4/8/2014 Disclosures None Kari Simonsen, MD Associate Professor of Pediatrics, Division of Infectious Diseases University of Nebraska Medical Center April 11, 2014 OBJECTIVES: 1. Discuss updated recommendations for management of neonatal HSV exposure and infection 2. Describe the current effort in perinatal testing for HIV in Nebraska, and strategies for improvement 1. Skin, Eye, Mouth (SEM) disease 2. CNS disease 3. Disseminated disease 3. Describe current management recommendations for HIV-exposed infants SEM disease Now accounts for 45% of cases Presentation usually around 10-12 days of life Lesions may appear anywhere on the body CNS disease 30% of neonates with HSV infection May have seizures (focal or generalized) Irritability, lethargy, tremors, poor feeding, temp instability, bulging fontanelle 60-70% of those classified as CNS will have skin lesions at some point in course Mortality is related to devastating brain destruction with neuro and autonomic dysfunction 1 4/8/2014 Disseminated disease Historically 2/3 of patients, but with early tx, now ~25% are classified as disseminated Presents earliest, 7-12 days of life CNS involvement in 60-75%, skin involvement in 80% Also severe coagulopathy, liver dysfunction, pulmonary involvement which are greatest causes of mortality Laboratory work-up Skin testing Scrape lesion for viral culture and for DFA, EIA for viral antigen is also avail. Skin, eye/conjunctiva, rectum, mouth/oropharynx can also be cultured Tzanck test has low sensitivity and isn’t recommended. CSF testing PCR testing –sensitivity 80%, specificity 71% Viral culture –yield lower ~40% in those with clinical CNS involvement Kari Simonsen, MD © Laboratory work-up Serum testing PCR testing is possible in many centers Serum viral load correlates with disease classification based on small data series (disseminated>CNS>SEM) Serology Can distinguish IgG Ab for HSV-1 vs HSV-2, but not diagnostically helpful in infants who have maternal IgG present Recommendations for LP Infants with skin lesions likely to be HSV should get an LP “Rule out sepsis” babies with: Seizure activity Coagulopathy, elevated LFTs Diffuse pneumonitis Multiple organ failure Decompensation on anti-bacterial abx All babies? Consider this approach if the turnaround time for a CSF PCR is fast. (i.e. its available in house) 2 4/8/2014 HSV Treatment: Acyclovir SEM disease Acyclovir 60mg/kg/d div. TID x 14 d CNS or disseminated disease Acyclovir 60mg/kg/d div. TID x 21d Repeat LP at end of therapy, if PCR still positive, continue acyclovir until CSF PCR negativity Acquisition of HSV in neonate HSV infection of newborns can be acquired in utero, intrapartum, and postpartum. ~85% of infected infants acquire the virus during delivery 5% in utero 10% postpartum Risk of neonatal infection Infants born to mothers with first episode genital HSV near term have the greatest risk. Lower concentration of maternal type-specific antibodies passed transplacentally Higher quantity of virus shed for longer duration in maternal genital tract Factors which influence transmission from mother to child 1. Type of maternal infection (primary vs recurrent) 2. Maternal antibody status 3. Duration of rupture of membranes (>4 hrs increases risk) 4. Integrity of mucus membranes (use of scalp electrodes, etc) 5. Mode of delivery Risk of maternal infection during pregnancy ~10% of HSV-2 seronegative pregnant women have a HSV-2 seropositive partner (estimated chance of conversion 1.7 %) Women who are seronegative for HSV-1 and HSV-2 can also seroconvert for HSV-1 through oral-genital contact (estimated chance of seroconversion 3.7%) Brown ZA, et al: The acquisition of herpes simplex virus during pregnancy. N Engl J Med 337:509-515, 1997. 3 4/8/2014 Risk of symptomatic maternal infection during pregnancy ~2/3 of women who acquire genital HSV during pregnancy have no clinical symptoms This is consistent with the finding that 60-80% of women whose infants develop HSV disease have no history or clinical evidence of genital HSV infection Yeager AS, Arvin AM: Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus. Pediatrics 73:188-193, 1984. Risk of transmission by type of maternal infection First genital episode, primary HSV-1 or HSV-2 = 57% First genital episode, non-primary HSV-1 or HSV-2 = 25% Recurrent genital HSV-1 or HSV-2 = 2% Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289(2):203–209 Indication for Caesarean ACOG 1999 recommends c-section if active genital HSV lesions are present at time of delivery However, as stated, 60-80% of infants with HSV are born to mothers without PMH of genital HSV Neonatal infection has also occurred despite c-section prior to membrane rupture Maternal acyclovir prophylaxis The use of oral acyclovir for suppression in HSV positive women in the 3rd trimester is increasingly common Several small studies have suggested that this decreases the need for c-section for clinically active HSV Giving acyclovir reduces viral shedding and recurrences at delivery, reducing cesarean deliveries Whitley R, Kimberlin D. Herpes Virus Infections: Updates in Clinical Knowledge. Sem Ped Inf Dis Vol 16(1), 2005. Hollier LM, Wendel GD. Cochrane Reviews. Third trimester antiviral prophylaxis for preventing maternal genital HSV recurrences and neonatal infection, 2008. 