Effects of Growth Hormone Releasing Hormone in HIV

Study Overview
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Brief Summary
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HIV-infection and its treatment are often associated with an increase in belly fat, as well as abnormal cholesterol and problems metabolizing sugar. People with HIV infection and increased belly fat often have decreased growth hormone (GH) levels. Low GH levels may contribute independently to increased belly fat and to increased cardiovascular risk through effects on sugar metabolism, inflammation, and other mechanisms. Tesamorelin, a growth hormone releasing hormone (GHRH) analogue, has been shown to to reduce belly fat in patients with HIV-associated abdominal fat accumulation. However, the effects of tesamorelin on fat accumulation in the liver and muscle, sugar metabolism, and cardiovascular health are not yet known. The current study is designed to determine the effects of tesamorelin treatment on fat accumulation in the muscle and liver, insulin sensitivity and sugar metabolism, and markers of cardiovascular health including blood vessel thickness (carotid intima media thickness [cIMT]) and markers of inflammation in the body. The investigators hypothesize that tesamorelin will decrease fat accumulation in the liver and muscle and will decrease markers of inflammation, with either neutral or beneficial effects on glucose metabolism.

Official Title
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Effects of Growth Hormone Releasing Hormone on Fat Redistribution, Cardiovascular Indices, and Growth Hormone Secretion in HIV Lipodystrophy

Conditions
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HIV, HIV Lipodystrophy

Intervention / Treatment
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* Drug: tesamorelin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women age 18-65 Previously diagnosed HIV infection Stable antiviral regimen for at least 12 weeks prior to enrollment WC>95 cm and WHR>0.94 for male, WC>94 cm and WHR>0.88 for female occurring in the context of treatment for HIV disease Subjective evidence of at least one of the following recent changes, occurring during the treatment of HIV disease: increased abdominal girth, relative loss of fat in the extremities, or relative loss of fat in the face For female subjects 40yo or older, negative mammogram within one year of baseline Exclusion Criteria: Use of anti-diabetic agents, Megace, testosterone or any steroid use within 6 months of the study. Stable use of testosterone (> 6 mos) at dose equivalent to 200 mg IM q 2 weeks or < 10g/day to skin will be permitted. Use of GH or GHRH within the past 6 months Change in lipid lowering or antihypertensive regimen within 3 months of screening Fasting blood sugar > 126 mg/dL, SGOT > 2.5 times ULN, HgB < 12.0 g/dL, creatinine > 1.4 mg/dL, CD4 count < 200 Severe chronic illness or active malignancy or history of pituitary malignancy or history of colon cancer For men, history of prostate cancer or evidence of prostate malignancy by PSA > 5 ng/mL Prior history of hypopituitarism, head irradiation or any other condition known to affect the GH axis For women, positive urine hCG Oral contraceptives, depo provera or combined progesterone-estrogen injections, transdermal contraceptive patches, estrogen or progestin coated IUD's within 6 months of the study. Routine MRI exclusion criteria such as the presence of a pacemaker or cerebral aneurysm clip.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tesamorelin<br>Tesamorelin (growth hormone releasing hormone) 2mg daily given subcutaneously x 6 months during randomized phase, followed by 6 months of open-label tesamorelin at same dose | Drug: tesamorelin<br>* Tesamorelin (growth hormone releasing hormone) 2mg daily given by subcutaneous injection x 6 months during randomized phase, followed by 6 months of open-label tesamorelin at same dose<br>* Other names: Egrifta, growth hormone releasing hormone, TH9507;|
| Placebo Comparator: Placebo (inactive injection)<br>Placebo 2mg daily given subcutaneously for the first 6 months of the study, followed by 6 months of tesamorelin (growth hormone releasing hormone) 2mg daily during an open label phase | Drug: placebo<br>* Placebo 2mg daily given by subcutaneous injection for the first 6 months of the study, followed by an open-label phase of 6 months of tesamorelin (growth hormone releasing hormone) treatment, 2mg daily given by subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver Fat | Hepatic fat as measured by magnetic resonance (MR) spectroscopy, and expressed by normalizing lipid to water and expressing as a percent (lipid-to-water percent). | 6 months | 
| Visceral Adipose Tissue | Change in visceral adipose tissue area as measured by single-slice computed tomography (CT) scan at the L4 vertebra. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intramyocellular Lipid | Intramyocellular lipid (IMCL) as measured by magnetic resonance (MR) spectroscopy of the calf. Soleus IMCL normalized to creatinine (IMCL/Cr based on areas determined by spectroscopy) was measured. The change over 6 months is reported. | 6 months | 
| Endogenous Growth Hormone Secretion | Endogenous growth hormone (GH) concentrations measured by overnight frequent blood sampling every 20 minutes. Mean overnight GH concentration is given. | 6 months | 
| Insulin Sensitivity | In a subgroup of 1/2 of the subjects, euglycemic hyperinsulinemic clamp will be performed to assess insulin-stimulated glucose uptake. Insulin stimulated glucose uptake (M) calculated using the method of DeFronzo is shown. | 6 months | 
| HbA1c | Hemoglobin A1c. | 6 months | 
| Insulin Like Growth Factor 1 (IGF-I) | Insulin Like Growth Factor 1 (IGF-I). | 6 months | 
| Lipid Panel | Fasting lipids. Triglyceride value is given. | 6 months | 
| Carotid Intimal Medial Thickness (cIMT) | Carotid Intimal Medial Thickness (cIMT). | 6 months | 
| Glucose Tolerance | Glucose tolerance as measured by standard oral glucose tolerance test. 2-hour glucose is given. | 6 months | 
| Adiponectin | adiponectin. | 6 months | 
| Hemostatic Markers | Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) measured in serum. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, lipodystrophy, tesamorelin, Egrifta, growth hormone releasing hormone