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Neonatal HSV and Congenital CMV Infections: the Intersection of Drugs, Diagnostics and the Natural History of Disease

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Neonatal HSV and Congenital CMV Infections: the Intersection of Drugs, Diagnostics and the Natural History of Disease Neonatal HSV and Congenital CMV Infections: The Intersection of Drugs, Diagnostics and the Natural History of Disease Richard Whitley South Carolina Chapter of the AAP Asheville, North Carolina August 11, 2017 Disclosure I am on the Board of Gilead Sciences and will not discuss any of their products I have received remuneration from the NIH, and IDSA (Associate Editor JID) I serve on Data Safety and Monitoring Boards for clinical trials sponsored by the NIH, GSK, and Merck My grant support is from NIAID I do intend to discuss an unapproved/investigative use of a commercial product/device in my presentation. Objectives Understand the differences in the pathogenesis of congenital CMV and neonatal HSV infections Define diagnostic approaches Know therapeutic approaches to these diseases Be able to define outcome with therapy Neonatal HSV and Congenital CMV Infections: The Intersection of Drugs, Diagnostics and the Natural History of Disease Asympt HSV End of Rx PCR ACV Rx ACV Rx of for Persistent Vidarabine Rx of CNS of Neonatal CNS HSV Neonatal HSV Infection Chickpo HSV Disease x-pox PCR for High dose HSV CNS ACV Rx of Suppressive Disease Rx of Neo Vidarabine Vidarabine Neo HSV HSV Rx of HSE Rx of ACV Rx HSV Chickenpox Oral ACV Rx of of HSE Neo HSV: PK and PD 1970 1980 1990 2000 2010 Ganciclovir Rx Valganciclovir Ganciclovir Rx Rx of CMV CMV of Congenital of Congenital CMV: PK/PD CMV 6 Months of Valganciclovir New Drug Applications: Ten (Defining the Standard of Care) Rx Where Were We in 1980? Neonatal Herpes Simplex Virus (HSV) Infection – No Established Therapy – Mortality of 75%; Morbidity of 90% Congenital Cytomegalovirus (CMV) Infection – No Established Therapy – Mortality of 15%; Morbidity of 25% Therapeutic Opportunities: HSV Versus CMV Infections of the Newborn Herpes Simplex Virus Cytomegalovirus • Acquired during delivery • Acquired early in gestation • Usually occurs with • Majority of cases occur with maternal primary infection maternal primary infection • Relatively short incubation • Infection progresses over period months • Disease of the newborn is • Disease can be usually obvious asymptomatic • Should be amenable to • Should be less amenable to therapy therapy than HSV Neonatal HSV Infection: Vesicular Rash Neonatal HSV Disease CNS Disease HSV Liver with coagulative necrosis and HSV intranuclear inclusions Pathogenesis of Neonatal HSV Infection Maternal Genital Herpes Simplex Virus Infection Intrauterine Infection (5%) (transplacental or ascending) Intrapartum Infection (85%) Superficial Replication on Skin or Eye or in Mouth Postnatal Infection (10%) 45% VIREMIA = NEURONAL SPREAD = Disseminated Disease 30% Localized Encephalitis 25% SEM CNS Disseminated Risk of Vertical Transmission Factors increasing risk of transmission: – primary genital herpes infection, particularly in last trimester – no maternal HSV antibodies before pregnancy and seropositive partner – use of fetal scalp monitors or instrumented delivery Risks of Neonatal Infection Primary genital herpes 30-50% Recurrent genital herpes < 3% Intrapartum and Postpartum HSV Infection • Disseminated disease ~ 25% – DIC – Pneumonia – Hepatitis – CNS involvement (60% to 75%) • Encephalitis (CNS disease) ~ 30% – Seizures – Lethargy – Irritability – Poor feeding – Temperature instability • Skin, eyes, and/or mouth (SEM disease) ~ 45% Characteristics of Babies with Neonatal HSV Infection Disease Classification Characteristic Disseminated CNS Skin, eye, mouth No. of babies 93 (32) 96 (33) 102 (35) No. premature (<36wk) 33 (35) 20 (21) 24 (24) Enrollment age, days 11.6+0.7 17.4+0.8 12.1+1.1 Clinical findings Skin lesions 72 (77) 60 ( 63) 86 (84) Brain involvement 69 (74) 96 (100) 0 ( 0) Pneumonia 46 (49) 0 ( 0) 0 ( 0) Evolution of Therapy for Neonatal HSV Infections: The Early Days • 1981 – Vidarabine (adenine arabinoside) vs. placebo – Mortality of DIS is decreased – Morbidity is improved – Progression from SEM to CNS or DIS decreased • 1983 – Confirmation of controlled trial data Survival Following Vidarabine Therapy for Babies with CNS and Disseminated Disease Pediatrics Vol 66 No. 4 October 1980, pgs 497-498 Failure of Vidarabine Therapy to Improve Survival with High Dose Therapy Pediatrics 1983;72:778-785 Evolution of Therapy for Neonatal HSV Infections: The Decades • 1991 – Direct comparison of acyclovir and vidarabine No difference in mortality • 1996 – Establishment of PCR as the gold standard of diagnosis of CNS infections: both babies and adults • 2001 – High dose acyclovir is established as the standard of care • 2005 – Value of end of treatment CSF PCR assessment