DESCRIPTION (provided by applicant): In South Africa, HIV-infected children in poorer families are often responsible for the parental care of younger (often uninfected) siblings and so any disease events they experience have far-reaching consequences. As in adults, atherosclerosis due to HIV-related chronic inflammation despite adequate viral suppression is a growing concern for children on antiretroviral therapy (ART). Effective lifestyle, diet and therapeutic interventions are available but efficacy is limited unless instituted early in pathogenesis of atherosclerosis. Diagnosis of asymptomatic increased atherosclerosis risk requires effective nationwide surveillance at primary health clinic level. This longitudinal cohort
control study intends to quantify excess atherosclerosis risk in HIV-infected children on ART and to generate and validate a low tech screening algorithm to identify affected asymptomatic individuals using simple input variables that can be routinely collected during primary healthcare follow-up. AIM 1 will investigate the magnitude and longitudinal evolution of atherosclerotic vascular disease (AVD) risk in virally-suppressed perinatally-infected children on ART. Aorto-femoral pulse wave velocity (PWV), a measure of arterial elasticity, predicts incident cardiovascular events in asymptomatic adults and is a reliable gold- standard marker of subclinical atherosclerosis. We will compare longitudinal change in PWV Z-score over 5 years in children with and without HIV. PWV in this Primary Cohort will be adjusted for systolic blood pressure, fasting lipids, glucose, BMI, diet and tobacco smoke exposure. AIM 2 will generate a low tech, low cost, scalable diagnostic screening algorithm to detect asymptomatic increased AVD risk (defined as abnormally raised PWV) in a resource limited setting. We will compare various candidate screening tests that are predictive of incident cardiovascular events in adults, with PWV as a gold standard. Measures collected in the Primary Cohort will be used to develop the algorithm. Measures will be repeated in a Validation Cohort of 75 additional pre-pubertal HIV-infected children receiving the national first- line ART regimen in a programmatic setting, who will be recruited in year 3 and followed longitudinally until year 5 to validate the sensitivit and specificity of the algorithm. AIM 3 will investigate whether the circulating biomarkers most strongly predictive of vascular disease in adults correlate with abnormal PWV in virally-suppressed children and are useful for identifying increased AVD risk. Expected outcomes: A simple surveillance tool will enable nurse-driven, low-cost, high-efficacy country-wide surveillance for increased AVD risk in HIV-infected children on ART using widely-available equipment and easily-obtainable skills, facilitating therapeutic intervention early in pathogenesis Ultimately, early intervention will substantially reduce overall AVD burden in adulthood in this high-risk population, preserving their ability to care for the needs of family members and younger siblings.