1. Leptin Replacement Therapy Improves Insulin Resistance in Highly Active Antiretroviral Therapy (HAART) Induced Lipodystrophy and Metabolic Syndrome in HIV+ Patients Jennifer H. Lee 1, Jean L. Chan 1, Robyn Murphy 2, Alex M. DePaoli 2, Christos S. Mantzoros 1 1 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 2 Amgen Inc., Thousand Oaks, CA 1 contains effects for treatment, period, and treatment-by-period interaction 2 contains effects for treatment, period, treatment-by-period interaction, and change in visceral fat mass. Mean (SE)Range Age (yrs)45.8 (2.0)39 - 53 Sex (male)7N/A BMI (kg/m 2 )21.8 (0.8)19.4 – 24.8 Fasting insulin (  IU/ml) 11.5 (2.7)1.7 – 19.5 Fasting glucose (mg/dl)81.1 (6.7)60-108 HbA1c (%)5.1 (0.3)4.2 – 6.9 Leptin (ng/ml)1.34 (0.2)0.89 – 2.59 Triglyceride (mg/dl)530 (53.8)305 - 669 CD4 count (cells/  l) 454 (94)80 - 820 HIV viral load (copies/ml)24,524 (13,693)<50 – 80,500 Background Highly active antiretroviral therapy (HAART) for HIV infection may cause a metabolic syndrome characterized by insulin resistance, hyperlipidemia and lipodystrophy. A previously published uncontrolled study showed that leptin replacement therapy dramatically improves the metabolic syndrome associated with congenital or acquired non-HIV lipoatrophy. We conducted a double-blinded, randomized, placebo-controlled, cross-over study to test the hypothesis that leptin replacement to physiologic levels would improve the metabolic abnormalities associated with HAART-induced HIV lipoatrophy. Methods 7 HIV-1-infected lipoatrophic and leptin-deficient adults on HAART were randomized to receive recombinant-methionyl human leptin at a physiologic dose or placebo for 2 months. After a one-month washout period, the subjects were crossed-over to the alternate therapy for 2 additional months. We determined the effect of leptin therapy on insulin resistance (Boost challenge test and insulin suppression test), lipid and apolipoprotein levels, lipoprotein particle size, hormone levels (insulin, TNF-α, IL-6, CRP, adiponectin), glycemia, free fatty acids, body composition (anthropometry, BIA, DEXA, abdominal CT scan), HIV viral load, lymphocyte subsets, blood pressure. Repeated-measures ANOVA and linear models with independent factors controlling for treatment, period, treatment-by-period interaction, and visceral fat mass were used. Baseline Characteristics Leptin Placebo P<0.03P=0.22 Rpt-measures ANOVA Absolute Changes in Insulin Sensitivity, Body Composition & Lipids Main Model 1 (LSM ± SE)VFat Model 2 (LSM ± SE) LeptinPlacebop-valueLeptinPlacebop-value Insulin Sensitivity Fasting Insulin-4.90 ± 3.775.69 ± 4.220.103-4.89 ± 2.866.78 ± 3.220.035 Fasting Glucose1.50 ± 2.453.25 ± 2.740.6481.50 ± 2.643.24 ± 2.980.679 HOMA-B-83.04 ± 43.4944.98 ± 48.620.091-82.96 ± 31.2558.07 ± 35.260.024 HOMA-IR-1.03 ± 0.821.31 ± 0.920.099-1.03 ± 0.621.54 ± 0.710.035 Body Composition Weight (kg)-1.30 ± 0.812.20 ± 0.900.024 Fat mass (gm)-598.30 ± 98.91257.08 ± 110.59<0.001 Visceral Fat (gm)-12.50 ± 18.72-5.00 ± 20.930.797 Liver Fat (mL)0.06 ± 0.69-0.16 ± 0.770.839 Liver Volume (mL)-174.50 ± 101.1-5.42 ± 113.030.302 Lipids Cholesterol (mg/dL)24.08 ± 9.30-15.67 ± 10.400.025 Triglycerides (mg/dL)100.92 ± 104.2471.13 ± 116.540.854 HDL (mg/dL)3.78 ± 2.19-3.52 ± 2.450.062 LDL (md/dL)4.03 ± 14.36-11.98 ± 16.060.482 Summary  Baseline insulin levels decline significantly after 2 months of leptin therapy compared to placebo  HOMA also decreases significantly on leptin therapy.  Leptin therapy causes a decrease in fat mass and weight.  There were no significant changes in triglyceride levels, liver fat or visceral fat content. Conclusion  Leptin replacement therapy mildly improves insulin resistance in HIV-1-infected adults with HAART-induced lipoatrophy and metabolic syndrome. Leptin P=0.04 Placebo P=0.24 Rpt-measures ANOVA