PubMed2005
Introduction of antiretroviral combination therapy has profoundly altered both the course and prognosis of the disease in HIV-infected persons. Indeed, protease inhibitor-containing antiretroviral combination therapy dramatically decreased morbidity and mortality and improved quality of life of HIV-infected persons. Recent data, however, have raised concerns that antiretroviral combination therapy is associated with premature manifestation of coronary artery disease. In particular, protease inhibitors have been linked to metabolic changes such as insulin resistance, abnormalities in lipid metabolism and lipodystrophy and increased coronary artery calcification. Previous studies have reached conflicting conclusions whether the incidence of myocardial infarction is indeed increased in this patient population. The most substantial database has recently been provided by the D:A:D study group who demonstrated an increased incidence of myocardial infarction in HIV-infected persons on protease inhibitors or non-nucleoside reverse transcriptase inhibitor-containing therapy in a prospective observational cohort study. Much about the mechanisms involved leading to this finding remain elusive. Surrogate markers such as endothelial function may help to delineate potential mechanisms. Endothelial dysfunction is a key event in the initiation and progression of atherosclerotic vascular disease. It is characterized by decreased nitric oxide (NO) bioavailability. Furthermore endothelial "activation" leading to a pro-inflammatory, proliferative and prothrombotic state of the endothelium occurs. The observed accelerated atherosclerosis could either be caused by the virus infection itself or by a side effect of antiretroviral therapy, protease inhibitors in particular. Experimental studies demonstrate a direct impact of viral components (gp120, TAT) on the endothelium, as they lead to expression of adhesion molecules (intercellular adhesion molecule [ICAM], E-selectin), a prothrombotic state (increase of von Willebrand factor, plasminogen activator inhibitor-[PAI-]1, tissue plasminogen activator [t-PA], tissue factor). In addition, soluble adhesion molecules (sE-selectin, ICAM) were found to be increased in HIV-infected persons. Impaired flow-mediated dilation can already be detected in HIV-infected children, independent of antiretroviral therapy. Another study showed a correlation between viral load and flow-mediated dilation, supporting the notion of infection/inflammation as a contributor to endothelial dysfunction. The influence of protease inhibitor therapy on the endothelium was investigated in several studies in vitro and in vivo. In experimental studies certain protease inhibitors downregulated eNOS expression, and induced CD36 scavenger receptor expression. Furthermore, apoptosis, radical oxygen species (ROS), proliferation of vascular smooth muscle cells and endothelin-1 were found to be increased. There is conflicting evidence about adhesion molecules, as some investigators detected a decrease by therapy, others did not see an effect. In clinical studies all but one investigator found endothelial function to be impaired in HIV-infected persons on protease inhibitor-containing regimens. An important study to underline the hypothesis of a link between protease inhibitor therapy comes from Dubé et al. showing that in healthy volunteers, indinavir caused impaired endothelial-dependent vasodilation after 4 weeks. In a wide variety of clinical conditions lipid-lowering therapy using statins has shown to improve endothelial function as well as hard clinical endpoints. Drug interactions caused by common metabolism of protease inhibitors and most statins by the P450 3A4 pathway limit the use of these drugs it this setting. Pravastatin, which is being metabolized independently of P450 enzymes, was tested in several studies. In one study a trend toward improvement of endothelial function was observed. In an own similar study the authors recently provided evidence of a significant improvement of endothelium-dependent vasodilation in 30 HIV-infected persons. These studies support current guidelines of treating protease inhibitor-associated dyslipidemia with statins, preferably pravastatin.. Many questions remain unanswered in the context of antiretroviral therapy and cardiovascular risk. Results gained from research of endothelial function have served to delineate certain potential mechanisms, much work is yet to be done.