HIV Infections, Lipodystrophy
Conditions
Keywords
Lipodystrophy, HIV, HAART, HIV Lipodystrophy Syndrome, Lipodystrophy syndrome, HIV-Associated Lipodystrophy, HIV-Associated Lipodystrophy Syndrome, Treatment Experienced
Brief summary
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.
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.
Interventions
DRUGLeptin
weight based, sub-cutaneous injection, twice daily
OTHERPlacebo
weight based, sub-cutaneous injection, twice daily
Sponsors
Amylin Pharmaceuticals, LLC.
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
14 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Fasting Serum Triglycerides | 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Body Weight (kg) | 6 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Leptin Randomized to receive leptin. | 7 |
| Placebo Randomized to receive placebo. | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Drug Dispensing error | 0 | 2 |
Baseline characteristics
| Characteristic | Leptin | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 13 Participants | 7 Participants |
| Age, Continuous | 50.4 years STANDARD_DEVIATION 10.4 | 49.3 years STANDARD_DEVIATION 7.6 | 48.1 years STANDARD_DEVIATION 3.7 |
| Body Weight | 71.2 kg STANDARD_DEVIATION 6.2 | 73.4 kg STANDARD_DEVIATION 7.2 | 75.6 kg STANDARD_DEVIATION 7.8 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 14 Participants | 7 Participants |
| Triglycerides | 336 mg/dL | 377 mg/dL | 471 mg/dL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 5 |
| other Total, other adverse events | 4 / 7 | 1 / 5 |
| serious Total, serious adverse events | 1 / 7 | 0 / 5 |
Outcome results
Primary
Fasting Serum Triglycerides
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Leptin | Fasting Serum Triglycerides | 237 mg/dL |
| Placebo | Fasting Serum Triglycerides | 341 mg/dL |
p-value: 0.84Mixed Models Analysis
Secondary
Body Weight (kg)
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leptin | Body Weight (kg) | 68.6 kg | Standard Deviation 5.7 |
| Placebo | Body Weight (kg) | 73.3 kg | Standard Deviation 6.7 |
p-value: 0.4Mixed Models Analysis