CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: Longitudinal assessment of DASB binding in the SIV infected animals by PET suggests SERT upregulation in these animals. Increased DASB binding positively correlated with the duration of infection but did not correlate with VL or CSF cytokine levels. Upregulated SERT leading to lower synaptic levels of serotonin is a possible mechanism of depression in HIV+ patients and should be further evaluated.

decrease in sCD14 (p=0.008), and increases in IFABP and TNF-RI levels (p=0.05, 0.03). Cellular flowmarkers showed increase in naïve CD4 and CD8 T cells (HLA- DR-CD38+), suggesting active T cell proliferation (p=0.02, 0.05). Conclusion: This switch study observed a decrease in CNS oxidative stress with lowering of GSH levels, and changes in GABA, Asp, Glu consistent with improved neuronal function. These CNS changes were associated with less systemic inflammation. Together these data suggest EFV exert CNS toxicity partially through oxidative and inflammatory pathways. The correlation of improved NP performances with neurometabolite changes provides insight into possible cellular mechanisms of EFV neurotoxicity.

Poster Abstracts

428 CHANGES IN BRAIN VOLUME AND COGNITION IN MICE EXPOSED IN UTERO TO ABC/ 3TC-ATV/ RTV Kayode Balogun 1 , Monica Guzman Lenis 1 , Lindsay Cahill 2 , Howard Mount 3 , John Sled 3 , Lena Serghides 1 1 University Health Network, Toronto, ON, Canada, 2 The Hospital for Sick Children, Toronto, ON, Canada, 3 University of Toronto, Toronto, ON, Canada Background: Combination antiretroviral therapy (cART) has facilitated the radical reduction of perinatal transmission of HIV. However, there are concerns about the effects of cART on fetal development and long-term health outcomes of the offspring. Studies have reported several adverse neurological outcomes in HIV-exposed uninfected children. Our objective was to investigate the impact of in utero exposure to cART on infant brain development and cognitive behavior using advanced imaging techniques and well-validated behavioral testing methods in a mouse pregnancy model. Methods: Gravid C57BL/6 mice were exposed to human-relevant plasma concentration of Abacavir (ABC)/Lamivudine (3TC)-atazanavir (ATV)/ritonavir (RTV) or water (control) starting from gestational day (GD) 1 to delivery. At GD 16, mice were euthanized; fetal weights were recorded and fetal morphology was assessed using micro-CT. A subset of the pregnant mice was allowed to carry to term and pups were accessed for developmental milestones (motor, tactile, auditory, and olfactory reflexes) from postnatal day 1-21. Postweaning, all mice were subjected to the novel object recognition test to assess non-spatial learning and memory. Alterations in brain regional volumes were assessed by magnetic resonance imaging. Results: Fetuses exposed to cART were smaller than the controls [mean (SD); 0.32g (0.09) vs. 0.41g (0.06); P=0.007] and continued to remain smaller until sacrifice at 8 months after birth [mean (SD); 27.95g (1.78) vs. 30.95g (1.87) P=0.00025]. Micro-CT imaging showed significant volumetric changes in different regions of the fetal brains including a significant 7% decrease in the volume of the neocortex and amygdala (P<0.05) and a 7% increase in the hypothalamus in the cART-exposed group compared to controls (P<0.05); similar changes were observed in the adult brains by MRI at 8 months. The development of motor skills, tactile and olfactory reflexes were delayed in the cART-exposed offspring compared to controls (P<0.01). The cART-exposed mice had lower memory indices (MI) compared to controls (P<0.0001), and there was a positive correlation between MI vs. hippocampus CA1 and CA2 (r=0.68, P<0.0001), and MI vs. cingulate cortex (r=0.4, P=0.024). Conclusion: Our data suggest that the in utero exposure to ABC/ 3TC-ATV/ RTV is associated with volumetric changes in key regions of the brain, developmental delays and cognitive deficits in a mouse model of pregnancy.

427 IMMUNOLOGICAL AND NEUROMETABOLITE CHANGES ASSOCIATED WITH SWITCH FROM EFV TO AN INSTI Nina Lin 1 , Yvonne Robles 2 , Alan Landay 3 , Tyler Starr 2 , Jennifer Kinslow 3 , Joshua Ladner 2 , Rebeca M. Plank 2 , Laura F. White 1 , Kathy Melbourne 4 , Alexander Lin 2 , Daniel R. Kuritzkes 2 1 Boston University, Boston, MA, USA, 2 Brigham and Women’s Hospital, Boston, MA, USA, 3 Rush University Medical Center, Chicago, IL, USA, 4 Gilead Sciences, Inc, Foster City, CA, USA Background: The mechanisms by which efavirenz (EFV) causes central nervous system (CNS) adverse effects are unclear, but clinically pertinent given the persistent widespread use of EFV globally. We conducted an EFV switch study using magnetic resonance spectroscopy (MRS) to assess changes in specific neurometabolites on brain function, inflammation and oxidative stress. Methods: 20 HIV-infected adults on EFV+FTC/TDF without overt CNS adverse effects were enrolled into two parallel single-arm switch studies. Participants were switched to either EVG/COBI/FTC/TDF or RAL+FTC/TDF for 8 weeks. Neurometabolites were measured by MRS using single voxel spin echo and spectroscopy. Neuropsychological (NP) assessments were performed: 1) affective symptoms (HAMD, DASS-21, STAI), 2) global brain function (WAIS-R and FRSBE), and 3) sleep quality (PSQI). Cellular (HLA-DR and CD38) and peripheral immunological markers (sCD14, IP-10, sCD163, MCP-1, IL-6, IFABP) were correlated with MRS changes. Pre- and post-EFV measures were evaluated using Wilcoxon matched-paired test. Results: In paired analyses glutathione (GSH) was decreased (p=0.03), suggesting reduced CNS oxidative stress, while gamma-aminobutyric acid (GABA) levels was increased (p=0.03) following EFV switch. Levels of glutamate (Glu) and aspartate (Asp), neurotransmitters associated with neuronal excitability, were significantly decreased (p=0.04, 0.001) and indicates reduced neurotoxicity. CNS function (attention, memory, spatial skills) tested by WAIS-R (p=0.0002) improved. FRSBE index decreased, suggesting improved executive function and processing (p=.0037). Measures of depression, anxiety and stress (HAMD, DASS and STAI) (p=0.002, =0.01, =0.003, respectively), and sleep quality (PSQI) all improved (p=0.0005). Switch from EFV was associated with a

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