Lifelong Monitoring of HIV-Exposed Uninfected Infants is CRUCIAL! Jennifer Jao, MD, MPH Icahn School of Medicine at Mount Sinai

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1 Lifelong Monitoring of HIV-Exposed Uninfected Infants is CRUCIAL! Jennifer Jao, MD, MPH Icahn School of Medicine at Mount Sinai

2 Increasing numbers of HEUs Worldwide New HIV+ infections in children HIV+ pregnant women requiring ARVs for PMTCT UNAIDS 2013: AIDS by the numbers.

3 Increasing numbers of HEUs Worldwide New HIV+ infections in children HIV+ pregnant women requiring ARVs for PMTCT UNAIDS 2013: AIDS by the numbers.

4 Follow-up of children with exposure to ARVs should continue into adulthood because of the theoretical concerns regarding the potential for carcinogenicity of nucleoside analogue ARV drugs. Information regarding such exposure should be part of ongoing permanent medical records for children, particularly those who are uninfected. (DHHS Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2014) the potential long-term toxicity in healthy exposed infants and the continuing emergence of new ARVs make it advisable to devise a mechanism whereby the identification and registration of potential adverse long-term effects of such exposures may be recorded.. (Recommendations by the Spanish Society of Pediatric Infectious Diseases for the follow up of the child exposed to HIV and to ARV drugs during pregnancy and the neonatal period, 2012) Do we need long term monitoring of HEUs? Long term follow up of symptomatic children may be justified and should be guided by best clinical practices. Families should alert the child s physician and/or the physician who treated the child during the first months of life of any significant clinical events. (Medical Management of Persons Living with HIV, Report from Expert Panel of CNS and ANRS, 2013)

5 Drug/ Toxin, Stress, Infection Reorganization/ Adaptation Cellullar Epigenetic Organ

6 In utero milieu and Fetal Programming have lasting effects Maternal Infection Metabolic Changes Drug/Toxin Example: Influenza, Toxoplasmosis Example: IUGR Example: Diethylstilbestrol Schizophrenia Insulin resistance, Type 2 DM, CV Disease Cervical, Vaginal, Breast Cancer; Infertility Risk for Chronic Disease Later in Life

7 Short and Long Term Concerns for In Utero HIV/ARV Exposure In Utero HIV/ARV Exposure SGA Mitochondrial Toxicity Preterm Birth Congenital anomalies Poor Bone Health?! Metabolic Complications?! Neurologic/ Cognitive Complications?! Cardiovascular Disease?! Diabetes?! Genotoxicity Mental Health Problems?! Malignancy?!

8 HIV/ARV is associated with Preterm Birth Authors Cohort Sample size Finding Cotter et al 2006 JID U.S. 999 Increased risk with PI vs. non-pi Sibiude et al 2012 CID French Perinatal Cohort 1253 Increased risk with boosted PI Lopez et al 2012 AIDS Spain 1557 Increased risk with HIV exposure; Increased risk with cart Watts et al 2013 JID PHACS 1869 Increased risk with 1 st trimester PI ECS 2000 AIDS Schulte et al 2007 Pediatrics Townsend et al 2010 BJOG European Collborative Study and Swiss Mother+Child Cohort 3920 Increased risk with cart (PI and non-pi based) Increased risk with 1 st trimester cart U.S Increased risk with PI Pediatric Spectrum of HIV Disease, European Collaborative Study, National Study of HIV in Pregnancy and Childhood 19,585 Increased risk with cart Chen et al 2012 JID Botswana 33,148 Increased risk with HIV exposure; increased risk with cart

9 n=19,585 Pediatric Spectrum of HIV Disease, European Collaborative Study, National Study of HIV in Pregnancy and Childhood Townsend C et al BJOG 2010

10 n=19,585 Pediatric Spectrum of HIV Disease, European Collaborative Study, National Study of HIV in Pregnancy and Childhood Townsend C et al BJOG 2010

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14 By the time HEU s are diagnosed as HEU s at 4 months, most of the significant medical issues they might have such as prematurity, low birth weight, and congenital defects are already identified and managed appropriately.

