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 a project supported by the Comprehensive International Program for Research on AIDS in South Africa (CIPRA-SA), that has been following a cohort of children born with HIV. Controls were recruited by an interlinking vaccine trial also supported by CIPRA-SA. This is a unique and extremely well characterized cohort of children in three treatment arms in which (1) ART was delayed until immunological/clinical criteria were met, (2) ART commenced before 12 weeks and was interrupted after 40 weeks and (3) ART 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%. As an addendum to the CHER study, Dr. Barbara Laughton is performing comprehensive neurodevelopmental testing on the participants at the Cape Town Site. The children in the study will be turning 5 years old and returning for their last visit starting June 2010, and this is a unique opportunity to perform magnetic resonance neuroimaging in the children already enrolled to better understand the neural correlates of HIV/AIDS and effects of ART on the developing brain. Neurodevelopment studies in children with HIV in developing countries are rare and brain imaging studies of young children with HIV are rare anywhere. The Cape Town subset of the CHER cohort and controls (210 children) is being studied just a few minutes'walk from the Cape Universities Brain Imaging Center (CUBIC). This facility houses a state-of-the-art Siemens 3 T Allegra MRI research scanner optimized for brain imaging and is unique in Africa. We propose a comprehensive brain imaging study that includes morphometry, spectroscopy and diffusion tensor imaging.
We aim to correlate cognitive and clinical metrics with quantitative imaging results, and hope to identify non-imaging metrics providing the best assessment of impaired brain development to guide intervention in resource-poor environments where imaging may be unavailable. This project represents a new collaboration between Dr. Barbara Laughton (Stellenbosch University), Dr. Ernesta Meintjes (University of Cape Town) and Dr. Andri van der Kouwe (Massachusetts General Hospital) and builds on an existing collaboration between the latter two investigators who are developing motion correction technology. The project will build capacity for advanced image acquisition and brain analysis methods in young children without the risk of sedation or anesthesia.

Public Health Relevance

Most of the world's children born with HIV live in sub-Saharan Africa. With increased access to antiretroviral treatment (ART), these children are surviving longer with chronic HIV infection. There is a concomitant increase in cognitive deficits and impaired brain development by the time the children reach school age. In this project we will establish collaboration between the Universities of Stellenbosch and Cape Town and the Massachusetts General Hospital, to build infrastructure for motion-corrected MRI to study the brains of an existing cohort of 5-year old children started early on ART (CIPRA-SA/CHER). We will correlate clinical and neurocognitive measures with structural, diffusion and spectroscopic data to better understand HIV-infected brain development and identify the best methods to assess impaired brain development in resource-limited settings where MRI is not available.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH096559-02
Application #
8333355
Study Section
Special Emphasis Panel (ZRG1-ICP2-B (51))
Program Officer
Brouwers, Pim
Project Start
2011-09-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$124,625
Indirect Cost
$18,625
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Ackermann, C; Andronikou, S; Saleh, M G et al. (2016) Early Antiretroviral Therapy in HIV-Infected Children Is Associated with Diffuse White Matter Structural Abnormality and Corpus Callosum Sparing. AJNR Am J Neuroradiol 37:2363-2369
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
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
Alhamud, A; Taylor, Paul A; van der Kouwe, Andre J W et al. (2016) Real-time measurement and correction of both B0 changes and subject motion in diffusion tensor imaging using a double volumetric navigated (DvNav) sequence. Neuroimage 126:60-71
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
Alhamud, A; Taylor, Paul A; Laughton, Barbara et al. (2015) Motion artifact reduction in pediatric diffusion tensor imaging using fast prospective correction. J Magn Reson Imaging 41:1353-64
Reuter, Martin; Tisdall, M Dylan; Qureshi, Abid et al. (2015) Head motion during MRI acquisition reduces gray matter volume and thickness estimates. Neuroimage 107:107-15
Taylor, Paul A; Jacobson, Sandra W; van der Kouwe, André et al. (2015) A DTI-based tractography study of effects on brain structure associated with prenatal alcohol exposure in newborns. Hum Brain Mapp 36:170-86
Hinds, Oliver; Wighton, Paul; Tisdall, M Dylan et al. (2014) NEUROFEEDBACK USING FUNCTIONAL SPECTROSCOPY. Int J Imaging Syst Technol 24:138-148
Hess, Aaron T; van der Kouwe, André J W; Mbugua, Kenneth K et al. (2014) Quality of 186 child brain spectra using motion and B0 shim navigated single voxel spectroscopy. J Magn Reson Imaging 40:958-65

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