Suppressive antiretroviral therapy slows progression of atherosclerosis

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Antiretroviral therapy that reduces viral load to an undetectable level was linked to slower progression of sub-clinical atherosclerosis, as indicated by carotid intima-media thickness, researchers reported last week at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.

Atherosclerosis ('hardening of the arteries') is an inflammatory condition in which plaques (accumulations of lipids, immune cells, scar tissue and cell debris) build up in artery walls. This leads to narrowing of the arteries, and ruptured plaques and the resulting clots can block blood vessels, causing a heart attack or stroke. Several studies have shown that people with HIV have more rapid atherosclerosis progression than HIV-negative people, but data have not always been consistent.

Jason Baker and fellow investigators evaluated artery changes amongst participants in the SUN study, an observational cohort of HIV-positive people in four US cities enrolled during the modern antiretroviral therapy era (2004-2006). Most (78%) were men, about 60% were white and the median age was 42 years.

Glossary

cardiovascular

Relating to the heart and blood vessels.

body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.

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.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

cholesterol

A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

The researchers measured sub-clinical or pre-symptomatic atherosclerosis using ultrasound to assess the thickness of artery walls – known as intima-media thickness or IMT – in the carotid arteries that supply blood to the brain.

IMT was assessed in the common carotid, the main part of the artery before it splits into two branches. Another study presented at CROI showed that carotid IMT can vary considerably depending on where in the artery it is measured.

The SUN researchers measured IMT at entry to the study and then two years later. The researchers undertook analyses to determine factors associated with carotid artery thickening among this group at low risk for progression to AIDS.

Many of the participants had traditional risk factors for cardiovascular disease when they entered the study. The median body mass index was about 26 (considered overweight), about 40% were smokers and about 30% had high blood pressure or metabolic syndrome. However, total cholesterol and LDL (bad) cholesterol levels were generally low and within recommended ranges. The median Framingham Risk Score (a frequently used indicator of cardiovascular risk) was low, at 2, but 30% had a score of 5 or higher.

At baseline, 78% of participants were taking antiretroviral therapy, about evenly divided between non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors. The median CD4 cell count was near normal at 481 cells/mm3 – though the nadir or lowest-ever count was about 200 cells/mm3 – and 71% had a viral load below 400 copies/ml.

Over two years of follow-up, the overall median common carotid IMT increased from 0.710 mm at baseline to 0.720 mm (a median increase of +0.013 mm); the largest proportion of patients, however, showed no change.

Presenter Jason Baker noted that whilst general population studies have also shown carotid IMT increases in the range of +0.01 to +0.02 mm, those patients were typically around ten years older than the SUN cohort.

SUN participants whose viral load was consistently suppressed below 400 copies/ml at all study visits experienced a significantly smaller increase in common carotid IMT (+0.011 mm) than those with one or more higher viral load measurements (+0.019 mm).

But the researchers saw some difference between antiretroviral drug classes. NNRTI use was associated with a significantly smaller common carotid IMT increase (+0.009 mm) compared with protease inhibitor use (+0.016 mm), a difference of -0.007 mm.

They did not find a significant difference, however, between patients who took tenofovir (Viread, also in the Truvada and Atripla combination pills) and those who took abacavir (Ziagen, also in the Kivexa and Trizivir coformulations) (+0.013 vs +0.015, respectively).

After adjusting for traditional cardiovascular risk factors, negative predictors of carotid IMT progression – that is, those associated with smaller increases – were baseline viral suppression (difference of -0.010 mm), persistent viral suppression during follow-up (difference of -0.014 mm) and baseline antiretroviral therapy use (difference of 0.009 mm). Though small, these differences were statistically significant.

The SUN investigators also found that older age and being overweight were associated with larger IMT increases. Each additional ten years of age increased carotid IMT by a further 0.005 mm, whilst having a body mass index above 25 was linked to an additional 0.013 mm increase. However, high sensitivity C-reactive protein (CRP), a biomarker of inflammation, was not a significant predictor of increased IMT.

"Maintaining a suppressed HIV viral load decreased progression of sub-clinical atherosclerosis (carotid IMT)," the investigators concluded. "Factors related to both HIV infection and the type of antiretroviral therapy independently associate with the rate of carotid IMT progression."

Dr Baker said that the study found changes in atherosclerosis "at the level of the arterial wall" that are consistent with the elevated risk of cardiovascular events like heart attacks seen in the D:A:D observational cohort and other studies.

Further information

You can view the abstract on the official conference website.

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

References

Baker J et al. Progression of carotid intima-media thickness in a contemporary cohort. Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 126, 2010.