Atazanavir and Endothelial Function in Older HIV Patients

HIV Clinical Trial

Official title:

Atazanavir and Endothelial Function in Older HIV Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03019783
• Other study ID #: AI424-469
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: December 8, 2016
• Last updated: January 11, 2017
• Start date: December 2011
• Est. completion date: June 2016

Study information

• Verified date: January 2017
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: June 2016
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• HIV

Intervention

Drug:
• Atazanavir
The active group will switch from a non-atazanavir regimen to an atazanavir-based regimen.

Other:
• Placebo
The control group will stay on their baseline regimen

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Brigham and Women's Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in flow-mediated, endothelium-dependent vasodilation	The investigators will evaluate flow-mediated, brachial artery vasodilation at study entry and then after 28 days, with the change between the two measurements being the primary endpoint.	4 weeks	No
Secondary	Change in plasma total antioxidant capacity	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.	4 weeks	No