HIV-Affected but not Infected - PDF Free Download

HIV-Affected but not Infected The Dilemma of HIV-Exposed Uninfected Infants and Children Kate Powis, MD, MPH, MBA

Disclosures No financial conflicts or disclosures

Objectives HIV-exposed uninfected (HEU) child population HEU selected infant/child outcomes Mortality Morbidity Review HEU child health surveillance challenges

1.600.000 HIV+ Women by ARV Access in Pregnancy 1.400.000 Total Estimated # of Pregnant Women Living with HIV 1.200.000 Pregnant Women Living with HIV Women without ARV Use in Pregnancy 1.000.000 800.000 600.000 Pregnant Women Living with HIV with ARV Use in Pregnancy 400.000 200.000 0 2010 2011 2012 2013 2014 2015 UNAIDS-SPECTRUM 2016

1.600.000 HIV+ Women by ARV Access in Pregnancy & New HIV Infections among Children 1.400.000 1.200.000 Pregnant Women Living with HIV Women without ARV Use in Pregnancy 1.000.000 800.000 600.000 Pregnant Women Living with HIV with ARV Use in Pregnancy 400.000 200.000 Newly HIV-Infected Children 0 2010 2011 2012 2013 2014 2015 UNAIDS-SPECTRUM 2016

After climbing a great hill, one only finds that there are many more great hills to climb Nelson Mandela

1.600.000 Infants Born to Women Living with HIV by Infant HIV Status 1.400.000 1.200.000 1.000.000 HIV Exposed Uninfected Infants 800.000 600.000 400.000 200.000 HIV-Infected Infants 0 2010 2011 2012 2013 2014 2015 New Child HIV+ HIV-Exposed Uninfected Children UNAIDS-SPECTRUM 2016

1.600.000 Infant born to Women Living with HIVby HIV and ARV status 1.400.000 1.200.000 1.000.000 HIV & ARV Exposed Uninfected Infants 800.000 600.000 400.000 HIV Exposed ARV Unexposed Uninfected Infants 200.000 HIV-Infected Infants 0 2010 2011 2012 2013 2014 2015 New Child HIV+ New Child HEU ARV- New HIV/ARV Exposed Infant UNAIDS-SPECTRUM 2016

Prevalence of Infant HIV & ARV In Utero Exposure Number of children under age 5 6.000.000 5.000.000 4.000.000 3.000.000 2.000.000 1.000.000 2015: 7.1 million HEU under 5 year olds ~ 5.6 million also ARV-exposed 0 2010 2011 2012 2013 2014 2015 HIV+ HEU ARV- HEU ARV+ UNAIDS-SPECTRUM 2016

Objectives HIV-exposed uninfected (HEU) child population HEU selected infant/child outcomes Mortality Morbidity Review HEU child health surveillance challenges

Elevated HEU Mortality Source: le Roux et al TMIH 2016;21:829-845 Source: Brennan et al AIDS 2016;30:2351-2360

Elevated HEU Mortality RR birth 12 months: 1.8 (1.1, 2.8) RR 12 24 months: 1.6 (1.1, 2.3) RR > 24 months: 1.7 (1.1, 2.6) Source: le Roux et al TMIH 2016;21:829-845 Source: Brennan et al AIDS 2016;30:2351-2360

Botswana Child Mortality Bending the Curve http://www.who.int/maternal_child_adolescent/epidemiology/profiles/neonatal_child/bwa.pdf

Botswana Child Mortality Bending the Curve Maikaelelo Study HEU Mortality 47.3 2012-2013 Maikaelelo Study HU Mortality 16.0 2012-2013 http://www.who.int/maternal_child_adolescent/epidemiology/profiles/neonatal_child/bwa.pdf Zash et al.. BMC Pediatrics 2016;16:103 Lockman et al. Lancet Global Health 2017;5:e491-500.

Botswana Child Mortality Bending the Curve Maikaelelo Study HEU Mortality 47.3 Mpepu Study HEU Mortality 22.5 2012-2013 Maikaelelo Study HU Mortality 16.0 2011-2015 2012-2013 http://www.who.int/maternal_child_adolescent/epidemiology/profiles/neonatal_child/bwa.pdf Zash et al.. BMC Pediatrics 2016;16:103 Lockman et al. Lancet Global Health 2017;5:e491-500.

