Hepcidin modifies the relationship between anemia, erythrocyte indices, and neurocognitive performance in virally suppressed people with HIV.

OBJECTIVE: Neurocognitive impairment in people with HIV (PWH) is associated with erythrocyte indices, which may serve as indicators of iron metabolism, inflammation, and related factors. Erythropoiesis requires iron, regulated by a multifaceted system of peptide hormones, including hepcidin. This study postulated that hepcidin might modify the relationship between erythrocyte indices and neurocognitive performance in PWH. METHODS: Plasma hepcidin and erythrocyte indices were quantified in 88 virally suppressed PWH who underwent comprehensive neurocognitive assessments. Global neurocognitive performance was summarized by global T -scores. Associations of global T -scores with anemia and erythrocyte indices were determined in univariable analyses. To examine the influence of hepcidin on the relationship between neurocognitive performance and erythrocyte indices, we evaluated interactions between these covariates in relation to global T -scores and then performed stratified analyses. RESULTS: In multivariable analyses, hepcidin detectability interacted with age ( P  = 0.007) and mean corpuscular volume (MCV; P  = 0.031) in relation to the global T -score. Interactions between anemia and erythrocyte indices on global T -scores were significant (anemia × MCV, P  = 0.008; anemia × MCH, P  = 0.011). Stratified analyses identified that lower global T -scores were associated with older age ( P  = 0.001) and higher MCV ( P  = 0.0046) and mean corpuscular hemoglobin (MCH, P  = 0.026) only when hepcidin was undetectable. Among the anemic, worse global T -score was associated with higher MCV ( P  = 0.001) and MCH ( P  = 0.002). CONCLUSION: Findings suggest that iron-related factors (hepcidin, anemia, MCV, MCH) and age influence neurocognitive health. This cross-sectional study underscores hepcidin as an effect modifier in the associations of erythrocyte indices, anemia, and age with neurocognitive function in PWH.