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Inflammation Is Associated with Endothelial Dysfunction Among Individuals with Treated and Suppressed HIV Infection
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2 links to studies at CROI linking CVD to inflammation in HIV+, activation and enescence:
CROI: Rapid Progression of Atherosclerosis at the Carotid Bifurcation Is Linked to Inflammation in HIV-infected Patients - "These data strongly suggest that inflammation contributes to the higher risk of atherosclerosis noted in HIV-infected persons." - (02/22/10)
CROI: T-cell Senescence and T-cell Activation Predict Carotid Atherosclerosis in HIV-infected Women - (02/22/10)
Reported by Jules Levin
17th CROI Feb 16-19 2010 SF
Priscilla Y. Hsue, Peter Hunt, Amanda Schnell, Jennifer E. Ho, Yuaner Wu, Rebecca Hoh, Jeffrey N. Martin, Peter Ganz, and Steven G. Deeks
University of California, San Francisco
"Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among treated HIV patients with undetectable viral loads..... levels of inflammation were more predictive of worsened endothelial function than traditional risk factors in individuals with HIV..... These findings suggest that even treated and suppressed HIV-infected individuals may be at increased risk for cardiovascular disease, and that chronic inflammation in the setting of treated HIV disease underlies the higher rates of atherosclerosis in this patient population. Our findings also argue for an independent role of direct drug toxicity in driving early cardiovascular disease"
HIV-infected individuals had lower FMD compared to controls (3.5% vs. 5.2% respectively, p=0.016) a finding that persisted after adjusting for traditional risk factors. The median hsCRP was higher in HIV patients compared to controls and a higher hsCRP was independently associated with HIV infection after adjustment for traditional risk factors (p=0.035). As shown in Figure 1, higher hsCRP levels were associated with impaired FMD (rho: -0.21, p=0.03) in contrast to uninfected individuals in whom age was most predictive of FMD (rho:- 0.48, p=0.004). Current abacavir exposure, but not PI exposure, was associated with impaired FMD, even after adjustment for all other factors, including GFR (p=0.043). Even individuals on PI and ABC sparing regimens appeared to have lower FMD as compared to controls (Figure 2. Duration of HAART, CD4 nadir, and proximal CD4 count were not associated with FMD. Current DDI or TFV use were also not associated with reduced FMD. Examples of FMD studies are shown in Figure 3.
CONCLUSIONS:
Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among treated HIV patients with undetectable viral loads. Levels of inflammation were more predictive of worsened endothelial function than traditional risk factors in individuals with HIV. These findings suggest that even treated and suppressed HIV-infected individuals may be at increased risk for cardiovascular disease, and that chronic inflammation in the setting of treated HIV disease underlies the higher rates of atherosclerosis in this patient population. Our findings also argue for an independent role of direct drug toxicity in driving early cardiovascular disease. Further studies will need to determine if ARV-associated changes in endothelial function contribute to the clinically observed relationship between treatment exposure and cardiovascular risk.
BACKGROUND
Recent studies suggest that HIV-infected patients are at increased risk for cardiovascular events. This may be due to both HIV disease-related factors (including inflammation) and treatment-related factors. Although treatment with antiretroviral therapy (ART) improves endothelial function, it is not clear if this impairment is fully reversed. As endothelial dysfunction is central to the pathogenesis of atherosclerosis and is predictive of adverse cardiovascular outcomes including myocardial infarction, we investigated the association between both treatment- and disease-associated factors on endothelial function, focusing on patients responding to antiretroviral therapy. We hypothesized that endothelial function would remain impaired during long-term ART, and that this impairment would be due to both inflammation and direct drug toxicity.
METHODS
Patient selection - We studied HIV-infected adults enrolled in SCOPE cohort at San Francisco General Hospital and healthy HIV-uninfected controls.
Entry criteria for HIV-infected subjects:
treated HIV patients who have achieved full viral suppression defined as >24 weeks HAART with two most recent HIV RNA levels <75 copies/mL
stable antiretroviral regimen for at least 12 weeks prior to being studied without any medication changes
no new antihypertensive or lipid lowering therapy, or changes indoses of pre-existing medication, within 12 weeks of the study
Assessment of endothelial function –Endothelial function was assessed as flow-mediated vasodilation (FMD) of the brachial artery. A 10MHz linear array probe in conjunction with the GE VividSeven Imaging System was used. To assess endothelium-dependent vasodilation, brachial artery diameter was measured under basal conditions and during reactive hyperemia following 5 minutes of an ischemic stimulus. The maximal increase in brachial artery diameter was assessed at 1 minute of reactive hyperemia. To assess endothelium-dependent vasodilation, after rest, brachial artery diameter was determined under basal conditions and following the administration of sublingual nitroglycerin (0.4 mg). Maximal dilation was assessed 3 minutes after the administration of sublingual nitroglycerin. Acquisition and analysis of the digitized images was performed using dedicated software (Information Integrity Inc., Iowa City, Iowa). Images were analyzed by a technician who was blinded to the subject's HIV disease and treatment status.
Statistical Analysis
Multivariable linear models were used to identify predictors of endothelial function. We assessed predictors of FMD after adjustment for traditional risk factors and HIV characteristics. Both treatment exposure factors and measures of inflammation (hsCRP) were considered as potential predictors.
RESULTS
Table 1: Characteristics of HIV-Infected and Uninfected Subjects
In this figure in the graph on upper left, untreated HIV had higher inflammation than HIV-negs, patients on HAART had even higher CRP; endothelial dependent FMD was higher in HIV-negs, the lowest for HIV-untreated and in between on HAART.
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