4 4/8/2014 AAP guideline for management of infant delivered with active maternal HSV lesions present: OB testing DFA/culture and PCR for maternal lesions Maternal antibody testing if no prior history of lesions Infant testing If maternal first episode (primary or non-primary) FULL evaluation If maternal recurrence, serum PCR and surface cultures If maternal recurrence, no empiric treatment. If primary maternal episode, empiric acyclovir until tests return. Pediatrics Vol. 131 No. 2 February 1, 2013 pp. e635 -e646 Mortality from HSV in infants Mortality from HSV in infants Prior to anti-viral therapy Disseminated disease 85% mortality at 1yr CNS disease 50% mortality at 1yr Disseminated disease Lethargy, pneumonitis, and severe hepatitis (with DIC) are most closely associated with mortality With current acyclovir treatment Disseminated 29% mortality at 1 yr CNS disease 4% mortality at 1 yr CNS disease Lethargy, prematurity, and seizures are most closely associated with mortality Kimberlin D. HSV, meningitis, and encephalitis in neonates. Herpes Vol11, suppl.2 2004 Morbidity in Neonatal HSV Prior to antiviral therapy, neurological impairment in survivors SEM: 38% CNS: 67% Disseminated: 50% Morbidity in Neonatal HSV Disseminated disease Proportion of survivors with normal neurologic development has increased from 50% to 83% with treatment CNS disease 33% vs 31% (no significant difference) in neurological outcome with treatment Seizure activity is associated with worse outcome in both types 5 4/8/2014 Morbidity in Neonatal HSV SEM disease 38% had abnormal development at 1 yr prior to anti-viral treatment Now fewer than 2% of acyclovir recipients have developmental delays Risk of Recurrence after neonatal HSV Kari Simonsen, MD © Kari Simonsen, MD © Suppressive therapy after neonatal HSV Neonates with HSV disease should receive oral acyclovir suppression for 6 months after completion of IV acyclovir treatment. Infants with CNS disease have been shown to have improved developmental outcomes. Infants with skin lesions have been shown to have fewer skin recurrences. Kimberlin D, Whitley RJ, Wan W, et al. N Engl J Med 2011;365(14):1284-92. Transmission of HIV from Mother to Child Without management of HIV in the mother 16-25% of infants will also become infected Maternal treatment with anti-retrovirals (ARVs) combined with infant prophylaxis reduces infant infections to <2% 6 4/8/2014 HIV testing for pregnant women How are we doing locally? Perform HIV testing routinely for pregnant women Nebraska women all have the option of having HIV early in pregnancy Follow-up testing in the third trimester or when presenting in labor is recommended for high-risk women testing in pregnancy, but rates of testing are variable based on practice setting HIV consent laws in Nebraska are restrictive, with either formal consent to testing, or formal language regarding HIV consent embedded within the “consent to treatment” document for a practice organization Those with potential new risk factors from partners or needle-sharing during the pregnancy Some states have actually changed their statutes to mandate third-trimester screening HIV test during labor if results not available prior What can be done locally? Affordable Care Act policy will cover HIV testing as a routine test for all pregnant women Routine HIV testing will for all pregnant women will help normalize testing and increase test acceptance Reducing administrative burdens of consent would improve testing procedures in Nebraska 7 4/8/2014 (DHHS Guidelines) Maternal HIV treatment recommendations: Factors affecting women’s adherence in pregnancy Assess the woman's HIV disease status and make “Morning sickness” recommendations about initiating or altering an ARV(anti-retroviral) regimen Recommend ARV prophylaxis to all pregnant women regardless of HIV viral load or CD4 count. Ensure that the woman has access to and coordination of services among perinatal, primary care, and HIV providers as well as mental health and drug abuse services and income support as needed. ARV associated gastrointestinal side effects Role of Intrapartum treatment Recommendations: Continue ART on schedule during labor and