Background:
Cognitive impairment (CI) in people with HIV (PWH) is associated with abnormal erythrocyte indices, which may result from inflammation, disturbed iron metabolism, and other factors. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) are indices of erythrocyte volume and hemoglobinization, which help to classify anemia. Erythropoiesis requires bioavailable iron, levels of which are regulated by a complex system of peptide hormones, including the acute-phase peptide, hepcidin.
Methods:
Iron biomarkers (hepcidin, erythropoietin, ferritin, erythroferrone, total iron-binding capacity, soluble transferrin receptor) and erythrocyte indices were quantified using commercial assays in 88 virally suppressed antiretroviral therapy (ART) treated PWH. All participants underwent comprehensive cognitive testing, and their performance was summarized by T-scores. Multivariable regression analysis of cognitive performance was performed using the Akaike Information Criterion and backward selection.
Results:
Participants were mostly middle-aged (mean age 44 years), white (52.3%), and men (84.1%). Hepcidin levels were detectable (>1.0 ng/mL) in 42 (47.7%) and modified the relationship between global T-score and either age (interaction p-value=0.0072) or MCV (interaction p-value=0.0185). Stratified analyses identified that lower global T-scores were associated with older age (p=0.001) or higher MCV (p=0.0046) only when hepcidin was undetectable. A similar analysis was performed to assess interactions between anemia and iron indices in relation to global T-scores and this identified statistically significant interactions between anemia and either MCV (p=0.0119) or MCH (p=0.0127). Stratified analyses identified that lower global T-scores were associated with higher MCV (p=0.0015), and higher MCH (p=0.0026) only among anemic participants. These associations remained statistically significant after adjustment for sex, race, ethnicity, duration of HIV infection, CD4+ T-cell count and nadir, duration of ART, and HCV serostatus.
Conclusions:
These findings suggest that a combination of iron-related (hepcidin, MCH) and iron-unrelated (age, higher MCV) mechanisms influence cognitive health. While these cross-sectional results require confirmation in larger, longitudinal studies with more women, they highlight hepcidin as a potential modifying factor in associations of age and erythrocyte indices in relation to cognitive performance in PWH.