Complexity of HEU Child Health Outcomes Disparities HEU Risk Areas Morbidity Mortality Growth Cognition Behavioral NCDs Adapted from Slogrove et al Pediatr Infect Dis J 2017;36:e38-e44

The Tsepamo Study Preterm Delivery by ARV Regimen 30% 16% 22% 19% 25% 24% 3,7% 4,1% 5,2% 5,9% 5.2% 9,0% *Models adjusted for maternal age, educational attainment and gravida Zash CROI 2017 Oral Presentation

The Tsepamo Study Small-for-Gestational-Age 25% 29% 28% 15% 17% 21% 5.4% 7,3% 11% 13% 14% 13% HIV- Unexposed (N=34,616) SGA arr* (95% CI) Very SGA arr* (95% CI) TDF/FTC/EFV (N=2,503) TDF/FTC/NVP (N=775) ZDV/3TC/NVP (N=1,403) TDF/FTC/LPV-r (N=237) ZDV/3TC/ LPV-r (N=169) ref 1.4 (1.2,1.7) 1.7 (1.5,1.9) 1.6 (1.3,2.0) 1.1 (0.8,1.6) ref 1.5 (1.2,1.9) 1.8 (1.4,2.2) 1.8 (1.3,2.6) 1.7 (1.1,2.6) *Models adjusted for maternal age, educational attainment and gravida Zash CROI 2017 Oral Presentation

HEU Child and Lung Health Slogrove; Pediatric Respiratory Reviews 2017

Passive Immunity to Respiratory Pathogens - Brazil Geometric mean (95% CI) antibody concentration (EU/ml) against Respiratory Viruses and Pneumococcus at Birth HIV Exposed Uninfected Infants HIV-Unexposed Infants Respiratory Infection Type N Concentration N Concentration P Value Influenza A 198 52 (44, 63) 88 197 (175, 222) <0.0001 Respiratory Syncytial Virus 200 77 (67, 90) 88 50 (42, 59) 0.0002 Parainfluenza Virus 1 202 4 (3, 6) 88 11 (10, 13) <0.0001 Parainfluenza Virus 2 200 8 (6, 11) 88 26 (22, 30) <0.0001 Parainfluenza Virus 3 195 11 (9, 15) 88 26 (24, 29) <0.0001 Pneumococcus 5 188 0.8 (0.8, 0.9) 88 1.1 (1.0, 1.2) <0.0001 Pneumococcus 6B 188 0.7 (0.6, 0.7) 88 0.9 (0.7, 1.0) 0.002 Pneumococcus 14 199 2.9 (2.6, 3.1) 88 3.8 (3.3, 4.4) 0.0001 Weinberg et al AIDS 2017;31:669-679

HEU Children and Immune Abnormalities Afran et al; Clinical and Experimental Immunology 2013 doi:10.1111/cei.12251

Infant Viral Respiratory Infections and Outcomes South Africa Incidents Rates of Viral Lower Respiratory Tract Infections per 100,000 Population of Hospitalized Infants > 2 Days of Life but 6 Months of Life Viral Infection Type HIV Exposed Uninfected Infants Incident Rates (95% CI) HIV-Unexposed Infants Incident Rates (95% CI) Incidence RR All LRTIs Mortality 14,097 from (13,252-14,982) Viral Respiratory Infections in 10,313 the First (9,858-10,784) Six Months of Life 1.4 (1.3-1.5) by Infant HIV-Exposure Status RSV 5003 (4,505-5,541) 3,507 (3,244-3,787) 1.4 (1.3-1.6) HEU HUU Rhinovirus Infection Type 4,581 (4,105-5,097) Case Fatality Ratio Case Fatality 3,074 Ratio (2,827-3,357) OR (95% CI) 1.5 (1.3-1.7) Adenovirus RSV 1,563 (1,291-1,8770 5/592 (2%) 0/5231,253 (0%) (1,097-1,424) 12.2 (1.7- ) 1.2 (1.0-1.6) Enterovirus Influenza 1,196 (959-1,474) 2/28 (7%) 1/54 (2%) 680 (567-809) 4.1 (0.4-17.1) 1.8 (1.3-2.3) hmpv Rhinovirus 816 (622-1,050) 7/288 (2%) 9/477 (2%) 573 (470-692) 1.3 (0.5-3.5) 1.4 (1.1-2.0) Influenza Adenovirus 503 (354-693) 3/119 (3%) 2/228 (1%) 434 (344-539) 2.9 (0.5-17.7) 1.2 (0.8-1.8) hmpv 0/9 (0%) 1/86 (1%) 1.7 (0-64.5) Enterovirus 0/59 (0%) 2/76 (3%) 0.5 (0.6.9) Cohen et al Pediatrics 2016;e20153272

