Endothelial Dysfunction as a Risk Factor in HIV Study

Overview

Highly active antiretroviral therapy (HAART) has proven effective in altering the natural history of HIV infection in many patients. However, this therapy may not be sustainable because of the toxicities of the medications. Evidence suggests that HIV-infected patients on HAART may be at risk for premature coronary artery disease. The exact cause is unknown. It is possible that the medications directly affect the endothelium (the lining of the arteries that supply blood to the heart) and lead to premature heart disease. Or because the medications cause lipid abnormalities (high cholesterol) and a condition of relative insulin resistance, in which the body has a difficult time processing sugars; known risk factors for endothelial dysfunction and heart disease. Therapeutic intervention that reverses these lipid abnormalities and/or insulin resistance may lower these risk factors, normalize endothelial function, and decrease the risk of heart disease. This protocol aims to assess endothelial function among a group of HIV-infected patients with varying degrees of viral activity and levels of immune function on a variety of HAART regimens. It also aims to evaluate the effect of three different medications on lipids, insulin resistance, and thus endothelial function. Understanding the factors involved in causing endothelial dysfunction will help better characterize the relative risks and benefits of early versus late and continuous versus intermittent HAART therapy. The research may offer some insights into the causes of premature heart disease among HIV-infected patients on HAART that could be more thoroughly investigated in subsequent clinical trials. A total of 75 patients will be recruited: 25 for each arm of the study. Each arm evaluates the potential benefit of a particular medication and will enroll sequentially. An endothelial function test will be performed on an outpatient basis. The first 25 patients will be assigned at random to receive pravastatin sodium or placebo; the next 25 will receive gemfibrozil or placebo; the final 25 will receive rosiglitazone or placebo. Patients will take the pills for 6 weeks, no pills for the next 4 weeks, and then the opposite treatment for 6 more weeks. Two weeks after the start of the study drug, blood will be taken to check for potential toxic side effects. After each 6-week treatment, blood will be drawn and endothelial function tests will be performed.

The natural history of HIV infection in many patients has been dramatically altered through the use of highly-active antiretroviral therapy (HAART). However, this treatment paradigm of chronic chemotherapy may not be sustainable given the short and long-term toxicities of these medications. Among the more concerning are the development of atherogenic lipoprotein abnormalities and a state of relative insulin resistance. Logically, there has been concern that such metabolic disturbances may predispose towards cardiovascular morbidity and mortality. Although these therapies have only been in widespread use for a short period of time, a growing body of evidence from case reports and cohort studies has suggested that HIV-infected patients on HAART may experience premature coronary artery disease. The explanation of this phenomenon is most likely multifactorial. In terms of pathophysiology, the relative contributions of HIV viral replication, host immune response, and the use of antiretroviral agents remains unknown. HIV-1 could possibly have a direct effect on the endothelium as has been suggested for other infectious agents such as chlamydia, herpes simplex, and cytomegalovirus. One could postulate that the virus might have some capacity to effect the production of nitric oxide (NO), as a pathogenic mechanism. It is unknown whether the medications have direct toxicities or whether the common underlying mechanism is drug-induced abnormalities in lipid and/or glucose metabolism. Furthermore, intervention with therapeutics that reverse these metabolic disturbances might ameliorate these risk factors, normalize endothelial function, and thus decrease the risk of cardiovascular disease among this patient population. Even if such patients are at no higher risk than HIV-negative patients with similar metabolic profiles, attention must be paid to modifiable risk factors as patients are living longer. This protocol aims to assess endothelial function among a group of HIV-infected patients with varying degrees of virologic control and levels of immune function on a variety of different HAART regimens. These patients will then be administered medications with known effects on lipid and glucose metabolism to determine if they might serve a role in improving these parameters and thus endothelial function. The results of this study will hopefully yield effective strategies to maintain the efficacy of HAART therapy while minimizing or reversing toxicities. Understanding the factors important to causing endothelial dysfunction will help better characterize the relative risks/benefits of early vs. late and continuous vs. intermittent HAART therapy. Additionally, it will hopefully offer some insights as to the underlying pathophysiology of the phenomenon of premature cardiovascular disease among HIV-infected patients on HAART that could then be more thoroughly investigated in subsequent clinical trials. We may ultimately learn that either the virus or antiretroviral drugs or the consequent lipid and insulin abnormalities they induce alters NO function at the level of the endothelium.