Therapeutic Approaches to HAART-Induced Lipodystrophy

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.

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