Thesis (Ph.D. (Physiology and Environmental Health)) -- University of Limpopo, 2021 / Background: Human immunodeficiency virus (HIV)-infection remains a major public health burden where approximately 38 million people are affected globally. Human immunodeficiency virus infection is associated with chronic inflammation which can lead to endothelial dysfunction and thrombosis, which are precursor events for cardiometabolic abnormalities such as dysglycaemia and dyslipidaemia. The degree of chronic inflammation, endothelial dysfunction, and hypercoagulation among HIVpositive adults on highly active antiretroviral therapy are not well understood in Sub- Saharan Africa. The objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) on chronic inflammation, endothelial dysfunction, and hypercoagulation among HAART-exposed adult South African participants in a rural setting. Aim: The study aimed to determine the effects of HAART on early biomarkers of cardiovascular disease in the HIV-positive subjects. Methods: The study was cross-sectional, descriptive, and quantitative in design. The research population consisted of 158 participants of males and females within the age range of 18 – 81 years from Mankweng Hospital and surrounding clinics. The study population comprised of three groups, HIV-negative (control group), HIV-positive treatment naïve (HAART-naïve group), and HIV-positive participants on HAART (HAART-exposed group). Weight and height were measured using Omron BF 400 and a portable stadiometer respectively, to calculate the body mass index. Glucose and lipid levels were determined on Cobas® Integra 400 plus auto-analyser. The CD4+ T cell count was determined on the Cytomics FC500 Flow Cytometer Multi-Platform loader. The concentration of fibrinogen, c-reactive protein (CRP), L-selectin, D-dimers, P-selectin, von Willebrand factor (VWF), soluble intercellular adhesion molecule (sICAM-1), and soluble vascular cell adhesion molecule (sVCAM-1) in serum samples were determined on the Luminex 200TM. Data were analysed using SPSS version 25.0. Descriptive statistics were performed on all variables and analysis of covariance was used to determine differences across all groups. Correlation coefficients and multiple regression analyses were used to determine associations. Results: Body mass index (BMI) and glucose metabolism were not significantly affected by HAART exposure. However, the HAART-exposed group had significantly increased LDL-C (F (2, 154) = 7.501, p = 0.001) and TC (F (2, 154) = 9.174, 0.0002) levels. The prevalence of high LDL-C levels was significantly elevated in the HAART-exposed group (29.6%) (p = 0.041). The prevalence of pre-diabetes (11.3%) was the highest among the HAART-exposed group (non-significant), although, no significant difference was observed. While P-selectin was significantly reduced in the HAART-exposed group (F (2, 154 = 7.253, p = 0.001). On the other hand, the HAARTexposed group also significantly increased VWF (F (2, 154 = 4.556, p = 0.011). The HAART-exposed group showed no significant effect on L-selectin, sICAM-1, sVCAM- 1, CRP, fibrinogen and D-dimer levels. However, D-dimer was negatively associated with HAART (r = -0.249, p = 0.011). There were significant independent association between the combined HAART regimens and P-selectin (Std β = 0.219, p = 0.032), first-line regimen with both P-selectin (Std β = 0.434, p = 0.004) and sVCAM-1 Std β = 0.328, p = 0.031), second-line regimens with L-selectin (Std β = 1.032, p = 0.005) and, a positive independent association between first-line regimen and D-dimer (β = 0.741, p = 0.0001). Although BMI and glucose metabolism were not significantly affected in both the HAART-exposed and HAART-naïve groups, dyslipidaemia was present across the three groups (HAART-exposed, HAART-naïve and control). HAART-exposure showed a protective effect by reducing endothelial dysfunction (ED) and hypercoagulation. Yet, ED was still present among this rural South African HAART-exposed population. The HAART-exposed group may be at increased risk for CVD. Therefore, CVD should be regularly monitored in the HAART-exposed population. / National Research Fund, the Health and Welfare Sector Education and Training Authority, and the University of Limpopo (UL)