Objective: Cognitive impairment and frailty are critical aging-related phenotypes prevalent among people living with HIV (PLWH). Yet, limited data exist isolating the determinants of cognitive function among persons with a history of injection drug use (PWID) with and at risk for HIV, or on the intersecting relationship of cognitive function and frailty with mortality in this population.

Design/methods: Standard cognitive assessments were performed among PWID with and without HIV in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort. Frailty was assessed using the 5 Fried physical frailty phenotype criteria. An inflammatory index score was constructed from IL-6 and soluble TNF-α receptor-1 data. Cox proportional hazards models were utilized to estimate mortality risk.

Results: Among 519 ALIVE participants, the median age was 52 years and 41% were PLWH. Hazardous alcohol use and older age were significantly associated with reductions in processing speed, motor function, and global cognitive function. In multivariable models, reduced processing speed, motor function, and global cognitive function were significantly associated with increased mortality. Reduced global cognitive function and frailty were independently associated with mortality. Reduced processing speed, motor function, executive function, and global cognitive function were significantly associated with heightened inflammation.

Conclusion: Reduced cognitive function is a significant predictor of death among people living with HIV and PWID, independent of frailty, HIV disease stage, and comorbidity. Interventions that target both cognitive function and frailty, including those targeting inflammation pathways, among PLWH and PWID may improve aging outcomes for these populations.