Elite Controller and ART-treated HIV+ Statin Versus ASA Treatment Intervention Study

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02081638
• Collaborator: (none)
• Enrollment: 53
• Locations: 2
• Arms: 2
• Actual Duration (Months): 65.9
• Patients Per Site: 26.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Background:

• The immune system protects the body from infection. But it can also cause harm. For example, the clotting system makes blood clot and protects from bleeding. But blood clots are sometimes harmful. People with human immunodeficiency virus (HIV) infection have increased inflammation and clotting. This may increase their risk for diseases like stroke or heart attack. Researchers want to know how aspirin or HMG-CoA reductase inhibitors (so-called statin medications) affect the immune and clotting systems of people with HIV. Aspirin is a medicine to decrease clotting. Statins are medications given to lower cholesterol and decrease inflammation.

Objectives:

• To see how aspirin or statins change immune and clotting systems in people with HIV.

Eligibility:

• Adults 18 and older with HIV and a low viral load, not on aspirin or a statin medication. They must also have either: (1) never taken anti-HIV medications (ARVs), have a suppressed viral load, have stable CD4 counts, and never had an opportunistic infection; or (2) been taking ARVs for 5 continuous years and have a suppressed viral load for more than 3 years.

Design:

• Participants will be screened with medical history, physical exam, and blood and lab tests.

• Participants will repeat screening tests and have an MRI. An MRI is a way to visualize blood vessels in the neck and head. Participants will lie on a table that slides in and out of a cylinder surrounded by a magnetic field.

• Participants will take either study drug once daily for 9 months.

• Participants will have a blood procedure twice. Blood will be removed through a needle in one arm and circulated through a machine that removes white blood cells. The blood, minus white blood cells, is returned through a needle in the other arm.

• All participants will be observed for 3 months before and after treatment.

Condition or Disease	Intervention/Treatment	Phase
Human Immunodeficiency Virus	Drug: Aspirin; Drug: Atorvastatin	Phase 2

Detailed Description

Despite dramatic improvements in mortality with antiretroviral therapy (ART), HIV-infected persons remain at risk of developing non-infectious complications, including cardiovascular, renal, and neurological disease. A small subset of the HIV-infected population achieve durable control of HIV virus in the absence of ART. These individuals, termed elite controllers (ECs), remain ART na(SqrRoot) ve, have stable CD4 T cell counts for many years and have no history of opportunistic infections. Despite the lack of AIDS complications, recent evidence suggests ECs may exhibit heightened immune activation that may contribute to a potentially increased risk for non-infectious complications, similar to successfully treated progressors.

In the current 2 group, randomized, open label trial, we intend to study the effects of a lipid lowering agent vs aspirin (ASA) on immune activation in HIV-1 infected participants. One group will consist of ECs who are HIV-1 infected, maintain HIV-RNA levels of less than the LLD of commercially available assays in the absence of ART, have no history of ART or opportunistic infections (OIs) and have stable CD4 T cell counts for greater than 3 years. The second group will enroll HIV-1 infected Treated Progressors (henceforth referred to as ART <50) who have maintained HIV-RNA below the limit of detection in commercially available assays (<40, <48, or <50 copies/mL) for greater than 3 years on ART (treatment duration greater than 4 years). Up to 2 months after the screening and enrollment visit, each group will enter a 3 month observation period (to establish baseline values for biomarkers/cellular markers). After 3 months, participants from each group will be randomized to either ASA, 81 mg PO daily, or atorvastatin (ATV), 40 mg (dose adjusted for subjects on antiretroviral regimens with significant interactions, and will be treated for 9 months, followed by 3 months of a wash out period (see Figure 1). The primary end point will be change of sCD14 after 9 months of study intervention from Month 3 to Month 12 in each treatment arm, with groups combined (EC and ART <50). Secondary objectives will be to compare changes in soluble biomarkers (sCD14, IL-6, D-dimer, hsCRP, sTF, sCD163 and other relevad treatment arms (ASA vs statin and EC vs ART<50 and with groups combined), to evaluate cardiovascular (CV) disease prevalence in EC vs ART<50 and with groups combined), to evaluate cardiovascular (CV) disease prevalence in EC vs ART <50 by MR imaging of carotids, to determine MR measurements and correlations with biomarkers and cellular activation markers, and to investigate changes in plasma viremia as measured by single copy assay over time.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Elite Controller and ART-Treated HIV+ Statin Versus ASA Treatment Intervention Study
• Actual Study Start Date: Apr 18, 2014
• Actual Primary Completion Date: Oct 16, 2019
• Actual Study Completion Date: Oct 16, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Elite Controller Elite controllers not on ART	Drug: Aspirin; Daily Asprin daily; Drug: Atorvastatin; Daily Atorvastatin Daily
Active Comparator: Treated Progressors HIV infected on ART	Drug: Aspirin; Daily Asprin daily; Drug: Atorvastatin; Daily Atorvastatin Daily

