Modulation of Immune Activation by Aspirin
Condition: HIV-1 Infection
Intervention: Aspirin; Placebo
Intervention description: Aspirin is a nonsteroidal antiinflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body.; Placebo for aspirin
Intervention MeSH terms: Aspirin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Enrollment: 121.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Since people started taking HIV medications, illness from AIDS has decreased, but other
      serious diseases like heart disease, cancer, and kidney, and liver disease have increased.
      HIV causes inflammation (irritation) inside the body that cannot be felt but can be measured
      by blood. Inflammation can lead to diseases that have become some of the leading causes of
      death in people with HIV. HIV therapy can partially lower levels of inflammation measured in
      blood, however, levels of inflammation in people who have HIV may remain high compared with
      people not infected with HIV.

      Aspirin is a drug that is commonly used for pain relief but is also approved by the Food and
      Drug Administration (FDA) for preventing heart attacks and stroke in those who are at
      increased risk for heart attack and stroke. Aspirin also is used (but is not approved by the
      FDA) to decrease the risk of some cancers in people who are at increased risk. Aspirin is
      thought to decrease risk of heart attack and stroke because it blocks the activation of
      platelets and prevents blood clots from clogging narrowed blood vessels, a disease called
      atherosclerosis. It is unknown how aspirin might decrease the chance of developing cancer in
      some people at higher risk, but aspirin has been shown to modulate (or change) the immune
      system. In HIV-infected people who have been taking antiretroviral therapy and have an
      undetectable HIV viral load it was recently shown that low-dose aspirin 81 mg (baby aspirin),
      given for one week, lowers platelet activation and reduces blood markers of inflammation
      which may improve the function of the immune system.

      The purpose of this study was to evaluate whether aspirin improves inflammation and immune
      activation when compared to a placebo (inactive medication like a dummy pill) and to
      determine if 12 weeks of aspirin 300 mg and aspirin 100 mg is safe for HIV-infected persons
      on antiretroviral therapy. Additionally, it studied whether a higher dose and longer duration
      of aspirin provides further anti-inflammatory and immune-modulating benefit. This was done
      using blood and urine tests that measure inflammation and also with a test that uses
      ultrasound to measure the flow of blood in your arm, called flow-mediated vasodilation (FMD)
      of the brachial artery (BART). This is a painless test that bounces sound waves off of a
      blood vessel in your arm.
    

Eligibility criteria:

        Inclusion Criteria:

          -  HIV-1 infection.

          -  Currently on continuous ART for ≥48 weeks prior to study entry. NOTE: This is defined
             as continuous active therapy with no treatment interruption longer than 7 consecutive
             days and a total duration off-treatment of no more than 14 days during the 48 weeks
             prior to entry.

          -  No change in ART regimen within the 12 weeks prior to study entry (except as noted
             below).

        NOTE: Modifications of ART dosing during within the 12 weeks prior to entry are permitted.
        In addition, the change in formulation (eg, from standard formulation to fixed dose
        combination or single tablet regimen) or dosing (eg, from once a day to twice a day) is
        allowed within 12 weeks prior to entry. Within-class single drug substitution (eg, switch
        from nevirapine to efavirenz or from atazanavir to darunavir), are not allowed within 12
        weeks prior to entry. No other changes in ART in the 12 weeks prior to entry are permitted.

          -  Screening HIV-1 RNA must be <50 copies/mL and performed by any FDA-approved assay at
             any US laboratory that has a CLIA certification or its equivalent within 45 days prior
             to study entry.

          -  Maintain ART-mediated viral suppression for at least 48 weeks prior to study entry
             defined as:

        A. At least one HIV-1 RNA test result obtained at any time point greater than 48 weeks
        prior to study entry must be BLQ and must be performed by any FDA-approved assay at a
        CLIA-certified laboratory or its equivalent.

        AND

        B. All HIV-1 RNA tests reported during the 48 weeks prior to study entry must be BLQ and
        must be performed by any FDA-approved assay at a CLIA-certified laboratory or its
        equivalent.

        NOTE: A single RNA "blip" of ≤500 copies/mL is permissible if RNA levels most recent before
        and after (may include the screening HIV-1 RNA test) are below the level of quantification
        (BLQ) for the assay. If the RNA level after the blip is the screening HIV-1 RNA test, the
        result must be <50 copies/mL.

