HIV-Infektion, antiretrovirale Therapie und Endothel

Abstract

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 s...

Prevalence of microalbuminuria and diagnostic value of dipstick proteinuria in outpatients from HIV clinics in Bukavu, the Democratic Republic of Congo

“…Experimental studies demonstrate a direct impact of viral components (gp120, TAT) on the endothelium, as they lead to the 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 (selectin, ICAM) were found to be increased in HIV-infected persons [20]. HIV-associated nephropathy (HIVAN) is the commonest biopsy finding among patients with HIV infection who present with proteinuria.…”

HIV-associated vascular diseases: Structural and functional changes, clinical implications

“…Experimental studies have demonstrated a direct impact of HIV envelop protein gp120 and HIV Tat protein respectively on the expression of endothelial adhesion molecules ICAM-1 and VCAM-1 [17,18]. Finally, antiviral therapy with a protease inhibitor, especially ritonavir, has also been recognized to play a facilitating role in this intercellular cross-talk [19].…”

Atherogenesis: Diseases that May Affect the Natural History “Schistosomiasis and HIV Infection”

“…The development of cardiovascular disease in HIV-infected individuals is related to endothelial dysfunction. This dysfunction and accelerated atherosclerosis is a consequence of HIV itself that activates the endothelial directly or indirectly through production of citocinas [57].…”