Traditional Risk Factors Predict Cardiovascular Risk in People with HIV

		SUMMARY: Traditional risk factors including male sex, family history, smoking, abnormal blood lipids, and high blood pressure were among the predictors of atherosclerosis and cardiovascular events in 2 recently published studies. One analysis found that certain inflammation biomarkers were associated with elevated risk, and the other observed that use of tenofovir (Viread, also in the Truvada and Atripla coformulations) might actually have a protective effect, but neither saw a link between cardiovascular disease and lower CD4 cell count.

By Liz Highleyman

Several studies have shown that people with HIV have a higher risk of cardiovascular disease and associated events such as heart attacks compared with the HIV negative general population. It is not yet clear, however, whether this is due to HIV infection itself, chronic immune activation and inflammation, antiretroviral drugs, a higher prevalence of traditional risk factors, or some combination of these.

FRAM Study

As described in the September 10, 2010 issue of AIDS, Joseph Delaney, Carl Grunfeld, and fellow investigators with the Fat Redistribution and Metabolic Change in HIV (FRAM) study looked at an early indicator of cardiovascular disease, carotid intima-media thickness (IMT).

Increased carotid IMT -- or greater thickness of the lining of the carotid arteries supplying blood to the brain -- is a sign of atherosclerosis, or buildup of plaque and loss of elasticity in the arteries. Atherosclerosis of the coronary arteries supplying the heart can lead to a heart attack, while carotid atherosclerosis is a risk factor for strokes.

The FRAM team aimed to identify HIV-related risk factors associated with increased carotid IMT, including CD4 T-cell count, HIV viral load, and use of antiretroviral therapy (ART).

This retrospective analysis looked at medical records from 538 HIV positive FRAM participants. A majority (about 70%) were men, about 40% were African-American, the mean age was 48 years, and the average estimated duration of HIV infection was 13 years; almost all were on combination ART. With regard to traditional cardiovascular risk factors, more than half were current or former smokers.

All participants had at least 1 carotid artery ultrasound scan. The researchers focused on IMT in the common carotid (the main segment of the artery before it forks into 2 branches), the internal carotid (1 of the 2 branches), and the carotid bulb (the bulging segment around the bifurcation where the artery forks); prior research has shown that the site of measurement can affect likelihood of detecting carotid artery thickening.

Results

	In a Bayesian mathematical model, predictors of increased IMT in the common carotid artery included:
	Older age, black race, systolic and diastolic blood pressure: all at least 95% probability; Lower high-density lipoprotein (HDL) "good" cholesterol: 85% probability; Hispanic ethnicity: 51% probability.
	Of all the HIV-related factors included in the analysis, only tenofovir use was a significant predictor (51% probability), but it was associated with decreased IMT (-0.0094 mm per year of use).
	Predictors of increased internal carotid IMT included older age and smoking (both 100% probability).
	For internal carotid IMT there were no HIV-related risk factors above the 50% probability threshold.

"We observed an inverse association between duration of tenofovir use and common carotid IMT," the study authors concluded. "Whether this association is causal or due to confounding by indication needs further investigation."

The investigators were unable to explain the apparent modest protective effect of tenofovir. Participants taking this drug had similar demographic characteristics, somewhat lower total cholesterol, but a history of worse HIV disease (lower nadir CD4 cell count, higher percentage with an AIDS diagnosis).

Inflammation Biomarkers

In the second study, described in the June 19, 2010 issue of AIDS, Emily Ford from the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues performed a retrospective case-control study to assess the association between cardiovascular events and traditional cardiovascular risk factors, HIV disease, and inflammation.

A growing body of evidence indicates that chronic immune activation and persistent inflammation contribute to several non-AIDS conditions -- including cardiovascular disease and non-AIDS cancers -- seen with increasing frequency as people with HIV survive longer due to effective ART.

This analysis included HIV positive participants enrolled in National Institutes of Health clinical protocols between 1995 and 2009. A total of 52 individuals who experienced an incident (new) cardiovascular disease event (for example, a heart attack) were matched 2:1 with HIV positive people without cardiovascular disease.

The researchers measured several biomarkers of inflammation and immune cell activation in blood serum or plasma and in peripheral blood mononuclear cells. These included the acute phase inflammation marker high-sensitivity C-reactive protein (CRP), the coagulation (thrombosis or clotting) biomarker D-dimer, the endothelial dysfunction marker soluble vascular cell adhesion molecule-1 (VCAM-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1).

Results

	The 52 case patients with cardiovascular events were significantly more likely to have traditional risk factors compared with control subjects, either at baseline or after up to 2 years of follow-up:
	Smoking: 49% among cases vs 25% among controls; Family history of cardiovascular disease: 30% vs 11%, respectively; Abnormal blood lipids: 87% vs 72%, respectively; Higher total cholesterol; Higher low-density lipoprotein (LDL) "bad" cholesterol; Higher blood glucose.
	After 4 months of follow up, HIV viral load was significantly lower among case patients compared with control subjects (2500 vs 14000 copies/mL).
	CD4 cell count and type or duration of ART, however, did not differ between the 2 groups.
	Several inflammation markers were elevated in patients with cardiovascular events: D-dimer, soluble VCAM-1, TIMP-1, soluble tissue factor, CD41 cells.
	Levels of high-sensitivity CRP, however, were similar in both groups.
	The immune activation markers CD38 and HLA-DR also did not differ between the groups.
	In a multivariate analysis adjusting for other factors, smoking, family history, D-dimer, and glucose remained independent predictors of cardiovascular disease risk.

Based on these findings, the study authors concluded, "In this cohort, cardiovascular disease risk was related to traditional cardiovascular disease risk factors and markers of thrombosis and endothelial damage, but not to high-sensitivity C-reactive protein or markers of T-cell activation such as CD38/human leukocyte antigen-DR co-expression."

Taken together, these studies shed more light on factors associated with cardiovascular disease risk in HIV positive people on ART, but do not offer definitive answers given that they conflict with prior research.

Neither of these studies, for example, saw an association between cardiovascular disease and lower CD4 cell count, contradicting 2 other recent reports indicating that a decline in CD4 count -- even at relatively high levels -- increased the risk of cardiovascular disease and heart attacks.

Investigator affiliations:

Delaney study: University of Florida, Gainesville, FL; University of California, San Francisco, CA; Department of Veterans Affairs, San Francisco, CA; Department of Biostatistics, University of Washington, Seattle, WA; Tufts Medical Center, Boston, MA; University of California, Los Angeles, California, USA.

Ford study: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

8/31/10

References
JA Delaney, R Scherzer, ML Biggs, C Grunfeld, and others (FRAM study team). Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima-media thickness. AIDS 24(14): 2201-2209 (Abstract). September 10, 2010.

ES Ford, JH Greenwald, AG Richterman, and others. Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS 24(10): 1509-1517 (Abstract). June 19, 2010.