Targeting Platelets in Chronic HIV Infection

This is a randomized, double-blind, placebo-controlled trial of 40 HIV-1 infected
participants on stable ART randomized in a 1:1:1 ratio to aspirin 81mg daily vs clopidogrel
75mg daily vs placebo for 24 weeks. A subset of patients in each arm will participate in a
sub-study to evaluate thrombogenicity, to be performed prior to the first study treatment and
at 24 weeks of study treatment. 10 HIV uninfected control subjects will participate the study
to evaluate baseline characteristics.

The primary endpoint is to determine the impact of aspirin as compared to clopidogrel on
immune activation and inflammation in HIV infected, ART treated adults. This will be
determined by measuring the change in the clinically relevant soluble marker of inflammation
sCD14 over 24 weeks of study drug. Secondary objectives will be to measure safety and
tolerability, to measure the effects of study drugs on important soluble markers of
inflammation (sCD163, IL-6, d-dimer, sTNFRI and II), by measuring monocyte subsets (CD14,
CD16, CD69), by measuring platelet activation by light transmission aggregometry,
monocyte-platelet aggregates, and soluble CD40L, by measuring clot formation kinetics by
thromboelastography, and in a subset of patients, by measuring thrombogenicity by Badimon
Chamber and cholesterol uptake by monocytes.

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.