Effects of antiretroviral drugs on the vascular system

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

The introduction of antiretroviral drugs has dramatically increased the lifespan of human immunodeficiency virus (HIV)-infected patients, shifting the major concern towards long-term morbidity and mortality, particularly an increased risk of cardiovascular complications. Antiretroviral therapy has been proposed to be one of the contributing factors. However, existing evidence for the role of antiretroviral therapy in the development of cardiovascular diseases is controversial. Therefore, in the present thesis, the effects of several antiretroviral drugs on the vascular system were investigated. \nIn view of the contribution of vascular inflammation in the development of cardiovascular diseases, the first study examined the effects of acute treatment of efavirenz, indinavir, saquinavir, lopinavir and ritonavir on the release of major inflammatory markers, interleukin (IL)-8, soluble intercellular adhesion molecule 1 (ICAM-1) and monocyte adhesion molecule 1 (MCP-1) in human umbilical vein endothelial cells in the absence or presence of lipopolysaccharide, a pro-inflammatory stimulus. The results demonstrated that efavirenz and the combination of lopinavir and ritonavir, at concentrations present in human plasma, reduced the IL-8 release, but not that of soluble ICAM-1 and MCP-1 in endothelial cells exposed to lipopolysaccharide. The data, therefore, suggest that efavirenz and lopinavir plus ritonavir may possibly have anti-inflammatory effects. Since these findings seems to contradict with the increased incidence of cardiovascular diseases associated with antiretroviral therapy, in vivo experiments were performed to further characterized the effects of antiretroviral drugs on the cardiovascular system. \nIn the second study, the atherogenic effects of long-term treatment (eight weeks) with efavirenz, abacavir and lamivudine, alone or in combination (as used clinically), were investigated in apolipoprotein E deficient (Apo-E-/-) mice (hyperlipidemic/atherosclerotic model) and the corresponding wild-type mice of both genders. All drug treatments had no effects on the lipid profile, nitrotyrosine expression in the liver (an indication of oxidative stress) and the degree of atherosclerotic lesions in all mice. Efavirenz and lamivudine did not have any significant effects on acetylcholine- and sodium nitroprusside-induced relaxations in all mice. Abacavir and the combination of the three drugs did not have any effects on acetylcholine-induced relaxation in aortae of wild-type mice, but impaired acetylcholine-induced relaxation in those of male Apo-E-/- mice without affecting sodium nitroprusside-induced relaxation. The reduction in relaxation was likely mediated by the cyclooxygenase pathway since indomethacin restored the reduction in relaxation. In male Apo-E-/- mice, IL-6 levels were increased by abacavir and the combined treatment, whereas serum amyloid P component (SAP) levels remained unchanged. Although no differences in the development of atherosclerotic lesions were observed, female Apo-E-/- mice receiving abacavir had better lipid profiles, no impairment in acetylcholine-induced relaxation and decreased serum IL-6 and SAP levels compared to male Apo-E-/- mice, revealing a vasculoprotective role of the female gender. \nIn conclusion, the data suggest that certain, but not all, antiretroviral drugs may increase the risk of cardiovascular diseases, and that this risk may be exacerbated in hyperlipidemia but reduced in females. Antiretroviral drugs should be cautiously prescribed to HIV-infected patients to minimize cardiovascular adverse effects.