Congenital Cytomegalovirus Infection Shannon Ross, MD, MSPH Department of Pediatrics Division of Pediatric Infectious Diseases University of Alabama at Birmingham School of Medicine

2 DISCLOSURE STATEMENT Speaker: Shannon Ross, MD, MSPH Dr. Ross has disclosed the following relevant financial relationships. Any real or apparent conflicts of interest related to the content of this presentation have been resolved. Affiliation/ Financial Interest Grant Organization GSK

3 Congenital cytomegalovirus (CMV) infection Most common congenital infection affecting 20,000-30,000 infants annually (0.5-1% newborns) Leading non-genetic cause of sensorineural hearing (SNHL) loss in children Overall, ~15% of CMV infected children have SNHL Can result in long term sequelae including retinitis and/or cerebral palsy

4 Estimates of Causes of Deafness at Birth and at Four Years in the United States Morton and Nance. New Engl J Med 354: , 2006

5 The Natural History of CMV-Related Hearing Loss and the Feasibility of CMV Screening as Adjunct to Hearing screening in the Newborn CHIMES study Multi-site investigation, 7 sites >100,000 newborns screened for congenital CMV (March November 2012) Audiometric follow-up of all CMV positive infants for 4 years Objectives: 1. Define the relative contribution of congenital infection to hearing loss in children 2. Evaluate diagnostic methods for neonatal CMV screening

6 Fowler et al, unpublished Congenital CMV Epidemiology Overall prevalence of congenital CMV infection in the Multicenter NIDCD CHIMES Study 0.46% (95% CI, )

7 Congenital CMV: Newborn Disease Clinical observation of infection in the newborn period identifies ~10% infants with congenital CMV infection 85%-90% of infants do not have clinical findings at birth (asymptomatic) 10-15% Symptomatic Range from mild nonspecific findings to multiple organ involvement No standard definition of symptomatic CMV

8 Congenital CMV: Newborn Disease Screened Clinical Suspicion (N = 78) (N = 100) P-value % Jaundice Petechiae Hepatosplenomegaly <0.001 Purpura Microcephaly Seizures 1 7 NS Small for Gestational Age* Single Clinical Finding 42 8 < or more Clinical Findings <0.001 *Weight less than 10 th percentile for gestational age. Dreher et al. J Pediatr Jan 13

9 Congenital CMV: Newborn Disease Elevated Alanine Aminotransferase (>80 IU/ml) Screened Clinical P-value Suspicion (N=78) (N=100) % Thrombocytopenia (<100,000/mm3) <0.001 Direct Hyperbilirubinemia (>2mg/dl) NS Head CT Abnormalities NS Calcifications NS Dreher et al. J Pediatr Jan 13

10 Sequelae following congenital CMV infection Asymptomatic Symptomatic Screened (n=78) Clinical Suspicion (n=100) IQ<70 3.7% 25% 47% Motor abnormalities 2.7% 16% 27% Chorioretinitis 2.5% 9% 18% Seizures 0.9% 11% 23% No Sequelae 85% 51% 28% Death 0.3% 5.8% Britt W. In: Remington JS, Klein JO, Wilson CB and Baker CJ, eds. 2011: Dreher et al. J Pediatr Jan 13

11 Hearing loss following congenital CMV infection Overall, ~15% of CMV infected children have SNHL Hearing loss incidence higher in those with symptomatic infection compared with asymptomatic Hearing loss may be present at birth or occur later 33% to 50% CMV-related SNHL is late-onset

12 Hearing loss following congenital CMV infection Asymptomatic Symptomatic Total Number of Children % Hearing Loss Characteristics of Loss Unilateral Bilateral Delayed Onset Loss Median Age 44mo (24-182) 33mo (6-197) Progressive Loss Dahle AJ., J Am Acad Audiol. 11: , 2000

13 Degree of SNHL Degree of Loss Asymptomatic Symptomatic Mild (21 45 db HL) Moderate (46 70 db HL) Severe (71 90 db HL) Profound (>90 db HL) 17% 15% 17% 51% 12% 13% 31% 44% Fluctuating SNHL- Improvement in threshold levels in 48% of asymptomatics and 21% of symptomatics Dahle AJ., J Am Acad Audiol. 11: , 2000

