The Effect of Lopinavir/Ritonavir on Endothelial Function
This study will examine how the anti-HIV protease inhibitor lopinavir/ritonavir (Kaletra® (Registered Trademark)) affects the function of the endothelium (lining of the arteries). Medications such as protease inhibitors can dramatically change the course of HIV infection in many patients; however, among their side effects is development of abnormal lipid levels resulting in high cholesterol and insulin resistance. These side effects may damage the lining of the arteries that supply blood to the heart, leading to premature coronary artery disease. The study will determine whether lopinavir/ritonavir directly affects endothelial function and whether it alters cholesterol levels, glucose tolerance, and markers of inflammation in people who take the drug for 4 weeks.
Healthy normal volunteers between 18 and 40 years of age may be eligible for this study. Candidates must be HIV-negative and have no history of heart disease, hypertension, or diabetes mellitus. They must not have smoked for at least 6 weeks before entering the study. Volunteers will be screened with a medical history, physical examination, blood tests (including a pregnancy test for women of childbearing potential), and electrocardiogram. In addition, candidates will have an oral glucose tolerance test (see description below).
Participants will undergo the following procedures:
- Lopinavir/ritonavir: 4 weeks (3 capsules twice a day) beginning study day 1
- Flow-mediated vasodilatation test (study days 0 and 29) - An ultrasound device for measuring the size of the brachial artery (artery in the upper arm) is placed just above the elbow. The size of the artery is measured before and 5 minutes after blood flow to the arm is stopped for 5 minutes, using a blood pressure cuff. The artery is also measured before and after taking nitroglycerin, a medicine that dilates blood vessels. These measurements tell how well the drug treatment works on the cells lining the brachial artery, which is an indicator of coronary artery function. This test takes about 1.5 hours.
- Forearm blood-flow test (study days 1 and 30): Small tubes are inserted into an artery and vein in the forearm at the inside of the elbow. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm. When the blood pressure cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. When the devices are in place, a salt water solution is injected in the small tube in the artery. After 20 minutes, small doses of the following drugs are given through the catheter at various intervals: 1) L-NMMA (blocks production of nitric oxide, a substance produced by the blood vessels that causes them to dilate); 2) sodium nitroprusside (dilates blood vessels, increasing blood flow); 3) acetylcholine (lowers blood pressure); and 4) acetylcholine plus L-NMMA. The effect of the different drugs on blood flow in the forearm is measured. The study takes about 2 hours to complete.
- Blood tests (screening and study days 1,15, 30, and 44)
- Electrocardiogram (at screening and on study day 30)
- Oral glucose tolerance test (at screening and on study day 30) - A blood sample is collected. Then, the subject drinks 300 milliliters of a glucose solution (a liquid that contains sugar dissolved in water). Two hours after drinking the solution, blood is drawn again to examine how the body responds to the increase blood sugar levels.
|Study Design:||Endpoint Classification: Safety Study
Primary Purpose: Treatment
|Official Title:||The Effect of Lopinavir/Ritonavir on Endothelial Function in Normal Volunteers|
|Study Start Date:||January 2004|
|Estimated Study Completion Date:||September 2005|
With the advent of the highly active antiretroviral (ARV) therapy era, patients with human immunodeficiency virus (HIV) have had significantly decreased mortality and morbidity. Concomitant with more patients chronically taking antiretroviral therapy, there has been an increase in atherogenic lipoprotein profiles (high cholesterol, high triglycerides, low HDL's), insulin resistance, fat redistribution and coronary artery disease. HIV viral replication, anti-retroviral treatment regimens, lipids, glucose intolerance, host immune response or a combination of factors may contribute to the increase in cardiovascular risk factors. HIV positive patients, independent of the effect on lipids, appear to have increased cardiovascular risk. Studies are not entirely consistent, but the most convincing study to date, the D.A.D. study from EURO-SIDA, shows a 27% relative increased rate of myocardial infarction per year of exposure over the first seven years of ART.
Lopinavir-ritonavir is one of the most commonly used antiretroviral therapy. It also produces lipid abnormalities. Thus, an important part of the investigating factors contributing to atherosclerosis would be to determine if this drug can adversely influence endothelial cells in the absence of HIV infection or low CD4 counts. This would suggest that this drug directly or indirectly could predispose to atherosclerosis. Endothelial function is an important contributor to atherosclerosis. Invasive and non-invasive methods to evaluate endothelial cell function have been validated as predictors of coronary artery disease. These techniques have been used at NIH for clinical investigation for many years.
This protocol is designed to determine whether there is a pathologic effect on endothelial function from the lopinavir/ritonavir. By measuring endothelial function in HIV non-infected subjects both before and after four weeks of therapy, we will be able to investigate whether the medications have a direct toxic effect on the endothelium. Collection of metabolic data will allow us to evaluate whether endothelial function occurs in conjunction or separate from lipoprotein and glucose metabolic changes. As ARV options increase, it may be possible to choose specific regimens that may minimize acceleration of cardiovascular risk factors associated with endothelial dysfunction, especially in patients with other cardiovascular risk factors. These findings may help elucidate the pathophysiology of premature cardiovascular disease in HIV positive patients and also plan interventions to minimize endothelial dysfunction and subsequent cardiovascular disease.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00076414
|United States, Maryland|
|National Institutes of Health Clinical Center (CC)|
|Bethesda, Maryland, United States, 20892|