CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

better at week 48. HU and HEU cohorts were comparable. On most major outcomes, there was either little change or improvement within each cohort fromweek 0 to week 48. The magnitude of HIV cohort deficits were consistent across time, although HIV children improved less than the HEU and HU on KABC-II Planning (Story Completion, Pattern Reasoning). KABC scaled scores were worse for children with lower developmental, higher disability scores (P<0.01) and for families with social grants (P-values depend on outcome, most <0.01). They were better for children whose caregivers had completed high school (P <0.01). Conclusion: Testing at more than one time point allowed us to evaluate the consistency of deficits in neuropsychological development for HIV-affected children. Other social and environmental factors can compound these deficits. 827 PLASMA HEME OXYGENASE-1 IS ASSOCIATED WITH COGNITIVE DECLINE IN CHILDREN WITH HIV David Bearden 1 , Alexander J. Gill 2 , Paige L. Williams 3 , Dennis L. Kolson 2 , Laura Schankel 4 , Allison Agwu 5 , Russell B. Van Dyke 6 , Steven D. Douglas 4 , for the Pediatric HIV/AIDS Cohort Study (PHACS) Network and the IMPAACT 219C StudyTeam 1 Univ of Rochester, Rochester, NY, USA, 2 Univ of Pennsylvania, Philadelphia, PA, USA, 3 Harvard Univ, Boston, MA, USA, 4 Children’s Hosp of Philadelphia, Philadelphia, PA, USA, 5 The Johns Hopkins Univ, Baltimore, MD, USA, 6 Tulane Univ, Metairie, LA, USA Background: Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that has emerged as a critical effector for limiting cellular injury associated with oxidative stress and inflammation within the central nervous system (CNS) in several disease states, including HIV infection. HO-1 protein expression has been described in association with neurocognitive impairment and elevated CNS markers of immune activation in adults with HIV, but has not previously been studied in children. Methods: Data and plasma samples were taken from the IMPAACT 219C cohort and plasma HO-1 levels were measured by ELISA in two separate populations. First, samples from subjects aged 6-16 with perinatal HIV (PHIV, 74 pre-HAART and 75 post-HAART) were compared to age-matched HIV-exposed uninfected (HEU) controls (n=24). In a second 219C population, PHIV subjects with neurocognitive decline (defined as a sustained drop in full scale IQ of 15 or more points on the WISC3 or WISC4 during the period of the study) were compared to PHIV controls without decline (n=65 per group) using adjusted conditional logistic regression models to account for matching. Results: Plasma HO-1 levels were significantly elevated in PHIV subjects compared to HEU controls (mean 3.59 vs. 2.88, p=0.04). This difference was most pronounced in subjects prior to initiation of HAART (mean=3.71 vs. 2.88, p=0.01). HO-1 levels decreased after HAART initiation, and in the post-HAART group HO-1 was not significantly different than in controls (3.48 vs. 2.88, p=0.07). HO-1 levels correlated negatively with CD4 T-cell count (p = 0.04), and positively correlated with markers of macrophage activation, including sCD163 (p=0.001), sCD14 (p=0.04), and tumor necrosis factor receptor 1 and 2 (p<0.001). In the second study population, PHIV subjects in the highest quartile of HO-1 had increased risk of neurocognitive decline vs. those in the bottom three quartiles (OR 5.0, 95% CI 1.1-22.1, p=0.04). This association was significant after adjusting for age, race, sex, viral load, and CD4 count. Conclusion: These results demonstrate a significant increase in HO-1 plasma levels in HIV infection and an association between HO-1 levels and cognitive decline. Plasma HO-1 may represent a novel peripheral marker of HIV neuropathogenesis. 828 BIOMARKERS OF COGNITIVE DECLINE IN PERINATALLY INFECTED CHILDREN WITH HIV David Bearden 1 , Alexander J. Gill 2 , Paige L. Williams 3 , Dennis L. Kolson 2 , Laura Schankel 4 , Allison Agwu 5 , Russell B. Van Dyke 6 , Steven D. Douglas 4 , for the Pediatric HIV/AIDS Cohort Study (PHACS) Network and the IMPAACT 219C StudyTeam 1 Univ of Rochester, Rochester, NY, USA, 2 Univ of Pennsylvania, Philadelphia, PA, USA, 3 Harvard Univ, Boston, MA, USA, 4 Children’s Hosp of Philadelphia, Philadelphia, PA, USA, 5 The Johns Hopkins Univ, Baltimore, MD, USA, 6 Tulane Univ, Metairie, LA, USA Background: Cognitive impairment is common in children with perinatally acquired HIV (PHIV). An association between immune activation, inflammation and cognitive impairment has been described in adults with HIV but there is limited data in PHIV children. Methods: Data and plasma samples were obtained from IMPAACT 219C PHIV youth ages 6-16. 