Selected highlights from the 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Some attendees at the above conference noticed that at previous lipodystrophy workshops there seemed to be excessive focus on describing and documenting the lipodystrophy syndrome. At the most recent workshop more effort was made to try to understand the cause(s) of lipodystrophy. One workshop attendee said (with tongue in cheek):
There seemed to be a lot of presentations by older male scientists who showed slides of mice and told the audience about how they interfered with the animals' immune systems. When asked about the relevance of their findings to people, the scientists replied they only knew about mice.
While there was some truth to this description, there were also reports from studies in people presented at the workshop. But before we get to those, we will highlight some important test-tube research. The results of this research provide insight into some aspects of the lipodystrophy syndrome. Note that all references, unless otherwise noted, are from the workshop.
Because changes in fat have a large and visible impact on body shape, much research is taking place on fat cells (adipocytes). Researchers want to know how anti-HIV drugs affect the growth of these cells.
One team in Paris, France, led by Dr. Jacqueline Capeau, grew fat cells in the test-tube. There they were exposed to the protease inhibitor indinavir (Crixivan) at levels found in people who take the drug. The team found that indinavir affected the ability of young fat cells to mature. Indeed, this protease inhibitor impaired the growth and development of about 50% of fat cells. This occurred because indinavir appears to damage certain key proteins that fat cells need in order to mature.
The experiments with indinavir are useful, however, because PHAs take combination therapy consisting of several drugs, studies of different drugs would also be of interest. To this end, another team of scientists, in Liverpool, UK, conducted test-tube studies on fat cells, exposing them to combinations of nukes (AZT, d4T, ddI, 3TC) as well as protease inhibitors (indinavir, nelfinavir, ritonavir and saquinavir).
This team found that, in general, nukes do not appear to be toxic to fat cells. Moreover, nukes did not appear to affect the growth or development of fat cells. Protease inhibitors, however, had a different effect. PIs appeared to decrease the build-up of triglycerides (TG) inside cells (thus possibly pushing TG into the blood). PIs also increased the breakdown of fat cells, which release their contents into the blood, again adding to the load of fat that builds up there.
When AZT or d4T was combined with indinavir, suppression of the growth of fat cells greatly increased. For instance, with d4T alone, only about 1% of fat cells had reduced growth. However, when a combination of d4T and indinavir was used, technicians detected a 28% reduction in the growth and development of fat cells.
In addition to reducing the growth and development of fat cells, PIs also impaired the ability of insulin to help cells absorb sugar. In the body, this affects the ability of cells to get energy, and excess sugar gets turned into fat. Based on these experiments, the PI with the strongest anti-insulin effect is listed first, followed in descending order by the others:
Bear in mind that these results are from test-tube studies. They could, however, serve as a guide when conducting studies in people.
REFERENCES
1. Caron M, Auclair M, Kornprobst M, et al. Indinavir-induced nuclear lamina alterations are correlated with adipocyte dysfunctions in cultured adipocytes. Abstract 1.
2. Janneh O, Hoggard PG, Sales SD, et al. Intracellular disposition of zidovudine, stavudine and protease inhibitors and their metabolic effects in cultured adipocytes. Abstract 2.
3. Jones SP, Janneh O, Maher B, et al. Altered TNF-alpha and IL-6 levels and the antiadipogenic effects of antiretrovirals on cultured adipocytes: possible mechanisms for their role in lipodystrophy in HIV-infected patients. Abstract 3.
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