Cardiovascular Disease, HIV Infection, HIV Infections, Inflammation
Conditions
Keywords
HIV, endothelium, inflammation, Treatment Experienced
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.
Interventions
DRUGraltegravir
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
DRUGPlacebo
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
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Merck Sharp & Dohme LLC
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Function Measured by Brachial Artery Flow-mediated Dilation(FMD) | 24 weeks | Measurements in the change of brachial artery diameter from pre and post treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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 | 30 |
| 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
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 | 26 |
| Total | 56 |
Baseline characteristics
| Characteristic | Placebo | Raltegravir | Total |
|---|---|---|---|
| Age, Continuous | 53 Years | 54 Years | 53 Years |
| Race/Ethnicity, Customized African-American | 5 participants | 3 participants | 8 participants |
| Race/Ethnicity, Customized Caucasian | 19 participants | 20 participants | 39 participants |
| Race/Ethnicity, Customized Latino | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Other | 4 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 29 Participants | 24 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 30 | 1 / 26 |
| serious Total, serious adverse events | 1 / 30 | 1 / 26 |
Outcome results
Primary
Endothelial Function Measured by Brachial Artery Flow-mediated Dilation(FMD)
Measurements in the change of brachial artery diameter from pre and post treatment.
Time frame: 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Endothelial Function Measured by Brachial Artery Flow-mediated Dilation(FMD) | 3.4 millimeters |
| Raltegravir | Endothelial Function Measured by Brachial Artery Flow-mediated Dilation(FMD) | 2.9 millimeters |