Outcome Measures

Primary Outcome Measures

1. Changes in sCD14 After 9 Months of Treatment With Aspirin or Atorvastatin [Month 12]

   sCD14 change between baseline (average of month 0 and month 3 in the study) and month 12

Secondary Outcome Measures

1. Changes in sCD14 in EC and ART <50 Groups Treated With Aspirin or Atorvastatin. [Month 12]

   sCD14 change between baseline (average of month 0 and month 3 in the study) and month 12

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

EC Arm

1. Age greater than or equal to 18 years.

2. Documented HIV-1 infection confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blot tests (will not be repeated if performed previously at NIH).

3. Categorized as a long term non-progressor EC as defined by viral loads typically less than the LLD of commercially available assays and clinical and laboratory criteria (no OIs, no ART, stable CD4 T cell counts for more than 3 years). Viral load blips are allowed as long as they are less than 500 copies/mL and flanked by viral load measurements less than 100copies/mL. Viral load <100c/mL will be acceptable for eligibility at screening.

4. In women of childbearing potential, with no plans for pregnancy for the next 15 months and willing to use 2 investigator approved highly reliable methods of birth control consistently while on the study or in 3 month follow up.

5. Willingness to have samples stored for future research.

6. Not on a statin or ASA for the past 6 months.

ART <50 Arm

1. Age greater than or equal to 18 years.

2. Documented HIV-1 infection confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blot tests.

3. In women of childbearing potential, with no plans for pregnancy for the next 15 months and willing to use 2 investigator approved highly reliable methods of birth control consistently while on the study or in 3 month follow up.

4. On continuous combination ART >4 years.

5. HIV RNA <50 copies/mL (or less than 40 or less than 48 copies/mL, depending on the lower limit of detection of the assay used; transient periods of low level (<300) detectable virus, blips, acceptable if isolated and followed by viral loads less than the lower limit of detection) >3 years and current HIV-RNA less than the LLD of the commercially available assay used. Subject will be rescreened if HIV is detectable at screening visit.

6. Willingness to have samples stored for future research.

7. Not on a statin or ASA for the past 6 months.

EXCLUSION CRITERIA

1. Diagnosis of cardiovascular disease or hypercholesterolemia (LDL cholesterol 190 mg/dL).

2. Known hypersensitivity or allergy to ATV or ASA, including a history of myositis or rhabdomyolysis with statin or ASA use.

3. Other contraindication for ASA or statin therapy (active liver disease, peptic ulcer disease, etc.).

4. Women who are lactating, pregnant, or actively trying to become pregnant or considering pregnancy over the likely span of the study (including women of childbearing potential who are unwilling to use adequate contraception throughout the study).

5. Any chronic inflammatory condition either requiring anti-inflammatory medication (systemic corticosteroids, daily NSAID use,immunomodulating medications) which may, in the opinion of the investigator, confound the interpretation of soluble inflammatory biomarkers. While on study, short term (less than 5 days) NSAID use will be allowed at the discretion of the investigator.

6. Active drug use or alcohol abuse that, in the opinion of the investigator, may interfere with the ability of the subject to participate in the study or that may unacceptably increase the risk of the study intervention..

7. Safety laboratory cut offs: coagulation (INR >2 upper limit of normal [ULN], PLT<75K), renal function (GFR<60), liver function (ALT or Alkaline phosphatase or direct bilirubin >2x ULN), aldolase <1.5 ULN and anemia (Hg <9 mg/dL).

8. Antiretroviral therapy with tipranivir, or any therapy which combines non-nucleoside reverse transcriptase inhibitors with protease inhibitors.

