Clinical trial NCT03019783: Atazanavir and Endothelial Function in Older HIV Patients
Official title: Atazanavir and Endothelial Function in Older HIV Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: HIV
Keywords: Endothelial function
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2017-01-13
Enrollment: 60
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Flow-mediated, Endothelium-dependent Vasodilation
timeFrame: 4 weeks
Secondary outcomes:
measure: Change in Plasma Total Antioxidant Capacity
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Joshua Beckman
role: PRINCIPAL_INVESTIGATOR
References:
citation: Beckman JA, Wood BR, Ard KL, Price CN, Solomon DA, Zuflacht JP, Milian J, Prenner JC, Sax PE. Conflicting effects of atazanavir therapy on atherosclerotic risk factors in stable HIV patients: A randomized trial of regimen switch to atazanavir. PLoS One. 2017 Oct 12;12(10):e0181993. doi: 10.1371/journal.pone.0181993. eCollection 2017.