Treatment Failure Mortality Pneumonia Treatment Failure/Mortality among HEUs Infants/Children in Botswana Botswana hospital based prospective cohort study of infants/children 1-23 months admitted for pneumonia 153 (64%) HIV-unexposed 64 (27%) HIV-exposed uninfected 8 (20%) HIV-infected Kelly et al. Journal of Pediatric Infectious Disease Society 2015;4:e117-126

Treatment Failure Pneumonia Treatment Failure/Mortality among HEUs Infants/Children in Botswana HEU children experienced higher risk of treatment failure at 48 hours ALL [RR 1.83; 95% CI 1.27-2.64; p=0.001] < 6 mos [RR 2.10; 95% CI 1.42-3.08; p=0.001] Mortality HEU children experienced higher risk of inhospital mortality ALL [RR 4.31; 95% CI 1.44-12.87; p=0.01] < 6 mos [RR 6.05; 95% CI 2.08-17.58; p=0.0009] Kelly et al. Journal of Pediatric Infectious Disease Society 2015;4:e117-126

HEU Children and Growth Botswana Studies In utero AZT Exposure Breastfed HEU Infants in the Mashi (n=303) and Mma Bana (n=516) studies In utero Triple ARV Exposure In utero exposure to triple ARVs compared with AZT monotherapy associated with lower mean length-for-age z-score at 24 months [-0.34; 95% CI -0.53 to -0.15; p=0.0004] Powis et al AIDS 2016;30:211-220 Cross-sectional survey conducted in 5 health districts in Botswana enrolling caregiver-child pairs attending monthly under 5 well child clinics 67% of the excess risks of stunting in children 2 years of age attributable to birth weight < 2500 grams Sudfeld et al. JAIDS 2016;73:182-189 < 1 year HEU Children (n=100) HUU Children (n=283) 1 year to < 2 years HEU Children (n=109) HUU Children (n=282) 2 years to < 5 years HEU Children (n=187) HUU Children (n=544) Stunting Prevalence 20.0% 11.0% 22.9% 29.8% 31.0% 20.8% Multivariate Relative Risk of Stunting 1.91 (1.17 3.09) REF 0.64 (0.43 0.95) REF 1.42 (1.07 1.87) REF P-value 0.01 0.03 0.01

HEU Children and Neurodevelopment AIDS PSYCHOLOGICAL CARE AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV 160 HEU and 167 HU children age and gender matched controls in the PREDICT Trial in Thailand and Cambodia age 2-15 years. HEU children with statistically lower scores in verbal IQ, full scale IQ, and Binet Bead Memory Conclusions: Small differences in some but not all neurodevelopmental outcomes among HEU children Unclear as to the immediate and long-term clinical significance Kerr et al AIDS Care 2014;26;1327-1335

Objectives HIV-exposed uninfected (HEU) child population HIV-exposed uninfected infant/child outcomes Mortality Morbidity Review HEU child health surveillance challenges

Maternal ARV Use in Pregnancy over Time Canadian Perinatal HIV Surveillance Program 100 90 80 70 60 50 40 30 20 10 0 2002 2004 2006 2008 2010 2012 2014 2016 Tenofovir Zidovudine Abacavir PIs NNRTIs INSTIs Courtesy of Dr. Jason Brophy

Zash CROI 2017 Oral Presentation Maternal ARV Use in Pregnancy over Time Botswana Research Data % of Women on ART from Conception 100 90 80 70 60 50 40 30 20 10 0 Before 2012 PMTCT: WHO Option A - ZDV if CD4 >250 - ZDV/3TC/NVP if CD4 <250 2012-2016 PMTCT: WHO Option B -TDF/FTC/EFV (life-long if CD4 <350) 2009 2010 2011 2012 2013 2014 2015 2016 TDF/FTC/EFV ZDV/3TC/NVP ZDV/3TC/LPV/r TDF/FTC/NVP TDF/FTC/LPV/r Other

HEU Health Disparities Etiology Matters

Establishing an HEU Child Outcomes Agenda Maternal-Child Health Care Infrastructure Bench Research Clinical Research Community Advocacy Ministry of Health & Public Health Policy

AIDS is clearly a disaster, effectively wiping out the development gains of the past decades and sabotaging the future. - President Nelson Mandela, South Africa

It always seems impossible until it is done Nelson Mandela FOR EVERY CHILD END AIDS Seventh Stocktaking Report, 2016

Text

Acknowledgements Elaine Abrams Jason Brophy Stanzi le Roux Lynne Mofenson Landon Myer Amy Slogrove