Progression of atherosclerosis is linked to inflammation in people with HIV

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People with HIV experience more rapid progression of atherosclerosis than uninfected individuals, especially as measured in a specific part of the carotid artery known as the bifurcation region, researchers reported last week at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.

Faster progression was associated with inflammation, and was seen even in 'elite controllers' who naturally control the virus.

Cardiovascular disease is a growing concern as people with HIV live longer. Atherosclerosis ('hardening of the arteries') is an inflammatory condition in which artery walls develop plaques (accumulations of lipids, immune cells, calcium, scar tissue and cell debris).

Glossary

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.

atherosclerosis

A disease of the arteries in which fatty plaques develop on the inner walls, eventually leading to obstruction of blood flow.

cardiovascular

Relating to the heart and blood vessels.

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

cardiovascular disease

Disease of the heart or blood vessels, such as heart attack (myocardial infarction) and stroke.

Atherosclerosis narrows arteries and ruptured plaques can block blood vessels, causing a heart attack or stroke.

Several past studies have shown that people with HIV have more atherosclerosis than HIV-negative individuals, but results have not always been consistent, in part because of differences in how artery injury is measured.

Intima-media thickness

One common method is using ultrasound to assess the thickness of artery walls – known as intima-media thickness (IMT) – in the carotid arteries that supply blood to the brain. However, results can vary depending on whether a measurement is taken in the main artery, in one of its two branches (the internal and external carotid) or at the bifurcation or 'fork' where they split.

Priscilla Hsue from the University of California, San Francisco and colleagues compared IMT progression in the common carotid, internal carotid and bifurcation regions in individuals with and without HIV.

Dr Hsue – who gave a comprehensive overview of inflammation, atherosclerosis and cardiovascular disease earlier in the conference – explained that due to blood flow dynamics, the bifurcation may be more susceptible to inflammation and atherosclerosis. As a result, early injury may be detectable in this region before it appears in other parts of the artery. But the bifurcation region is harder to measure, so many researchers have favoured the other sites.

The study included 285 HIV-positive participants, primarily from the observational SCOPE cohort at San Francisco General Hospital. Most (72%) were on antiretroviral therapy and 47% had suppressed viral load on treatment. In addition, 22 participants were from a cohort of elite controllers who maintained undetectable virus without therapy. Finally, 40 HIV-negative people served as controls.

About 85% of participants were men, roughly 70% were white and the median age was about 45 years. HIV-positive participants had been infected for a median 13 years and had been on antiretroviral therapy for nearly four years. The current CD4 cell count was 433 cells/mm3, but the nadir (lowest-ever level) had been 150 cells/mm3.

With regard to traditional cardiovascular risk factors, HIV-positive participants had significantly lower LDL (bad) cholesterol at baseline, but higher levels of triglycerides and high-sensitivity C-reactive protein (CRP), a biomarker of inflammation. HIV-positive people were also somewhat more likely to smoke than their HIV-negative counterparts (68% vs 53%) and had higher prevalence of high blood pressure (28% vs 13%), diabetes (7% vs 3%) and prior heart disease or strokes (8% vs 3%), but none of these differences reached statistical significance.

The researchers measured IMT at twelve segments of the carotid artery and calculated annualised rates of progression. At baseline, IMT was greater amongst HIV-positive people than HIV-negative controls, both overall (0.86 vs 0.71 mm) and in each carotid region.

After a median two years of follow-up, overall IMT progression was significantly more rapid in HIV-positive people compared with HIV-negative controls (0.046 vs 0.012 per year). The difference remained significant after adjusting for traditional risk factors such as smoking.

However, the effect varied depending on measurement site. Amongst participants with HIV, IMT progression was most evident in the bifurcation region followed by the internal carotid and then the common carotid. The difference in progression between HIV-positive and HIV-negative people was largest in the bifurcation region (0.074 vs 0.013 mm/year), followed by the internal carotid (0.046 mm/year vs none), but was not statistically significant in the common carotid (0.074 vs 0.013 mm/year).

Amongst people on suppressive therapy and elite controllers, IMT progression was significantly greater compared with uninfected people in the bifurcation region but not in the common carotid.

CRP levels were more closely linked to IMT progression in the bifurcation region. After adjusting for traditional risk factors and HIV status, CRP was independently associated with IMT progression in the bifurcation region, whilst traditional risk factors were more predictive in other regions. When the analysis was adjusted to take CRP levels into account, the independent effect of HIV was reduced.

Based on these findings, the researchers concluded that, "HIV-related inflammation contributes to increased risk of atherosclerosis in the setting of HIV."

Asked about the clinical relevance of the findings, Dr Hsue said that although the measured IMT changes were very small, IMT progression has been strongly correlated with increased risk of cardiovascular disease in the HIV-negative general population.

Flow-mediated dilation

In a related poster presentation, Dr Hsue and colleagues used another indicator of atherosclerosis called flow-mediated dilation. This technique assesses the function of the endothelial lining of arteries by measuring how much an artery (typically the brachial artery in the upper arm) expands in response to changes in blood flow.

This study included 139 HIV-positive people from the same SCOPE cohort who had suppressed viral load on antiretroviral therapy, as well as 32 HIV-negative control participants.

Compared with the larger SCOPE population, the HIV-positive participants in this analysis had a longer duration of infection (median 17 years) and had been on treatment longer (9 years); 41% were currently taking abacavir (Ziagen, also in the Kivexa and Trizivir coformulations). About half were smokers and about 40% had high blood pressure.

People with HIV had significantly lower – that is, worse – endothelium-dependent flow-mediated dilation compared with uninfected people (4.1% vs 5.2%), a finding that remained after adjusting for traditional risk factors. Exposure to abacavir was linked to impaired flow-mediated dilation, but protease inhibitor exposure, overall duration of antiretroviral therapy, and current or nadir CD4 count were not significant predictors.

HIV-positive people had a higher median CRP level than HIV-negative participants, and CRP was independently associated with HIV infection after adjusting for traditional risk factors. In the HIV group, higher CRP was a stronger predictor of impaired flow-mediated dilation than older age; the opposite was the case for HIV-negative people.

Here, the researchers concluded that endothelial function – a central mechanism in atherosclerosis – is impaired among treated HIV patients with undetectable viral load, and that CRP was more predictive of impaired endothelial function than traditional risk factors in this population.

"These findings suggest that even patients doing well on combination antiretroviral therapy (as defined by viral load) may be at increased risk for cardiovascular disease, and that chronic inflammation in the setting of treated HIV disease likely contributes to this increased risk," they wrote. "Our findings also argue for an independent role of direct drug toxicity in driving early cardiovascular disease."

Further information

You can view abstract 125 and abstract 708 on the official conference website.

You can also view a webcast and slides of this session on the official conference website.

References

Hsue P et al. Progression of atherosclerosis at the carotid bifurcation is linked to inflammation in HIV-infected patients. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 125, San Francisco, 2010.

Hsue P et al. Inflammation is associated with endothelial dysfunction among individuals with treated and suppressed HIV infection. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 708, San Francisco, 2010.