Researchers at the Columbus Children's Research Institute Center of Developmental Pharmacology and Toxicology in Ohio have discovered direct toxicity of protease inhibitors (PIs) to the endothelial cells that line blood vessels. "There has been evidence in the last year or two that particularly associated with protease inhibitor drugs there seems to be a form of aggressive atherosclerosis, artery coronary disease," said John Anthony Bauer, associate professor of pediatrics at Ohio State University and an investigator at the Institute. Investigators had speculated that HIV drugs caused the problem by affecting lipid levels. The question unanswered was whether PIs have direct action, or direct toxicity, on endothelial cells.

"What we found was, yeah, these drugs actually had quite striking effects on endothelial cells," Bauer said. "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," he said. "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 explained. The cells also prevent stickiness and clotting, he said.

Researchers have found in recent years that an impairment of that function in the endothelial cells promotes atherosclerosis and is now considered an early event of atherosclerosis. With the knowledge that PIs impair the process of endothelial cells, the next step is to find out what exactly goes wrong, Bauer added. "We think there are fairly specific events that influence very specific proteins that are important for endothelial survival," he said. Further research could explore whether this effect is specific to PIs or whether other antiretrovirals could have a negative impact on endothelial cells.

Another clinical implication may involve PI treatment of pregnant women because the placenta is made up of endothelial cells, which help the placenta maintain its integrity, Bauer said. Other 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 PIs and very low birth-weight, according to a National Institutes of Health-sponsored study published in the New England Journal of Medicine (2002;346(24):1863-1870).

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 is important that clinicians know about the side effects of PIs, such as increased lipid levels. Also, clinicians should keep in mind that HIV patients appear to have a variety of cardiovascular problems unrelated to drug treatment, Bauer said.

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