Therapeutic Approaches to HAART-Induced Lipodystrophy

To determine the efficacy and safety of 4 therapeutic interventions on HAART-Induced lipodystrophy. The interventions are: 1) Dietary - the effect of a high carbohydrate vs.a high cis-monounsaturated fatty acid diet. 2) The effect of aerobic exercise with dietary advice. 3) The effect of Omega-3 Fish Oil Capsules. 4) The effect of leptin therapy. These interventions are aimed at improving the metabolic complications of HAART therapy such as elevated lipids, and insulin resistance or diabetes.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Lipodystrophy
• Intervention / Treatment: Drug: Leptin; Other: Placebo

Detailed Description

Patients with HAART-induced lipodystrophy report loss of subcutaneous (sc) fat from the extremities and face and excess fat accumulation in the neck and truncal region. They also are predisposed to metabolic complications of insulin resistance, such as, dyslipidemia and diabetes mellitus. The pathogenesis of HAART-induced lipodystrophy is not fully understood although PIs have been strongly implicated as the cause. The metabolic complications pose an increased risk of atherosclerosis and acute pancreatitis whereas changes in body fat distribution cause physical discomfort and psychological distress. Management of these problems poses a therapeutic challenge. We propose potentially safe therapeutic lifestyle changes as well as novel therapies for management of HAART-induced lipodystrophy and its metabolic complications. The hypotheses to be tested and the aims are:

Hypothesis 1: A diet rich in cis-monounsaturated fatty acids improves HAART-induced glucose intolerance and dyslipidemia in HIV-infected patients.

Aim 1: To compare acceptability and effects of isocaloric diets rich in carbohydrates and cis-monounsaturated fats, each given for 6 wk, on glucose and lipid metabolism in patients with HAART-induced dyslipidemia in a randomized, cross-over study.

Hypothesis 2: A regimen of aerobic exercise improves insulin resistance, dyslipidemia and body fat distribution in HIV-infected patients with HAART-induced lipodystrophy.

Aim 2: To determine the effects of a supervised aerobic exercise regimen and dietary advice on glucose and lipid metabolism, and body fat distribution in HIV-infected patients with HAART-induced lipodystrophy.

Hypothesis 3: The n-3 polyunsaturated fats improve HAART-induced dyslipidemia in HIV-infected patients.

Aim 3: To determine the lipid-lowering effects of n-3 polyunsaturated fats in a randomized, double-blind, placebo-controlled, crossover trial in HIV-infected patients with HAART-induced dyslipidemia.

Hypothesis 4: Leptin replacement improves insulin resistance, dyslipidemia and body fat distribution in patients with HAART-induced lipodystrophy and hypoleptinemia.

Aim 4 To study efficacy and safety of recombinant methionyl leptin (r-metHuleptin) in improving insulin sensitivity, dyslipidemia and body fat distribution in patients with HAART-induced lipodystrophy and hypoleptinemia using a randomized, double-blind, placebo-controlled, parallel design.

Results from these studies may help in designing therapeutic approaches to HAART-induced lipodystrophy and its metabolic complications as well as for prevention of these problems in HIV-infected patients being placed on HAART.

We are only reporting the results of Aim 4 - (Leptin Study) here.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria - General inclusion:

• Age > 14 years
• HIV infection being treated with HIV-1 protease inhibitors for >6 months currently, or previous protease inhibitor therapy of at least 2 years duration with development of lipodystrophy and current stable therapy preferably for past 4 months.
• Fasting serum triglycerides > 200 mg/dL

Exclusion Criteria - General exclusion:

• Acute, ongoing AIDS-defining opportunistic infections.
• Blood CD4 positive lymphocyte count < 200/mm3
• Known liver disease due to causes other than nonalcoholic steatohepatitis with elevation of liver transaminases by more than two and a half times above the upper limits of normal (SGOT>105 U/L, SGPT>120 U/L) or total bilirubin (>1.5 mg/dL).
• Hematocrit of less than 30%.
• Current alcohol abuse (>7 drinks or 210 g per wk for women and >14 drinks or 420 g per wk for men).
• Current substance abuse.
• Uncontrolled diabetes mellitus with fasting plasma glucose > 180 mg/dL or hemoglobin A1c > 9%.
• History of weight loss during the last 3 months.
• Use of anorexiogenic drugs, thiazolidinediones, anabolic steroids and human growth hormone.
• Major Neuro-psychiatric illnesses impeding competence or compliance.
• Pregnant and lactating women.
• Cancer excluding skin cancer other than melanoma.
• Acute medical illnesses precluding participation in the studies.
• Chronic renal insufficiency with serum creatinine > 2 mg/dL.
• Untreated thyroid disorders such as hypothyroidism and hyperthyroidism. Each of the 4 treatment arms has additional specific inclusion and exclusion criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Leptin; Leptin weight and gender based dose, sub-cutaneous, twice daily. Leptin versus placebo for entire 6 months double-blind.	Drug: Leptin; weight based, sub-cutaneous injection, twice daily; Other Names: Metreleptin
Placebo Comparator: Placebo; Placebo , sub-Q injection twice daily.	Other: Placebo; weight based, sub-cutaneous injection, twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Fasting Serum Triglycerides	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Body Weight (kg)	6 months

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: Amylin Pharmaceuticals, LLC.
• Investigators: Principal Investigator: Abhimanyu Garg, M.D., Univeristy of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start: January 1, 2003
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: April 16, 2007
• First Submitted That Met QC Criteria: April 17, 2007
• First Posted (Estimate): April 18, 2007

Study Record Updates

• Last Update Posted (Actual): May 9, 2019
• Last Update Submitted That Met QC Criteria: May 7, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: HIV; Treatment Experienced; HAART; Lipodystrophy; HIV-Associated Lipodystrophy Syndrome; HIV Lipodystrophy Syndrome; Lipodystrophy syndrome; HIV-Associated Lipodystrophy
• Additional Relevant MeSH Terms: Metabolic Diseases; Skin Diseases; Lipid Metabolism Disorders; Skin Diseases, Metabolic; Lipodystrophy
• Other Study ID Numbers: 063656