HIV-infected patients now live longer because of the availability of highly active antiretroviral therapy (HAART). There is growing evidence however that HIV-infected subjects in the era of HAART are at increased risk of cardiovascular (CV) morbidity and mortality. While dyslipidemia and insulin resistance induced by protease inhibitors and other classes of HIV medications likely contribute to this increased risk, there is now substantial evidence to suggest that much of the increased CV risk may stem from the inability of these potent antiretroviral medications to completely eliminate the immune mediated chronic inflammatory effects of HIV per se on the vascular system. HMG-CoA reductase inhibitors (statins) are medications commonly prescribed to lower levels of low density lipoprotein cholesterol (LDL-C) in individuals with dyslipidemia and increased CV risk. In the general non-HIV-infected population, statins have been demonstrated to have efficacy for both primary and secondary prevention of CV events and mortality. In these studies, the reduction in CV morbidity cannot be explained completely by the known ability of statins to lower LDL-C levels and it has been hypothesized that much of the beneficial effects of these medications may be due to the anti-inflammatory properties of this class of medications. We hypothesize that the increased CV risk in the HIV population on HAART has an inflammatory component secondary to incompletely suppressed HIV-induced chronic inflammation and that statins may have efficacy in reducing such inflammation. We propose to evaluate, in 100 HIV subjects at intermediate CV risk, the effect of low dose atorvastatin on surrogate markers of CV risk over a 2 year period;specifically its effect on flow-mediated vasodilation of the brachial artery, on deposition of coronary artery calcium by electron beam tomography, and on changes in levels of hs-CRP. Within this clinical trial, we propose to assess the role of Th17 lymphocytes and their secretory compounds interleukin 17 in perpetuating the HIV-induced inflammatory process leading to increased CV risk in individuals on HAART. In addition, we propose to assess the impact of HIV-induced inflammatory processes on insulin resistance and on oxidative phosphorylation enzyme and activity levels. HIV-infected individuals may be at high risk for cardiovascular (CV) disease. We propose to establish a 150 patient cohort to look at the role of oxidative stress and inflammation as causes for this high CV risk. In addition, we propose a small clinical trial of rosuvastatin (a lipid lowering drug) in 50 patients from the cohort with evidence of inflammation (high C- reactive protein levels in blood) but low cholesterol levels, to see if the anti-inflammatory properties of this class of medication will decrease CV risk.

Public Health Relevance

HIV-infected individuals may be at high risk for cardiovascular (CV) disease. We propose to establish a 150 patient cohort to look at the role of oxidative stress and inflammation as causes for this high CV risk. In addition, we propose a small clinical trial of rosuvastatin (a lipid lowering drug) in 50 patients from the cohort with evidence of inflammation (high C- reactive protein levels in blood) but low cholesterol levels, to see if the anti-inflammatory properties of this class of medication will decrease CV risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095135-05
Application #
8321529
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Mcdonald, Cheryl
Project Start
2008-09-25
Project End
2014-06-30
Budget Start
2012-08-06
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$890,691
Indirect Cost
$229,542
Name
University of Hawaii
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
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Shikuma, Cecilia M; Barbour, Jason D; Ndhlovu, Lishomwa C et al. (2014) Plasma monocyte chemoattractant protein-1 and tumor necrosis factor-* levels predict the presence of coronary artery calcium in HIV-infected individuals independent of traditional cardiovascular risk factors. AIDS Res Hum Retroviruses 30:142-6
Barbour, Jason D; Jalbert, Emilie C; Chow, Dominic C et al. (2014) Reduced CD14 expression on classical monocytes and vascular endothelial adhesion markers independently associate with carotid artery intima media thickness in chronically HIV-1 infected adults on virologically suppressive anti-retroviral therapy. Atherosclerosis 232:52-8
Shikuma, Cecilia M; Chow, Dominic C; Gangcuangco, Louie Mar A et al. (2014) Monocytes expand with immune dysregulation and is associated with insulin resistance in older individuals with chronic HIV. PLoS One 9:e90330
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Gangcuangco, Louie Mar A; Chow, Dominic C; Liang, Chin-Yuan et al. (2013) Predictors of 25-hydroxyvitamin D levels in HIV-infected patients in Hawai'i. Hawaii J Med Public Health 72:197-201
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Jalbert, Emilie; Shikuma, Cecilia M; Ndhlovu, Lishomwa C et al. (2013) Sequential staining improves detection of CCR2 and CX3CR1 on monocytes when simultaneously evaluating CCR5 by multicolor flow cytometry. Cytometry A 83:280-6
Nakamoto, Beau K; Shikuma, Cecilia M; Ogata-Arakaki, Debra et al. (2013) Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder. J Neurovirol 19:601-5