Diagnosis Culture – Skin Lesions – Oropharynx – Eye – Cerebrospinal Fluid – Stool Polymerase Chain Reaction – Cerebrospinal Fluid Sensitivity and Specificity of PCR Biopsy Biopsy Positive Negative PCR Positive 53 3 PCR Negative 1 44 Sensitivity 98% Specificity 94% Positive Predictive Value 95% Negative Predictive Value 98% Direct Comparison of Vidarabine and Acyclovir: Impact on Survival by Disease Classification No Differences Why Did Acyclovir Not Improve Outcome? • Did we use the correct dose? • Did we treat long enough? • Conclusion: Probably not – thus, we increased both dose and duration of therapy • But what do we not know about this disease? Improved Mortality with High Dose Acyclovir: CNS Disease 1 0.9 0.8 0.7 0.6 30mg/kg/d (n=35)* 0.5 45mg/kg/d (n=5) 0.4 60mg/kg/d (n=23) 0.3 * historical cohort Proportion Surviving Proportion 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Pediatrics 2001;108:230-238 Improved Mortality with High Dose Acyclovir Therapy: Disseminated Disease 1 0.9 0.8 0.7 0.6 30mg/kg/d (n=18)* 0.5 45mg/kg/d (n=7) 0.4 60mg/kg/d (n=34) 0.3 * historical cohort Proportion Surviving Proportion 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Pediatrics 2001;108:230-238 Definitions of Morbidity Mild Recurrent keratoconjunctivitis Mild motor delay (no hemiparesis) Minimal Speech delay Moderate With/Without Hemiparesis Persistent seizure disorder < 3 month developmental delay Severe Microcephaly Spastic quadriplegia Blindness/chorioretinitis > 3 month developmental delay Morbidity Among Survivors With Known Outcomes (High versus Low Dose) After 12 Months 100 80 60 Severe 40 Moderate Percentage Mild 20 Normal 0 30 60 30 60 30 60 mg/kg/day SEM CNS Disseminated Disease Disease Disease Pediatrics 2001;108:230-238 Prognostic Factors SEM Disease Relative Risk Dominant Factors Mortality Morbidity # of cutaneous recurrences < 3 NA 1 3 NA 21 Virus Type HSV-1 NA 1 HSV-2 NA 14 N Engl J Med 1991;324:450-4 Confounding Variables • Is SEM disease really SEM disease? • What have we learned about PCR evaluation of the CSF at the conclusion of therapy? • Risk factors for impaired neurologic outcome with SEM disease imply chronic replication in the CNS – can we prove it? Why Do Babies With Disease Apparently Localized to Skin, Eye, Mouth Develop Neurologic Impairment? 8/11 PCR positive for HSV DNA in CSF at presentation with normal CSF findings 11/11 >3 recurrences first 3 months post-therapy Proof of asymptomatic infection of the CNS End of Therapy PCR Evaluation: Impact of Disease Classification Infant PCR Negative* PCR Positive** Characteristic (N=11) (N=19) Diseases Classification CNS 4 (36.4%) 14 (73.7%) P<0.001 Disseminated 0 ( 0.0%) 5 (26.3%) SEM 7 (63.6%) 0 ( 0.0%) Antiviral Therapy Vidarabine 2 (18.2%) 13 (68.4%) P=0.008 Acyclovir 9 (81.8%) 6 (31.6%) * Only negative PCR results from CSF specimens obtained after treatment ** At least one positive PCR result from CSF specimens obtained after therapy End of Therapy PCR Evaluation: By Virus Type Infant Characteristic PCR Negative* PCR Positive** (N=11) (N=19) Viral Type HSV-1 5 (45.4%) 2 (10.5%) P<0.018 HSV-2 5 (45.4%) 17 (89.5%) Not typed 1 ( 9.1%) 0 ( 0.0%) * Only negative PCR results from CSF specimens obtained after treatment ** At least one positive PCR result from CSF specimens obtained after therapy Morbidity And Mortality By Virus Type 100 80 60 Dead Severe 40 Moderate Percentage 20 Mild Normal 0 HSV-1 HSV-2 HSV-1 HSV-2 HSV-1 HSV-2 SEM CNS Disseminated Disease Disease Disease End of Therapy PCR Evaluation: Neurologic Outcome Infant Characteristic PCR Negative* PCR Positive** (N=11) (N=19) Morbidity and mortality after 12 months Normal 6 (54.5%) 1 ( 5.3%) P<0.001 Mild 0 ( 0.0%) 0 ( 0.0%) Moderate 1 ( 9.1%) 3 (15.8%) Severe 2 (18.2%) 10 (52.6%) Dead 0 ( 0.0%) 5 (26.3%) Unknown 2 (18.2%) 0 ( 0.0%) * Only negative PCR results from CSF specimens obtained after treatment ** At least one positive PCR result from CSF specimens obtained after therapy Defining the Requirement for End of Treatment PCR Assessment of the CSF: Neurologic Outcome and PCR Status* 100% 90% 80% 70% 60% PCR - 50% 40% PCR+ 30% 20% 10% 0% Normal Moderate/ Dead Severe *Completion of therapy Does Suppressive Acyclovir Therapy Improve Outcome of Neonatal Herpes? • To determine if suppressive oral acyclovir therapy improves neurologic outcome • To determine if continuous administration of oral acyclovir suspension suppresses recurrent skin lesions following neonatal HSV disease N Engl J Med 2011;365(14):1284-92 Neonatal HSV Suppression Studies Endpoints • Primary endpoint – Neurologic impairment at 12 months of life – Bayley Scales of Infant Development N Engl J Med 2011;365(14):1284-92 Bayley Mental Score at 12 Months CNS Disease SEM Disease Acyclovir Placebo Acyclovir Placebo N=16 N=12 N=8 N=7 Median 90.5 66.5 95 84 Adjusted 88.24† 68.12† 91.82‡ 84.92‡ Mean P-value by 0.046* 0.263 ANCOVA
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