Modulation of Monocyte Activation by Atorvastatin in HIV Infection

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01263938
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 5
• Location: 1
• Arm: 1
• Duration (Months): 73
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Dementia	Drug: Atorvastatin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study to Evaluate Effects of Atorvastatin on Monocyte Activation in HAART-treated HIV Infected Individuals
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Oct 1, 2017
• Actual Study Completion Date: Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: Atorvastatin	Drug: 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.; Other Names: Lipitor

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania School of Medicine	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Ronald G Collman, MD, University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 5, 2011

More Information

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01263938
• Other Study ID Numbers: IRB Protocol #: 812196; P30AI045008
• First Posted: Dec 21, 2010
• Last Update Posted: May 1, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by University of Pennsylvania: HIV; monocytes; CD16+; statins; mcp1; inflammation
• Additional relevant MeSH terms: AIDS Dementia Complex; Atorvastatin

Study Results

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 Detail	Enrolled participants were assigned to treatment groups based on the nature of HAART therapy (PI- or non-PI based).

Arm/Group Title	Atorvastatin
Arm/Group Description	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.
Period Title: Overall Study
STARTED	5
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Atorvastatin
Arm/Group Description	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.
Overall Participants	5
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 20%
Male	4 80%
Race/Ethnicity, Customized (Count of Participants)
African American	3 60%
Caucasian	2 40%
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Change in Monocyte Surface Markers Expression (Expressed as Percentage), Following Treatment of Chronic HIV+/ HAART+ Subjects With Atorvastatin (T=12wks Versus T=0wk).
Description	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)

Outcome Measure Data

Analysis Population Description

1) Percentage of peripheral blood monocyte surface markers: CD16, CD163, CCR2

Arm/Group Title	Atorvastatin
Arm/Group Description	For subjects on PI-based HAART: 10mg/day X 2weeks followed by 20mg/day. For subjects on non PI-based HAART: 20mg/day X 2weeks followed by 40mg/day. For all subjects treatment was stopped at 12 weeks.
Measure Participants	5
Total CD14+CD16+ monocytes	1.5 (10.2)
CD14+CD163+ monocytes	-4.4 (18)
CD14+CCR2+ monocytes	0.5 (7.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.625
	Comments	Threshold for statistical significance: p<0.05
	Method	Wilcoxon signed rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.813
	Comments	Threshold for statistical significance: p<0.05
	Method	Wilcoxon signed rank
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	Threshold for statistical significance: p<0.05
	Method	Wilcoxon signed rank
	Comments

2. Primary Outcome

Title	Change From Baseline in Levels of Plasma Inflammatory Marker MCP-1 of Chronic HIV+/ HAART+ Subjects.
Description	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)

Outcome Measure Data

Analysis Population Description

Plasma MCP-1 levels

Arm/Group Title	Atorvastatin
Arm/Group Description	For subjects on PI-based HAART: 10mg/day X 2weeks followed by 20mg/day. For subjects on non PI-based HAART: 20mg/day X 2weeks followed by 40mg/day.
Measure Participants	5
Mean (Standard Deviation) [pg/ml (Change from T0 to T12)]	10 (176.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	Threshold for statistical significance: p<0.05
	Method	Wilcoxon signed rank
	Comments

3. Primary Outcome

Title	Change From Baseline in Levels of Plasma Inflammatory Marker sCD14 of Chronic HIV+/ HAART+ Subjects.
Description	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)

Outcome Measure Data

Analysis Population Description

Plasma sCD14 levels

Arm/Group Title	Atorvastatin
Arm/Group Description	For subjects on PI-based HAART: 10mg/day X 2weeks followed by 20mg/day. For subjects on non PI-based HAART: 20mg/day X 2weeks followed by 40mg/day.
Measure Participants	5
Mean (Standard Deviation) [ug/ml (Change fromT=0 to T=12wk)]	-0.22 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.813
	Comments	Threshold for statistical significance: p<0.05
	Method	Wilcoxon signed rank
	Comments

4. Primary Outcome

Title	Change From Baseline in Levels of Plasma Inflammatory Marker sCD163 of Chronic HIV+/ HAART+ Subjects.
Description	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)

Outcome Measure Data

Analysis Population Description

Plasma sCD163 levels

Arm/Group Title	Atorvastatin
Arm/Group Description	For subjects on PI-based HAART: 10mg/day X 2weeks followed by 20mg/day. For subjects on non PI-based HAART: 20mg/day X 2weeks followed by 40mg/day.
Measure Participants	5
Mean (Standard Deviation) [ng/ml (Change fromT=0 to T=12wk)]	-18 (81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.625
	Comments	Threshold for statistical significance: p<0.05
	Method	Wilcoxon signed rank
	Comments

Adverse Events

Time Frame	Data was collected over a period of sixteen weeks.
Adverse Event Reporting Description	To determine whether an adverse event had occurred or not, regular laboratory testing as well as investigator assessment was carried out during the Study period.
Arm/Group Title	Atorvastatin
Arm/Group Description	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.
All Cause Mortality
	Atorvastatin
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Serious Adverse Events
	Atorvastatin
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Other (Not Including Serious) Adverse Events
	Atorvastatin
	Affected / at Risk (%)	# Events
Total	0/5 (0%)

Limitations/Caveats

This study had a very small sample size of 5 subjects. Therefore due to lack of power the data is inconclusive.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.