Atazanavir and Endothelial Function in Older HIV Patients

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03019783
• Collaborator: (none)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 54
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The investigators hypothesize that older subjects with HIV randomly assigned to atazanavir will have increased bilirubin levels, reduced oxidative stress, and improved flow-mediated, endothelium-dependent vasodilation compared to subjects not switched to atazanavir.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: Atazanavir; Other: Placebo	Phase 2/Phase 3

Detailed Description

The mortality induced by HIV has dropped significantly due to effective antiretroviral therapy. Epidemiological data suggest a less than 5% 10-year mortality for patients treated with HAART. As a result of the reduction in early AIDS-related deaths, HIV has become a chronic disease manifesting the common components of chronic disease such as inflammation, vascular dysfunction, and oxidative stress. The combination of these trends put HIV patients at increased risk of myocardial infarction compared with age-matched subjects over the long term. Several studies suggest that some protease inhibitors might increase the risk of myocardial infarction. The leading theory behind this association derives from the relationship between protease inhibitor use and the onset of an atherogenic dysmetabolism including the development of insulin resistance, dyslipidemia, and oxidative stress.

In contrast to the older protease inhibitors, atazanavir induces neither insulin resistance nor dyslipidemia. In addition, atazanavir has a property unique among protease inhibitors: elevation of unconjugated bilirubin by inhibiting the enzyme uridine diphosphate glucuronyltransferase (UGT) 1A1. Bilirubin is a potent intracellular antioxidant. The investigators have demonstrated that higher levels of bilirubin within the normal range are associated with reduced rates of stroke and peripheral artery disease. Patients with Gilbert's Syndrome (chronic elevations of bilirubin as a result of genetically reduced UGT 1A1) have a lower rate of myocardial infarction compared with age-matched controls. It is plausible that use of atazanavir compared with other protease inhibitors, by reducing oxidative stress, may improve vascular function and, ultimately, reduce the rate of cardiovascular complications with chronic therapy.

The benefit of atazanavir may be particularly important now with the aging of the HIV population. Aging is associated with higher levels of oxidative stress and endothelial dysfunction, both of which are associated with heightened rates of cardiovascular morbidity and mortality. Accordingly, the investigators hypothesize that the use of atazanavir in stable HIV patients age 45 years or older will improve endothelial dysfunction and reduce oxidative stress compared with continuing the current therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Atazanavir and Endothelial Function in Older HIV Patients
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Remains on baseline HIV regimen Subjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator.	Other: Placebo; The control group will stay on their baseline regimen
Active Comparator: Atazanavir switch These subjects are switched to an atazanavir-based regimen.	Drug: Atazanavir; The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.; Other Names: Reyataz

Outcome Measures

Primary Outcome Measures

1. Change in Flow-mediated, Endothelium-dependent Vasodilation [4 weeks]

   The investigators will evaluate flow-mediated, brachial artery vasodilation (percentage increase in diameter in response to a 5 minute ischemic challenge) at study entry and then after 28 days, with the change between the two measurements being the primary endpoint.

Secondary Outcome Measures

1. Change in Plasma Total Antioxidant Capacity [4 weeks]

   The investigators will evaluate plasma total antioxidant capacity at study entry and then after 28 days, with the change between the two measurements being the secondary endpoint.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 45 years

• Stable non-atazanavir-containing regimen consisting of co-formulated tenofovir/emtricitabine as the NRTIs plus a third agent for 3 months or longer. The third agent can be any FDA-approved PI, NNRTI, or raltegravir.

• HIV RNA < 200 cop/mL at screening and at least once within the prior year,

• No treatment interruptions > 7 days in the 3 months prior to study entry

• The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.

• Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)

• Signed Written Informed Consent. Before any study procedures are performed, subjects will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel.

• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of study drug to minimize the risk of pregnancy.

• WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

• Amenorrhea that has lasted for 12 consecutive months without another cause, or

• For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.

• Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.

• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of the investigational product.

Exclusion Criteria:

• Sex and Reproductive Status

• WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the last dose of study drug.

• Women who are pregnant or breastfeeding.

• Women with a positive pregnancy test.

