The proposed study will add to the growing understanding of platelet activity and platelet inhibition in subjects with HIV. It will examine the relationship between platelet activity and its inhibition by antiplatelet therapy (aspirin monotherapy and clopidogrel monotherapy) in this high-risk cohort. Furthermore, it will provide important data on the mechanism of platelet activity and its inhibition using biomarkers of platelet activity, inflammation, immune activity and endothelial function and genetic expression profiling.

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)