before scheduled C-section. (AIII) Give IV ZDV to women with VL ≥400 copies/mL (or unknown VL) near delivery, regardless of antenatal regimen or mode of delivery. (AI) IV ZDV not required for women on ART with VL <400 copies/mL. (BII) Obstetric factors associated with transmission: Concern about whether ARVs could have adverse fetal effects For some women, discovering they are pregnant coincides with testing results confirming they have HIV Factors influencing HIV transmission Timing-intrapartum is the the time period where most infections occur Viral load-Maternal HIV RNA level is associated with transmission, however, transmission has been reported from mothers with low/undetectable PVL Maternal ARV treatment-in addition to suppression of viral load, ARVs with demonstrable transplacental passage may also offer infant pre- and post-exposure prophylaxis Infant risk factors for infection: Increased duration of ruptured membranes (linear Premature birth association when viral load detectable) Invasive procedures during gestation and delivery: amniocentesis, fetal scalp electrode, forceps delivery, artificial membrane rupture, episiotomy Mode of delivery: C-section delivery reduces transmission for mothers with PVL >1000 c/mL, unclear advantage if membranes have ruptured Low birth weight Skin barrier breakdown including thrush Breastfeeding—increases risk by 5-20% 8 4/8/2014 Breastfeeding Breastfeeding presents a risk for HIV transmission from mother to baby after delivery ARVs reduce the risk of breastmilk transmission, but do not eliminate this risk In the US and other resource-abundant countries breastmilk alternatives (infant formula) are recommended as the only source of neonatal nutrition In resource-limited settings there may be places where maternal ARVs and breastfeeding are actually safer than reconstituting infant formula Infant ARV Management All HIV-exposed infants should receive a 6-week course of ZDV prophylaxis. (AI) Infants born to mothers who did not receive antepartum ARV drugs Standard 6-week course of ZDV, plus 3 doses of NVP in the first week of life (AI) 1st dose at birth 2nd dose 48 hours later 3rd dose 96 hours after 2nd dose Begin regimen as soon as possible Infant ARV Prophylaxis Safety Considerations Safety considerations Limited data on most ARVs in infants, particularly if given in combination NRTIs: ZDV generally safe, may cause transient anemia 3TC + ZDV may increase hematologic toxicity NVP: rare cases of severe rash and hepatotoxicity; resistance may occur in infants who become HIV infected Protease inhibitors not recommended for neonates No PK data for most LPV/r: possible cardiac and other toxicity HIV Testing for exposed infants Diagnostic HIV tests for infants: (AII) HIV DNA PCR Optimal test for diagnosis in the neonatal period HIV RNA Improves likelihood of identification of “non-B” HIV subtypes Standard antibody tests cannot be used to diagnose HIV infection in infants Detect maternal HIV antibodies up to 18 months HIV testing-usual timeline Virologic tests should be performed at: (AII) 14-21 days, 1 to 2 months, and 4 to 6 months Virologic tests at birth may be performed: If mother did not have good virologic control during pregnancy If adequate follow-up cannot be assured 9 4/8/2014 Making the HIV diagnosis in infants HIV infection in an infant is diagnosed by two positive virologic tests on separate specimens. HIV infection is excluded: Presumptively by two negative virologic tests, one at age ≥14 days and one at age ≥1 month Definitively (in non-breast-fed infants) by two negative virologic tests, one at age ≥1 month or older and one at age ≥4 months Negative status may be confirmed by antibody testing at age 12-18 months Management of HIV-exposed neonates PCP prophylaxis should begin at age 4-6 weeks, after completion of ARV prophylaxis. (AII) Unless HIV infection can be presumptively excluded (2 negative tests at >2 weeks and >1 month of age) HIV-exposed infants should follow the routine immunization schedule Including rotavirus vaccine which is a live vaccine given at 2 months of age See guidelines for diagnosis of non-subtype-B HIV. What are we doing locally? Success at home and abroad! Family Clinic Team based support for pregnant mother and her newborn Meet and Greet with the pediatric team prenatally Pediatric team sees infant after delivery in the hospital (Standing order set available for deliveries outside Omaha) Infant is followed in the family clinic during prophylaxis, follow-up testing, through 18 months for confirmatory Ab. Available to support the PCP if any questions/concerns arise during infancy. http://www.pepfar.gov/ June 2013, PEPFAR announcement that the program has reached 1 million babies with PMTCT over 10 years 10