9. Chronic hepatitis C co-infection. However, if a subject has more than 24 weeks of sustained virologic response (SVR), the subject can be considered for eligibility.

10. If either MR or apheresis is contraindicated, subject may still participate without this procedure. In the case of missed apheresis, a 30 mL research blood draw will be substituted (see Appendices B and C).

• If statin initiation is indicated per current guidelines, subject will be counseled to consult with their PMD. If the subject then chooses to take part in the study, we will provide their PMD with all pertinent lab results during the course of the study, if requested.

Co-enrollment Guidelines: Co-enrollment in other trials will be restricted, other than enrollment on observational studies. Study staff should be notified of co-enrollment as it may require the approval of the Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892
2	Hennipen County Medical Center	Minneapolis	Minnesota	United States

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Irini Sereti, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 21, 2018
• Informed Consent Form - Sep 25, 2018

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ. 2009 Jan 26;338:a3172. doi: 10.1136/bmj.a3172. Review.
• Funderburg NT, Mayne E, Sieg SF, Asaad R, Jiang W, Kalinowska M, Luciano AA, Stevens W, Rodriguez B, Brenchley JM, Douek DC, Lederman MM. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood. 2010 Jan 14;115(2):161-7. doi: 10.1182/blood-2009-03-210179. Epub 2009 Oct 14.
• Krishnan S, Wilson EM, Sheikh V, Rupert A, Mendoza D, Yang J, Lempicki R, Migueles SA, Sereti I. Evidence for innate immune system activation in HIV type 1-infected elite controllers. J Infect Dis. 2014 Mar;209(6):931-9. doi: 10.1093/infdis/jit581. Epub 2013 Nov 1.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02081638
• Other Study ID Numbers: 140039; 14-I-0039
• First Posted: Mar 7, 2014
• Last Update Posted: Dec 29, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Treated Progressors; Immune Activation
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Aspirin; Atorvastatin

Study Results

Participant Flow

Arm/Group Title	Daily Aspirin	Daily Lipitor
Arm/Group Description	HIV Infected on ART HIV Infected off ART	HIV Infected on ART HIV infected off ART
Period Title: Overall Study
STARTED	26	27
COMPLETED	24	20
NOT COMPLETED	2	7

Baseline Characteristics

Arm/Group Title	Daily Aspirin	Daily Atorvastatin	Total
Arm/Group Description	HIV Infected on ART Elite controllers not on ART	HIV Infected on ART Elite controllers not on ART	Total of all reporting groups
Overall Participants	24	20	44
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	54	54	54
Sex: Female, Male (Count of Participants)
Female	6 25%	6 30%	12 27.3%
Male	18 75%	14 70%	32 72.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 54.2%	13 65%	26 59.1%
White	9 37.5%	4 20%	13 29.5%
More than one race	1 4.2%	1 5%	2 4.5%
Unknown or Not Reported	1 4.2%	2 10%	3 6.8%
Region of Enrollment (participants) [Number]
United States	24 100%	20 100%	44 100%
CD4 (cells/μL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/μL]	595	717	650
Total Cholesterol (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	174	173	173
Hypertension (Count of Participants)
Count of Participants [Participants]	6 25%	4 20%	10 22.7%

Outcome Measures

1. Primary Outcome

Title	Changes in sCD14 After 9 Months of Treatment With Aspirin or Atorvastatin
Description	sCD14 change between baseline (average of month 0 and month 3 in the study) and month 12
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daily Aspirin	Daily Atorvastatin
Arm/Group Description	HIV Infected on ART Elite controllers not on ART	HIV Infected on ART Elite controllers not on ART
Measure Participants	24	20
Median (95% Confidence Interval) [pg/mL]	-0.131	-0.09

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daily Atorvastatin
	Comments	Wilcoxon rank sum test was used to compare the change of sCD14 from baseline and month 12 measurement within each arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Threshold for statistical significance was a priori set to <0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daily Aspirin
	Comments	Wilcoxon rank sum test was used to compare the change of sCD14 from baseline and month 12 measurement within each arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Changes in sCD14 in EC and ART <50 Groups Treated With Aspirin or Atorvastatin.
Description	sCD14 change between baseline (average of month 0 and month 3 in the study) and month 12
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daily Aspirin on ART	Daily Aspirin Not on ART	Daily Atorvastatin on ART	Daily Atorvastatin Not on ART
Arm/Group Description	Treated Individuals on Chronic Antiretroviral Therapy	Elite controllers not on Chronic Antiretroviral Therapy	Treated Individuals on Chronic Antiretroviral Therapy	Elite controllers not on Chronic Antiretroviral Therapy
Measure Participants	15	9	12	8
Median (95% Confidence Interval) [pg/mL]	-0.1249	-0.1353	-0.3242	0.1758

