'Weight of evidence' suggests that HAART increases the risk of heart disease, says NEJM editorial

Evidence suggests that HIV-positive individuals treated with HAART are at increased risk of premature hardening of the arteries, a major risk factor for cardiovascular disease, an editorial in the November 20^th edition of the New England Journal of Medicine concludes.

The editorial accompanied an article in the same issue of the journal presenting the final results from Data Collection of Adverse Events of Ant-HIV Drugs (DAD) Study Group. The DAD investigators concluded that HAART was independently associated with a 26% relative increase in the risk of heart attack per year of exposure in the first four to six years of use. These findings were reported at aidsmap when they were presented to an international conference earlier this year (see link below).

Between 1998 and 2003 several reports have been published examining the risk of heart disease in HIV-positive HAART treated patients. The editorial outlined these studies, focusing on their apparently contradictory findings.

An increased risk of heart disease was revealed by the French Hospital Database on HIV, which found that patients treated with a protease inhibitor had twice the risk of heart attack seen in patients with less drug exposure. A trend towards an increased risk of heart attack was found by the US HIV Outpatient Study investigators in their cohort since the introduction of protease inhibitors.

Further evidence to support the hypothesis that the use of HAART was associated with an increased risk of heart disease was provided by data from the Kaiser Permanente Medical care Program in California, which also indicated that HIV-positive individuals were at increased risk of heart disease even if they did not take HAART.

Contradicting the findings of these studies are data from the Veterans Affairs cohort in the US which found that the use of HAART was associated with a decreased risk of death from any cause.

The editorial’s authors examine how the VA study could have reached results seemingly at variance with the DAD study. They note that although both studies assessed large patient cohorts, neither study compared HIV-positive individuals with uninfected controls. In addition, the follow-up periods of both the VA study (three and a third years), and the DAD study (a little over one and a half years) are limited compared to the 16 years of follow-up which drive many risk estimates.

If an increased risk of cardiovascular illness is accepted, the authors posit a number of possible causes, noting "it must be recognized that as HIV-infected patients live longer, their risk of cardiovascular disease, compounded by their preexisting burden of risk factors, inevitably increases." Indeed, the authors emphasise that the DAD investigators found a high burden of traditional cardiovascular risk factors in their patient cohort.

Nevertheless, the authors state that it is plausible that the inflammatory effects of HIV infection itself could increase the risk of heart disease. In addition, HIV is associated with a reduction in “good” HDL cholesterol, and the progression of HIV disease and a high viral load has been linked with an increase in triglycerides.

Or is it antiretroviral drugs? The authors point to evidence from the indinavir clinical trials which showed that healthy volunteers given the drug experienced endothelial dysfunction, which has been correlated with coronary artery disease.

Metabolic complications, including increases in cholesterol and triglycerides, insulin resistance, and body shape changes, which have all been linked to the use of HAART, could also increase the risk of heart disease.

What’s more, the authors point to evidence from computed tomography (CT) scans showing that HAART-treated individuals have increased rates of coronary-artery calcification, and ultrasounds showing evidence of carotid intimal thickening as further suggesting an increased risk of heart disease.

The authors conclude "taken on aggregate, the weight of evidence suggests that HIV-infected patients treated with combination antiretroviral regimens are at increased risk of developing premature atherosclerotic complications." In order to develop the best strategies for the use of HAART it is necessary to investigate the extent of the risk of heart disease, its exact causes, the value of investigative procedures, and the best treatment approaches. Lifestyle changes such as stopping smoking and diet changes to reduce lipids are recommended as `logical`, and the use of statins could be considered `prudent`.

However, the authors also caution that given the complexities of HIV care and therapy "we need to have unequivocal evidence that changes in our successful treatment paradigm are warranted. Antiviral therapies have been among the miracles of recent decades, yet we must work toward mitigating the toxic effects that have the potential to diminish quality and duration of patients’ survival over the long term."

Further information on this website

Cardiovascular risks of HAART: More data but little more clarity? - news story reporting on DAD findings

PIs not linked to heart attack in large studies, but being HIV-positive is - news story reporting on Kaiser Permanente findings

HAART patients have increased risk of heart disease say French - news story on French Hospital Database study

Heart disease and HAART - overview