HIV Dementia
Conditions
Keywords
HIV, monocytes, CD16+, statins, mcp1, inflammation
Brief summary
Activated monocytes play a key role in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Individuals with HAND have expanded populations of activated monocytes. These monocytes are thought to emigrate into the CNS, where they produce neurotoxic proinflammatory factors, and also carry virus into the CNS. Statins are cholesterol lowering drugs with pleiotropic immunomodulatory / anti-inflammatory properties that are currently being explored for immunomodulation of T cell activation in several diseases, in addition to their established role to treat hyperlipidemia and atherosclerosis. The investigators in vitro data suggests that these drugs can downregulate monocyte activation patterns seen in HIV infection. No in vivo studies have yet been carried out to assess the effects of statins on the pro-inflammatory monocyte population in chronic HIV disease. This will be a pilot study of whether statin treatment will reduce the inflammatory monocyte phenotype and downregulate the inflammatory cytokines that have been linked to neuropathogenesis in HIV infection. If so, they may have potential as adjunctive therapy in HIV-associated neurological disease. The investigators propose to: * Determine the effect of Atorvastatin on peripheral blood monocyte populations in a 12-week pilot study in chronically HIV-infected people on HAART therapy. * Determine the relationship between changes in monocyte phenotype following Atorvastatin treatment, and soluble markers of activation/inflammation linked to neuropathogenesis, as well as activation status of T cells.
Interventions
DRUGAtorvastatin
For subjects on PI-based HAART therapy: 10mg/day X 2weeks followed by 20mg/day. For subjects on non PI-based HAART therapy: 20mg/day X 2weeks followed by 40mg/day.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Chronic HIV-1 infected individuals presently on HAART with no change in drug combination for at least 3 months at time of enrollment 2. Plasma viral load \<200 copies / ml for at least 6 months prior to enrollment in the study 3. CD4 T cell count more than 350/ul 4. Willingness to use a method of contraception during the study period 5. Willingness to have blood drawn 6. If female, willingness to undergo pregnancy testing on a monthly basis and are not breastfeeding 7. Ability to understand and willingness to sign the informed consent 8. hs-CRP levels above the upper limit of normal (\>3mg/L)
Exclusion criteria
1. Concomitant use of fibric acid derivatives or other lipid lowering agents including patients on statins and Ezetimibe 2. Use of any anti-inflammatory drugs (OTC or prescription) on a daily basis 3. Pregnancy or breast feeding 4. Active drug use or alcohol abuse/dependence, which in the opinion of the investigators will interfere with the patient's ability to participate in the study 5. Allergy or hypersensitivity to statins or any of its components 6. History of myositis or rhabdomyolysis with use of any statins 7. Patients who are on concurrent immunomodulatory agents, including systemic corticosteroids will be ineligible for 3 months after completion of therapy with the immunomodulating agents 8. History of inflammatory muscle disease such as poly or dermatomyositis 9. Serious intercurrent illness requiring systemic treatment and/or hospitalization within 30 days of entry 10. Evidence of active opportunistic infections requiring treatment or neoplasms that require chemotherapy during the study period 11. Creatine phosphokinase elevations (CPK) greater than 3 times the upper limit of normal 12. Known active liver disease or AST/ALT greater than 2x the upper limit of normal 13. Renal insufficiency, indicated by serum creatinine 2 mg/dl 14. Absolute neutrophil count (ANC) 1000/mm3, hemoglobin \< 10.0 g/dL for males and \<9 g/dL for females, platelet count 100,000/mm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Monocyte Surface Markers Expression (Expressed as Percentage), Following Treatment of Chronic HIV+/ HAART+ Subjects With Atorvastatin (T=12wks Versus T=0wk). | Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends) | Effects of Atorvastatin on immune activation associated surface markers (CD16, CD163 and CCR2) of monocytes were assessed in chronic HIV+/HAART+ subjects following 12 weeks of treatment. Whole blood drawn from these subjects were stained with fluorochrome tagged antibodies to the surface markers. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the percentage of cells (monocytes) expressing the specific marker. This was done before starting and after completing drug treatment to assess the effect of drug. |
| Change From Baseline in Levels of Plasma Inflammatory Marker MCP-1 of Chronic HIV+/ HAART+ Subjects. | Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends) | Monocyte specific inflammatory soluble factor MCP-1 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment. |
| Change From Baseline in Levels of Plasma Inflammatory Marker sCD14 of Chronic HIV+/ HAART+ Subjects. | Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends) | Monocyte specific inflammatory soluble factor sCD14 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment. |
| Change From Baseline in Levels of Plasma Inflammatory Marker sCD163 of Chronic HIV+/ HAART+ Subjects. | Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends) | Monocyte specific inflammatory soluble factor sCD163 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the AIDS Clinical Trial Unit (ACTU) at the Hospital of University Of Pennsylvania, Philadelphia, PA. The screening and recruitment process was carried out during the period September 2011 thru April 2012.
Pre-assignment details
Enrolled participants were assigned to treatment groups based on the nature of HAART therapy (PI- or non-PI based).
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Atorvastatin: For subjects on PI-based HAART therapy: 10mg/day X 2weeks followed by 20mg/day.
For subjects on non PI-based HAART therapy: 20mg/day X 2weeks followed by 40mg/day. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Atorvastatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Race/Ethnicity, Customized Race African American | 3 Participants |
| Race/Ethnicity, Customized Race Caucasian | 2 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
Change From Baseline in Levels of Plasma Inflammatory Marker MCP-1 of Chronic HIV+/ HAART+ Subjects.
Monocyte specific inflammatory soluble factor MCP-1 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment.
