Project 1: IMAGE

PROJECT 1

BACKGROUND

There is a growing number of children exposed to HIV who remain uninfected (CHEU) alongside increasing antiretroviral (ARV) use in pregnancy for either HIV treatment or prevention.^1-3 CHEU experience higher risk of impaired neurodevelopment, including poorer language, motor function, and school performance.^4-6 Several factors may potentially affect sensitive periods of brain maturation among CHEU, including in-utero HIV exposure, inflammation, antiretroviral therapy (ART) neurotoxicity, and socioenvironmental factors of families affected by HIV. Drivers of neurodevelopmental differences observed among CHEU remain unclear.⁶ Neuroimaging offers the opportunity to identify neurobiological pathways underlying developmental outcomes in children and adolescents with differing HIV/ARV exposures and elucidate factors that compromise neurodevelopment. Magnetic Resonance Imaging (MRI) studies of young CHEU suggest structural brain differences compared to children without HIV exposure (CHU), associated with functional outcomes like language.⁷ Yet, no longitudinal neuroimaging studies of CHEU map brain development trajectories through older childhood into adolescence, and data from the era of dolutegravir (DTG) do not exist to date.

Prospective neuroimaging data following HIV/ARV exposure is needed to assess brain development beyond early childhood and identify pathways associated with neurocognitive outcomes. Large, multi-country evaluations are especially needed as population-level standard distributions of brain metrics and neurodevelopment scores are not yet defined¹. This study addresses key knowledge gaps by characterizing brain maturation of CHEU into adolescence for the first time in a large multi-country cohort, identifying pathways for developmental differences (e.g., ARV, HIV exposure), and understanding the impact of neurobiological alterations on neurodevelopmental outcomes among children HEU. We will use novel MRI approaches now accessible in high HIV prevalence settings and create a large paediatric neuroimaging repository.

REFERENCES

1. Slogrove AL, Powis KM, Johnson LF, Stover J, Mahy M. Estimates of the global population of children who are HIV-exposed and uninfected, 2000-18: a modelling study. Lancet Glob Health. Jan 2020;8(1):e67-e75. doi:10.1016/S2214-109X(19)30448-6

2. Lee S, Allison S, Brouwers P. Strengthening the evidence to improve health outcomes of children with perinatal HIV exposure. J Int AIDS Soc. Oct 2023;26 Suppl 4(Suppl 4):e26160. doi:10.1002/jia2.26160

3. World Health Organization. WHO Technical brief: Preventing HIV during pregnancy and breastfeeding in the context of pre-exposure prophylaxis (PrEP). 2017.

4. Wedderburn CJ, Weldon E, Bertran-Cobo C, et al. Early neurodevelopment of HIV-exposed uninfected children in the era of antiretroviral therapy: a systematic review and meta-analysis. Lancet Child Adolesc Health. Jun 2022;6(6):393-408. doi:10.1016/S2352-4642(22)00071-2

5. Benki-Nugent SF, Yunusa R, Mueni A, et al. Lower Neurocognitive Functioning in HIV-Exposed Uninfected Children Compared With That in HIV-Unexposed Children. J Acquir Immune Defic Syndr. Apr 01 2022;89(4):441-447. doi:10.1097/QAI.0000000000002881

6. Powis KM, Lebanna L, Schenkel S, et al. Lower academic performance among children with perinatal HIV exposure in Botswana. J Int AIDS Soc. Oct 2023;26 Suppl 4(Suppl 4):e26165. doi:10.1002/jia2.26165

7. Wedderburn CJ, Yeung S, Subramoney S, et al. Association of in utero HIV exposure with child brain structure and language development: a South African birth cohort study. BMC Med. Mar 22 2024;22(1):129. doi:10.1186/s12916-024-03282-6

8. Abate F, Adu-Amankwah A, Ae-Ngibise KA, et al. UNITY: A Low-Field Magnetic Resonance Neuroimaging Initiative to Characterize Neurodevelopment in Low and Middle-Income Settings. Developmental Cognitive Neuroscience. 2024/05/31/ 2024:101397.

OBJECTIVES

We will undertake novel low-field neuroimaging in established cohorts in Botswana (FLOURISH, Motheo) and Kenya (HOPE, PrIMA-X) of CHEU with varied ART exposure (including DTG), children with only ARV exposure (PrEP), and children unexposed to HIV or ARV (CHU) to create one of the largest pediatric neuroimaging repositories in a combined cohort of n=2050 children (5-10 years; Aims 1-2) and n=330 adolescents (14-16 years; Aim 3) to assess neurobiological effects of ARV/HIV exposure.⁸

Approach: We will leverage ongoing CHEU cohorts in Botswana and Kenya, followed from early life with in-utero exposure to various ART regimens (e.g., DTG), children with only ARV exposure (PrEP), and children without HIV or ARV exposure. We will extend follow up through age 10 years with longitudinal neuroimaging on all children (up to 3 timepoints per child). We will use Low Field(LF)-MRI to quantify global and regional brain volumes and high-field MRI to measure detailed brain structure and microstructure in a subset . We will compare structural brain metrics by ARV exposure (duration, gestational timing, and ARV drug type/class), HIV exposure, and country (Kenya, Botswana) at each timepoint and longitudinally.

Hypothesis: Mean subcortical brain volumes will be smaller in CHEU vs. CHUU with and without PrEP exposure.

Approach: We will conduct age-appropriate batteries (Executive Function [EF] Touch, Kaufman Assessment Battery for Children [KABC], Penn Computerized Neurocognitive Battery [PennCNB]) in ongoing cohorts from ages 5-10. We will identify correlates of complex cognition, EF, and language (by HIV/ARV exposure and overall), incl. brain volumes from Aim 1, social (e.g., food security) and biological (e.g., preterm birth) factors.

Hypothesis: Smaller brain volumes will be associated with worse neurocognitive function, especially for CHEU.

Hypothesis: Poor school performance in adolescents who are HEU will be associated with smaller brain volumes.

STUDY TEAM

MULTIPLE PRINCIPAL INVESTIGATOR AND SENIOR ADVISOR