Effect of Raltegravir on Endothelial Function in HIV-Infected Patients

Study Description

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Brief Summary:

Recent studies suggest that HIV patients are at increased risk for cardiovascular events; however, the mechanisms underlying this increased risk remain unclear. Our group was one of the first to demonstrate that HIV infection is independently associated with accelerated atherosclerosis, as measured by carotid artery-intima media thickness (IMT), and that HIV-associated inflammation may be driving this accelerated atherosclerosis. The mechanism by which HIV disease independent of any drug-specific toxicity increases the risk of cardiovascular disease during HAART is not known. We hypothesize that even well controlled HIV infection is independently associated with cardiovascular risk and that further decreasing HIV-associated inflammation adding newer antiretroviral agents will also decrease cardiovascular risk.

We will perform a small clinical trial of approximately 50 HIV-infected patients each to study the relationship between HIV infection, inflammation, thrombosis, atherogenic lipoproteins, and measures of atherosclerosis. We propose the following specific aims: Aim 1: To determine the influence of traditional and novel markers of inflammation on endothelial function and IMT progression; Aim 2: To determine if "intensification" with raltegravir in subjects on long-term antiretroviral therapy with clinically undetectable HIV RNA levels will improve endothelial function, and to determine if this effect is mediated by alterations in inflammatory markers, lipoproteins and/or thrombotic factors. For Aim 2, subjects from 2 randomized, double-blind, placebo-controlled raltegravir intensification studies will be asked to co-enroll in this cardiovascular study.

Condition or disease	Intervention/treatment	Phase
HIV Infection; Inflammation; Cardiovascular Disease; HIV Infections	Drug: raltegravir; Drug: Placebo	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	56 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Randomized, Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection
Study Start Date :	January 2009
Actual Primary Completion Date :	November 2013
Actual Study Completion Date :	February 2014

Arms and Interventions

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Arm	Intervention/treatment
Placebo Comparator: Placebo; For subjects assigned to the placebo group, patients will take a matching placebo pill of 400 mg by mouth twice daily for 24 weeks in addition to taking their current HIV medication	Drug: Placebo; For the patient assigned to the placebo group, subjects will take a matching placebo pill 400mg to be taken by mouth twice daily for 24 weeks in addition to taking their current HIV medication
Active Comparator: Raltegravir; For subjects assigned to the active comparator group, they will receive raltegravir at 400 mg by mouth twice daily for 24 weeks in addition to continuing to take their current HIV medication	Drug: raltegravir; For patients assigned to the raltegravir group, subjects will receive raltegravir 400mg to be taken by mouth twice daily for 24 weeks in addition to taking their current HIV medication

Outcome Measures

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Primary Outcome Measures :

1. Endothelial Function Measured by Brachial Artery Flow-mediated Dilation(FMD) [ Time Frame: 24 weeks ]
   Measurements in the change of brachial artery diameter from pre and post treatment.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Stable antiretroviral therapy for at least 12 months
2. All plasma HIV RNA levels within the past year must be below level of detection (< 50 copies RNA/mL), although isolated single values > 50 but < 200 copies will be allowed.
3. Screening plasma HIV RNA levels < 50 copies RNA/mL
4. >90% adherence to therapy within the preceding 30 days, as determined by self-report
5. Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
6. CD4<350 cells/mm3 for at least one year ("immunologic non-responder") or CD4>=350 cells/mm3 for at least one year ("immunologic responder").

Exclusion Criteria:

1. Ongoing or prior use of any integrase inhibitor or R5 inhibitor.
2. Patients who plan to modify existing antiretroviral therapy in the next 24 weeks for any reason
3. Serious illness requiring hospitalization or parental antibiotics within preceding 3 months
4. Concurrent or recent exposure to any immunomodulatory drugs
5. Advanced liver disease or active hepatitis B or C
6. Patients with systolic blood pressure <100/70
7. Starting or stopping statin therapy during the trial

Contacts and Locations

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Locations

United States, California
University of California, San Francisco
San Francisco, California, United States, 94110

Sponsors and Collaborators

University of California, San Francisco

National Heart, Lung, and Blood Institute (NHLBI)

Merck Sharp & Dohme Corp.

Investigators

Principal Investigator:	Priscilla Hsue, MD	San Francisco General Hospital

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hatano H, Scherzer R, Wu Y, Harvill K, Maka K, Hoh R, Sinclair E, Palmer S, Martin JN, Busch MP, Deeks SG, Hsue PY. A randomized controlled trial assessing the effects of raltegravir intensification on endothelial function in treated HIV infection. J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):317-25. doi: 10.1097/QAI.0b013e31826e7d0f.

Responsible Party:	Priscilla Hsue, Associate Professor, University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT00843713 History of Changes
Other Study ID Numbers:	1R01HL095130-01 ( U.S. NIH Grant/Contract )
First Posted:	February 13, 2009
Results First Posted:	June 10, 2015
Last Update Posted:	June 10, 2015
Last Verified:	May 2015

Keywords provided by Priscilla Hsue, University of California, San Francisco:

HIV; endothelium; inflammation; Treatment Experienced

Additional relevant MeSH terms:

HIV Infections; Acquired Immunodeficiency Syndrome; Infection; Communicable Diseases; Inflammation; Cardiovascular Diseases; Pathologic Processes; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases	Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Raltegravir Potassium; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action