• Differential Effects between HIV-Integrase Inhibitor S-1360 and HIV-Protease Inhibitors on Fat Metabolism and Retinoid Signaling In Vitro (Abstract H-1919)
  Authored by J.E. Weiel, D.C. Clancy, D.A. Winegar, J.M. Lenhard
  Poster Presentation: View the original abstract

HIV integrase inhibitors are a new class of HIV drugs that are in early development. Little is known about their potential side effects, especially metabolic side effects. Protease inhibitors clearly affect lipids. They can raise cholesterol and triglycerides in normal volunteers, and may be associated (in a complicated way, yet to be fully understood) with changes in fat distribution.

Studies of the effects of HIV drugs in isolated fat cells in the laboratory have shown effects on fat metabolism and triglyceride production. While it is not known how these observations relate to changes in people on these medications, laboratory studies on isolated fat cells have been of great interest.

To examine the effects of the new integrase inhibitor S-1360 on fat cells and to try and predict possible metabolic side effects, these investigators at GlaxoSmithKline compared the effects of S-1360 with the protease inhibitor nelfinavir (NFV, Viracept) in cultured fat cells.

In contrast to nelfinavir, S-1360 did not affect the break down of fat, the synthesis of triglycerides or lipolysis. Nelfinavir increased expression of the gene beta actin and reduced expression of the genes for PPAR gamma, aP2, and c/EBPa. S-1360 had no effect on these genes. S-1360 also had no effect on retinoid signaling, which had previously been shown to be affected by indinavir (IDV, Crixivan).

While these lab results seem obscure, they show that protease inhibitors have direct effects on fat cells, which probably correlates with the changes we have seen in patients. These lab results would suggest that the integrase inhibitor S-1360 will not share these side effects. However, there is at present very limited human data on this drug, and none on the long term effects. We have learned the hard way that it's impossible to know the long term side effects of a drug until many patients have been on it for many months. It is reasonable to assume that integrase inhibitors may have some unanticipated side effects, but based on these and other studies, they seem unlikely to cause the same effects on fat and cholesterol we have seen with earlier protease inhibitors. Within the next 12 months, we should begin to see some more extensive human data.