AIDS cocktails may increase risk of CVD

April 2005

While combination antiretroviral therapy (ART) has effectively extended the lives of patients living with HIV, the drug cocktail may drastically increase the risk of heart attacks and cardiovascular complications, according to recent studies.

In the years since combination therapy became widely prescribed for HIV, clinicians and researchers have noticed coronary heart disease occurring at surprising rates among HIV patients on ART.

A French study of 20,000 men exposed to a protease inhibitor concluded that patients who had taken the therapy for more than 18 months had twice the myocardial infarction (MI) risk as patients with less drug exposure.

Moreover, a Kaiser Permanente Medical Care Program of Northern California epidemiology study found that people with HIV had higher rates of hospitalization for coronary heart disease, regardless of whether they were taking antiretroviral drugs, than their uninfected counterparts.

And a study of 28,000 California Medicaid patients with HIV found that patients between the ages of 18 and 33 exposed to antiretroviral drugs had twice the risk of coronary heart disease as age-matched, untreated patients, suggesting the effect may be more pronounced in younger patients.

Such studies pointed to an association between HIV infection and coronary heart disease but none clarified which factor – antiretroviral drugs or HIV itself – is responsible for the observed effect.

Jens D. Lundgren, MD, researcher at the University of Copenhagen, Denmark, offered more insight into this perplexing phenomenon at the 12th Annual Conference on Retroviruses and Opportunistic Infections, held in Boston.

DAD study

Lundgren reported results of a prospective observational study of 23,468 patients conducted by a team of international researchers, known collectively as the DAD (Data collection of Adverse events of anti-HIV Drugs) Study Group. The DAD study found that 126 of the 23,468 patients experienced a myocardial infarction during the 1.6-year follow-up period, and the incidence increased with longer exposure to antiretroviral therapy.

“We find a 17% increased risk of MI per additional year of exposure,” said Lundgren. “There’s some debate regarding whether that’s an important risk factor, but if we treat for many years, that risk adds up.”

Put in different terms, a five-year exposure to ART is equivalent to the risk of having ever smoked, both which roughly double the risks of MI, said Lundgren.

“Combination therapy is a very important risk factor for coronary heart disease in HIV patients, probably one of the strongest ones ever identified,” he argued.

Importantly, the effect observed in the DAD study was found to be true regardless of gender or age. The data did not suggest that any subgroups of this population experience excess risk.

Association questioned

While the association between ART and cardiovascular disease is clear, the causal relationship is much murkier. Does HIV itself increase lipid abnormalities, or work in concert with HIV drugs to produce the effect? Or is ART the sole culprit?

It’s clear that HDL-cholesterol and triglyceride levels play a role in the mix of interactions, said Lundgren.

“If we start to introduce lipids into our model, we start to see some reduction in association from 1.17 to 1.10 (relative rate) after adjustment,” he said.

Preliminary research suggests protease inhibitors may elevate triglyceride and cholesterol levels while antiretrovirals, in general, have been associated with insulin resistance and diabetes. But because ART consists of a drug cocktail, DAD researchers have, so far, been unable to isolate which drug classes — if any individual ones in particular — are responsible for the effect.

However, Lundgren expects researchers will have collected enough data on MIs in this population to tease out the role of individual drugs and drug classes in the next few years.

Predictive models, such as the Framingham equation, suggest metabolic complications from treatment are driving the increase in myocardial infarction events. However, these models predicted fewer events than the DAD group actually saw, and therefore the results should be taken with a grain of salt, noted Lundgren.

Future research

As future studies attempt to illuminate the underlying mechanisms involved in the relationship between ART and MI, researchers may see changes in the study environment.

Therapy has effectively made HIV a chronic disease rather than a cause of mortality, and as the HIV population ages, patients may begin to make lifestyle and behavioral changes, such as quitting smoking or taking lipid-lowering drugs that will reduce their risk of cardiovascular complications, according to Lundgren.

He predicted that such changes will likely affect future risk estimates and the overall risk observed in the DAD study will likely decrease in coming years.

“The clinical take home message is: individual lipid responses to ART provide partial information as to whether a person’s cardiovascular disease risk has been adversely affected by ART,” Lundgren summarized.

“We need to conduct further analysis to understand a possible direct role of specific drug classes,” he added.

For more information:

• Lundgren JD. Cardiovascular outcomes in HIV infection. Session 17-Symposium. Oral Session 62. Presented at the 12th Annual Conference on Retroviruses and Opportunistic Infections. Feb. 22-25, 2005. Boston.