CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

837 LONGITUDINAL STUDY OF NEUROCOGNITIVE DISORDERS AND BRAIN STRUCTURE IN ADOLESCENT HIV Jackie Hoare 1 , Landon Myer 1 , Sarah Heany 1 , Jean-Paul Fouche 1 , Nicole Phillips 1 , Heather Zar 1 , Dan Stein 1 1 University of Cape Town, Cape Town, South Africa Background: Neurocognitive disorders (NCD) despite ART are well known in perinatally-infected HIV+ adolescents (PHIV) but there are few data on longitudinal changes in NCD and brain structure in PHIV over time. Methods: Within this sub-study of the Cape Town Adolescent Antiretroviral Cohort, PHIV on ART >6m completed baseline and 3-year follow-up assessments including a comprehensive neurocognitive battery assessing function in 10 domains. We applied the youth HIV-associated NCD diagnostic criteriato classify each as having either a major NCD, a minor NCD, or no impairment. Diffusion tensor imaging and structural brain magnetic resonance imaging was done to determine fractional anisotropy (FA), mean diffusivity (MD), grey and white matter volumes, cortical thickness and cortical surface area. In analysis we examined changes over the 3-year period in NCD and neurostructural measures in PHIV compared to age- and sex-matched HIV- controls. Results: Overall 122 PHIV ages 9-12 years (mean CD4 cell count 953 cells/µL and 85.3% VL<50 copies/mL) and 37 age-matched HIV- controls completed baseline and 3-year follow-up assessments. 48% PHIV had a NCD at baseline and 60% at follow-up: NCD diagnosis was stable over time in 60 (49%) of participants, 22 (18%) improved NCD status and 40 (33%) deteriorated. At baseline, PHIV with major NCD showed the highest whole brain MD (p=.007); at follow-up whole brain grey (p=.004) and white matter volumes (p=.032) were lowest in PHIV, with whole brain MD remaining highest in PHIV with a major NCD (p=.02). Higher MD is suggestive of inflammation and myelin loss. In addition significant regional brain changes were observed at follow-up compared to baseline in PHIV vs controls. Structural changes over time were observed mainly in cortical surface area of the bilateral orbitofrontal, anterior cingulate, medial orbitofrontal, middle frontal, superior temporal, transverse temporal gyri and insula (all p<.05). White matter microstructural changes over time were observed in the internal capsule, cerebral peduncle and the cingulum (all p<.05). Conclusion: NCD and brain structural alterations in PHIV increased over the 3 years of follow-up compared to HIV- controls. Studying the participants who improved vs deteriorated over time may provide insight into future interventions for NCD in PHIV. 838 BRAIN DEVELOPMENT IN TREATED PERINATAL HIV: A LONGITUDINAL NEUROIMAGING STUDY Malon Van den Hof 1 , Pien Jellema 1 , Anne Marleen Ter Haar 1 , Henriëtte J. Scherpbier 1 , Anouk Schrantee 2 , Antonia Kaiser 2 , Matthan W. Caan 2 , Peter Reiss 3 , Ferdinand Wit 3 , Henk-Jan M. Mutsaerts 2 , Dasja Pajkrt 4 1 Emma Children's Hospital/Academic Medical Center, Amsterdam, Netherlands, 2 Academic Medical Center, Amsterdam, Netherlands, 3 Stichting HIV Monitoring, Amsterdam, Netherlands, 4 Emma Children's Hospital/Academic Medical Center, Amsterdam, Netherlands Background: Cross-sectional studies, including our NOVICE study (Neurological Visual and Cognitive performance in treated perinatally HIV-infected [PHIV] children compared to age-, sex-, ethnicity- and socioeconomic status [SES]- matched HIV-uninfected controls), have reported lower white matter (WM) and grey matter (GM) volumes, higher WM hyperintensity (WMH) volume and poorer WM integrity measures in treated PHIV children. It is however unknown whether these differences originated before treatment initiation, or may be progressive over time. This longitudinal study compares the rates of change over time. Methods: We approached all NOVICE participants, to repeat 3T magnetic resonance imaging (MRI) at the Amsterdam University Medical Centers, the Netherlands, after a mean of 4.6±0.3 years. We repeated GM and WM volume, WMH volume and WM integrity measures (total fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]), obtained by T1-weighted-, FLAIR and DTI MRI, respectively. We compared rates of change between groups using multivariable linear mixed effects models, adjusted for sex and age at first MRI, and we investigated disease- and treatment related factors as determinants of poorer outcomes.¬ Results: 20 out of 31(65%) PHIV and 20 out of 37(54%) controls completed a second MRI examination. Those who gave consent for follow-up MRI were not statistically different compared to those who did not gave consent in volumetric outcomes and FA at first MRI (all p-values>0.05). Those who completed two