          -  The following laboratory values obtained within 45 days prior to study entry by any US
             laboratory that has a CLIA certification or its equivalent.

               -  Absolute neutrophil count (ANC) ≥750/mm^3

               -  Hemoglobin ≥9.0 g/dL for female subjects and ≥10.0 g/dL for male subjects

               -  Platelet count >100,000/mm^3

               -  Prothrombin time (PT) <1.2 x upper limit normal (ULN)

               -  Partial thromboplastin time (PTT) <1.5 x ULN

               -  Calculated creatinine clearance (CrCl) ≥30 mL/min, as estimated by the
                  Cockroft-Gault formula NOTE: Calculation for the Cockcroft-Gault equation is
                  available at https://www.fstrf.org/apps/cfmx/apps/common/Portal/index.cfm

               -  Aspartate aminotransferase (AST) (SGOT) ≤2 x ULN.

               -  Alanine aminotransferase (ALT) (SGPT) ≤2 x ULN.

               -  Alkaline phosphatase ≤2 x ULN.

               -  Total bilirubin ≤2.5 x ULN. If the subject if taking an indinavir- or
                  atazanavir-containing regimen at the time of screening, a total bilirubin of ≤5 x
                  ULN is acceptable.

          -  Female study volunteers of reproductive potential (pre-menopausal women who have not
             had a sterilization procedure (eg, hysterectomy, bilateral oophorectomy, tubal
             ligation, or salpingectomy) must have a negative serum or urine pregnancy test
             performed within 24 hours prior to study entry. Women are considered menopausal if
             they have not had a menses for at least 12 months and have a FSH (follicle stimulating
             hormone) of greater than 40 IU/L or, if FSH testing is not available, they have had
             amenorrhea for 24 consecutive months.

        If the female volunteer is not of reproductive potential (women who are menopausal, defined
        as not having had a menses for at least 12 months with an FSH of greater than 40 IU/L, or
        if FSH testing is not available, have had amenorrhea for 24 consecutive months, or women
        who have undergone surgical sterilization, (eg, hysterectomy, bilateral oophorectomy, tubal
        ligation or salpingectomy)), she is eligible without requiring the use of a contraceptive
        method. Acceptable documentation of sterilization is subject reported history of
        hysterectomy, bilateral oophorectomy, tubal ligation, tubal micro-insert, menopause, or the
        partner with vasectomy/azoospermia.

        - If participating in sexual activity that could lead to pregnancy, the female study
        volunteer must be willing to use contraception while receiving protocol-specified
        medication(s) and for the washout period of 4 weeks. At least one of the following methods
        MUST be used:

          -  Condoms (male or female), with or without a spermicidal agent

          -  Diaphragm or cervical cap with spermicide

          -  Intrauterine device (IUD)

          -  Hormone-based contraceptive

        As hormone-based contraceptives (oral, transdermal, or subdermal) can affect coagulopathy
        biomarkers, subjects who plan on using such a contraceptive during the study must be taking
        the same product for ≥4 weeks prior to screening and be encouraged to continue throughout
        the duration of the study, if medically feasible.

          -  No documented opportunistic infections within 24 weeks prior to study entry

          -  Karnofsky performance score >/= 70 within 45 days prior to study entry

          -  Ability and willingness of subject or legal guardian/representative to provide written
             informed consent.

          -  Willingness to refrain from the use of aspirin or any aspirin-related product (other
             than the study drug), including NSAIDs, from time of screening visit through the end
             of the 16 week trial.

        NOTE: Acetaminophen-based products may be used before and during the trial when analgesics
        are required.

          -  Completion of the pre-entry FMD assessment NOTE: The FMD must be performed at the site
             and confirmed as acceptable by the University of Wisconsin Atherosclerosis Imaging
             Research Program (UW AIRP) core lab prior to study entry.

          -  Confirmation of the availability of the stored pre-entry fasting specimens (plasma and
             serum); the site must confirm that these specimens have been entered into the
             Laboratory Data Management System (LDMS).

        Exclusion Criteria:

        - Current malignancy (except non-melanoma cancer of the skin not requiring systemic
        chemotherapy or radiation therapy).

        NOTE: Carcinoma in situ of the cervix or anus is not considered exclusionary.

          -  Prior history of malignancy if the subject is not disease free for 24 or more weeks
             prior to study entry.