14 CMV Detection in Newborns Virus shed in urine and saliva in large quantities in congenital CMV Viral culture methods have traditionally been gold standard Standard culture techniques take 2-4 weeks Rapid culture methods using monoclonal antibodies to early viral antigens and centrifugation enhancement replaced traditional culture Shell vial, microtiter plate method

15 DBS PCR for Newborn CMV Screening Total positive: 92 (saliva, DBS or both) DBS PCR Saliva Rapid Culture P N Total P N Total Sensitivity <40% Boppana, et al. JAMA 2010;303:

16 Saliva PCR for Newborn CMV Screening Boppana SB et al. N Engl J Med 2011;364:2111

17 PCR for diagnosis of CMV in the newborn Urine PCR Saliva PCR Culture P N Total Culture P N Total P P N N Total Total Ross SA, et al. J Infect Dis 2014

18 Viral Load Screen saliva (1-2 days old) Enroll saliva (3-4 weeks old) Enroll urine (3-4 weeks old) Ross SA, et al. Unpublished

19 Newborn Hearing Screening and congenital CMV Newborn Hearing Screen Refer Pass SNHL NO SNHL Newborn hearing screening identified 60% (95% CI, 42% - 76%) of CMV-Related SNHL in the newborn period

20 Newborn Hearing Screening and congenital CMV CMV Screen Hearing Refer* % (95% CI) CMV Positive (n=461) 7.1% ( %) CMV Negative (n=99,317) 0.9% ( %) P <

21 Utah Cytomegalovirus Public Health Initiative H.B. 81 (2013 General Session) UCA Chief Sponsor was Representative Ronda Rudd Menlove Directs the Utah Department of Health to create a public education program to inform pregnant women and women who may become pregnant about the occurrence of CMV, the transmission of CMV, the birth defects that CMV can cause, methods of diagnosis, and available preventative measures. Directs medical practitioners to test infants who fail two newborn hearing screening tests for congenital CMV and inform the parents of those infants about the possible birth defects that CMV can cause and the available treatment methods.

22 Diagnosis of CMV in the newborn-summary DBS PCR lacks sensitivity for newborn screening Saliva real-time PCR is a as good as urine for diagnosing ccmv High viral load in saliva Saliva overall is preferred due to Convenient and non-invasive sample collection High throughput method Less expensive Newborn Hearing Screening will only detect 60% of SNHL due to congenital CMV infection Refer rate for NBHS higher in newborns with congenital CMV infectionconsider testing

23 Treatment of congenital CMV infection Most common sequelae is SNHL 10-15% of infants with asymptomatic infection 40-50% of infants with symptomatic infection Controlled trials of antiviral therapy only performed in infants with SYMPTOMATIC infection with primary outcome of improvement in hearing function Ganciclovir or oral equivalent valganciclovir Collaborative Antiviral Study Group (CASG)

24 What is symptomatic congenital CMV infection? Definition widely varies by institution/study For CASG Studies: Thrombocytopenia Petechiae Hepatomegaly Splenomegaly IUGR Hepatitis (elevated transaminases and/or direct bilirubin) CNS involvement Microcephaly, radiographic abnormalities, abnormal CSF indices, chorioretinitis, hearing deficits by ABR, and/or positive CMV PCR in CSF

25 Treatment of congenital CMV infection Phase III Randomized Controlled Investigation of the Effect of Ganciclovir On Hearing In Symptomatic Congenital Cytomegalovirus Disease Symptomatic ccmv WITH CNS involvement 32wga, 1200gm 6 weeks IV ganciclovir (n=25) vs. no treatment (n=17) Over half of study subjects were not evaluable at end of trial

26 IV Ganciclovir Treatment Study 6 weeks vs. no treatment in symptomatic with CNS involvement N=49 ears N=36 ears N=49 ears N=36 ears OR (95% CI): 9.96 (2.05,48.45) OR (95% CI): 4.25 (1.25,14.44) J Pediatr 2003;143:16-25

27 IV Ganciclovir Treatment Study 6 weeks vs. no treatment in symptomatic with CNS involvement No difference in improvement in clinical symptoms in treated group More rapid improvement in ALT in treated group, but not thrombocytopenia or hyperbilirubinemia Neutropenia significantly more common in treated group 63% of treated vs 21% untreated with Grade 3-4 ANC (p<0.01) J Pediatr 2003;143:16-25

28 Treatment of congenital CMV infection If parenteral ganciclovir or oral valganciclovir are used in management of neonates congenitally infected with CMV, their use should be limited to patients with symptomatic congenital CMV disease involving the CNS who are able to start treatment within the first month of life.

