Study suggests that HIV infection and use of antiretroviral therapy both can have negative effects on arteries

Dutch researchers have found associations between HIV infection and unfavourable changes in the arteries, contributing to the ongoing effort to understand why some people with HIV appear to be at elevated risk for cardiovascular problems. Their cross-sectional study, reported in the February 1^st edition of the Journal of Acquired Immune Deficiency Syndromes, measured artery wall thickness and artery stiffness in HIV-positive individuals and in a control group of HIV-negative people. HIV infection was independently associated with both of these indicators of cardiovascular risk, and there was also an association between antiretroviral therapy (ART) use and artery stiffness.

Since the late 1990s, when treatment advances greatly reduced AIDS-related mortality in wealthy countries, there has been widespread concern about whether using anti-HIV drugs, particularly protease inhibitors, puts people at higher risk for heart attack, stroke and related health problems. Meanwhile, there is growing evidence that HIV itself harms the cardiovascular system. Because numerous factors may contribute to cardiovascular risk in HIV-positive people, it is difficult to isolate specific causal pathways.

The Dutch study enrolled 77 HIV-positive men and 52 healthy HIV-negative men. Twenty-two members of the HIV-positive group had never taken antiretroviral therapy. Twenty-three members of the HIV-positive group had lipodystrophy.

Researchers measured several properties of the arteries. The thickness of the wall of an artery in the neck (carotid artery intima-media thickness, C-IMT) was of interest because this is recognised as an indicator of atherosclerosis, a disease characterised by the build-up of plaque in the arteries. The study also assessed the distensibility coefficient (DC) and compliance coefficient (CC) – both indicators of the stiffness of arteries and markers of cardiovascular risk - for the carotid (neck), femoral (thigh) and brachial (upper arm) arteries.

After adjusting for key confounding factors such as age, body mass index and smoking, researchers found that HIV-positive study participants had significantly greater C-IMT than healthy controls, i.e., greater thickness in the carotid artery, which averaged 0.69 mm rather than 0.62 mm (p = 0.001).

HIV-positive people also had lower DC and CC values for the carotid and femoral arteries, indicating greater artery stiffness (adjusted mean differences as percentages, HIV-positive versus control: –13.6% for carotid artery DC, –14.1% for carotid artery CC, –29.5% for femoral artery DC, and –31% for femoral artery CC).

HIV infection was independently associated with C-IMT; carotid artery DC and CC; femoral artery DC and CC; and brachial artery CC. The current CD4 cell count levels, nadir (lowest-ever) CD4 cell count levels, and viral load levels of HIV-positive study participants were not associated with C-IMT or arterial stiffness.

When HIV-positive people who were treatment-experienced and those who were treatment-naïve were compared to each other, there was no significant difference in C-IMT. However, the treatment-experienced group had significantly increased femoral artery stiffness as reflected by both DC and CC measures (adjusted mean differences as percentages, ART-experienced versus ART-naïve: –25.9% and –21.7% for femoral artery DC and CC, respectively). Analysis of the full HIV-positive cohort indicated that use of HIV treatment was independently associated with femoral artery stiffness, as were cumulative use of protease inhibitors and nucleoside reverse transcriptase inhibitors.

No significant differences were found between patients with and without lipodystrophy, but the small size of the lipodystrophy subgroup and the use of lipid-lowering drugs by some study participants with lipodystrophy may have contributed to this result.

The researchers note that chronic inflammatory diseases such as rheumatoid arthritis have been shown to increase C-IMT, as have chronic infections. They propose that “chronic HIV infection may therefore also lead to vascular endothelial damage and increase in vessel wall thickness by sustaining a low degree of inflammation.” The endothelium is a smooth layer of tissue lining the insides of blood vessels.

There is not enough knowledge currently to determine why antiretroviral therapy appears to affect femoral artery stiffness but not carotid or brachial artery stiffness. Furthermore, the researchers express uncertainty about the causal pathway for this outcome: the drugs may be damaging the femoral artery directly, or the stiffening may result from metabolic side-effects of the drugs. At the same time, by reducing the inflammation caused by HIV infection, antiretroviral therapy may simultaneously protect the arteries.

“The balance between the beneficial effects of diminishing active infection/inflammation and the negative effects of ART such as dyslipidemia may be essential to determine the net effect in an individual patient and in different arterial segments,” the researchers observe.

Protease inhibitors have long been suspected of increasing cardiovascular risk, in part because they appear to cause changes in blood fat levels. A large cohort study published in 2007 reported that study participants taking protease inhibitors were slightly more likely to experience heart attacks than those who were not. However, a 2008 analysis of data from another large cohort found that the use of anti-HIV drugs did not increase the risk of serious cardiovascular illness.

The matter remains unresolved, and there is also ongoing debate about whether one of the nucleoside reverse transcriptase drugs, abacavir, elevates heart attack risk. At the same time, other evidence has emerged to show that in some ways antiretroviral therapy may benefit cardiovascular health.

As for the role of HIV itself, a lower CD4 count has been associated with higher cardiovascular risk, and researchers have also tied HIV infection to specific biomarkers of cardiovascular functioning such as endothelial activation levels. However, much remains unknown about the specific mechanisms that might enable the virus to damage blood vessels.

Although the debate about the negative effects of particular anti-HIV drugs is ongoing, the overall benefits of treatment far outweigh the potential drawbacks for most people. It is hoped that by developing greater insight into the interplay between HIV infection, antiretroviral therapy and other factors including heredity and lifestyle, researchers and clinicians will be able to identify the best strategies for managing cardiovascular risk in HIV-positive people in accordance with individual risk profiles.