February 13, 2003
This is a substudy of a larger study (ESS40010), which was presented during last year's Retrovirus conference by Dr. Grace McComsey: "Improvements in Lipoatrophy (LA) Are Observed After 24 Weeks When Stavudine (d4T) Is Replaced by Either Abacavir (ABC) or Zidovudine (ZDV)" (Abstract 701-T).
It is important to remind readers of what the original study showed: The study evaluated a switch from d4T (stavudine, Zerit) to abacavir (ABC or ABV, Ziagen) or AZT (ZDV, zidovudine, Retrovir) in 118 patients with lipoatrophy. Some of the patients also had high lactic acid levels. There was a significant, but modest, increase of fat in the extremities and in the 16 persons with hyperlactatemia, the treatment switch resulted in normalization of the lactic acid levels.
In the substudy presented this year, 13 patients who substituted d4T with either ABC (in 12 cases) or AZT (one case), underwent fat biopsies at baseline (before the switch) and then eight of them repeated a fat biopsy after 48 weeks. This group of patients is then compared with 25 HIV-negative controls, although we are not told very much about them, except that they are similar in age to the cases. In the methods section the authors implied that some of the measurements were in fact done in peripheral blood mononuclear cells, but this was never very clear in the poster.
The patients on the d4T-containing regimens had a lower mitochondrial copy number per adipocyte cell than the HIV-negative controls. This number increased after the switch to ABC or AZT. These patients also had increases in peripheral fat as measured by DEXA, and obviously these two parameters correlated to one another.
The researchers also observed improvements in apoptosis scores after the switch, and there was an overall trend to normalization of these values.
This study is interesting because it is one of the first longitudinal studies correlating changes in peripheral fat with changes in mitochondrial DNA, supporting one of the most prevailing hypotheses about the cause of this problem. However there are also limitations to this study: It included a very small sample of patients, and for that reason no statistics about the significance of the changes are provided, and the whole methodology was a little bit confusing (in house assay for the mitochondrial DNA copy number, not very many details about what sample was used for the measurement: fat, muscle or blood).
Readers should remember the fact that if two things change in the same direction, this does not mean that one is the cause of the other. A statistician I know used to use an example: the kids with larger feet tend to read better (and this is true), so one could think that the length of the feet has something to do with the ability to read, obviously a false proposition. The explanation is that as you grow older your feet tend to become bigger, and that the older a kid is, the better he/she reads. I know it is a silly example but it clearly conveys what I am trying to say.
In any case, there is growing evidence, from multiple sources now, that d4T is somewhat related to the development of lipoatrophy. This study is another piece in the puzzle to understand the mechanism of this problem.