Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV

Phase 2

Completed

Conditions: Coronary Artery Disease
Human Immunodeficiency Virus

Interventions: Drug: Placebo
Drug: Colchicine

Registration Number: NCT02624180

Lead Sponsor: Johns Hopkins University

Brief Summary: The investigators are studying whether an anti-inflammatory intervention improves impaired coronary endothelial function (CEF) in HIV+ people with no clinical coronary artery disease (CAD).

Detailed Description: Survival in people with HIV has significantly improved with the use of antiretroviral therapy (ART) but HIV+ people now experience an increasing burden of chronic diseases, including coronary atherosclerosis and coronary artery disease (CAD). HIV patients manifest an increased risk of CAD and its consequences possibly due to interplay of inflammation with traditional risk factors (smoking, high cholesterol, and poor diet), some of the latter accentuated by ART.

What the investigators are studying in this program is the function of the coronary arteries and in particular the inner lining of the arteries called the endothelium in patients with HIV. The endothelium has several important functions; one of them is that under conditions of stress it releases a substance called nitric oxide which increases the size of the artery and increases blood flow. When it is not functioning normally the artery does not increase as much and blood flow does not increase during stress.

The investigators study coronary artery function with magnetic resonance imaging, or MRI. MRI is a method of obtaining images of what is happening inside the body. MRI does not involve radiation, x-ray, or injection of contrast. The investigators can measure flow in the artery and the dimension of the artery at rest and with a handgrip stress and learn the extent to which the artery dilates and flow increases with the stress. The investigators believe that inflammation can interfere with normal function and that by decreasing inflammation abnormal endothelial function may be improved.

Colchicine is an anti-inflammatory agent approved by the Food and Drug Administration (FDA) to treat arthritis and some other conditions. This drug is not approved for use to suppress inflammation in patients with coronary artery disease and improve coronary artery endothelial function. The FDA is allowing the use of colchicine or a placebo in this research study.

This study will involve 24 weeks of colchicine or placebo and 3 Magnetic Resonance Imaging (MRI) scans of the heart and other study procedures.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 81

Inclusion Criteria

Patients of either gender who are 21 years of age (no upper age limit), HIV positive and taking stable ART (no change in ART regimen in last 3 months),
HIV viral load <100 copies/mL (plasma HIV RNA concentration),
Abnormal CEF at baseline (<7ml/min change in CBF during IHE as compared to resting value).

Exclusion Criteria

Patients unable to understand the risks, benefits, and alternatives of participation and give meaningful consent,
Patients with contraindications to MRI such as implanted metallic objects (pre-existing cardiac pacemakers, cerebral clips) or indwelling metallic projectiles,
History of clinical CAD, including acute coronary syndrome, myocardial infarction or revascularization,
Resting ECG with evidence of Q wave myocardial infarction,
Pregnant women,
Recent history, within the past 3 months, of cocaine or heroin use,
Moderate or greater renal impairment (estimated glomerular filtration rate <45ml/min),
Moderate-severe hepatic disease (elevation in hepatic transaminases >3x upper limit of normal),
Leukopenia (<3000/mm3) or thrombocytopenia (<100,000/mm3),
CD4<200 cell/mm3,
Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease,
Requirement for, or intolerance to, colchicine,
Women of childbearing potential (even if using oral contraceptive agents) or intention to breastfeed,
Chronic, continuous use of oral or IV steroid therapy or other immunosuppressive or biologic response modifiers or anti-inflammatory agents (chronic NSAIDs or acetylsalicylic acid (ASA) >81mg daily),
History of chronic pericardial effusion, pleural effusion, ascites or peripheral neuropathy manifested by both signs and symptoms,
Taking protease inhibitors (PI), cobicistat, or CYP3A4 inhibitors.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo for colchicine 1 tablet by mouth daily
Colchicine	Colchicine	Colchicine 0.6 mg daily by mouth

Primary Outcome Measures

Name	Time	Method
Coronary Endothelial Function Measured by Percent Change in Coronary Blood Flow With Exercise (%) at 8 Weeks	Difference between measurements at baseline compared to measurement at 8 weeks	Percent change in coronary blood flow (CBF) from rest to that during isometric handgrip exercise (IHE) stress at 8 weeks.

Secondary Outcome Measures

Name	Time	Method
Change in Coronary Artery Cross-sectional Area (CSA) at 24 Weeks	At 24 weeks	Change in CSA as measured by the difference between CSA at rest and under IHE stress at 24 weeks
High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks.	At 8 weeks.	High-sensitivity C-reactive protein (hsCRP) at 8 weeks
Change in Coronary Artery Cross-sectional Area (CSA) at 8 Weeks	Difference between measurements at baseline compared to measurement at 8 weeks	Change in CSA as measured by the difference between CSA at rest and under IHE stress at 8 weeks
Coronary Endothelial Function at 24 Weeks;	At 24 weeks.	Change in coronary blood flow (CBF) from rest to that during isometric handgrip exercise (IHE) stress at 24 weeks.
Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.	At 24 weeks	Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.
Brachial Flow Mediated Dilatation (FMD) at 8 Weeks.	At 8 weeks	Brachial flow mediated dilatation (FMD) at 8 weeks.
Interleukin-6 (IL-6) at 8 Weeks	At 8 weeks	Interleukin-6 (IL-6) at 8 weeks
High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks	At 24 weeks	High-sensitivity C-reactive Protein (hsCRP) at 24 weeks