15 SGA/Preterm Birth have long-lasting sequelae: Adult Metabolic and Cardiovascular Disease Author Study Finding Barker et al 1989 Lancet Cohort Low BW associated with death from ischemic heart disease in adulthood De Jong et al 2012 Hypertension Hofman et al 2006 NEJM Rotteveel et al 2009 Pediatrics Whincup et al 2008 JAMA Lawlor et al 2006 Diabetologia Meta analysis Cohort POPS cohort Pooled analysis Cohort Preterm birth and VLBW are associated with HTN in adulthood Preterm birth is associated with insulin resistance in adulthood Preterm birth is associated with insulin resistance and HTN in adulthood Lower BW and SGA are associated with insulin resistance in adulthood BW and GA are inversely associated with diabetes in adulthood

16 In utero HIV/ARV perturbs intermediary metabolism DIRECTLY, independent of SGA/ prematurity Abnormal Fatty-Acid Oxidation in HIV-Exposed Uninfected Neonates in the United States. Kirmse B, Yao T, Hofher S, Williams P, Kacanek D, Hazra R, Borkowsky W, Van Dyke R, Summar M. CROI 2014; Boston.

17 Preterm Birth is well-documented to cause neurocognitive sequelae In Utero HIV/ARV exposure may confer an independent risk for neurocognitive dysfunction later in life

18 Preterm Birth is well-documented to cause neurocognitive sequelae In Utero HIV/ARV exposure may confer an independent risk for neurocognitive dysfunction later in life

19 Preterm Birth is well-documented to cause neurocognitive sequelae In Utero HIV/ARV exposure may confer an independent risk for neurocognitive dysfunction later in life

20 Preterm Birth is well-documented to cause neurocognitive sequelae In Utero HIV/ARV exposure may confer an independent risk for neurocognitive dysfunction later in life

21 Not all congenital defects are evident at birth. Among 12,888 children, 1 st trimester AZT exposure was significantly associated with CHD (aor=2.2; CI= ).

22 Not all congenital defects are evident at birth. Among 12,888 children, 1 st trimester AZT exposure was significantly associated with CHD (aor=2.2; CI= ).

23 In utero HIV/ARV is associated with mitochondrial toxicity Authors Study Sample size Findings Poirier et al 2003 WITS 30 Decreased mtdna Ross et al 2011 U.S. 46 Abnormal mtdna levels Decreased Complex II:IV Gingelmaier et al 2009 Aldrovandi et al 2010 Germany 77 Decreased mtdna Decreased Complex II:IV WITS, PACTG Abnormal mtdna levels Côté et al 2008 Canada 154 Increased mtdna levels Abnormal mitochondrial gene expression McComsey et al 2008 ACTG Increased mtdna levels Torres et al 2009 U.S. 108 Increased mitochondrial mutations

24 In utero HIV/ARV is Associated with Clinically Significant Mitochondrial Dysfunction 18 month incidence of neuro-mitochondrial disease was 0.26% (95% CI: ) in HIV-exposed children compared to 0.01% in the general pediatric population

25 In utero tenofovir exposure affects postnatal growth and bone mineral content CID June 2015 epub print

26 HEU s have high rates of mental health problems Amongst HEUs, the prevalence of any psychiatric disorder (57%) remained high and mood disorders INCREASED ( %, p<0.05) over time compared to HIV-infected children in the CASAH cohort. Mental health problems were more prevalent in HEU children than HIV-infected children (38 vs. 25%, p<0.01) in the PHACS cohort

27 Both AZT and TDF confer genotoxicity Elevations in GPA N/N variants persisted even up to 1 year of age.

28 Both AZT and TDF confer genotoxicity p<0.05 Frequency of aneuploidy was significantly higher with AZT exposure, but both AZT and TDF exhibited altered gene expression for DNA repair and telomere maintenance pathways.

29 Lifelong follow-up will increase stigma to HEU infants. Stigma is a small price to pay if lifelong follow-up uncovers a serious late adverse effect of in utero HIV/ARV exposure!

30 Lifelong follow up may not be warranted in all settings. With the scale up of PMTCT and Pediatric ART programs there are already competing resources in resource-limited settings. Given that the HIV burden in women is greatest in resource-constrained countries where rapid expansion in ARV use in pregnancy is expected with implementation of WHO guidelines, there is an ethical imperative to systematically and critically evaluate the safety of these recommendations for the fetus/infant both in terms of potential teratogenicity but also long term outcomes. Mofenson LM & Watts DH PLOS Medicine

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32 Vote YES! for long term follow up of HEUs Si! ใช نعم kyllä 예 THANK YOU!