By grouping patients with similar metabolic profiles after exposure to HAART using a powerful clustering approach, we identified a subgroup of patients that was especially vulnerable to the metabolic side effects caused by HAART. This subgroup of patients had slightly elevated lipids at baseline, which were made worse after exposure to HAART, suggesting that HAART exacerbated underlying predisposition to dyslipidemia and insulin resistance.
Our work suggests a potential basis for managing lipodystrophy in high-risk individuals. As increased resistin is associated with obesity and insulin resistance, agents that reduce resistin including the marketed peroxisome proliferator-activated receptor agonists pioglitazone and rosiglitazone could potentially have a beneficial impact on HAART-induced lipodystrophy. In fact, consistent with this idea, rosiglitazone can reduce elevated circulating resistin levels in individuals with HIV lipodystrophy . Another study  did not find significant correlation between circulating serum resistin and lipodystrophy; possibly because the different diagnostic criteria used to define lipodystrophy in that study led to individuals with normal lipid levels being classified as lipodystrophic. It is also possible that the paracrine effects of resistin are crucial to HIV lipodystrophy, and circulating resistin levels as measured in plasma in these studies do not accurately capture resistin levels at the site of its action.
We thank patients for participating in the study. We thank David Haas and Cara-Ballard Sutcliffe at the Vanderbilt DNA repository for providing high-quality DNA. We thank T. Delmonte, L. Hui and E. Emison for help with genotyping and haplotype analyses and N. Dracopoli and R. Parker for helpful discussion.
This work was supported by grants to the Adult AIDS Clinical Trials Group from the National Institute of Allergy and Infectious Diseases (AI38558 and AI068636). The parent protocol (ACTG 384) was supported in part by Agouron Pharmaceuticals, Inc., Bristol-Myers Squibb Company, DuPont Pharmaceutical Company, GlaxoSmithKline, Inc., and Merck and Co., Inc. The genetic analysis was funded by Bristol-Myers Squibb Co.
P.T., K.M., W.P., S.G. and M.D. ran the clinical trial and collected patients. K.R., W.G., O.F., M.N. designed and executed the genetic analysis. K.R., W.G., O.F., M.N. P.T., S.G., M.D. drafted the manuscript.
K.R., O.F., W.G. are employees of Bristol-Myers Squibb Co. M.N. is currently employed by GlaxoSmithKline.
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