Evaluating the Impact of Blood–Brain Barrier-Penetrant ACE Inhibitors on HIV-Associated Neurocognitive Disorders

BACKGROUND: As people with HIV (PWH) live longer because of effective antiretroviral therapy, age-related comorbidities-including cognitive impairment-are increasingly prevalent. HIV-associated neurocognitive disorders (HAND) remain a major cause of morbidity. In prior work, we identified an association between blood-brain barrier (BBB)-penetrant angiotensin-converting enzyme inhibitors (ACEi) and reduced risk of dementia in PWH. We are now expanding our work and methodology to more the effects of BBB ACEi on the risk of HAND. METHODS: Using the Veterans Affairs Informatics and Computing Infrastructure, we conducted a retrospective cohort study to evaluate the association between BBB ACEi exposure and incident HAND among PWH. We used natural language processing to identify clinically documented HAND cases-including HIV-associated dementia, mild neurocognitive disorder, and asymptomatic neurocognitive impairment-from unstructured electronic medical notes. Eligible patients initiated ACEi therapy after HIV diagnosis between 2000 and 2024. Cox proportional hazards models, propensity score matching, and inverse probability treatment weighting were used to estimate adjusted hazard ratios. RESULTS: Among 10,512 eligible PWH, 10,110 were exposed to BBB ACEi and 402 to non-BBB ACEi. In the unmatched cohort, HAND incidence was similar between groups (5.13% vs. 5.47%). However, after propensity score matching (n = 349 per group), BBB ACEi exposure was associated with a significantly lower risk of HAND (hazard ratio = 0.401; 95% confidence interval: 0.175-0.917). CONCLUSIONS: BBB-penetrant ACEi were associated with a reduced risk of incident HAND in a propensity score-matched cohort of PWH. These findings support further investigation into repurposing centrally acting ACEi as a potential neuroprotective strategy in the HIV population.