Is atherosclerosis connected to PI therapy?
Is atherosclerosis connected to PI therapy?
Study discovers direct toxicity from PIs
In a breakthrough study, researchers at the Columbus (OH) Children’s Research Institute Center of Developmental Pharmacology and Toxicology have discovered direct toxicity of protease inhibitors to the cells that line blood vessels. "Basically, what we were trying to do is something very simple, but it’s the first time it’s been done," says John Anthony Bauer, PhD, associate professor of pediatrics at Ohio State University and an investigator at the Columbus Children’s Research Institute, both in Columbus.
"There has been evidence in the last year or two that particularly associated with protease inhibitor [PI] drugs there seems to be a form of aggressive atherosclerosis, artery coronary disease," he says. "These are young patients with cardiovascular disease, and that is abnormal."
HIV investigators had speculated that HIV drugs affected lipid levels, and that was the cause of the problem. The question unanswered in the literature was whether PI drugs have direct action on endothelial cells or direct toxicity on endothelial cells. "No one had really asked that question," Bauer says. "What we found was, yeah, these drugs actually had quite striking effects on endothelial cells."
The findings could have an important impact on future therapies, Bauer predicts. "The only fighting chance we have of having good therapy is to find out how these problems go and try to fix them, and this is more information." Another clinical implication may involve PI treatment of pregnant women because placentas are made up of endothelial cells, which help the placenta maintain its integrity, he says.
Other recent research has shown that while, in general, antiretroviral drugs given to pregnant women do not appear to have a negative impact on their newborns, there is an association between protease inhibitors and very low birth-weight babies, according to a National Institutes of Health-sponsored study published in the June 2002 issue of The New England Journal of Medicine.
"The endothelial cells are the Teflon coating of blood vessels, a single cell lining of all blood vessels, and they modulate and control the extent of the constriction of blood vessels," he explains. "The second thing it does is prevent stickiness, prevents clotting, and keeps the surface smooth so blood products don’t clot and form clots on the inside of the blood vessel."
Researchers have found in recent years that an impairment of that function in the endothelial cells promotes atherosclerosis, and it’s now considered an early event of atherosclerosis, Bauer says. "In the last five to 10 years, there has been overwhelming evidence that this matters."
With the knowledge that PIs impair the process of endothelial cells, the next step is to find out what exactly goes wrong, he adds. "We think there are fairly specific events that influence very specific proteins that are important for endothelial survival." Also, further research could explore whether this effect is specific to PI drugs or whether other antiretroviral drugs also have a negative impact on endothelial cells.
Finally, investigators will want to devise strategies to prevent the problem, and they’ll need to explore what factors make a person more susceptible to this damage, Bauer suggests. "That’s an important part of what we’re interested in, the genetic aspects that play a role in cardiovascular disease in general," he says. "Are there people particularly vulnerable to this type of toxicity? We’re just getting to the point of asking these questions, and it’s probably important for understanding cardiovascular disease."
Until more answers are available, the best strategy for clinicians is to continue to monitor patients’ cardiovascular status. Since there is no easy marker for endothelial injury, it’s important that clinicians know about the side effects of PI drugs, such as increased lipid levels. Also, clinicians should keep in mind that separate from any antiretroviral-related cardiovascular toxicity, HIV patients appear to have a variety of cardiovascular problems that are unrelated to the drugs, Bauer says. "How does HIV promote cardiovascular disease itself?" he muses. "It turns out to be an interesting story because it seems that many HIV patients are becoming cardiovascular patients, independent of their treatment."
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