• S20: Abnormalities of Body Composition and Lipids Associated with HAART: Pathogenesis, Clinical Manifestations and Case Definitions (Authored by Kathleen Mulligan, San Francisco Gen. Hosp., Univ. of California, San Francisco)
  Click here to view the original abstract

• S21: Lactic Acidosis and Hepatic Dysfunction Associated with HAART: Pathogenesis, Clinical Manifestations, and Predictors (Authored by David Cooper, National Ctr. in HIV Epidemiology and Clin, Res., Univ. of New South Wales, Sydney, Australia)

• S22: Evaluation of the Metabolic Complications of HAART: An Industry and Academic Initiative (Authored by David Pizzuti, Abbott Labs., Abbott Park, IL)
  Click here to view the original abstract

• S23: Fat Redistribution and Metabolism (FRAM) Study: A U.S. National Investigative Collaboration (Authored by Carl Grunfeld, VA Med. Ctr., Univ. of California, San Francisco)
  Click here to view the original abstract

• Summary/Conclusions: The Clinical Impact of Metabolic Dysfunction and the Future of Antiretroviral Therapy (Authored by William Powderly, Washington Univ. Sch. of Med., St. Louis, MO)

At the Retrovirus conference on Monday I attended a highly anticipated symposium on the metabolic complications of antiretroviral therapy. I was hoping that some of the mysteries about lipodystrophy/metabolic abnormalities (LD/MA) would be clarified. No such luck. Lipodystrophy and the variety of metabolic complications remain among the most unclarified issues in HIV today. As Kathleen Mulligan said at the symposium, this area is "more complex than initially appreciated." Mulligan went on to summarize our current clinical knowledge base on this topic.

We do know that the metabolic changes include glucose and lipid metabolic abnormalities and that the body morphologic abnormalities include fat accumulation as well as fat depletion. Though we thought that these complications were due to protease inhibitors, we now suspect that this assumption was both premature and incomplete.

Aside from the obvious physical changes that patients develop, there are a number of potential long-term implications of these associated problems. The constellation of glucose intolerance/diabetes, elevated levels of triglycerides, lowered levels of HDL cholesterol, insulin resistance, central obesity and hypertension are known to greatly increase the risk of cardiovascular disease in non-HIV settings. Whether this will also occur in people with HIV infection remains unclear. Also unclear is how often these abnormalities occur. The fat distribution abnormalities have been reported to occur in from 2% to 80% of patients taking protease inhibitors. It now seems likely that we cannot lump all of the fat distribution problems together. Fat accumulation probably has different cause and effects than does fat depletion. And fat redistribution may or may not have similar causes as the metabolic abnormalities.

We do know that there is an association with protease inhibitor therapy and probably with nucleoside therapy as well. We also know that different patterns of fat distribution occur with different frequencies related to the type of therapy and the gender of the patient. In addition, we now have data that non-ART factors are also associated with these problems, including older age (over 40), duration of HIV infection (>7 years), duration of AIDS (>2 years), nadir CD4 <200 as well as loss or changes in BMI (body mass index).

The likelihood of developing LD/MA increases with increasing numbers of these non-drug factors and, interestingly, does not seem to occur in the absence of these factors. Protease inhibitor use is definitely associated with an increased likelihood of LD/MA, as shown in multiple studies, including exposing healthy HIV negatives to short courses of ritonavir.

A potential strategy designed to exploit the potency of PI-based ART, but also prevent or treat LD/MA is the "switch." A number of studies have looked at this: utilizing non-protease inhibitors such as abacavir, efavirenz or nevirapine in place of protease inhibitors in patients who have achieved maximal viral suppression. At present there is not a clear consensus on the benefit of the switch strategy. Though lipid and other metabolic parameters improve, body habitus changes improve only modestly at best.

Other therapeutic interventions include lifestyle changes (exercise and dietary), lipid lowering drugs (stations and fibroses), anti-diabetic drugs (hypoglycemic and insulin-sensitizers), anabolic agents (growth hormone and androgen anabolic steroids), and, finally, surgical interventions (liposuction, implants). However, we have very little evidence at all to support any of these interventions at this time.

David Cooper of Australia discussed the pathogenic mechanisms that cause LD/MA. At present, research is pointing at two main areas: mitochondrial toxicity, as associated with nucleosides, and interference with human protease enzymes by protease inhibitors. We certainly do know that one pathogenic mechanism does not explain all of the associated toxicities, and it is unlikely that two mechanisms will either. The clinical problem is multi-factorial and probably requires multi-factorial causation.

Weller, Pizzuti and Grunfeld discussed industry and academic responses to this problem and what direction these responses will take. Indeed, we may eventually have more answers.

Finally, Bill Powderly attempted to summarize the clinical impact of LD/MA and did so very well. He stressed that we need more directed research. He also stressed that our antiretroviral strategies may need to be rethought -- especially the timing of initial ART -- because of the clinical impact of LD/MA. Though we still want to "hit hard," maybe we don't want to "hit early." Indeed we need long-term thinking in the face of lots of current uncertainty.