Atherosclerosis, Cardiovascular Disease, HIV, HIV Infections, Inflammation, Statins, HMG-CoA
Conditions
Keywords
Cardiovascular Disease, HIV, Atherosclerosis, Inflammation, Statins, treatment experienced
Brief summary
In HIV patients, statin therapy will attenuate plaque inflammation, thus, making plaques less vulnerable, will deter plaque progression, and improve endothelial function. In addition to known cholesterol-lowering and C-reactive protein lowering effects, immunomodulatory effects of statins will lead to a shift from pro-inflammatory monocyte and T cell subsets to less atherogenic subpopulations.
Interventions
DRUGatorvastatin
20 mg PO QD for the first 3 months, followed by 40 mg PO QD for the final 9 months.
DRUGPlacebo
Placebo
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Massachusetts General Hospital
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 60 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women age 18-60 with previously diagnosed HIV disease 2. Subclinical coronary artery disease as defined by presence of one or more plaque on coronary CTA without history of cardiac events or cardiac symptoms and no evidence of critical coronary stenosis. Target to background ratio (TBR) as determined by PET of \> 1.6. 3. Stable anti-retroviral (ARV) therapy as defined by no changes in ARV regimen for \>6 months 4. LDL-cholesterol \>70 mg/dL and \<130 mg/dL
Exclusion criteria
1. History of acute coronary syndrome 2. Contraindication to statin therapy 3. Current statin use 4. AST or ALT two times greater than the upper limit of normal or receiving treatment for active liver disease 5. Renal disease or creatinine \>1.5 mg/dL (given the risk of contrast nephropathy during CT angiography of the heart) 6. Infectious illness within past 3 months 7. Contraindication to beta-blocker (including moderate to severe asthma or heart block) or nitroglycerin use as these drugs are given as part of the standard cardiac CT protocol. Previous allergic reaction to beta blocker or nitroglycerin. 8. Body weight greater than 300 lbs due to CT scanner table limitations 9. Patients with previous allergic reactions to iodine-containing contrast media 10. Active illicit drug use 11. Patients who report any significant radiation exposure over the course of the year prior to randomization. Significant exposure is defined as: 1. More than 2 percutaneous coronary interventions (PCI) within 12 months of randomization 2. More than 2 myocardial perfusion studies within the past 12 months 3. More than 2 CT angiograms within the past 12 months 4. Any subjects with history of radiation therapy. 12. Patients already scheduled or being considered for a procedure or treatment requiring significant radiation exposure (e.g., radiation therapy, PCI, or catheter ablation of arrhythmia) within 12 months of randomization 13. Pregnancy or breastfeeding 14. Coronary artery luminal narrowing \>70% seen on coronary CTA
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Coronary and Aortic Plaque Inflammation | Measured at baseline and 1 year | 12 month change in mean FDG-PET TBR (18-fluorodeoxyglucose positron emission tomography target-to-background ratio) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Function | 1 year | Assessment of endothelial function was to be measured by endothelial vasodilator function. |
| Immune Function | Measured at baseline and 1 year | 12 month change in CD4 T-lymphocytes |
| Lipid Profile | Measured at baseline and 1 year | 12 month change in lipid profile |
| Plaque Progression | Measured at baseline and 1 year | 12 month percent change in plaque volume |
| Adipocytokines | Measured at baseline and 1 year | 12 month change in IL-6 |
| Liver Function Tests (LFTs) | Measured at baseline, 1, 3, 6, 9, and 12 months | Number of participants with LFT abnormalities (greater than or equal to 3 times the upper limit of normal). For reference, the normal ranges for AST and ALT are shown below. Please note that the normal range for ALT at Labcorp changed over the course of the study. AST and ALT elevations were determined based on the normal range at the time the lab test was performed. ALT: 0-40 IU/L, 0-44 IU/L, or 0-55 IU/L AST: 0-40 IU/L |
| C-reactive Protein (CRP) | Measured at baseline and 1 year | 12 month change in Log CRP concentration |
Countries
United States
Participant flow
Recruitment details
This study enrolled men and women with HIV disease, no history of cardiovascular disease or cardiac symptoms, and evidence of subclinical atherosclerosis at Massachusetts General Hospital in Boston, MA USA. The study was done from November, 2009 to January, 2014.