Time frame: Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)
Population: Plasma MCP-1 levels
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin | Change From Baseline in Levels of Plasma Inflammatory Marker MCP-1 of Chronic HIV+/ HAART+ Subjects. | 10 pg/ml (Change from T0 to T12) | Standard Deviation 176.5 |
Comparison: Sample size calculations were based on having sufficient power to detect a change in each of the outcome variables from baseline to week 12.The effect size was calculated as (detectable difference in change in outcome) / (SD of the change). Based on preliminary in vitro data, the smallest effect size was 1.88. Assuming that only 40% of this effect will be present in vivo (effect size=0.75), alpha = 0.05 and 80% power, n=16 is needed to complete the study.p-value: >0.999Wilcoxon signed rank
Primary
Change From Baseline in Levels of Plasma Inflammatory Marker sCD14 of Chronic HIV+/ HAART+ Subjects.
Monocyte specific inflammatory soluble factor sCD14 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment.
Time frame: Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)
Population: Plasma sCD14 levels
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin | Change From Baseline in Levels of Plasma Inflammatory Marker sCD14 of Chronic HIV+/ HAART+ Subjects. | -0.22 ug/ml (Change fromT=0 to T=12wk) | Standard Deviation 0.7 |
Comparison: Sample size calculations were based on having sufficient power to detect a change in each of the outcome variables from baseline to week 12.The effect size was calculated as (detectable difference in change in outcome) / (SD of the change). Based on preliminary in vitro data, the smallest effect size was 1.88. Assuming that only 40% of this effect will be present in vivo (effect size=0.75), alpha = 0.05 and 80% power, n=16 is needed to complete the study.p-value: 0.813Wilcoxon signed rank
Primary
Change From Baseline in Levels of Plasma Inflammatory Marker sCD163 of Chronic HIV+/ HAART+ Subjects.
Monocyte specific inflammatory soluble factor sCD163 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment.
Time frame: Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)
Population: Plasma sCD163 levels
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin | Change From Baseline in Levels of Plasma Inflammatory Marker sCD163 of Chronic HIV+/ HAART+ Subjects. | -18 ng/ml (Change fromT=0 to T=12wk) | Standard Deviation 81 |
Comparison: Sample size calculations were based on having sufficient power to detect a change in each of the outcome variables from baseline to week 12.The effect size was calculated as (detectable difference in change in outcome) / (SD of the change). Based on preliminary in vitro data, the smallest effect size was 1.88. Assuming that only 40% of this effect will be present in vivo (effect size=0.75), alpha = 0.05 and 80% power, n=16 is needed to complete the study.p-value: 0.625Wilcoxon signed rank
Primary
Change in Monocyte Surface Markers Expression (Expressed as Percentage), Following Treatment of Chronic HIV+/ HAART+ Subjects With Atorvastatin (T=12wks Versus T=0wk).
Effects of Atorvastatin on immune activation associated surface markers (CD16, CD163 and CCR2) of monocytes were assessed in chronic HIV+/HAART+ subjects following 12 weeks of treatment. Whole blood drawn from these subjects were stained with fluorochrome tagged antibodies to the surface markers. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the percentage of cells (monocytes) expressing the specific marker. This was done before starting and after completing drug treatment to assess the effect of drug.
Time frame: Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)
Population: 1\) Percentage of peripheral blood monocyte surface markers: CD16, CD163, CCR2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Change in Monocyte Surface Markers Expression (Expressed as Percentage), Following Treatment of Chronic HIV+/ HAART+ Subjects With Atorvastatin (T=12wks Versus T=0wk). | Total CD14+CD16+ monocytes | 1.5 Change T=0 to T=12 (percentage change) | Standard Deviation 10.2 |
| Atorvastatin | Change in Monocyte Surface Markers Expression (Expressed as Percentage), Following Treatment of Chronic HIV+/ HAART+ Subjects With Atorvastatin (T=12wks Versus T=0wk). | CD14+CD163+ monocytes | -4.4 Change T=0 to T=12 (percentage change) | Standard Deviation 18 |
| Atorvastatin | Change in Monocyte Surface Markers Expression (Expressed as Percentage), Following Treatment of Chronic HIV+/ HAART+ Subjects With Atorvastatin (T=12wks Versus T=0wk). | CD14+CCR2+ monocytes | 0.5 Change T=0 to T=12 (percentage change) | Standard Deviation 7.5 |
Comparison: Sample size calculations were based on having sufficient power to detect a change in each of the outcome variables from baseline to week 12.The effect size was calculated as (detectable difference in change in outcome) / (SD of the change). Based on preliminary in vitro data, the smallest effect size was 1.88. Assuming that only 40% of this effect will be present in vivo (effect size=0.75), alpha = 0.05 and 80% power, n=16 is needed to complete the study.p-value: 0.625Wilcoxon signed rank
Comparison: Sample size calculations were based on having sufficient power to detect a change in each of the outcome variables from baseline to week 12.The effect size was calculated as (detectable difference in change in outcome) / (SD of the change). Based on preliminary in vitro data, the smallest effect size was 1.88. Assuming that only 40% of this effect will be present in vivo (effect size=0.75), alpha = 0.05 and 80% power, n=16 is needed to complete the study.p-value: 0.813Wilcoxon signed rank
Comparison: Sample size calculations were based on having sufficient power to detect a change in each of the outcome variables from baseline to week 12.The effect size was calculated as (detectable difference in change in outcome) / (SD of the change). Based on preliminary in vitro data, the smallest effect size was 1.88. Assuming that only 40% of this effect will be present in vivo (effect size=0.75), alpha = 0.05 and 80% power, n=16 is needed to complete the study.p-value: >0.999Wilcoxon signed rank