A Randomized Placebo Controlled Trial of Aspirin Effects on Immune Activation in Chronically Human Immunodeficiency Virus-Infected Adults on Virologically Suppressive Antiretroviral Therapy

Abstract

Background: Immune activation persists despite suppressive antiretroviral therapy (ART) in human immunodeficiency virus (HIV) infection and predicts non-Acquired Immune Deficiency Syndrome (AIDS) comorbidities including cardiovascular disease. Activated platelets play a key role in atherothrombosis and inflammation, and platelets are hyperactivated in chronic HIV infection. Aspirin is a potent inhibitor of platelet activation through the cyclooxygenase-1 (COX-1) pathway. We hypothesized that platelet activation contributes to immune activation and that aspirin would reduce immune activation and improve endothelial function in ART-suppressed HIV-infected individuals.

Methods: In this prospective, double-blind, randomized, placebo-controlled 3-arm trial of 121 HIV-infected participants on suppressive ART for >48 weeks, we evaluated the effects of 12 weeks of daily aspirin 100 mg, aspirin 300 mg, or placebo on soluble and cellular immune activation markers, flow-mediated dilation (FMD) of the brachial artery, and serum thromboxane B₂, a direct readout of platelet COX-1 inhibition.

Results: The 300-mg and 100-mg aspirin arms did not differ from placebo in effects on soluble CD14, interleukin (IL)-6, soluble CD163, D-dimer, T-cell or monocyte activation, or the other immunologic endpoints measured. Endothelial function, as measured by FMD, also was not significantly changed when comparing the 300-mg and 100-mg aspirin arms to placebo.

Conclusions: Aspirin treatment for 12 weeks does not have a major impact on soluble CD14, IL-6, soluble CD163, D-dimer, T-cell or monocyte activation, or FMD, suggesting that inhibition of COX-1-mediated platelet activation does not significantly improve HIV-related immune activation and endothelial dysfunction. Although future studies are needed to further identify the causes and consequences of platelet activation in ART-treated HIV infection, interventions other than COX-1 inhibition will need to be explored to directly reduce immune activation in treated HIV infection.

Keywords: CD14; HIV; aspirin; platelets.

Figure 1.

Study flow chart of screening, enrollment, study completion, and analysis. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; RNA, ribonucleic acid.

Figure 2.

Effects of 12 weeks of aspirin 300 mg, aspirin 100 mg, and placebo with 4-week washout on serum thromboxane (TXB₂) and urinary TXB₂ 11-dehydrothromboxane to urine creatinine ratio, shown as mean-fold change (95% confidence interval [CI]) from baseline.

Figure 3.

(A) Effects of 12 weeks of aspirin 300 mg, aspirin 100 mg, and placebo on soluble markers soluble (s)CD14, sCD163, D-dimer, interleukin (IL)-6; *, sCD163, increased with 300-mg daily aspirin (14.7%; 95% confidence interval [CI], 0.8–30.4; P = .037) compared with placebo. (B) Effects of 12 weeks of aspirin 300 mg, aspirin 100 mg, and placebo on flow cytometry markers of T-cell activation (CD4⁺CD38⁺HLA-DR⁺, CD8⁺CD38⁺HLA-DR⁺), T-cell exhaustion (CD4⁺PD1⁺, CD8⁺PD1⁺), and inflammatory monocyte subsets (CD14^dimCD16⁺CD69⁺, CD14^dimCD16⁻CD69⁺, CD14⁺CD16⁺, CD14⁺CD16⁺CD69⁺), shown as mean-fold change (95% CI) from baseline.

Figure 4.

Effects of 12 weeks of aspirin 300 mg, aspirin 100 mg, and placebo on flow-mediated dilation, shown as mean change (95% confidence interval [CI]). Abbreviation: FMD, flow-mediated dilation.