Factor X Inhibition Reduces Coagulation Activity But Not Inflammation Among Persons Living with HIV: A Randomized Clinical Trial

Abstract

Background: Activation of coagulation among persons with HIV is associated with a broad spectrum of end-organ disease risk, but the underlying pathogenesis is not well characterized. Activated clotting factors, such as factor X, can stimulate leukocytes and amplify immune activation. We tested a hypothesis that hypercoagulation contributes to disease risk, in part, via upregulation of inflammatory pathways, in addition to direct effects from thrombosis. Methods: Treatment effects of oral edoxaban (30mg), a direct factor Xa inhibitor, versus placebo were investigated in a randomized, double-blind, cross-over clinical trial, among participants with HIV receiving ART with plasma HIV RNA <200 copies/mL and D-dimer levels ≥100 ng/mL Blood measures of coagulation, inflammation and immune activation were assessed during each 4-month cross-over treatment period. Soluble biomarkers were measured using ELISA, electrochemiluminescence, and immunoturbidmetric methods. Immunophenotyping was performed among a subset of participants. Analyses report the change on edoxaban versus change on placebo, calculated with linear mixed models. Results: Forty-four participants were randomized among 83 screened; 40 completed at least one on-treatment visit during each study period. Mean age was 49 years and CD4+ count was 739 cells/mm3; 34% with prior AIDS, and 70% were receiving an integrase strand transfer inhibitor. Edoxaban treatment led to declines in D-dimer (44%) and thrombin-antithrombin complex (26%). There was no evidence of a treatment effect on the inflammatory or immune activation measures evaluated. More non-laceration bruising or bleeding events occurred during edoxaban (n=28) than during placebo or no drug periods (n=15). Conclusions: Among persons with HIV receiving ART with viral suppression, the oral direct factor Xa inhibitor edoxaban led to a substantial reduction in coagulation but no effect on inflammation or immune activation. These results support the position that hypercoagulation may be a consequence of, but is not a significant contributor to, systemic inflammation during chronic HIV disease. Trial Registration: NCT02339415 (ClinicalTrials.gov). Funding Statement: This study was funded by the National Heart Lung and Blood Institute (NHLBI/NIH: R01 HL126542). Study drug was provided by Daiichi-Sankyo Pharmaceuticals. The work of IS and HM was supported by the intramural research program of NIAID/NIH. Declaration of Interests: The authors state that they have no conflicts of interest to disclose. Ethics Approval Statement: The trial protocol was approved by the clinical site institutional review board for conduct of human subjects research. All study participants underwent a verbal and written informed consent process prior to enrollment.