Targeting Platelets in Chronic HIV Infection

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.

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.