Developmental and Cognitive Effects of ARV Exposure in Ugandan and Malawian Children

1. Authors: Michael J. Boivin1,2, Limbika Maliwichi-Senganimalunje3,4, Lillian Wambuzi Ogwang5, Rachel Kawalazira3, Alla Sikorskii1,6, Itziar Familiar-Lopez1, Agatha Kuteesa5, Mary Nyakato5, Alex Mutebe5, Mai Nakitende5, MacPherson Mallewa3, Horacio Ruiseñor-Escudero1, Jim Aizire7, Taha Taha7, Mary Glenn Fowler8 Affiliations: 1Department of Psychiatry, Michigan State University; 2Department of Neurology & Ophthalmology, Michigan State University; 3Malawi College of Medicine - Johns Hopkins University; 4Department of Psychology, Chancellor College – University of Malawi; 5Makerere University-Johns Hopkins University; 6Department of Statistics & Probability, Michigan State University; 7Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; 8Department of Pathology, Johns Hopkins University Medical Institute FUNDING: NIH RO1 HD073296 (MPI: Boivin, Fowler) Presentation to the AIDS 2018 Meeting, Amsterdam, 25-July-2018 Developmental and cognitive effects of type of antepartum and postpartum ARV exposure for Ugandan and Malawian PROMISE HIV-exposed versus unexposed children at age 12, 24, 48, and 60 months.

2. Background – Neurodevelopmental Effects of ARV exposure in HEU children • Triple ARVs during pregnancy and breastfeeding dramatically decrease the risk of HIV transmission from mothers to infants • However, antepartum and postpartum exposure to Triple-ARV prophylaxis may disrupt infant neurodevelopment. • The present study evaluates developmental outcomes for Ugandan and Malawian HIV-exposed uninfected (HEU) from the PROMISE-BF RCT study, in comparison to matched HUU reference children.

3. Assessing Developmental Outcomes among ARV exposed Uninfected Infants in PROMISE 1077 BF Using a 2-Factor Design: Factor 1: Prenatal triple ARV regimens, or ZDV; Factor 2: Post-natal maternal triple ARVs or Infant NVP

4. Method– Neurodevelopmental Effects of ARV exposure in HEU children – PROMISE-BF RCT • Pregnant HIV-infected mothers were randomized to Triple-ARV prophylaxis (3TC-ZDV/LPV-RTV or FTC-TDF/LPV-RTV),VERSUSZidovudine (ZDV). • Postpartum, the mother/newborn dyads were randomized to maternal Triple-ARV or infant Nevirapine (NVP) during breastfeeding. • 942 children were enrolled between 9 and 12 months of age: • About half were HUU • About half were girls • About half were from Uganda or Malawi

5. Mullen Scales of Early Learning (MSEL) at 12, 24, and 48 months of age Kaufman Assessment Battery for Children, 2nded (KABC-II) at 48 and 60 months Note: Results adjusted for data collection site (Kampala – Uganda, Blantyre – Malawi)

6. Kampala MUJHU/GHU IMPAACT and PROMISE NeuroDev Testing QA Assessment Center Team (Left to Right: Ssesanga Titus Kisa, Mary Nyakato, NamukooliJackie Lydia , Agatha Kuteesa, M.J. Boivin

7. Malawi - Mullen Scales of Early Learning – Cognitive Composite Standard Score Uganda - Mullen Scales of Early Learning – Cognitive Composite Standard Score 12 Months 24 Months

8. Malawi - Mullen Scales of Early Learning Cognitive Composite Standard Score Uganda - Mullen Scales of Early Learning Cognitive Composite Standard Score 48 Months 48 Months

9. Kaufman Assessment Battery for Children (KABC-II) Standardized Mental Processing Index: Box Plot Comparison of PROMISE ARV Treatment Arms Infant NVP Box represents 3rd and 1st quartile bisected by median, with range of scores and outliers.

10. PROMISE Neurodevelopmental Study of ARV Exposure: Unadjusted Standardized (American Norms) Group Means and Standard Deviations for KABC-II Global Scales (48, 60 months) and MSEL Composite Cognitive Score (12, 24, 48 months)

11. Conclusions– Neurodevelopmental Effects of ARV exposure in HEU children • Children of mothers on antepartum triple ARV + postpartum maternal triple ARV were developmentally and cognitively similar to the unexposed reference group. • Triple maternal ARV and unexposed reference children had the highest point estimates, and were better than other exposure group combinations (e.g., mothers removed from triple ARV after birth of child). • Stunting (HAZ) was the most significant predictor of development and cognition, and not HIV exposure status per se. Our HUU reference group was well matched to the exposed groups at both sites.

12. Descriptive Statistics for PROMISE Neurodevelopmental Effects of ARV Exposure

13. When controlling for WHO Standardized Height-for-Age (HAZ) as a time-varying covariate • MSEL composite was significantly related HAZ (p<.01); overall differences by exposure at 48 months were attenuated (p=.07); • MSEL Receptive language score was significantly related to HAZ (p<.01); and HAZ mediates differences in receptive language by exposure. • KABC Mental Processing Index (MPI) and non-verbal index (NVI) were significantly related to HAZ (p<.01); no changes in the results (no significant differences by exposure group).

