Effectiveness of interventions on cognitive decline risk for people living with HIV on antiretroviral therapy: a systematic review.

Cognitive impairment remains common among people living with HIV despite effective antiretroviral therapy (ART), yet the effectiveness of additional interventions to reduce the risk of cognitive decline or dementia is unclear. Commissioned by WHO, this systematic review evaluates whether pharmacological or non-pharmacological interventions, delivered alongside ART, improve cognitive outcomes or reduce incident mild cognitive impairment (MCI) or dementia. Following a preregistered protocol, we searched MEDLINE, Embase, Cochrane, and PsycINFO from database inception to Dec 10, 2024. Eligible studies included those describing adults (aged 18 years and older) living with HIV on ART receiving interventions targeting cognition or dementia risk. Primary outcomes were incident dementia, incident MCI, and the change in cognitive function assessed using validated instruments. Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2 and ROBINS-I. Certainty was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Owing to clinical and methodological heterogeneity and incomplete reporting, meta-analysis was not feasible. Of the 5963 records screened, five studies met the inclusion criteria: three randomised controlled trials and two observational cohort studies, all assessing pharmacological interventions. No eligible non-pharmacological studies and no studies reporting incident MCI or dementia were identified. Across protease inhibitor monotherapy; simplified ART regimens; maraviroc intensification; dolutegravir-based and/or maraviroc-based intensification; and efavirenz discontinuation, effects on cognitive outcomes were small; inconsistent; and of very low certainty evidence. CIs consistently spanned potential benefit and harm, and sample sizes were small. Reporting of functional outcomes was sparse, and no study evaluated the quality of life. This systematic review found no evidence that ART modification or intensification improves cognitive outcomes or prevents cognitive decline or dementia in adults living with HIV on ART. The absence of non-pharmacological or multidomain trials, absence of long-term outcomes, and uniformly very low certainty highlight the important research gaps. High-quality trials evaluating comprehensive behavioural, lifestyle, and psychosocial interventions are urgently required to guide evidence-based, age-inclusive brain health strategies for people living with HIV.