The influence of HIV infection on vascular function in an African population
Fourie, Catharina Maria Theresia
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The prevention and treatment of non-communicable diseases, such as cardiovascular disease, is marginalized in South Africa by the overwhelming prevalence of human immunodeficiency virus (HIV). HIV infection and/or the treatment thereof paradoxically affects cardiovascular risk factors and may add to the burden of non-communicable diseases which are predicted to increase over the next decades. Antiretroviral therapy was introduced in the late 1990's in industrialized countries. In South Africa the antiretroviral roll-out programme was introduced in February 2004, giving HIV infected individuals access for the first time to free antiretroviral treatment. New legislation stipulates the commencement of antiretroviral therapy at a CD4 cell count of 350 cells/mm3 instead of the current 200 cells/mm3. Although the expansion of the anti retroviral therapy will probably lead to a further decline in the HIV related mortality, the effect thereof on the burden of non-communicable diseases (e.g. cardiovascular diseases) in South Africa remains largely unknown. There is an abundance of literature regarding research on HIV-1 infection and its cardiovascular effects in westernised Caucasian populations, but the literature concerning the HIV-1 infected black population of South Africa is lacking to a great extent. HIV-1 subtype C, prevalent in South Africa, differs genetically from subtype B, which is prevalent where most of the research was done. Furthermore, the black South African population has unique characteristics, living conditions and religious beliefs which make extrapolation from Caucasian populations difficult. Although the clinical consequences of the subtype variations still remain unclear, no study, to our knowledge, to date has been done to evaluate the influence of HIV-1 (subtype C) infection itself, and the treatment thereof on the vascular function and cardiovascular risk of the H IV-1 infected population of South Africa. Aim The aim of this study (thesis) was to assess the influence of the HIV-1 subtype C infection and the antiretroviral therapy of the roll-out programme on vascular function in black Africans of the North-West Province of South Africa. Methodology This study is embedded in the international PURE (Prospective Urban and Rural Epidemiology) study. The PURE study is an epidemiological study that addresses questions regarding the cause and development of cardiovascular risk factors and disease within populations, particularly of low and middle income countries, including South Africa. The South African leg of the study was performed in the North West Province where a total of 2000 black South Africans (1000 urban and 1000 rural) were randomly recruited from a rural and urban setting and screened during the baseline phase in 2005. Manuscripts presented in Chapters 2 and 3, made use of the data of three hundred newly identified HIV-1 infected participants of the baseline PURE study population. These infected participants were individually matched with 300 HIV-1 uninfected participants (case-control design), according to age, gender, body mass index and locality (urban and rural). Anthropometric and cardiovascular measurements, the lipid profile, inflammatory markers and pulse wave velocity were determined. Significant differences were determined by means of independent T-tests. Analysis of covariance (ANCOVA) was performed to compare the cardiovascular variables, lipid profile, glucose, inflammatory and coagulatory markers whilst adjusting for tobacco and alcohol use. Odds ratios were calculated and partial correlations were performed whilst adjusting for mean arterial pressure (MAP), tobacco and alcohol use. The manuscript presented in Chapter 4 made use of the follow-up data obtained three years after baseline. Anthropometric measurements, the lipid profile, pulse wave velocity and carotid intima media thickness were determined. Significant differences between baseline and follow-up were determined by dependent T-tests. All participants gave informed consent and the study was approved by the Ethics Committee of the North-West University, Potchefstroom, South Africa. The reader is referred to the methods section of each individual manuscript for a more elaborate description of the participants, study design and analytical methods. Results and conclusions of individual manuscripts • The aim of the first manuscript was to evaluate if HIV-1 infection itself is associated with dyslipidemia, inflammation and the occurrence of the metabolic syndrome in newly identified HIV-1 infected participants who have never received antiretroviral therapy. The results indicated that HIV-1 is associated with dyslipidemia and an inflammatory state of newly identified HIV-1 infected, never-treated, African individuals that may increase their risk for cardiovascular disease. The study showed that HIV-1 subtype C, though genetically different from subtype 8, has similar association with components of the metabolic syndrome than HIV-1 subtype B. The prevalence of the metabolic syndrome in the HIV-1 infected and uninfected participants did not differ. • The aim of the second manuscript was to assess whether newly identified, never-treated, HIV-1 infected South Africans of African ancestry show signs of inflammatory injury of the endothelium leading to endothelial dysfunction, accelerated atherosclerosis and increased coagulation which could lead to thrombosis. The results showed that the HIV1 infected participants had lower high-density lipoprotein cholesterol (HDL-C) levels and higher interleukin-6, C-reactive protein, intracellular adhesion molecule-1 and vascular adhesion molecule-1 levels compared to the uninfected controls. These results suggest inflammatory injury of the endothelium pointing to endothelial dysfunction. Attenuation of the protective effect of HDL-C might have worsened the endothelial inflammation. No indication of a prothrombotic state which could result in atherosclerotic disease could be detected. However, there is an indication of accelerated vascular aging and probable early atherosclerosis in the older HIV infected participants. • The aim of the third manuscript was to determine whether soluble urokinase plasminogen activator receptor (suPAR) levels are elevated in HIV-1 infected black South Africans (treated and never-treated) compared to uninfected controls before and after a three year follow-up study. The second aim was to investigate whether suPAR levels are correlated with similar cardiovascular and metabolic changes over the three year period in the HIV-1 infected individuals, treated and never-treated. This follow-up study showed that HIV-1 infected black South Africans had significantly higher suPAR levels than uninfected controls. However, the main result of this manuscript was that treated, normo-glycemic, HIV-1 infected participants showed signs of lipodystrophy and a greater increase in suPAR levels compared to the never-treated and uninfected participants after three years. In the treated HIV-1 infected group suPAR levels were correlated positively with an increased waist circumference and negatively with TC:HDLC ratio. No correlations were observed with either baseline CRP or IL-6. The never treated HIV-1 infected participants showed no increase in suPAR levels in the three year time-span and a worse lipid profile compared to the uninfected controls. Discussion South Africa has an overwhelming prevalence of HIV and AIDS, which may, paradoxically, Play a role in the predicted increase in non-communicable diseases (e.g. cardiovascular disease) over the next decades. The influence of HIV-1 subtype C on vascular function, how it influences the risk of cardiovascular disease and how the influence is affected by the antiretroviral treatment of the roll-out programme in HIV infected South Africans, remains largely unknown. The results of this study are, therefore, valuable in contributing to the limited knowledge regarding the probable influence of HIV-1 subtype C on vascular function. Further research should assess the contributions of HIV-1 infection itself and antiretroviral treatment to vascular dysfunction and cardiovascular disease risk.
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