14. HEU vs. HUU Neurodevelopment in Early Childhood: Inconsistent Findings • Uganda and Malawi – No differences (Boivin et al., 2018; AIDS 2018 Amsterdam • Botswana – No differences (Chaudhury et al., 2017; journal Pediatrics, vol. 140) • and No differences between cARV and mARV PMTCT treatment arms for HEU (Chaudhury et al., 2018; journal AIDS, vol. 32, pp 1173-1183) • South Africa (Cape Town) – Differences (Wedderburn et. al., 2018; HIV Pediatrics Workshop 21-July-2018 Amsterdam) • Kenya (Western) – Differences (Yunusa et al., 2018; HIV Pediatrics Workshop 21-July-2018 Amsterdam)

15. HEU vs. HUU Neurodevelopment in Early Childhood: Inconsistent Findings • Equivalence of HUU reference group to HEU population in terms of: • Standard of medical care (Triple ARV versus ZDV or no treatment; viral suppression and adherence) for mothers with HIV • Quality of caregiving due to functionality in daily caregiving activities in labor-intensive subsistence agricultural context • Quality of nutrition for HEU as opposed to HUU children in labor-intensive subsistence agricultural context • Socio-economic and educational risk factors for HIV infection in women in sub-Sahara Africa, and the corresponding risk for early childhood development

16. Breast Feeding and Early Child Development – Prevalence by Country • At 12 months in Uganda, breastfeeding=yes was • Antepartum Triple ARV and Post-Partum infant NVP - 53% • Ante- and Post-partum Maternal Triple ARV - 50% • Antepartum Maternal ZDV and Post-partum infant NVP - 59% • Antepartum Maternal ZDV and Post-Partum maternal Triple ARV - 36% • Unexposed controls 87% • At 12 months in Malawi, breastfeeding=yes was • Antepartum Triple ARV and Post-Partum infant NVP - 91% • Ante- and Post-partum Maternal Triple ARV - 89% • Antepartum Maternal ZDV and Post-partum infant NVP - 89% • Antepartum Maternal ZDV and Post-Partum maternal Triple ARV - 76% • Unexposed controls 98%

17. Breast Feeding and Early Child Development – Results by Country • In the longitudinal analysis of the MSEL composite cognitive ability scores in Uganda (12, 24, 48 months), breastfeeding status at 12 months was significantly related (P<0.008) to outcomes (in the expected direction), even after adjusting for HAZ. • This was NOT true in Malawi, in part probably because of the very high breast feeding prevalence. • We simply do not have many children who were NOT breast fed at 12 months in Malawi for either the HEU or HUU children, so we cannot evaluate the benefits of breast feeding on longitudinal neurodevelopment.

18. ARV and HIV immunopathogenesis and comorbidities Maternal Depression Early Childhood Development (ECD) Intervention Herba C, Glover V, Ramchandani P, Rondon M, Maternal depression mental health in and early-childhood: an examination of underlying mechanisms in low-income and middle-income countries. The Lancet, 2016:3 (10):983-992.

19. Caregiver Training for Early Childhood Development (ECD) Care for Childhood Development (CCD): A UNICEF/WHO Global Movement “Plasticity is a double-edged sword that leads to both adaptation and vulnerability” From Neurons to Neighborhoods Shonkoff, J. P. & Phillips, D. A. (Eds.), 2000 Nutrition and Early Cognitive Stimulation are the critical ingredients in the first 1000 days

20. Maternal functionality is a prerequisite of better quality of caregiving for Early Childhood Development Intervention

21. INTERPRETATION: Child Neurodevelopmental Benefits from Improved Maternal Health • Maternal triple ARV at both the antepartum and postpartum stage presumably results in better clinical management of HIV disease and viral suppression. Caregiving health and vitality outweighs triple ARV exposure risk for impoverished children. • Monthly clinic visits to obtain the medications may lead to better supportive health care for mother and child (e.g., treatment for anemia, malaria, micronutrient support). • Better gestational and post-natal care for the mom allows her to provide better quality of caregiving for the child, enhancing development in the first 1000 days.

22. Special thanks to the Makerere University – Johns Hopkins University (MUJHU) & Johns Hopkins University - Malawi College of Medicine teams. FUNDING: NIH RO1 HD073296 (MPI: Boivin, Fowler)

23. Thank you!

24. NEXT STEPS for present PROMISE Neurodev HEU treatment cohorts • Equivalence of HUU reference group to HEU population in terms of: • Standard of medical care (Triple ARV versus ZDV or no treatment; viral suppression and adherence) for mothers with HIV • Quality of caregiving due to functionality in daily caregiving activities in labor-intensive subsistence agricultural context • Quality of nutrition for HEU as opposed to HUU children in labor-intensive subsistence agricultural context • Socio-economic and educational risk factors for HIV infection in women in sub-Sahara Africa, and the corresponding risk for early childhood development

25. P1060/P1104s Study Sites Accrual completed on 17 December 2014, with 615 participants enrolled (246 into HIV+ cohort; 185 into HEU cohort; 184 into HU cohort) MUJHU, Kampala, Ugandan=89 participants (14%) FAM-CRU, Cape Town, South African=142 participants (23%) Malawi CRS, Lilongwe, Malawin=82 participants (13%) Soweto, Johannesburg, South African=100 participants (16%) Harare Family Care, Harare, Zimbabwen=133 participants (22%) Wits RHI Shandukani Research, Johannesburg, South African=69 participants (11%)