Antiplatelet Therapy in HIV

There is substantial evidence that the risk of serious non-AIDS conditions, such as
cardiovascular disease, kidney disease, liver disease, and non-AIDS-defining malignancies, is
increased in persons with HIV infection as compared to the general population. HIV-induced
activation of inflammatory and coagulation pathways have been implicated in this increased
risk. However, causative mechanisms linking HIV, inflammation, and increased risk of non-AIDS
diseases are poorly described. The investigators are interested in studying the link between
HIV induced inflammation and cardiovascular disease. Inflammation mediates many aspects of
disease pathogenesis in atherosclerosis, involving diverse cell types and mediating signals.
Specifically, platelets have been implicated in atherosclerosis because of their
pro-inflammatory and thrombogenic effects. Moreover, clinical studies have demonstrated the
importance of platelet activity in coronary artery atherosclerosis and thrombosis. Whereas
there is a great understanding of the pathogenesis of cardiac disease, there is a wide
knowledge gap in the understanding of mechanisms of cardiovascular disease in patients with
HIV.

A recent study by the investigators demonstrated that platelet activity is heightened in
subjects with HIV. Following 1-week of low-dose aspirin, platelet activity was inhibited. A
surprising finding of this study demonstrated that antiplatelet therapy with 1 week of
aspirin (325mg dose x1 day followed by 81mg daily) improved immune activity in subjects with
HIV. The current study is being performed to replicate those findings when compared with a
control group. Moreover, it remains unknown if the finding was specific to aspirin or whether
the results were attributed to the antiplatelet effect of the drug. Clopidogrel is another
antiplatelet therapy that targets the P2Y12 receptor (a different mechanism than aspirin)
that has been shown to lower the risk of cardiovascular events in various clinical settings.
The doses of aspirin and clopidogrel the investigators will be employing have been tested in
hundreds of studies with well-known benefits and risks. The investigators believe that
understanding the mechanistic role of platelet inhibitors in the setting of HIV will help
uncover a new strategic pathway of HIV pathogenesis. Also, subjects with HIV are at increased
risk for cardiovascular events and understanding the platelet inhibition of aspirin and
clopidogrel will help establish better designs for future trials aimed at preventing these
events in HIV infected persons.

The investigators have demonstrated that platelet activation is increased in HIV infection
and can be attenuated by low-dose aspirin in a non-randomized study without a control group.
Therefore, the Specific Aims of the study to be established are as follows:

- The effect of aspirin versus control on markers of platelet activity, inflammation,
immune activity, and endothelial function.

- The effect of Clopidogrel versus control on markers of platelet activity, inflammation,
immune activity, and endothelial function.

Inclusion Criteria:

- HIV infection

- Current Antiretroviral Therapy with no change in regimen in the 12 weeks prior to
study entry and no plans to change ART for the study duration

- Ability to sign consent and comply with the protocol

Exclusion Criteria:

- Known CD4+ T cell counts < 200 cells/mm3 during the 6 months prior to study entry

- Established cardiovascular disease (thereby necessitating antiplatelet therapy)

- NSAID use in the past week (including aspirin)

- Unable to be off NSAIDs for the duration of the trial

- Any antiplatelet or antithrombotic use

- Allergy to aspirin or clopidogrel

- Pregnancy

- Chronic kidney disease (GFR<45 ml/min)

- AIDS

- Active drug or alcohol use that would interfere with adherence to study requirements

- Any known bleeding disorder

- Use of regularly prescribed medication such as steroids, or immunosuppressive agents

- Known anemia (Hb <8mg/dL)

- Thrombocytopenia (platelet count <75) or thrombocytosis (Platelet count >600)