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Background: Monocyte activation may contribute to neuronal injury in aviremic HIV-infected adults; data are lacking in children. We examined the relation between monocyte activation markers and early and long-term neurodevelopmental outcomes in early-treated HIV-infected children. Setting: Prospective study of infant and child neurodevelopmental outcomes nested within a randomized clinical trial (NCT00428116) and extended cohort study in Kenya. Methods: HIV-infected infants (N = 67) initiated antiretroviral therapy (ART) at age <5 months. Plasma soluble (s) CD163 (sCD163), sCD14, and neopterin were measured before ART (entry) and 6 months later. Milestone attainment was ascertained monthly during 24 months, and neuropsychological tests were performed at 5.8-8.2 years after initiation of ART (N = 27). The relationship between neurodevelopment and sCD163, sCD14, and neopterin at entry and 6 months after ART was assessed using Cox proportional hazards models and linear regression. Results: Infants with high entry sCD163 had unexpected earlier attainment of supported sitting (5 vs 6 months; P = 0.006) and supported walking (10 vs 12 months; P = 0.02) with trends in adjusted analysis. Infants with high 6-month post-ART sCD163 attained speech later (17 vs 15 months; P = 0.006; adjusted hazard ratio, 0.47; P = 0.02), threw toys later (18 vs 17 months; P = 0.01; adjusted hazard ratio, 0.53; P = 0.04), and at median 6.8 years after ART, had worse neuropsychological test scores (adj. mean Z-score differences, cognition, -0.42; P = 0.07; short-term memory, -0.52; P = 0.08; nonverbal test performance, -0.39, P = 0.05). Conclusions: Before ART, monocyte activation may reflect transient neuroprotective mechanisms in infants. After ART and viral suppression, monocyte activation may predict worse short- and long-term neurodevelopment outcomes. [ABSTRACT FROM AUTHOR]