Lipodystrophy: Glaxo Researchers Suggest Mechanisms, Publish Data
At the recent Retroviruses conference (Chicago, Jan. 31 - Feb. 4), a research team from Glaxo Wellcome presented two posters proposing possible mechanisms for the lipid (fat) abnormalities which appear to be associated with use of protease inhibitors in some patients--together with supporting biochemical data from laboratory studies.1,2 Other mechanisms have been proposed, but without such laboratory data. Unfortunately the posters had limited impact at the conference, because this research is based on lipid biochemistry which is unfamiliar to most AIDS experts. We have met with the researchers and received additional documentation to help us explain this work to a larger audience.Part of the difficulty in research on lipodystrophy is that pharmaceutical companies have disincentives to highlight problems with their products. Glaxo has different incentives, because it has not marketed a protease inhibitor yet--and the lipid research suggest that its protease inhibitor amprenavir (Agenerase(tm), which was originally developed by Vertex Pharmaceuticals Inc. and formerly known as VX478 or 141W94), may not have the same problem. Also, according to Glaxo, there has been almost no lipodystrophy in its expanded-access program which so far has given the drug to over 1500 patients. But no one knows if these laboratory results will predict what happens in people; and the expanded-access program has not given amprenavir to enough people for long enough to know with confidence that they will not have as much lipodystrophy as those treated with other drugs, since this problem is most likely to occur after long-term use. While these results are interesting, only time will tell whether this drug will be associated with less lipodystrophy than other HIV protease inhibitors in human use.
Mechanisms
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--and metabolic complications which are often associated, including high triglycerides and cholesterol, and development of insulin resistance or even diabetes in some patients. Most experts today believe that protease inhibitors are probably involved, even though there were a few such cases before these drugs were used.
Many researchers believe that the fundamental problem in this syndrome is the loss of subcutaneous fat, rather than its abnormal accumulation. The loss of equilibrium between fat deposited in the body and lipids in the bloodstream may lead to very high blood levels of LDL cholesterol (the "bad cholesterol") and triglycerides. For unknown reasons, this excessive fat in the bloodstream can be deposited in certain parts of the body, causing abnormal fatty growth there--and also increasing the long-term risk of cardiovascular disease. In addition, the loss of fat due to certain illnesses is associated with a predisposition to insulin resistance--the relative ineffectiveness of insulin in the body, which can lead to diabetes if it becomes severe enough.
The Glaxo Wellcome researchers who did these studies had much previous experience in measuring lipid changes, through studies of other conditions including diabetes and obesity. They applied tests they were already familiar with to look for effects of HIV protease inhibitors on fat cells in the laboratory. Their work 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. (In both cases the tests were done with animal cells--a reminder that this work is still a theory of lipodystrophy, not a proven cause.)
One Possible Mechanism:
Preventing Development of Fat Cells
In one experiment,1 fat cells were grown in the laboratory, with or without HIV protease inhibitors. In this test, saquinavir, ritonavir, and nelfinavir greatly reduced the development 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 Mechanism:
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.
The same animal cells used above were also tested in this experiment.2 But here, instead of measuring the fat cells produced in a laboratory culture, the researchers used a certain gene in these cells, which is sensitive to retinoid signaling and also produces a product which is easy to measure in the laboratory. The protease inhibitors alone did not affect the activity of the gene.
When protease inhibitors were combined with retinoids 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.
This theory is related to the one published by Carr and others last summer,3 but there are biochemical differences.
References
1. Lenhard J, Weiel J, Paulik M, Miller L, Ittoop O, Blanchard S, and Furfine E. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Jan. 31 - Feb. 4 [abstract #666].
2. Lenhard J, Weiel J, Paulik M, Lehmann J, Koszalka G, and Furfine E. Indinavir enhances retinoic acid signaling: Nelfinavir, saquinavir, and ritonavir inhibit retinoid effects in vitro. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Jan. 31 - Feb. 4 [abstract #665].
3. Carr A, Samaras K, Chisholm DJ, and Cooper DA. Pathogenesis of HIV-1-protease-inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. June 20, 1998; volume 351 (9119), pages 1881-1883.
