HIV and cardiovascular disease: much ado about nothing?

Over the past two decades, a lot of hypotheses have been generated on whether HIV infection or the antiretroviral agents used to treat HIV infection are contributing/causing accelerated atherosclerosis. Due to the remarkable success of modern combination antiretroviral therapy (cART), HIV infection has become a chronic disease with a normal life expectancy in high-income countries. However, a concurrent rise in the incidence of non-communicable diseases, including liver, renal, and particularly cardiovascular disease, has been reported in regions with wide access to cART. The increased prevalence of coronary heart disease (CHD) in the HIV-infected population may be related to the longer life expectancy resulting from sustained suppression of HIV viral replication and to the increase of traditional risk factors for cardiovascular disease (CVD), common in the HIV-infected population. Globally, the rates of HIV infection are highest in subSaharan Africa. Eastern Europe and Southeast Asia are now faced with an emerging epidemic fuelled in part by the lack of preventative initiatives. However, in developed countries with easy access to cART, HIV-infected patients live longer, and diseases of older age (e.g. cancer and CVD) are now the most prominent cause of death. Despite the evidence that HIV infection carries a higher risk of developing CHD, the mechanisms responsible for the heightened risk are not completely understood. The pathogenesis of atherosclerosis in HIV infection most probably results from complex interactions between traditional risk factors, direct effects of uncontrolled HIV replication, and the harmful side effects of some antiretroviral medications; dyslipidaemia, insulin resistance, endothelial dysfunction, and other metabolic disorders may be caused by a certain class of antiretroviral drugs, particularly protease inhibitors. Moreover, it is well recognized that there is an increased prevalence of traditional risk factors for CHD in the HIV-infected population. Furthermore, the immune system also plays a critical role in the development and progression of atherosclerosis in the HIV-infected population. Higher levels of inflammatory markers, such as C-reactive protein, interleukin-6, and tumour necrosis (TNF) have been measured in HIV-positive compared with HIV-negative subjects. The risk for myocardial infarction (MI) is increased >4-fold in HIV-infected patients with elevated C-reactive protein levels. Higher levels of interleukin-6, soluble TNF receptor I, soluble TNF receptor II, and D-dimer, and a higher kynurenine to tryptophan ratio at 1 year postcART therapy have been associated with the occurrence of MI and stroke. Large observational studies in Europe and in the USA have investigated the epidemiology of CHD in the HIV-infected population. These and other studies suggest that HIV infection increases the overall risk for CHD by 1.5to 2.0-fold. Interestingly, an analysis of cohorts over different time frames suggests that the prevalence rates of CHD are falling, presumably due to early recognition and prevention of traditional risk factors and the use of newer antiretroviral drug regimens. Thus, the focus of research has shifted to the detection of subclinical atherosclerosis as a surrogate for clinical events. Non-invasive imaging studies, such as carotid intima-media thickness (cIMT) and coronary computed tomography angiography (CCTA), indicate an increased prevalence of subclinical atherosclerosis in HIVpositive compared with HIV-negative individuals. A meta-analysis of 13 observational studies suggests a trend toward an increase of cIMT in HIV-positive compared with HIV-negative subjects. Increased cIMT has been observed in early childhood in HIV-infected children receiving cART, suggesting that the atherosclerotic process is activated very early on in HIV-infected patients who do not have the traditional cardiovascular risk factors. The typical coronary plaque in HIV-infected patients is a non-calcified atherosclerotic plaque. A recent metaanalysis of 1229 asymptomatic HIV-infected patients on cART demonstrated a three-fold higher prevalence of non-calcified coronary artery plaques (so-called vulnerable plaques) on CCTA, compared with HIVnegative control subjects. In addition, patients with low CD4þ cell counts had evidence of more vulnerable plaques, further supporting the notion that uncontrolled and/or advanced HIV infection could contribute to a rise in CVD risks. Two studies in the USA have compared