MRI examinations had a mean age of 13.0±3.1 years and 17.6±3.1 years at first and second MRI, respectively. PHIV and controls were not statistically different in age, sex, ethnicity, and SES (all p-values>0.05). At p<0.1, WMH volume increased significantly more in PHIV participants (group*time 0.10mL, 95%CI 0.02–0.18, p=0.017) compared to controls (figure 1), which was not associated with disease- and treatment related factors (all p-values>0.05). GM volume decreased significantly less in PHIV (group*time 0.010L, 95% CI -0.001–0.020, p=0.078). We found no statistically different changes over time in WM volume (group*time 0.001, 95%CI -0.006–0.008, p=0.795), nor in WM integrity measures (group*time p-values>0.356). Conclusion: Results indicate progressive cerebral differences as WMH progress over time in long-term cART-treated PHIV adolescents. Future analyses should further investigate determinants of WMH progression.

Poster Abstracts

839 IDENTIFICATION OF AGE-APPROPRIATE DOSING STRATEGIES OF BICTEGRAVIR IN NEONATES Fazila S. Bunglawala 1 , Rajith Kumar Reddy Rajoli 1 , Hannah Kinvig 1 , Nicolas Cottura 1 , Andrew Owen 1 , Marco Siccardi 1 1 University of Liverpool, Liverpool, UK Background: Paediatric patients differ from older patients in terms of drug metabolism and disposition, which necessitates evaluation of age-appropriate dosing strategies. Historically, this has complicated drug development resulting in fewer treatment options for neonates. PBPK modelling can be employed in early drug development to help inform selection of appropriate medicines at appropriate doses for paediatric patients. Bictegravir (BIC) is a HIV-1 integrase inhibitor that elicits a potent virological response and has potential for treatment and prophylaxis within neonatal populations. The safety and pharmacokinetics (PK) of BIC have previously been studied in children older than 6 years and adolescents but not neonates. The aim of this study was to use PBPK modelling to inform identification of an age-appropriate dose within this population. Methods: A whole-body PBPK model was constructed in Simbiology (MATLAB 2018b) using neonatal physiological and anatomical descriptors. Neonatal PK simulations also utilised published experimental in vitro data for BIC. The ontogenies of key metabolic enzymes such as CYP3A4 and UGT1A1 were refined and validated using observed neonatal clinical data for raltegravir (RAL) and midazolam (MDZ). Published adult PK data for BIC were used to partially validate the simulated parameters, where the model was assumed to be qualified if simulated values were within 0.5 -1.5-fold of the mean reported values as per modelling convention. Results: All models were acceptably qualified with RAL, MDZ and BIC exhibiting absolute average fold errors of 1.05, 1.31 and 1.12, respectively. Several multi-dose regimens for orally administered BIC were simulated in 100 healthy neonates with the aim of achieving equivalent plasma concentrations to therapeutic exposures observed in adults (C trough : 2.61 mg/L and AUC24: 102 mg.h/L). These regimens and their resulting PK parameters are summarised in Table 1. Regimens 2 & 3 resulted in exposures comparable to that observed in

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