Targeting Platelets in Chronic HIV Infection
Condition: HIV-1 Infection
MeSH terms: Infections; Communicable Diseases; HIV Infections
Intervention: Clopidogrel; Aspirin; Placebo
Intervention description: Clopidogrel 75mg; 81 mg
Intervention MeSH terms: Aspirin; Clopidogrel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: HIV; Aspirin; Clopidogrel; Platelet; Inflammation; Cardiovascular disease; Arachidonic acid; Cyclooxygenase inhibitor; ADP inhibitor; Immune activation; Monocyte; Coagulation; Thrombogenicity

Summary:

      Advances in antiretroviral therapy (ART) have resulted in increased survival of the
      HIV-infected population; however, this gain in longevity is associated with an increased risk
      of cardiovascular disease (CVD). Although ART and traditional risk factors contribute to CVD
      in this population, heightened markers of immune activation, inflammation, and coagulation
      independently predict morbidity and mortality, suggesting that dysregulation of these systems
      plays a significant role in the increased risk of CVD. The investigators believe that
      platelet activation is an important driver in HIV-associated immune activation, inflammation,
      and coagulation, leading to an increased CVD pathophysiology and risk. Platelets initiate
      thrombus formation and also play a key role in vascular inflammation by releasing
      pro-inflammatory mediators and cross-talking with other relevant cell types including
      leukocytes. Researchers have described platelet hyperreactivity in chronic HIV infection.
      Importantly, the investigators demonstrated that one week of anti-platelet therapy (aspirin)
      decreased platelet activation and immune activation, with an improved trend in inflammation
      and immune parameters. The overall hypothesis is that platelet activation is a major driver
      of immune activation, inflammation, and thrombosis in ART-treated HIV infected patients. The
      purpose of the proposed proof-of-concept study is to understand the mechanism(s) by which
      anti-platelet therapy improves immune and inflammatory parameters in chronic HIV infection.
      To test this, the immune modulating and anti-inflammatory effects of 24 weeks of the
      anti-platelet drug aspirin as compared to the anti-platelet drug clopidogrel will be
      evaluated. Given their different mechanisms of action and inhibitory potency, the
      investigators can differentiate whether the potential benefits are mediated via inhibition of
      arachidonic acid (aspirin) or inhibition of ADP (clopidogrel) or by the antithrombotic
      activity. A secondary goal is to perform multidimensional assays of platelet activity and
      thrombogenicity alongside immune activation assays and careful assessments of traditional
      risk factors and medication regimens, to understand which parameters are highly associated
      with thrombogenicity.
    

Eligibility criteria:

        HIV infected participants:

        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 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.

        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.

        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 BLQ for the assay.

          -  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/mm3

               -  Hemoglobin ≥9.0 g/dL for female subjects and ≥10.0 g/dL for male subjects

               -  Platelet count >100,000/mm3

               -  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

               -  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 before initiating the protocol-specified medication(s)
             unless otherwise specified by product labeling. 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 24 week trial.

        NOTE: Acetaminophen-based products may be used before and during the trial when analgesics
        are required.

        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 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% at screening.

          -  Use of lipid-lowering medications including: 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 or clopidogrel.

          -  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.

          -  Heavy alcohol use as defined by the National Institute on Alcohol Abuse and Alcoholism
             (NIAAA)

          -  Alcohol or drug use or dependence that, in the opinion of the 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.

        HIV-uninfected participants:

        Inclusion criteria:

        • HIV uninfected

        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 of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin that cannot
             be interrupted for clinical reasons.

          -  Current diagnosis of diabetes with HbA1c ≥8% at screening.

          -  Use of lipid-lowering medications including: 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

          -  Known chronic active hepatitis C

          -  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 or clopidogrel.

          -  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.

          -  Heavy alcohol use as defined by the National Institute on Alcohol Abuse and Alcoholism
             (NIAAA)

          -  Alcohol or drug use or dependence that, in the opinion of the 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.