13 biomarkers of immune activation and inflammation were measured in plasma using ELISA or multiplex assays. PHIV youth with neurocognitive decline (defined as sustained drop in WISC3 or WISC4 full scale IQ ≥ 15 points during study follow-up) were compared to age-matched PHIV youth without decline (n=65 per group). Where possible, two samples were measured for each PHIV subject: one at the time of testing showing decline, and the other at the last assessment before the decline (baseline). Median interval between time points was 130 weeks (IQR 111-156 weeks.) Control samples were age-matched to both time points. Due to correlations between biomarkers, factor analysis was performed for variable reduction, and both unadjusted and adjusted linear and conditional logistic regression models were constructed to investigate associations between each factor and decline. Results: Cases and controls were well matched on age and sex, but cases were more likely to be of Hispanic race, and had lower CD4 counts and higher viral loads. In the univariate analysis, higher levels of IL-8 and interferon gamma at baseline, and higher levels of sCD163 at time of decline were significantly associated with cognitive decline, as was an increase over time in CD40 ligand, CRP, and sCD14 (all p<0.05). Heme oxygenase-1 (HO-1) was significantly associated with the outcome (p=0.04), but had a high level of uniqueness in the factor analysis and thus was analyzed separately. In the multivariable analysis, a factor at baseline characterized by Tumor Necrosis Factor Receptor 1 and 2 (TNFR1, TNFR2), and IL6 was significantly associated with cognitive decline (β=0.19, p=0.003), as was a factor at time of decline characterized by CRP, TNF-alpha, TNFR1 and TNFR2 (β=0.06, p=0.001). This association persisted in a multivariable linear regression model after adjusting for age, race, sex, viral load, and CD4 count. Conclusion: These results demonstrate a significant association between inflammatory biomarkers and cognitive decline in children with HIV. Further studies are necessary to confirm these associations and identify interventions that could reduce risk of cognitive decline. 829 MONOCYTES MAY BE ANTIVIRAL TARGETS TO LIMIT PEDIATRIC HIV-RELATED CNS MANIFESTATIONS Erica L. Johnson , Dominika Swieboda, Christina Gavegnano, Rana Chakraborty, Raymond F. Schinazi Emory Univ, Atlanta, GA, USA Background: In 2015, approximately 150,000 new HIV-1 infections occurred in children. Combination antiretroviral therapy (cART) has decreased the risk and severity of HIV-1- associated neurocognitive disorders (HAND), however, current cART regimens neither eradicate HIV-1 and rarely improve CNS manifestations, underscoring the inability of most ARVs to penetrate the CNS and mitigate pro-inflammatory events associated with viral replication . A hallmark of CNS HIV-1 infection is increased activation of mononuclear phagocytes (MPs), conferring HIV-induced inflammation. These cells are poorly characterized in neonates particularly in regard to HIV-1 susceptibility and ARV pharmacology. Methods: Cord blood was collected from 12 HIV-1 and HBV seronegative women (>18 years) at Emory Midtown and Grady Hospitals in Atlanta, GA. Peripheral blood was obtained from healthy adult donors. MPs were treated with various concentrations of AZT, 3TC, ABC, NVP, TDF, and RAL for 2 hr prior to or 6 days post infection with HIV-1BaL and maintained overtime before quantification of viral replication by HIV-1 p24, cytokine levels and cellular markers (CCR5, CD16, CD163, and HLA-DR) by FACS analysis. Data were analyzed using Student’s t-test and Mann-Whitney test. Results: Fetal monocyte-derived macrophages (MDM) were found to be more susceptible to HIV-1 than adult MDMs, and CCR5 was significantly upregulated on fetal CD14+ monocytes and MDM compared to adult subsets. CD163, a receptor that improves adherence of activated monocytes prior to CNS migration, is upregulated on fetal CD14+ compared to adults. In vitro HIV-1 infection of fetal monocytes induced further CCR5 and HLA-DR upregulation, along with CD16, which plays a role in monocyte trafficking to the brain. The overall fraction of fetal CD14+CD16+CCR5+monocytes is also upregulated by HIV-1. All ARVs inhibited acute HIV-1 infection of fetal macrophages, however the antiviral potency of AZT, 3TC and ABC was significantly (p< 0.05) decreased in the fetal MDMs compared to the adults (EC50 0.1–1.4 µM versus 0.02-0.2 µM). In chronically-infected cells, TDF exhibited potent viral inhibition (EC90 2.25 µM). The ARVs had no effect on surface expression of CCR5 or relevant activation markers in uninfected or HIV-1-infected fetal macrophages.

Poster and Themed Discussion Abstracts

CROI 2017 358