Protease inhibitors: Emerging research explores possible link with heart disease
Experts say PI therapy remains essential for most
Researchers have given clinicians a mixed view of HIV disease and coronary heart disease risk, including evidence that protease inhibitors increase the risk of heart disease. The problem isn't the evidence, but perspective, two investigators say.
"Antiretroviral therapy, be it protease inhibitors or nucleoside reverse transcriptase inhibitors, is highly effective at reducing morbidity and mortality from AIDS," says Carl Grunfeld, MD, PhD, a professor of medicine and division chief at the Veterans Affairs Medical Center (VAMC) in San Francisco, CA.
"This is huge compared to the small increase from cardiovascular risk," Grunfeld says. "Nonetheless, there is a small increase in cardiovascular risk in every study, although studies disagree on how much affect protease inhibitors have."
One recent study examines the 10-year predicted coronary heart disease risk of HIV-infected men and women and finds PI use does increase risk.1
"I think the totality of the best evidence we have now suggests there may be some harmful effects of PIs, as our data suggested, but there's more evidence suggesting the opposite," says Robert Kaplan, PhD, an associate professor of epidemiology at Albert Einstein College of Medicine in the Bronx, NY. Kaplan has co-authored a number of studies on this topic, including the recent 10-year predictive study.
Some studies show that ART can reduce cardiovascular disease substantially, Kaplan notes.
"We really try to emphasize that ART exposure is a small and uncertain piece of the picture here," Kaplan says.
Grunfeld, who treats cardiovascular patients including many infected with HIV, focused his research on the association between HIV infection, PI use, and fibrinogen levels. His recent study found that PI use is associated with elevated fibrinogen levels, and these might contribute to increased risk of atherosclerosis in patients who are HIV infected.2
"This is the first study with a possible explanation for how PIs cause an increase in atherosclerosis risk," Grunfeld says.
Fibrinogen is a clotting agent that is a useful tool in the body until there's a plaque that ruptures, Grunfeld explains.
"If you have a clot and it ruptures and you have high levels of fibrinogen then you're more likely to form a clot and have a heart attack," he says.
The fibrinogen levels are not as important for healthy individuals who do not have arteriosclerosis, but these can be a factor for those who already have lifestyle and other factors placing them at risk for heart disease, Grunfeld adds.
"I think people are increasingly aware that there's an increased risk of heart attacks and coronary problems with HIV infection," he says. "So they should aggressively look at reducing risk factors of arteriosclerosis by controlling blood pressure, cholesterol, and stop smoking."
There are many well-established factors that predict heart disease, including smoking and obesity, Kaplan notes.
A factor like fibrinogen is not well understood, and there are no medications to treat for fibrinogen problems, he says.
Also, while there is evidence that high fibrinogen levels are linked to heart disease in non-HIV patients, there is no evidence that high levels of fibrinogen in HIV patients is linked to heart disease, Kaplan adds.
In research that will be published later this year, Kaplan and co-investigators have found that classic vascular risk factors, such as being overweight, smoking, high blood pressure, and high cholesterol, were much more consistent with heart disease risk than HIV medications.
"The patients with the worst HIV disease had the highest rate of vascular disease or arteriosclerosis in that research," Kaplan says.
However, what both recently-published studies suggest is that HIV clinicians need to pay particular attention to cardiovascular risk factors, including any impact on the risk by HIV drugs — whether these are positive or negative.
The key point is that there's an increased risk of heart attacks and coronary problems with HIV infection, and clinicians should aggressively look at reducing risk factors of arteriosclerosis, Grunfeld says.
"They need to control blood pressure and cholesterol and have patients quit smoking," he says. "Most studies where HIV patients are compared to controls show they smoke twice as much as controls, and we don't know why."
Grunfeld aggressively works to prevent cardiovascular disease in his endocrinology clinic, where one-third of patients have HIV infection.
"I try to teach my residents and fellows to be aggressive about preventing heart disease, and I practice what I preach," Grunfeld says. "I eat a healthy diet so I can say to patients 'This is what I do;' I don't smoke, and I run and exercise, leading by example."
HIV patients who smoke are offered every intervention available, including counseling with behavioral modification professionals and a nicotine patch.
Grunfeld hasn't studied patient outcomes from his educational efforts, but he has had patients who've quit smoking.
Grunfeld also encourages patients to start walking and aim for a daily walk so that if they miss one or two, they'll still be exercising at least five times a week, as is recommended by national public health guidelines. And HIV patients are prescribed the statin drugs that are suitable for patients who are also on ARTs.
However, there is one risk factor for which there is no intervention: "Age is the strongest risk factor," Grunfeld says. "As you get older the mainstay is to treat cholesterol, treat blood pressure, and stop smoking."
HIV clinicians who are treating older patients might have to consider the impact of PIs and other ARTs on heart disease risk when all other efforts to reduce risk have been exhausted.
"If someone has a CD4 cell count of 10 and is on salvage therapy, then it's much more important to get the best HIV treatment," Grunfeld says. "But many of our patients will live and not be harmed by the consequences of HIV for a long time, and I don't want them harmed by heart disease."
Grunfeld uses the Framingham equation to predict patients' heart disease risk and to guide his decisions about how aggressively to treat them for heart disease prevention.3
"One thing of interest for clinicians is as their treated populations age and other vascular diseases come on the rise, then there might be more rationale for worrying about potential risks associated with certain medicines," Kaplan says. "But for the larger number of patients who are middle-aged or young, the dangers associated with inadequate control of their HIV disease far outweigh any hypothetical risks of heart disease."
References
- Kaplan RC, Kingsley LA, Sharrett AR, et al. Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis. 2007;45(8):1074-1081.
- Madden E, Grace L, Kotler DP, et al. Association of antiretroviral therapy with fibrinogen levels in HIV-infection. AIDS. 2008;22:707-715.
- Dawber TR, Kannel WB, Revotskie N, et al. Some factors associated with the development of coronary heart disease. Six years' follow-up experience in the Framingham Study. Am J Public Health 1959;49(10):1349-1356.
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