HIV-1 protease inhibitor (PI) agents have revolutionized HIV care, but have led to marked abnormalities in metabolism. These changes appear to place patients with HIV infection at considerably increased cardiovascular risk. In addition to insulin resistance and hyperlipidemia, endothelial dysfunction occurs and will heighten these risks. Endothelial dysfunction is a critical initial step of atherogenesis that subsequently contributes to the progression and clinical manifestations of atherosclerosis. Preliminary data show that the PI indinavir impairs endothelium-dependent, nitric oxide-mediated, vasodilation in normal subjects. To further define the factors contributing to endothelial dysfunction, identify antiretroviral agents with lesser cardiovascular risk, and identify potential interventions, this project addresses these Specific Aims: (1) Establish the physiologic mediators of endothelial dysfunction caused by indinavir: The hypothesis that insulin resistance mediates endothelial dysfunction due to indinavir will be tested. Normal subjects will receive indinavir for 4 weeks and undergo measurements of endothelium-dependent vasodilatory response both before and during hyperinsulinemia. (2) Compare the effects of PIs with divergent metabolic effects on endothelial function: To test the hypothesis that PIs with lesser tendencies to provoke insulin resistance or dyslipidemia will have lesser effects on endothelial function, normal subjects will be randomized to receive either amprenavir or atazanavir. Similar tests of endothelial function will be performed. (3) Determine if non PI-based combination therapy results in less endothelial dysfunction than a PI-based regimen. The hypothesis that a PI-based antiretroviral combination regimen will induce endothelial dysfunction, but a non-PI-based regimen will not, will be tested. HIV-infected subjects will be randomized to a PI-based regimen that is expected to cause dyslipidemia and insulin resistance, or a non-PI-based regimen that should not. Subjects will cross over to the other therapy after 12 weeks of treatment to establish the reversibility of the endothelial dysfunction. The results of these studies will provide a better understanding of the causes of increased cardiovascular risk among HIV-infected patients, foster the development of antiretroviral drugs that lack adverse effects on cardiovascular risk, and identify potential interventions to test for reduction of risks in HIV-infected patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072711-02
Application #
6666709
Study Section
Special Emphasis Panel (ZHL1-CSR-D (S2))
Program Officer
Goldberg, Suzanne H
Project Start
2002-09-30
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$581,124
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Gupta, Samir K; Shen, Changyu; Moe, Sharon M et al. (2012) Worsening endothelial function with efavirenz compared to protease inhibitors: a 12-month prospective study. PLoS One 7:e45716
Blodget, Emily; Shen, Changyu; Aldrovandi, Grace et al. (2012) Relationship between microbial translocation and endothelial function in HIV infected patients. PLoS One 7:e42624
Gupta, Samir K; Shen, Changyu; Mather, Kieren J et al. (2011) Neither proteinuria nor albuminuria is associated with endothelial dysfunction in HIV-infected patients without diabetes or hypertension. J Infect Dis 204:1946-50
Gupta, Samir K; Johnson, Raymond M; Mather, Kieren J et al. (2010) Anti-inflammatory treatment with pentoxifylline improves HIV-related endothelial dysfunction: a pilot study. AIDS 24:1377-80
Dube, Michael P; Shen, Changyu; Mather, Kieren J et al. (2010) Relationship of body composition, metabolic status, antiretroviral use, and HIV disease factors to endothelial dysfunction in HIV-infected subjects. AIDS Res Hum Retroviruses 26:847-54
Gupta, Samir K; Johnson, Raymond M; Saha, Chandan et al. (2008) Improvement in HIV-related endothelial dysfunction using the anti-inflammatory agent salsalate: a pilot study. AIDS 22:653-5
Torriani, Francesca J; Komarow, Lauren; Parker, Robert A et al. (2008) Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol 52:569-76
Dube, Michael P; Gorski, Jude Christopher; Shen, Changyu (2008) Severe impairment of endothelial function with the HIV-1 protease inhibitor indinavir is not mediated by insulin resistance in healthy subjects. Cardiovasc Toxicol 8:15-22
Dube, Michael P; Shen, Changyu; Greenwald, Martha et al. (2008) No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: a placebo-controlled trial. Clin Infect Dis 47:567-74
Gupta, Samir K; Mather, Kieren J; Agarwal, Rajiv et al. (2007) Proteinuria and endothelial dysfunction in stable HIV-infected patients. A pilot study. J Acquir Immune Defic Syndr 45:596-8

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