Systemic monocyte activation levels and developmental milestone attainment in HIV-infected infants initiating antiretroviral therapy

Background: Peripheral monocyte activation has been associated with poor neurocognitive outcomes in HIV-infected adults. We hypothesized that HIV infected infants with persistent systemic monocyte activation following antiretroviral treatment (ART) would have later attainment of developmental milestones. Materials and Methods: HIV infected infants initiated ART at age <5 months as part of the Optimizing Pediatric HIV-1 Therapy Study (OPH03) (NCT00428116). Plasma soluble CD14 (sCD14), soluble CD163 (sCD163) and neopterin concentrations were measured using enzyme-linked immunosorbent assays pre-ART and at 6 months post-ART. Concentrations were dichotomized based on published studies with thresholds of 3,800ng/ml for sCD14, 1,100 ng/ml for sCD163, and 7.9ng/ml for neopterin. Ages of milestone attainment were reported by caregivers at serial monthly follow-up visits. Paired t-tests and linear regression models were used to compare age of milestone attainment between infants with high versus low biomarker levels, at entry and at 6-months. Results: Among 69 infants, median age at enrollment was 3.8 months. Pre-ART median plasma HIV RNA level was 6.55 log10 copies/ml, median CD4% was 18%, and median WAZ was -2.20. Mean sCD14 was 3,421ng/ml, sCD163: 1,385ng/ml and neopterin: 11.7ng/ml. At 6-months post-ART, sCD14 increased (mean, 4,114ng/ml; p=0.08); sCD163 decreased (mean 1,088; p<0.001), and neopterin decreased (mean 7.01; p=0.04). At baseline, high sCD14 was associated with plasma HIV RNA (p=0.02) and high neopterin with lower CD4% (p=0.003). Infants with higher baseline sCD163 achieved earlier sitting (1.1 months earlier [95% confidence interval (CI) 0.3, 2.0 months); p=0.009], but had no differences in age at walking or speech. Infants with elevated sCD163 following 6 months ART had later speech (2 months later, p=0.03)], and this difference was more pronounced among the subset of infants with viral suppression [3.4 months later; 95% CI, 0.9, 5.9 months; p=0.01]. sCD14 and neopterin levels at baseline or 6-months were not associated with timing of milestone attainment. Conclusion: sCD163 levels were significantly associated with timing of milestone attainment. Prior to ART, elevated sCD163 was associated with earlier milestones and may reflect potentially beneficial immune activation in the absence of ART. Elevated sCD163 in the setting of viral suppression on ART had the opposite effect on milestone attainment – perhaps reflecting potentially deleterious persistent immune activation.