May 1999 Cover
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No one knows for sure what is causing symptoms such as "Crix belly" or "buffalo hump" and associated loss of fat in the face, arms, and legs among those
using protease inhibitors. Other metabolic complications are also often seen, including high triglyceride and cholesterol levels, and develo pment of insulin resistance or
even diabetes in some patients.
Work by Glaxo Wellcome researchers suggests that not all lipodystrophy is the same, but that there are at least two distinct mechanisms involved, depending
on which protease inhibitor is used.
One possible mechanism may involve preventing develo pment of fat cells. In one experiment, saquinavir, ritonavir, and nelfinavir greatly reduced the develo
pment of fat cells from stem cells; however, neither indinavir nor amprenavir had much effect. Saquinavir, ritonavir, and nelfinavir also increased the metabolic destruction
of fat in existing fat cells.
Another possible mechanism involves increasing "retinoid toxicity." Retinoids are compounds related to vitamin A; some of them are found naturally in the
body, where they have many different effects. Too much of certain retinoids causes toxic effects due to abnormal biochemical signaling in the body, and the toxicity
of excessive vitamin A can resemble some of those sometimes seen in the lipodystrophy syndrome.
When protease inhibitors were combined with retinoids in lab tests, the results were complex, depending on the protease inhibitor and the retinoid. But perhaps
the most important single result is that indinavir (alone among all the protease inhibitors in human use) clearly stimulated signaling by all-trans retinoic acid
(ATRA). ATRA is a retinoid produced naturally in the body from vitamin A. While it is too early to know that these laboratory studies apply to humans, the researchers
suggest that indinavir may cause some lipodystrophy problems by changing retinoid signaling-- in effect, causing retinoid toxicity not by increasing the amount of
ATRA present, but by increasing the body's sensitivity to it.
If this theory is correct (and no one knows yet), it would suggest that vitamin A supplementation might be harmful if one is taking indinavir, by making some of
the lipodystrophy problems more likely to occur. Possibly this theory could be tested by looking for correlations between lipodystrophy and vitamin A intake in
clinical databases-- if there are databases which have enough patients taking indinavir, keep consistent records on lipodystrophy, and record nutritional intake.
Editor's Note: from AIDS Treatment News
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