While sub-Saharan Africa is home to 10% of the world's population, 90% of the world's HIV-infected children live in the region. The majority of these (16% or 280,000) live in South Africa, where HIV/AIDS accounts for 57% of deaths in children below 5 years of age. With improving access to antiretroviral treatment (ART), the disease is changing from fatal to chronic. However, central nervous system penetration by ART is limited and the brain is a reservoir for the virus, with dramatic consequences to the developing fetal/child brain. The """"""""Children with HIV early antiretroviral therapy"""""""" (CHER) project is supported by the Comprehensive International Program for Research on AIDS in South Africa (CIPRA-SA), and has been following a cohort of children born with HIV. Controls were recruited by an interlinking vaccine trial supported by CIPRA-SA. This is a unique and extremely well characterized cohort of children in three treatment arms in which ART (1) was delayed until immunological/clinical criteria were met, (2) commenced before 12 weeks and was interrupted after 40 weeks and (3) commenced before 12 weeks and was interrupted after 96 weeks. After two years, results showed that early HIV diagnosis and ART reduced early infant mortality by 76% and HIV progression by 75%. In an addendum to the study, Dr. Barbara Laughton performed comprehensive neuropsychological testing on the Cape Town participants. The study will end after all children reach 5 years of age in June 2011. Studies of neurodevelopment in children with HIV in developing countries are rare and brain imaging studies of young children with HIV anywhere in the world are also scarce. Longitudinal brain imaging studies in children with HIV are non-existent. We have completed cognitive testing and MR imaging in a subset of the 210 children in the Cape Town branch of the CHER cohort at the age of 5 years. Imaging was done at the Cape Universities Brain Imaging Center (CUBIC), using motion-corrected brain morphometry, spectroscopy and diffusion tensor imaging protocols that were developed jointly by our groups. This facility houses a state- of-the-art research-dedicated Siemens 3 T Allegra MRI scanner optimized for brain imaging and is unique in sub-Saharan Africa. In this project, we will follow the children further with comprehensive neuropsychological testing and brain imaging at the ages of 7 and 9 years. The multi-time point longitudinal data will give us greater power to assess how cognitive and anatomical development proceeds in healthy children between 5 and 9 years and how this is affected by HIV infection and treatment with ART. We hope that our findings will help to guide treatment even in resource-poor environments where imaging may be unavailable. This project builds on a successful collaboration between Dr. Barbara Laughton (Stellenbosch University), Dr. Ernesta Meintjes (University of Cape Town) and Dr. Andri van der Kouwe (Massachusetts General Hospital). The project will build capacity including analysis methods for longitudinal data and advanced image acquisition techniques in young children, without the risk of sedation or anesthesia.

Public Health Relevance

The study builds on an existing collaboration between the Universities of Stellenbosch and Cape Town and the MGH to develop a data analysis infrastructure, collect, analyze and interpret pediatric data using MRI.
We aim to establish the effects of HIV and ART in children and guide treatment strategies in resource-limited settings.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD071664-01
Application #
8256461
Study Section
Special Emphasis Panel (ZRG1-BDCN-Z (50))
Program Officer
Mofenson, Lynne M
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2011-09-30
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$549,901
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Nwosu, Emmanuel C; Robertson, Frances C; Holmes, Martha J et al. (2018) Altered brain morphometry in 7-year old HIV-infected children on early ART. Metab Brain Dis 33:523-535
Toich, Jadrana T F; Taylor, Paul A; Holmes, Martha J et al. (2017) Functional Connectivity Alterations between Networks and Associations with Infant Immune Health within Networks in HIV Infected Children on Early Treatment: A Study at 7 Years. Front Hum Neurosci 11:635
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van Niekerk, Adam; van der Kouwe, Andre; Meintjes, Ernesta (2017) A Method for Measuring Orientation Within a Magnetic Resonance Imaging Scanner Using Gravity and the Static Magnetic Field (VectOrient). IEEE Trans Med Imaging 36:1129-1139
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Randall, Steven R; Warton, Christopher M R; Holmes, Martha J et al. (2017) Larger Subcortical Gray Matter Structures and Smaller Corpora Callosa at Age 5 Years in HIV Infected Children on Early ART. Front Neuroanat 11:95
Taylor, Paul A; Alhamud, A; van der Kouwe, Andre et al. (2016) Assessing the performance of different DTI motion correction strategies in the presence of EPI distortion correction. Hum Brain Mapp 37:4405-4424
Mbugua, Kenneth K; Holmes, Martha J; Cotton, Mark F et al. (2016) HIV-associated CD4+/CD8+ depletion in infancy is associated with neurometabolic reductions in the basal ganglia at age 5 years despite early antiretroviral therapy. AIDS 30:1353-62
Tisdall, M Dylan; Reuter, Martin; Qureshi, Abid et al. (2016) Prospective motion correction with volumetric navigators (vNavs) reduces the bias and variance in brain morphometry induced by subject motion. Neuroimage 127:11-22

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