Neuropsychiatric Tolerability of Long-Acting Cabotegravir and Rilpivirine in People With HIV With Prior INSTI-Related CNS Toxicity: A Real-World Cohort Study

Abstract Background Neuropsychiatric adverse events (NPAEs) are a recognized limitation of oral integrase inhibitors (INSTIs). Long-acting cabotegravir/rilpivirine (CAB/RPV LA) has expanded treatment options for people with HIV (PWH), but evidence regarding its neuropsychiatric tolerability in those with prior INSTI-related CNS toxicity remains limited. Methods We conducted a retrospective–prospective cohort study at a tertiary HIV center in Madrid, including all PWH initiating CAB/RPV LA between January 2023 and March 2025. Participants were stratified by documented history of neuropsychiatric intolerance to oral INSTIs. The primary outcome was the incidence of new or recurrent NPAEs following CAB/RPV LA initiation; the secondary outcome was treatment discontinuation due to neuropsychiatric intolerance. Results Of 393 patients initiating CAB/RPV LA, 36 (9.2%) had discontinued a prior oral INSTI due to CNS toxicity. New or recurrent NPAEs occurred in 12 individuals (3.1%), corresponding to an incidence density of 2.2 events per 100 person-years (95% CI, 1.1–3.6). Patients with prior INSTI-related neurotoxicity had a significantly higher risk of NPAEs after switching to CAB/RPV LA (19% vs 1.4%; P < .001) and a greater rate of discontinuation due to neuropsychiatric intolerance (14% vs .8%; P < .001). All discontinuations led to complete symptom resolution within 6–8 weeks of CAB/RPV LA withdrawal. Conclusions A history of CNS intolerance to oral INSTIs was associated with recurrence of neuropsychiatric symptoms and treatment discontinuation under CAB/RPV LA. These findings underscore the importance of individualized risk assessment and proactive neuropsychiatric monitoring when prescribing long-acting injectable ART to susceptible patients.