Antiretroviral regimen central nervous penetration, viral control, and age of attainment of developmental milestones in early treated HIV-infected infants

Abstract

Background: Pediatric HIV is associated with an increased risk of neurodevelopmental deficits. We hypothesized that lower cumulative viral load following early antiretroviral treatment (ART), and the use of central nervous system (CNS) penetrating antiretrovirals would improve delays in developmental milestone achievement. Methods: We conducted a secondary data analysis of a randomized clinical trial of HIV-infected children [Optimizing Pediatric HIV-1 Therapy 03 (OPH03) NCT00428116]. Infants initiated ART and were prospectively followed with 6-monthly CD4 counts, 3-monthly viral loads and monthly assessments of developmental milestone attainment. Viremia copy years were calculated for time periods: 1) up to the earliest age of milestone attainment, 2) at 6 months of age, 3) at 6 months post-ART and 4) up to the earliest age of milestone attainment for milestones attained in the second year of life while adjusting for viremia copy-years in the first year of life. The CNS penetration effectiveness (CPE) score of initial ART regimen was calculated after adjusting for baseline resistance. Linear regression analysis was used to evaluate the association of viremia copy-years and CPE score of initial ART regimen and age of developmental milestone attainment, adjusting for potential confounders. Logistic regression analysis was used to evaluate the association between viremia copy-years and developmental delay, adjusting for potential confounders. Results: Among 80 infants initiating ART, median age was 3.7 months [IQR: 2.95, 4.06], 53% were female, baseline median CD4% was 18% [IQR: 14%, 24%], and baseline viral load was 6.58 log10 copies/ml [IQR: 5.98, 7.14]. Median WAZ was -2.35 [IQR: -3.66, -0.93] and HAZ was -1.96 [IQR -3.16, -0.91]. Forty-five (56%) of infants initiated nevirapine-based ART. Mean age in months of sitting unsupported, walking unsupported, monosyllabic speech, and pointing/naming objects and pictures were 7.24 (SD 1.34), 16.64 (SD 3.28), 17.12 (SD 3.06), and 22.78 (SD 4.53), respectively. Median adjusted CPE score of initial ART regimen was 9 [IQR: 9, 10]. There was no association between viremia copy-years and age of developmental milestone attainment using any of the defined methods of copy-year estimation. Higher CPE regimens were associated with earlier supported and unsupported walking in univariate analyses (p=0.044 and 0.061), respectively, but these associations were not significant in analyses adjusted for WAZ. Conclusions: Viremia copy-years (which included time before and after ART) was not associated with developmental milestone attainment while antiretroviral CPE was associated with earlier walking, suggesting that antiretroviral CSF penetration may be relevant in neurodevelopment. Larger studies are needed to evaluate this association.