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Submitted on July 12, 2005
Accepted on April 17, 2006
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Boston University School of Public Health, Health Services Department, and Center for Health Quality, Outcomes and Economic Research at Veterans Affairs Health Services Research, Boston, MA; Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
* To whom correspondence should be addressed. E-mail: cmantzor{at}bidmc.harvard.edu.
Context. Highly active antiretroviral therapy (HAART) for HIV-1 infection has been associated with a metabolic syndrome characterized by insulin resistance, hyperlipidemia, and redistribution of body fat (lipodystrophy). A subset of patients with predominant lipoatrophy has low levels of the adipocyte-secreted hormone leptin.
Objective. To assess whether administration of recombinant methionyl human leptin (r-metHuLeptin) improves insulin resistance and other metabolic abnormalities in HIV+ leptin-deficient subjects with HAART-induced lipoatrophy.
Design, Setting, Patients and Intervention. We conducted a randomized, placebo-controlled, double-blinded, cross-over study from 2002 to 2004 in seven HIV+ men with HAART-induced lipoatrophy, serum leptin level <3 ng/ml, and fasting triglyceride level >300 mg/dl, who were administered placebo for two months before or after administration of r-metHuLeptin at physiologic doses for an additional two months.
Main Outcome Measures. Insulin resistance, lipid levels, inflammatory markers, body composition, HIV control.
Results. Compared with placebo, r-metHuLeptin therapy improved fasting insulin levels, insulin resistance (as expressed as the homeostasis model assessment index and based on an insulin suppression test), and HDL. Body weight and fat mass decreased on r-metHuLeptin mainly due to a decrease in truncal fat, but not peripheral fat or lean body mass. R-metHuLeptin was well tolerated, and HIV control was not adversely affected.
Conclusions. r-metHuLeptin replacement at physiologic doses in HIV+ leptin-deficient patients with HAART-induced lipoatrophy improves insulin resistance, HDL, and truncal fat mass. Future larger and more long-term studies in HAART-induced lipoatrophy, including patients with more severe metabolic abnormalities, are warranted to evaluate the physiologic and potentially therapeutic role of r-metHuLeptin for this condition, and to fully clarify the underlying mechanisms of action.
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