          -  Current use or indication for use of non-steroidal anti-inflammatory drugs (NSAIDs) or
             aspirin that cannot be interrupted for clinical reasons. Examples of clinical reasons
             include, but are not limited to, known and documented cardiovascular disease (history
             of MI, coronary artery bypass graft surgery, percutaneous coronary intervention,
             stroke, transient ischemic attack, peripheral arterial disease with ABI <0.9 or
             claudication).

          -  Current diagnosis of diabetes with HbA1c ≥8% within 24 weeks prior to screening.

          -  Changes in lipid-lowering or antihypertensive medication within 90 days prior to study
             entry or expected need to modify these medications during the study.

        NOTE: Lipid-lowering medication includes: statins, fibrates, niacin (dose ≥250 mg daily),
        and fish-oil/omega 3 fatty acids (dose >1000 mg of marine oils daily).

          -  Known cirrhosis

          -  Known chronic active hepatitis B NOTE: Active hepatitis B is defined as hepatitis B
             surface antigen positive and hepatitis B DNA positive within 24 weeks prior to study
             entry; subjects with hepatitis B virus (HBV) DNA BLQ for greater than 24 weeks prior
             to study entry are eligible.

          -  Known chronic active hepatitis C NOTE: Active hepatitis C is defined as a detectable
             plasma HCV RNA level within 24 weeks prior to study entry; subjects with HCV RNA BLQ
             for greater than 24 weeks prior to study entry are eligible.

          -  Known inflammatory conditions, such as, but not limited to, rheumatoid arthritis (RA),
             systemic lupus erythematosus (SLE), sarcoidosis, inflammatory bowel disease (IBD),
             chronic pancreatitis, autoimmune hepatitis, Adult Stills disease, Rheumatic heart
             disease, bursitis.

          -  Breastfeeding or pregnant

          -  Previous intolerance or allergy to aspirin or any aspirin products.

          -  Frequent use of aspirin or aspirin products (NSAIDs), defined as an average of 2 or
             more times per week in the last 12 weeks prior to study entry.

          -  Immunosuppressant use, such as, but not limited to, systemic or potentially systemic
             glucocorticoids (including injected, ie, intra-articular, nasal or inhaled steroids),
             azathioprine, tacrolimus, mycophenolate, sirolimus, rapamycin, methotrexate, or
             cyclosporine within 45 days prior to study entry.

          -  Use of any systemic antineoplastic or immunomodulatory treatment, investigational
             vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin
             (IVIG) within 45 days prior to study entry.

        NOTE: Routine standard of care, including hepatitis A and/or B, human papilloma virus,
        influenza, pneumococcal, and tetanus vaccines are permitted if administered at least 7 days
        before study entry and before biomarker/peripheral blood mononuclear cell (PBMC) blood
        collections.

          -  Concurrent use of prohibited medications as per section 5.4

          -  Heavy alcohol use as defined by the National Institute on Alcohol Abuse and Alcoholism
             (NIAAA)
             http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-dr
             inking

          -  Alcohol or drug use or dependence that, in the opinion of the site investigator, would
             interfere with adherence to study requirements.

          -  Current use of anticoagulation therapy or conditions requiring use of anticoagulants,
             use such as, but not limited to warfarin (Coumadin), rivaroxaban (Xarelto),
             clopidogrel (Plavix), dabigatran (Pradaxa), apixaban (Eliquis), heparin, ticlopidine
             (Ticlid), Presugrel (Effient).

          -  History of coagulopathy, deep venous thrombosis, pulmonary embolism.

          -  Known active or recent (not fully resolved within 4 weeks prior to study entry)
             invasive bacterial, fungal, parasitic, or viral infections.

        NOTE: Recurrent herpes simplex virus (HSV) is not exclusionary. Subjects on antiviral
        prophylaxis for HSV or VZV are encouraged to remain on treatment for the duration of the
        study if medically feasible.

          -  Serious illness or trauma requiring systemic treatment and/or hospitalization within 4
             weeks prior to study entry.

          -  History of bleeding conditions such as peptic ulcer disease, hemophilia, von
             Willebrand disease, idiopathic thrombocytopenic purpura.

          -  History of thrombotic disorders such as protein C or S deficiency.

          -  History of gastrointestinal (GI) bleeding within the past 6 months prior to study
             entry.

          -  History of intracranial hemorrhage.