IMPORTANCE: People living with HIV and atrial fibrillation (AF) often receive anticoagulation that may interact with their antiretroviral therapy (ART). No studies exist comparing the safety of oral anticoagulants in this population. OBJECTIVE: To compare the bleeding risks among warfarin, rivaroxaban, and apixaban users in a national US cohort with AF and HIV. DESIGN, SETTING, AND PARTICIPANTS: A new-user, active-comparator, propensity score overlap-weighted cohort study using the target trial emulation framework including Medicare claims database data (January 1, 2013, to December 31, 2020) was carried out. The analysis was conducted from July 2023 to April 2024. EXPOSURE: New initiators of warfarin vs apixaban, rivaroxaban vs apixaban, and rivaroxaban vs warfarin aged 50 years or older with nonvalvular AF and HIV. MAIN OUTCOMES AND MEASURES: The primary outcome was hospitalization for major bleeding. Secondary outcomes included hospitalization for gastrointestinal bleeding, ischemic stroke, and all-cause mortality. RESULTS: Overall, 2683 individuals (mean [SD] age, 66.22 [8.97] years
580 female individuals [21.6%]) in the warfarin vs apixaban cohort, 2176 (mean [SD] age, 66.61 [8.87] years
455 female individuals [20.9%]) in the rivaroxaban vs apixaban cohort, and 1787 (mean age, 65.47 years
377 female individuals [21.1%]) in the rivaroxaban vs warfarin cohort. After propensity score overlap weighting, warfarin initiation was associated with a higher rate of major bleeding than initiation of apixaban (hazard ratio [HR], 2.60
95% CI, 1.51-4.49), including major gastrointestinal bleeding (HR, 2.99
95% CI, 1.52-5.90). This association was intensified in the 71% of patients taking concurrent ART (major bleeding, HR, 6.68
95% CI, 2.78-16.02
gastrointestinal bleeding, HR, 5.28
95% CI, 2.08-13.42). Rivaroxaban vs apixaban was also associated with a higher rate of major bleeding (HR, 2.15
95% CI, 1.18-3.94) and gastrointestinal bleeding (HR, 3.38
95% CI, 1.57-7.25), with a stronger association in those using ART (major bleeding, HR, 4.83
95% CI, 2.11-11.08
gastrointestinal bleeding, HR, 4.76
95% CI, 1.78-12.70). Estimates were similar when comparing rivaroxaban with warfarin. No significant difference was observed in the rate of ischemic stroke or mortality among the 3 oral anticoagulants. CONCLUSIONS AND RELEVANCE: This study found that in patients with HIV and AF, especially those treated with ART, warfarin and rivaroxaban were associated with higher rates of major bleeding compared with apixaban, suggesting a superior safety profile for apixaban in this high-risk population.