29 Valganciclovir Pro-Drug of ganciclovir H 2 N HN O N N N HO O O H 2 N O HCl CASG 109: 6 Weeks Oral Valganciclovir PK/PD Study 16 mg/kg/dose of oral valganciclovir provides the same systemic exposure to ganciclovir as does 6 mg/kg/dose of IV ganciclovir H 2 N HN O N N N HO O OH J Infect Dis 2008;197: ClinPharmacol Therapeut 2007;81:

30 Treatment of congenital CMV infection A Phase III, Randomized, Placebo-Controlled, Blinded Investigation of Six Weeks vs. Six Months of Oral Valganciclovir Therapy in Infants with Symptomatic Congenital Cytomegalovirus Infection To compare the impact on hearing outcomes To compare the impact on neurologic outcomes To compare the safety profile of six weeks versus six months of antiviral therapy with valganciclovir To correlate change in whole blood viral load with hearing and neurologic outcomes 109 subjects enrolled All subjects received 6 weeks of open-label oral valganciclovir therapy, after which time they were randomized to continued oral valganciclovir for the next four and a half months or to a matching placebo. Kimberlin et al. IDWeek 2013, Late Breaker Abstract #43178

31 Valganciclovir Treatment Study 6 weeks vs. 6 months in symptomatic congenital CMV aor (95% CI): 1.70 (0.77,3.79) aor (95% CI): 3.34 (1.31,8.53) aor (95% CI): 2.66 (1.02,6.91) Kimberlin et al. IDWeek 2013, Late Breaker Abstract #43178

32 Valganciclovir Treatment Study 6 weeks vs. 6 months in symptomatic congenital CMV Trend towards improved developmental outcomes in 6 month treatment group Grade 3-4 neutropenia much less than with IV ganciclovir Kimberlin et al. IDWeek 2013, Late Breaker Abstract #43178

33 Treatment of CMV in the newborn-summary Treatment of symptomatic congenital CMV WITH CNS involvement for 6 weeks accepted practice to improve audiological outcomes New data suggests treating symptomatic congenital CMV disease with 6 months of valganciclovir, compared with 6 weeks, does not improve short-term hearing but modestly improves longer-term hearing and developmental outcomes No controlled data exist to support treatment of babies with asymptomatic congenital CMV infection

34 The CHIMES study Investigators and Personnel Sponsor: NIDCD University of Alabama at Birmingham Suresh Boppana Karen Fowler William Britt Mirjam Kempf David Kimberlin Faye McCollister Shannon Ross Masako Shimamura Nitin Arora Amita Bey Belinda Blackstone Valisa Brown Alice Brumbach Nazma Chowdhury Steven Febres-Cordero Monique Jackson Noelle Le Lievre Emily Mixon Zdenek Novak Misty Purser Julie Woodruff University of Mississippi Medical Center April Palmer Kathy Irving Delia Owens Suzanne Roark Mindy Ware St Peters University Hospital Robert Tolan Kristina Feja Maria Class Marci Schwab Carolinas Medical Center Amina Ahmed Edie Cox Julie Courtney Nubia Flores Molly Ricart Lisa Schneider Jennifer West Cincinnati Children s Medical Center David Bernstein Dan Choo Kurt Schibler Kate Catalanotto Linda Jamison Patty Kern Maureen Sullivan-Mahoney Stacie Wethington Pittsburgh Children s Hospital Marian Michaels Diane Sabo Jena Colaberardino Noreen Jeffrey Anne Maracek Gretchen E. Probst Cheryl Rosenberg University of Texas Southwestern Medical Center Pablo Sanchez Gregory L. Jackson Asuncion Mejías Peter S. Roland Oscar Rosado Angela G. Shoup Elizabeth K. Stehel Cathy Boatman Jessica Esquivel Kathy Katz-Gaynor April Liehr Kristine E. Owen David Sosa Jessica Santoyo Lizette Torres Fiker Zeray

35 QUESTIONS?? Acknowledgements: David Kimberlin-CASG Funding: NIH-NIDCD 1 R01 DC Kaul Pediatrics Research Institute Alabama Children s Hospital Foundation GlaxoSmithKline Biologicals