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daily Aspirin
	Comments	Wilcoxon rank sum test was used to compare the change of sCD14 from baseline and month 12 measurement within each arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daily Atorvastatin
	Comments	Wilcoxon rank sum test was used to compare the change of sCD14 from baseline and month 12 measurement within each arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daily Atorvastatin on ART
	Comments	Wilcoxon rank sum test was used to compare the change of sCD14 from baseline and month 12 measurement within each arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0269
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daily Atorvastatin Not on ART
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Daily Aspirin, Daily Atorvastatin, Daily Atorvastatin on ART, Daily Atorvastatin Not on ART
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Plasma biomarkers (CRP, sCD14, TF, IL-6) were log(e) transformed and a linear mixed effect model with the biomarker as outcome and with random slope per participant was used to calculate the percentage of change from baseline.

Adverse Events

Time Frame	Adverse event data were collected for 3 months after the end of the drug.
Arm/Group Title	Daily Aspirin		Daily Atorvastatin
Arm/Group Description	HIV Infected on ART Elite controllers not on Chronic Antiretroviral Therapy		HIV Infected on ART Elite controllers not on Chronic Antiretroviral Therapy
All Cause Mortality
	Daily Aspirin		Daily Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/23 (0%)
Serious Adverse Events
	Daily Aspirin		Daily Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/24 (8.3%)		1/23 (4.3%)
Investigations
Alanine aminotransferase increased	1/24 (4.2%)	1	0/23 (0%)	0
Aspartate aminotransferase increased	1/24 (4.2%)	1	0/23 (0%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/24 (0%)	0	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Daily Aspirin		Daily Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/24 (50%)		5/23 (21.7%)
Gastrointestinal disorders
Diarrhoea	0/24 (0%)	0	1/23 (4.3%)	1
Gastrooesophageal reflux disease	1/24 (4.2%)	1	0/23 (0%)	0
Infections and infestations
Gastroenteritis	1/24 (4.2%)	1	0/23 (0%)	0
Urinary tract infection	1/24 (4.2%)	1	1/23 (4.3%)	1
Gonorrhea	1/24 (4.2%)	1	0/23 (0%)	0
Oesophageal Candidiasis	0/24 (0%)	0	1/23 (4.3%)	1
Skin Infection	0/24 (0%)	0	1/23 (4.3%)	1
Herpes Zoster	0/24 (0%)	0	1/23 (4.3%)	1
Investigations
Neutrophil count decreased	1/24 (4.2%)	1	1/23 (4.3%)	1
Low density lipoprotein increased	1/24 (4.2%)	1	0/23 (0%)	0
Blood cholesterol increased	2/24 (8.3%)	2	2/23 (8.7%)	2
White Blood Cell Decreased	1/24 (4.2%)	1	0/23 (0%)	0
Blood Creatinine Increase	3/24 (12.5%)	3	0/23 (0%)	0
Metabolism and nutrition disorders
Hypophosphataemia	2/24 (8.3%)	2	2/23 (8.7%)	2
Hyperglycemia	4/24 (16.7%)	4	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Fracture	0/24 (0%)	0	1/23 (4.3%)	1
Psychiatric disorders
Suicidal Ideation	0/24 (0%)	0	1/23 (4.3%)	1
Mental Status Changes	0/24 (0%)	0	1/23 (4.3%)	1
Reproductive system and breast disorders
Erectile Dysfunction	0/24 (0%)	0	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary mass	1/24 (4.2%)	1	0/23 (0%)	0
Cough	1/24 (4.2%)	1	0/23 (0%)	0
Vascular disorders
Deep vein thrombosis	1/24 (4.2%)	1	0/23 (0%)	0

Limitations/Caveats

Small sample size, study was completed earlier compared to expected sample size.

More Information

Certain Agreements

All Principal Investigators ARE 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.