The Body Covers: The 39th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy
Managing HIV Disease for Life --
New Issues Challenges, and Opportunities
September 26, 1999
In this brief talk, Dr. Cooper reviewed the salient issues in our current understanding of the multiple disorders that are grouped under these headings. There remain wide ranges of the prevalence of these disorders, and the reasons for this range remain not entirely understood. There are objective abnormalities, such as increases in cholesterol and triglycerides, as well as glucose intolerance that is caused by insulin resistance. In addition are the ranges of physical abnormalites reported, including loss of subcutaneous fat in the extremities, buttocks and face, with an associated prominence of the veins in the upper arms and legs. There is also visceral fat accumulation, the increases in the abdomen, an increase in the dorsocervical fat pad, and breast enlargement noted. The diagnosis is made based on the constellation of patient self report, clinical exams, and lab data. DEXA and/or CT scans can also be used, as can other anthropometric measures, but there is no standard approach yet defined in identifying what would be considered a case of lipodystrophy.Abstract: Update on Lipodystrophy and Metabolic Disorders in HIV Infection
The factors that have been studied as correlated with an increased risk of these manifestations include patient variables, such as gender, age, weight, lifestyle variables such as dietary factors and exercise, as well as genetic factors. In addition, there is much work focussed on understanding the difference in prevalence that can be attributed to medication selection. Finally, there are differences that may be due to the course of HIV disease, including the nadir of CD4 counts, as well as the degree of immune reconstitution. What is clear is that there appear to be multiple factors that are playing a role in this syndrome and data continue to be conflicting on the contribution of any single factor implicated so far. Clearly, prospective data are urgently needed in order to sort out the true contribution from any specific factor, particularly with regard to the contribution from the selection of medications, so as to disentangle the potential for bias in the multiple retrospective cohorts studies that have been reported so far.
There have been proposed mechanisms for the role of protease inhibitors in this syndrome. The initial hypothesis is based on in vitro data showing an impact of at least some of the agents on increased lipolysis and decreased lipogenesis (Lenhard, CROI 1999 Chicago). As these drugs were thought to be implicated, studies have been done to substitute a nonnucleoside for the PI. Initial results reported minimal reversal of the syndrome, and more recent observations have suggested some reversal after 24 weeks, but other factors impacting improvements may have played some role as well (Moyle, ICAAC 99). More recently, there are data which have explored the potential for nucleoside RT inhibitors in the evolution of this syndrome, particularly in the abnormalities of fat redistribution. The proposed mechanism is through mitochondrial toxicity as a result of NRTI incorporation into mitochondrial DNA. There are reports of increases in serum lactate induced by NRTI's, and this may be a marker for mitochondrial toxicity.
In addition to substitutions, there are reports of treatments for each of the manifestations. Specifically, the lipid disorders respond to the available agents, with some potential advantage for decreased toxicity when using the two agents that are not metabolized by the P450 system, pravastatin and fluvastatin. Initial reports also suggest the potential for metformin, exercise, and growth hormone to reverse increases visceral fat, but additional data are needed to understand their ultimate role.
In sum, it is clear that while something is happening, there is more work needed to fully characterize this syndrome. We are still learning how many different features are presenting in this syndrome, and that there may be different factors responsible for the variety of manifestations seen. As there are still only correlative but no causative data yet available with any of the treatments, it remains key for investigations to continue to explore the impact of changes in regimens, since early reports of substitutions have not resulted in prompt reversibility when using blinded observers in carefully controlled studies.
Authored by: David Cooper, M.D., Director and Professor of Medicine, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
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