Protease Inhibitors, Coronary Disease Possibly Linked

UW RESEARCHERS SUGGEST POSSIBLE LINK BETWEEN HIV PROTEASE INHIBITORS AND CORONARY ARTERY DISEASE

MADISON, Wis.-One of the most celebrated medical breakthroughs of the 1990s, HIV protease inhibitors-key ingredients of the more popularly known "AIDS cocktail"-have conferred powerful health benefits on thousands of Americans suffering from the disease. As recently as 1995, HIV was the leading killer of Americans aged 25-44. Today, thanks in large part to the use of protease inhibitors that prevent the virus from replicating and attacking the body's immune system, HIV doesn't even crack the top ten.

But according to the results of a pilot study conducted by physicians at the UW Medical School, the same protease inhibitors that have returned countless HIV patients to health may also be putting them at risk of developing coronary artery disease-the underlying cause of heart attacks.

Dr. James H. Stein, assistant professor of medicine at UW Medical School and a UW Hospital cardiologist, and Dr. James Sosman, an assistant professor of medicine and associate director of the HIV program, co-conducted the study. Their findings suggest that use of HIV protease inhibitors may lead to dysfunction of the lining of blood vessels (endothelium) that regulates blood flow and blood clotting. Dr. Melissa Klein, a co-investigator, will present these findings Monday, Nov. 8 at the 72nd meeting of the American Heart Association's Annual Scientific Sessions in Atlanta, GA.

Researchers have been aware for the last several years that patients on HIV protease inhibitors tend to develop elevated blood sugar levels (hyperglycemia), weight gain and increased blood cholesterol and triglyceride levels (hyperlipidemia)- four risk factors for coronary artery disease.

"Patients are clearly getting tremendous benefits from the use of HIV protease inhibitors," said Sosman. "But this appears to be a significant side effect to that benefit."
Using a unique ultrasound technique to map blood flow through the brachial artery (located in the upper arm), Stein and Sosman examined the lining of blood vessels in 28 HIV-positive patients, looking for signs of endothelial dysfunction. The tests showed that the brachial arteries of 21 patients on protease inhibitors to control their HIV experienced a significantly impaired response to changes in blood-flow levels (flow-mediated dilation). The seven patients not taking HIV protease inhibitors showed normal levels of flow-mediated dilation.

According to Stein, results of the pilot study could substantially affect how doctors respond to the long-term cardiovascular needs of HIV patients.

"Up until recently, doctors have been reluctant to place their HIV patients on lipid-lowering drugs because they weren't certain that the changes caused by the inhibitors were leading to heart disease," said Stein. "We need to begin taking the long-term cardiac care of HIV patients who are using protease inhibitors more seriously. This study tells me we should be treating their lipid abnormalities."

Stein and Sosman reiterated that their findings are preliminary, and in no way suggest that HIV protease inhibitors in fact do more harm than good. Both agreed that further research is needed to examine the long-term impact of HIV protease inhibitors. To that end, Stein has applied to the National Institute of Health for a five-year grant to study the effects of HIV protease inhibitors on patients over time to see if they develop full-blown atherosclerosis. Stein would also like to explore a hypothesis: that the endothelial dysfunction in the test patients may be caused by HIV protease inhibitors cross-reacting with proteases naturally generated by the liver to clear cholesterol from the bloodstream after a person consumes a meal. "Our thinking is that HIV protease inhibitors are not specific, so they may be causing problems by inhibiting this other protease that we need," said Stein.

Stein believes the pilot study represents one of the first collaborative efforts between cardiologists and HIV specialists; before now, he said, cardiologists had little reason to devote more than passing attention to HIV-related research. "HIV isn't covered much in cardiology literature," noted Stein. "The heart usually isn't one of the organs ravaged by the virus."

EDITOR'S NOTE: Protease inhibitors used to control HIV are taken in pill form and differ sharply from other protease inhibitors, such as the nasal inhibitors UW Medical School researchers under the direction of Dr. James Gern are using to study the rhinovirus that causes the common cold.

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