Effects of Sacubitril/Valsartan on Subclinical Heart Failure in HIV (The ENCHANTMENT HIV Study)

Study Overview
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Brief Summary
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Persons with HIV, even those well-treated, are at increased risk for heart disease when compared to the general population. Two hormones called aldosterone and brain natriuretic peptide (BNP), which have been shown to be abnormal in HIV, may be associated with inflammation as well as early changes in structure and function of the heart. This study is being conducted to evaluate whether therapies to block aldosterone and increase BNP levels may reduce the burden and progression of heart failure to improve cardiovascular health.

Detailed Description
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This is a 6-month study enrolling persons with HIV with no known history of heart disease. Participants will be screened for early signs of heart failure using cardiac ultrasound (cardiac transthoracic echocardiography or cardiac TTE). Those participants who have early changes in the structure and function of the heart and may be at future risk for heart failure will be enrolled into the study. Additional imaging of the heart will occur using cardiac magnetic resonance imaging (cardiac MRI). Following baseline studies, participants will either receive a medication called sacubitril/valsartan or placebo for 6 months. Sacubitril/valsartan in an FDA approved medication currently being used for heart failure with reduced ejection fraction in the general population, and we are evaluating whether this medication could be useful to reduce HIV-related heart failure with preserved ejection fraction. Sacubitril/valsartan is an oral medication taken twice daily that may block aldosterone hormone and increase natriuretic peptide hormone. Overall, this study aims to investigate the effect of sacubitril/valsartan on measures of heart disease related to inflammation, structure and function of the heart muscle in HIV using cardiac TTE and cardiac MRI imaging as well as blood markers of heart failure and inflammation.

Official Title
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Ending Subclinical Heart Failure Using an Aldosterone and Natriuretic Peptide Targeted Treatment in HIV--The ENCHANTMENT HIV Study

Conditions
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HIV/AIDS, Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Sacubitril-Valsartan 49-51Mg Oral Tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Antiretroviral therapy use for >12 months HIV Viral Load <200 copies/mL Left Ventricular Ejection Fraction>50% Demonstration of one or more criteria for myocardial dysfunction on cardiac transthoracic echocardiogram, relevant to the progression of heart failure with preserved ejection fraction: Left Atrial Volume Index > 28 mL/m2 Global Longitudinal Strain <18% Left Ventricular Mass Index > 95g/m2 (female), 115 g/m2 (male) Exclusion Criteria: Known history of congestive heart failure or valvular disease Recent cardiac event or stroke within 3 months Current medication use acting along the RAAS pathway (ACEi, ARB, MR blockade, direct renin inhibitor), potassium (K) supplementation or diuretic Angioedema to ACEi or ARB SBP<100 mmHg Medication suspected to have contraindication with active study drug Steroid use within last 3 months Uncontrolled diabetes requiring insulin and/or HbA1c > 7.5% Creatinine (Cr)>1.5 mg/dL and estimated GFR<60 mL/min/1.73m2 K>5.5 mEq/L Hemoglobin <10.0 g/dL Known liver disease or ALT>3x upper limit normal Pregnant, actively seeking pregnancy or breastfeeding Estrogen, progestin derivative, or other sex steroid use within 3 months. Stable physiologic testosterone replacement (> 3 months) is acceptable Current bacterial or other infection Active substance abuse Known reaction to gadolinium

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 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: Sacubitril/Valsartan<br>Sacubitril/Valsartan 49-51mg twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months | Drug: Sacubitril-Valsartan 49-51Mg Oral Tablet<br>* By mouth twice daily<br>* Other names: Entresto;|
| Placebo Comparator: Placebo<br>Placebo twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months | Drug: Placebo oral tablet<br>* Placebo oral tablet By mouth twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial Inflammation/Fibrosis | Myocardial Inflammation/Fibrosis measured by extracellular volume fraction via cardiac magnetic resonance imaging | 6 months | 
| Myocardial Dysfunction | Left Atrial Volume Index or Global Longitudinal Strain measured by cardiac transthoracic echocardiography | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other Indices of Myocardial Dysfunction | Alterations in other cardiac structure and function as measured by cardiac magnetic resonance imaging or cardiac transthoracic echocardiogram | 6 months | 
| Markers of Myocardial Inflammation and Fibrosis | Circulating biomarkers of myocardial inflammation and fibrosis: Gal3, ST2, GDF15, hs-cTnT | 6 months | 
| Cardiac Natriuretic Peptides | Circulating cardiac natriuretic peptides: ANP, BNP, NT-proBNP | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Sacubitril/valsartan, Heart Failure with Preserved Ejection Fraction, Aldosterone, Natriuretic Peptides, Myocardial Dysfunction, Cardiovascular Disease