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High Plasma Soluble CD163 During Infancy Is a Marker for Neurocognitive Outcomes in Early-Treated HIV-Infected Children

Benki-Nugent, Sarah F., MS, PhDa; Martopullo, Ira, MPHb; Laboso, Tony, BAc; Tamasha, Nancy, BAc; Wamalwa, Dalton C., MBChB, MMed, MPHc; Tapia, Kenneth, MSa; Langat, Agnes, MBChB, MMed, MPHc,d; Maleche-Obimbo, Elizabeth, MBChB, MMed, MPHc; Marra, Christina M., MDe; Bangirana, Paul, PhDf; Boivin, Michael J., PhD, MPHg; John-Stewart, Grace C., MD, PhD, MPHh

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1, 2019 - Volume 81 - Issue 1 - p 102–109
doi: 10.1097/QAI.0000000000001979
Clinical Science
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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.

Departments of aGlobal Health; and

bEpidemiology, University of Washington, Seattle, WA;

cDepartment of Pediatrics & Child Health, University of Nairobi, Nairobi, Kenya;

dCurrently, Centers for Disease Control Kenya, Nairobi, Kenya;

eDepartment of Neurology, University of Washington, Seattle, WA;

fDepartment of Psychiatry, Makerere University, Kampala, Uganda;

gDepartment of Psychiatry, Michigan State University, East Lansing, MI; and

hDepartments of Global Health, Medicine, Epidemiology and Pediatrics, University of Washington, Seattle, WA.

Correspondence to: Sarah F. Benki-Nugent, MS, PhD, Department of Global Health, University of Washington, 325 9th Avenue, Box 359909, Seattle, WA 98104 (e-mail: benki@uw.edu).

Supported by the National Institute of Neurological Disorders and Stroke (K01 NS080637 to S.F.B.-N.) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (R01 HD023412 to G.C.J.-S.). S.F.B.-N. was supported by the University of Washington International and Biometrics Cores of the Center for AIDS Research (CFAR), an National Institutes of Health (NIH) funded program (P30 AI027757), supported by the following NIH Institutes and Centers: National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute; National Institute of Mental Health; National Institute on Drug Abuse; NICHD; National Heart, Lung, and Blood Institute; and National Center for Complementary and Alternative Medicine. Field site and biostatistical support were also provided by CFAR. G.C.J.-S. was supported by the NIH (K24 HD054314). REDCap at the Institute of Translational Health Science (ITHS) was supported by National Center for Research Resources/NIH (UL1 RR025014).

Presented at the Eighth International Workshop on HIV Pediatrics; July 15–16, 2016; Durban, South Africa.

The authors have no conflicts of interest to disclose.

S.F.B.-N. led and conceived the study, and performed and led analysis and manuscript writing. I.M. performed laboratory assays, conducted analysis, and drafted the manuscript. T.L. and N.T. performed neurocognitive assessments, D.C.W. led the field site, established the clinical trial cohort, and contributed to study design, K.T. provided statistical oversight, A.L. coordinated the clinical trial, contributed to study design, and led collection of neurodevelopmental data, E.M.-O. contributed to study design, C.M.M. contributed to study design and immune marker studies, P.B. and M.J.B. contributed to study design and provided oversight over neurocognitive assessments, and G.C.J.-S. conceived and led the initial clinical trial and contributed to study design for the neurodevelopmental study. All authors contributed to writing or critical review of the manuscript and provided final approval of the version to be published.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

S.F.B.-N. and I.M. are cofirst authors.

Received September 05, 2018

Accepted January 03, 2019

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