SUMMARY: Markers of endothelial dysfunction -- an early indicator of cardiovascular disease -- were elevated in HIV positive people who maintained a stable viral load and CD4 cell count without antiretroviral therapy (ART), and even among "elite controllers," according to a study presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) this week in Boston. This finding adds further evidence that factors other than waning CD4 T-cell function -- for example, persistent inflammation -- contribute to non-AIDS conditions in the ART era.

By Liz Highleyman

Several studies have shown that people with HIV have a higher rate of cardiovascular disease and associated events compared with the HIV negative general population, but it is not yet clear whether this is due to HIV infection itself, antiretroviral therapy, traditional risk factors, or some combination thereof.

As atherosclerosis progresses, arteries lose their elasticity, or ability to expand, as they become filled with plaques. Eventually the blockage can impair blood flow, and pieces of plaque or blood clots can break away and become lodged in vessels supplying the heart (causing a heart attack) or the brain (causing a stroke).

Atherosclerosis is an inflammatory process, and past research -- including the large SMART treatment interruption study -- has shown that people with HIV, especially those with uncontrolled virus, have higher levels of biomarkers (substances in the blood) associated with inflammation, coagulation (clotting), and damage to the endothelial lining of blood vessels. In addition, studies have shown that people with HIV are more likely to show thickening of the lining of the carotid arteries serving the brain (carotid intima-media thickness, or IMT), and that this is also linked to inflammation.

At ICAAC, Hector Bonilla from Summa Health System in Akron and colleagues presented a poster reporting findings from a cross-sectional case-control study of early cardiovascular disease as measured by carotid IMT and inflammation markers in long-term non-progressors (LTNPs), defined as people who were HIV positive for at least 5 years and able to maintain stable viral load and CD4 cell counts with no AIDS-defining illnesses in the absence of ART.

The study included 13 HIV positive LTNPs and 13 HIV negative control subjects matched by age, sex, and race; 4 of the non-progressors were "elite controllers," meaning they maintained long-term undetectable viral load without treatment.

In the HIV positive group, 9 participants were men, 7 were white, and 6 were black. The mean age was 44 years, and they had been living with HIV for an average of 13.5 years (range 5-24 years). They had relatively early HIV disease on average, with a mean current CD4 count of 440 cells/mm3 (all above 325) and a mean nadir or lowest-ever CD4 count of 380 cells/mm3 (all 300 or higher).

Traditional risk factors for cardiovascular disease were common, including smoking (more than half of both groups, but higher in the HIV negative group), abnormal blood lipids (more prevalent in the HIV positive group), and being overweight.

The researchers measured inflammation biomarkers including C-reactive protein (CRP), soluble tumor necrosis factor receptor type 2 (sTNF-RII), soluble vascular adhesion molecule (sVCAM), and adiponectin (a hormone produced by fat tissue). Carotid IMT was assessed using B-mode ultrasound.

Results

	Overall, carotid IMT was not significantly greater for HIV positive LTNPs compared with HIV negative control subjects.
	However, when measured at the carotid bulb -- where the artery bifurcates or forks and blood flow is turbulent -- there was a nearly significant trend toward greater thickening among the LTNPs.
	HIV positive participants had higher sTNF-RII compared with the HIV negative group -- the only biomarker than was significantly different according to HIV status (P = 0.002).
	Among the LTNPs, elevated sVCAM1 showed a trend toward correlation with greater carotid IMT (P = 0.014).
	LTNPs had lower high-density lipoprotein (HDL), or protective "good" cholesterol, compared with the HIV negative group.
	8 of 13 LTNPs had HDL < 40 mg/dL, the threshold for men considered to indicate greater cardiovascular risk.

"Endothelial markers are significantly elevated in long-term non-progressors compared to healthy controls, and correlate with carotid IMT measurements," the researchers concluded. "This emphasizes the effect of HIV itself vs. ART" on heightened cardiovascular disease risk in people with HIV.

In chronically infected, untreated HIV positive patients, they added in an ICAAC media advisory, "the persistent low grade viremia, the low levels of HDL-C ("good cholesterol"), [and] the increased levels of inflammation indicated by high levels of sTNF-RII, correlated with accelerated atherosclerosis."

Investigator affiliations: Summa Hlth.System, Akron, OH; NEOUCOM, Rootstown, OH; Case Western Reserve Cleveland, Cleveland, OH.

9/17/10

Reference
H Bonilla; J McShannic, D Chua, G. McComsey, and others. Cardiovascular Disease (CVD) and Inflammatory Markers in Long Term Non-Progressors (LTNP). 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. Abstract H-220.

Other Source
ICAAC. What is causing cardiovascular changes in HIV infected patients? Media advisory. September 12, 2010.