Pre-assignment details
Of the 81 patients screened for the study, 40 completed the screening and were randomized to the two study arms.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Participants received 20 mg atorvastatin given orally daily for the first 3 months, followed by 40 mg atorvastatin daily for the final 9 months. | 19 |
| Placebo Participants received 20 mg placebo given orally daily for the first three months followed by 40 mg placebo daily for the next 9 months. | 21 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Atorvastatin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 21 Participants | 19 Participants |
| Age, Continuous | 51.1 years STANDARD_DEVIATION 4.9 | 50.0 years STANDARD_DEVIATION 5.6 | 52.2 years STANDARD_DEVIATION 3.8 |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Black | 6 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Hispanic | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized More than one race | 3 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Unknown | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized White | 26 participants | 13 participants | 13 participants |
| Region of Enrollment United States | 40 participants | 21 participants | 19 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 32 Participants | 17 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 19 | 14 / 21 |
| serious Total, serious adverse events | 2 / 19 | 1 / 21 |
Outcome results
Primary
Coronary and Aortic Plaque Inflammation
12 month change in mean FDG-PET TBR (18-fluorodeoxyglucose positron emission tomography target-to-background ratio)
Time frame: Measured at baseline and 1 year
Population: All participants with baseline and 12 month PET and CT scans of acceptable image quality to permit assessment of change over time in identical regions in serial scans. As a result, only a limited number of participants could be included.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Atorvastatin | Coronary and Aortic Plaque Inflammation | Mean FDG-PET TBR of aorta | 0.04 ratio |
| Atorvastatin | Coronary and Aortic Plaque Inflammation | Mean FDG-PET TBR of most diseased segment of aorta | -0.03 ratio |
| Placebo | Coronary and Aortic Plaque Inflammation | Mean FDG-PET TBR of aorta | -0.05 ratio |
| Placebo | Coronary and Aortic Plaque Inflammation | Mean FDG-PET TBR of most diseased segment of aorta | -0.06 ratio |
Secondary
Adipocytokines
12 month change in IL-6
Time frame: Measured at baseline and 1 year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Atorvastatin | Adipocytokines | -1.25 pg/ml |
| Placebo | Adipocytokines | 0.41 pg/ml |
Secondary
C-reactive Protein (CRP)
12 month change in Log CRP concentration
Time frame: Measured at baseline and 1 year
Population: All available data were used.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Atorvastatin | C-reactive Protein (CRP) | -0.3 log(mg/L) |
| Placebo | C-reactive Protein (CRP) | 0.1 log(mg/L) |
Secondary
Endothelial Function
Assessment of endothelial function was to be measured by endothelial vasodilator function.
Time frame: 1 year
Population: Please note that we were unable to collect data for this outcome measure, entitled Endothelial Function due to equipment malfunction.
Secondary
Immune Function
12 month change in CD4 T-lymphocytes
Time frame: Measured at baseline and 1 year
Population: All available data were used; data were not available for one subject who completed the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Atorvastatin | Immune Function | 17 cells per microliter |
| Placebo | Immune Function | 4 cells per microliter |
Secondary
Lipid Profile
12 month change in lipid profile
Time frame: Measured at baseline and 1 year
Population: All available data were used.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Atorvastatin | Lipid Profile | 12 month change in total cholesterol | -1.23 mmol/L |
| Atorvastatin | Lipid Profile | 12 month change in HDL cholesterol | 0.02 mmol/L |
| Atorvastatin | Lipid Profile | 12 month change in direct LDL | -1.00 mmol/L |
| Atorvastatin | Lipid Profile | 12 month change in triglycerides | -0.10 mmol/L |
| Placebo | Lipid Profile | 12 month change in triglycerides | 0.08 mmol/L |
| Placebo | Lipid Profile | 12 month change in total cholesterol | 0.12 mmol/L |
| Placebo | Lipid Profile | 12 month change in direct LDL | 0.30 mmol/L |
| Placebo | Lipid Profile | 12 month change in HDL cholesterol | -0.04 mmol/L |
Secondary
Liver Function Tests (LFTs)
Number of participants with LFT abnormalities (greater than or equal to 3 times the upper limit of normal). For reference, the normal ranges for AST and ALT are shown below. Please note that the normal range for ALT at Labcorp changed over the course of the study. AST and ALT elevations were determined based on the normal range at the time the lab test was performed. ALT: 0-40 IU/L, 0-44 IU/L, or 0-55 IU/L AST: 0-40 IU/L
Time frame: Measured at baseline, 1, 3, 6, 9, and 12 months
Population: All available data were used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Liver Function Tests (LFTs) | 3 participants |
| Placebo | Liver Function Tests (LFTs) | 2 participants |
Secondary
Plaque Progression
12 month percent change in plaque volume
Time frame: Measured at baseline and 1 year
Population: All available data were used.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Atorvastatin | Plaque Progression | 12 month change in non-calcified plaque volume | -19.4 Percent change |
| Atorvastatin | Plaque Progression | 12 month change in total plaque volume | -4.7 Percent change |
| Placebo | Plaque Progression | 12 month change in non-calcified plaque volume | 20.4 Percent change |
| Placebo | Plaque Progression | 12 month change in total plaque volume | 18.2 Percent change |