• Target Disease Exceptions

• Prior treatment failure on or intolerance to atazanavir

• Known or suspected resistance to atazanavir

• Receiving ART different from co-formulated tenofovir/emtricitabine plus third agent (PI, NNRTI, or raltegravir) regimen

• Receiving Viagra, Levitra, or Cialis

• A new AIDS-defining condition diagnosed within the 30 days prior to screening

• Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline

• Medical History and Concurrent Diseases

• Patients with Gilbert's Syndrome or elevated bilirubin levels (>1.5 mg/dL) at baseline (for the randomized trial)

• Patients with uncontrolled diabetes (hemoglobin A1c > 11%)

• Patients allergic to nitroglycerin

• Prohibited Treatments and/or Therapies

• Recent initiation of hormones or immunomodulators (3 months)

• Current receipt of proton-pump inhibitor therapy

• Other Exclusion Criteria

• Prisoners, or subjects who are involuntarily incarcerated.

• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

• Subjects for whom the investigators believe there will be a low likelihood of medication compliance.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital

Investigators

• Principal Investigator: Joshua Beckman, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Joshua A. Beckman, MD, Associate Professor of Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT03019783
• Other Study ID Numbers: AI424-469
• First Posted: Jan 13, 2017
• Last Update Posted: May 16, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Joshua A. Beckman, MD, Associate Professor of Medicine, Brigham and Women's Hospital: Endothelial function
• Additional relevant MeSH terms: Atazanavir Sulfate

Study Results

Participant Flow

Arm/Group Title	Remains on Baseline HIV Regimen	Atazanavir Switch
Arm/Group Description	Subjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator. Placebo: The control group will stay on their baseline regimen	These subjects are switched to an atazanavir-based regimen. Atazanavir: The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.
Period Title: Overall Study
STARTED	29	31
COMPLETED	29	31
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Remains on Baseline HIV Regimen	Atazanavir Switch	Total
Arm/Group Description	Subjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator. Placebo: The control group will stay on their baseline regimen	These subjects are switched to an atazanavir-based regimen. Atazanavir: The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.	Total of all reporting groups
Overall Participants	29	31	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (6)	53 (6)	53 (6)
Sex: Female, Male (Count of Participants)
Female	6 20.7%	13 41.9%	19 31.7%
Male	23 79.3%	18 58.1%	41 68.3%
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	12 41.4%	18 58.1%	30 50%
White	17 58.6%	13 41.9%	30 50%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	29 100%	29 93.5%	58 96.7%

Outcome Measures

1. Primary Outcome

Title	Change in Flow-mediated, Endothelium-dependent Vasodilation
Description	The investigators will evaluate flow-mediated, brachial artery vasodilation (percentage increase in diameter in response to a 5 minute ischemic challenge) at study entry and then after 28 days, with the change between the two measurements being the primary endpoint.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remains on Baseline HIV Regimen	Atazanavir Switch
Arm/Group Description	Subjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator. Placebo: The control group will stay on their baseline regimen	These subjects are switched to an atazanavir-based regimen. Atazanavir: The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.
Measure Participants	29	31
Mean (Standard Deviation) [percentage vasodilation]	0.2 (2.4)	0.8 (4.6)

2. Secondary Outcome

Title	Change in Plasma Total Antioxidant Capacity
Description	The investigators will evaluate plasma total antioxidant capacity at study entry and then after 28 days, with the change between the two measurements being the secondary endpoint.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Remains on Baseline HIV Regimen	Atazanavir Switch
Arm/Group Description	Subjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator. Placebo: The control group will stay on their baseline regimen	These subjects are switched to an atazanavir-based regimen. Atazanavir: The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.
Measure Participants	29	31
Mean (Standard Deviation) [micromolar]	-21 (271)	219 (213)

Adverse Events

Time Frame	1 month
Adverse Event Reporting Description	No adverse events
Arm/Group Title	Remains on Baseline HIV Regimen		Atazanavir Switch
Arm/Group Description	Subjects are enrolled and either kept on their baseline regimen. This is being designated the placebo comparator. Placebo: The control group will stay on their baseline regimen		These subjects are switched to an atazanavir-based regimen. Atazanavir: The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.
All Cause Mortality
	Remains on Baseline HIV Regimen		Atazanavir Switch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/31 (0%)
Serious Adverse Events
	Remains on Baseline HIV Regimen		Atazanavir Switch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/31 (0%)
Other (Not Including Serious) Adverse Events
	Remains on Baseline HIV Regimen		Atazanavir Switch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/31 (0%)

Limitations/Caveats

There were no limitations.

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.