Cardiometabolic Effects of Eplerenone in HIV Infection

Study Overview
=================
Brief Summary
-----------------
Background: People with human immunodeficiency virus (HIV) are at a high risk of getting visceral or deep belly fat. Visceral fat can cause health problems like heart or liver disease. Researchers want to see if a blood pressure drug can help by blocking a hormone in the body. Objective: To see if eplerenone reduces fat stored in the heart muscle and liver in people with HIV and increased visceral fat. Eligibility: Adults ages 18 75 with HIV and increased waist circumference. Increased waist circumference is defined as more than 40 inches in men and more than 35 inches in women. Design: Participants will be screened with: Physical exam Medical history Blood tests Measurements of hips, waist, legs, arms, shoulders, and neck Magnetic resonance imaging (MRI) scan. They will lie on a table that slides into a machine. Electrocardiogram (EKG) to measure heart electrical activity Transient elastography, a special ultrasound to measure liver tissue stiffness A small piece their liver collected (optional) Participants will have a baseline visit: Physical exam Medical history Blood tests DEXA scan to measure body fat, muscle mass, and bone density. Participants will lie on a table while a very small dose of x-rays goes through the body. Resting energy expenditure (REE). This measures the amount of oxygen breathed in and carbon dioxide breathed out. Participants will get a 1-week supply of eplerenone. They will take one pill per day. Participants will have a follow-up visit 1 week later. They will have: Physical exam Medical history Blood tests 23-week supply of eplerenone Participants will have 5 more follow-up visits. Participants will have a final study visit, repeating many of the screening and baseline tests.

Detailed Description
-----------------
HIV-infected individuals are at higher risk than uninfected people for developing cardiovascular disease. Visceral adipose tissue is also increased in HIV-infected people compared to uninfected individuals. Animal studies suggest that blockade of the mineralocorticoid receptor (MR) may have beneficial effects on cardiovascular and metabolic parameters via inhibition of adipocyte differentiation and triglyceride accumulation. We will examine the effects of the MR antagonist eplerenone (50 mg daily) on HIV-infected adults with abdominal fat accumulation in a 24-week, open-label, proof-of-concept study. Magnetic resonance imaging will be conducted at screening and the final study visit to evaluate cardiac and hepatic steatosis. We anticipate that blocking the effects of increased aldosterone secretion with eplerenone will significantly reduce intramyocardial lipid content and hepatic steatosis in this population. These effects may be accompanied by decreases in visceral adipose tissue, and improvements in dyslipidemia and inflammation, thereby improving cardiovascular health.

Official Title
-----------------
Cardiometabolic Effects of Eplerenone in HIV Infection

Conditions
-----------------
Cardiac Steatosis, Hepatic Steatosis

Intervention / Treatment
-----------------
* Drug: Inspra /Eplerenone


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Increased waist circumference on the basis of National Cholesterol Education Program guidelines (> 102 cm in men and > 88 cm in women) Hepatic steatosis established by hepatic MRI greater than or equal to 5% and/or liver biopsy within the last 12 months HIV-infected, HIV viral load < 50 copies/mL and no change in ART regimen for at least 3 months Age greater than or equal to 18 and less than or equal to 75 years Agree to have samples stored for future research EXCLUSION CRITERIA: Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2, serum creatinine > 1.5 mg/dL Serum potassium > 5.5 mEq/L, alanine aminotransferase > 2.5 times the upper limit of normal, hemoglobin (Hgb) < 11 g/dL Uncontrolled hypertension: systolic blood pressure greater than or equal to 160 mm Hg or diastolic blood pressure greater than or equal to 100 mm Hg A blood pressure < 90mmHg systolic or < 50mm Hg diastolic Screening EKG with a significant heart block (e.g. PR > 300 ms) or an EKG determined significant by Cardiology consult. Current hepatitis C infection, unless there has been a sustained virologic response for at least 12 months Type 2 diabetes with microalbuminuria Current or prior steroid use within past 6 months (except short-course or single-dose administration). Stable use of inhaled or nasal steroids are allowed. Use of angiotensin converting enzyme (ACE) inhibitors, angiotensin reporter blockers (ARBs), potassium-sparing diuretics, and other medications that may increase the risk of hyperkalemia Use of potassium supplementation or other medications known to increase potassium Concomitant use of strong inhibitors and/or inducers ofof cytochrome P450 isozyme (CYP)3A4 If receiving testerone, estrogen or progesterone therapy, must be on a stable dose for at least 3 months. Current use of growth hormone or growth hormone-releasing hormone Current serious viral, bacterial, or other infection (excluding HIV) Current active substance abuse/dependence Substantial history of cardiovascular disease, including prior myocardial infarction (MI), congestive heart failure, or stroke Contraindication to MRI Pregnant or planning to become pregnant Breastfeeding Any condition that, in the opinion of the PI, may substantially increase the risk of participation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Intervention: Eplerenone will be administered for 6 months as follows: 25 mg once daily for 1 week and then 50 mg once daily for the remainder of the study. | Drug: Inspra /Eplerenone<br>* Eplerenone is provided as 25- or 50-mg tablets that are to be taken orally. Subjects will be dosed at 25 mg daily for 1 week, and then 50 mg daily for 23 weeks. The total duration of dosing for each subject is 24 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of Cardiac Steatosis: Mean Change in Intraventricular Septum Percentage of Lipid by MR Spectroscopy. | Mean change in intraventricular septum percentage of lipid by MR spectroscopy. This was calculated by subtracting the baseline intraventicular septum percentage value of lipid from the week 24 intraventicular septum percentage value of lipid by MR spectroscopy. | 24 weeks | 
| Improvement of Hepatic Steatosis: Mean Change in Hepatic Percentage of Lipid by MR Spectroscopy | Mean change in hepatic percentage of lipid by MR spectroscopy. This was calculated by subtracting the baseline hepatic percentage value of lipid from the week 24 hepatic percentage value of lipid by MR spectroscopy. | 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatic Steatosis, Cardiac Steatosis, Aldosterone, Eplerenone, Mineralcorticoid Receptor