CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

491 HIV DNA and Neurocognitive Impairment in Older Subjects on Suppressive ART Michelli Faria de Oliveira 1 ; Ben Murrell 1 ; Josué Pérez-Santiago 1 ; MilenkaVargas 1 ; Ronald J. Ellis 2 ; Scott Letendre 2 ; Igor Grant 2 ; Davey M. Smith 1 ; Steven P.Woods 2 ; Sara Gianella 1 1 University of California San Diego, La Jolla, CA, US; 2 HIV Neurobehavioral Research Center, San Diego, CA, US Background: Older adults are at high risk for HIV-associated neurocognitive impairment (NCI), but the underlying neurobiological mechanisms of this heightened risk are poorly understood. Methods: This study included 18 younger (22-40 years) and 26 older (50-71 years) chronically HIV+ subjects on suppressive ART. Subjects were characterized for NC functioning by Global Deficit Score (GDS) using a standardized battery consistent with Frascati recommendations for neuroAIDS. Levels of HIV DNA were measured in PBMC by droplet digital PCR, soluble markers of monocyte and general immune activation (sCD14, sCD163, MCP-1, IL-6, IL-8, TNF-a, IP-10 and Neopterin) were measured in blood and cerebrospinal fluid (CSF) by immunoassay. Associations between GDS and other variables were evaluated by regression analysis adjusted for estimated duration of infection (EDI) and age. Mann Whitney tests were used to detect differences between groups. Results: Sixteen (36.4%) subjects had NCI (GDS ≥ 0.5). GDS was not associated with current or nadir CD4 in either age group (p>0.5). Stepwise regression with AIC model selection starting with a model containing all identified predictors of GDS retained only age group (young vs old) and HIV DNA, with a significant interaction between age group and HIV DNA (p=0.022). In the younger group, no association was found between GDS and HIV DNA levels (r=-0.08, p>0.5). For older subjects, higher levels of HIV DNA were associated with GDS (r=0.57, p=0.003), which remained significant after adjusting for EDI and age. Higher HIV DNA levels were specifically associated with deficits in executive functions among older individuals (p= 0.004), while no differences were found for other abilities in either age group. Higher levels of IL-8 in blood plasma were associated with worse GDS among older subjects after adjusting for age (p=0.04), but not for the younger subjects. No associations were found between GDS and the other markers. Conclusions: Prior studies have linked the HIV DNA reservoir size to NCI and our findings identify that this association is strongest in HIV+ adults older than 50, along with IL-8, which we have previously linked to evidence of inflammation on brain magnetic resonance spectroscopy. These findings add to emerging evidence that the correlates of NCI differ in older and younger HIV+ adults, which supports tailoring therapy based on age. In addition, our findings suggest that interventions aiming to reduce the HIV DNA reservoir may impact the central nervous system. 492 Suppressive ART Is Key to Reduce Neurocognitive Impairment in Aging HIV+ Individuals Christina C. Yek 1 ; David M. Smith 1 ; GabrielWagner 1 ; Susan Morgello 2 ; Scott Letendre 1 ; Igor Grant 1 ; Sergei L. Kosakovsky Pond 1 ; Sara Gianella 1 On behalf of the CHARTER group 1 University of California San Diego, San Diego, CA, US; 2 Icahn School of Medicine at Mount Sinai, New York, NY, US Background: Little is known about how the HIV reservoir behaves and how it affects neurocognitive function as infected individuals age. Here, we evaluate these outcomes in a cohort of aging, chronically-infected individuals. Methods: CHARTER participants who were ≥ 45 years old, reported continual antiretroviral therapy (ART) use, and had ≥ 4 years of follow-up were studied (n=36). Neurocognitive assessments and biannual plasma viral loads were measured for all subjects. Longitudinal samples were available for 28 subjects. DNA was extracted from blood using a PAXgene Blood DNA Kit. Droplet digital PCR was performed using primers for total HIV DNA ( pol ), 2-LTR circles and RPP30 (for normalization). Deep sequencing of partial envelope ( env ), gag and reverse transcriptase (RT) regions was done using a Roche 454 FLX Titanium instrument. Phylogenetic and mutational spectra analyses were performed using a HIV-specific bioinformatics pipeline. Results: Subjects were divided into suppressed (<50 copies/ml with ≤ 1 blip, blip ≤ 200copies/ml [n=15]), partially-suppressed (<50 copies/ml for >50% time points with conseuctive blips [n=12]) and non-suppressed groups (n=9). Suppressed subjects had lower HIV DNA levels (p=0.0002), 2-LTR circle copies (p=0.002) and env diversity (p=0.03) than non-suppressed subjects. In cross-sectional analysis, older age was associated with decreased HIV DNA (p=0.005), decreased env and RT diversity (p=0.05 and 0.03, respectively), and decreased frequency of drug resistance-associated mutations in RT (DRAMs) (p=0.03) in suppressed subjects. In longitudinal analysis, env diversity decreased with time (p=0.002) and HIV DNA did not change among suppressed subjects, whereas HIV DNA increased (p=0.004) with no change in env diversity among the non-suppressed. Finally, subjects with neurocognitive impairment (NCI) were more likely to be partially- or non-suppressed (p=0.04) and have no DRAMs (p=0.05). Conclusions: In a cohort of aging chronically-infected individuals, suppressive ART was associated with decreased viral reservoir size, genetic diversity and less frequent drug resistance, consistent with sustained control of HIV infection. Furthermore, we found that DRAMs correlated with better neurocognitive performance, reflecting reduced fitness and therefore neurovirulence of these viral strains. Our findings suggest that continual suppressive therapy is necessary to control viral replication and reduce the incidence of HIV- associated neurocognitive disease in older individuals. 493 Mixed Membership Trajectory Model of Cognitive Impairment in the MACS Samantha A. Molsberry 1 ; Fabrizio Lecci 2 ; Brian Junker 2 ; Sandra Reynolds 3 ; Andrew Levine 4 ; Eileen Martin 5 ; Cynthia A. Munro 6 ; Ned Sacktor 6 ; JamesT. Becker 1 ; NeuropyschologyWorking Group O. Multicenter AIDS Cohort Study 7 1 University of Pittsburgh, Boston, MA, US; 2 Carnegie Mellon University, Pittsburgh, PA, US; 3 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US; 4 University of California Los Angeles, Los Angeles, CA, US; 5 Rush University Medical Center, Chicago, IL, US; 6 Johns Hopkins University School of Medicine, Baltimore, MD, US; 7 National Institutes of Health (NIH), Bethesda, MD, US Background: In spite of known risk factors for cognitive impairment in HIV Disease, the trajectories that individuals may take from a state of normal cognition to HIV-associated dementia are unknown. We applied a novel statistical methodology to identify: trajectories to cognitive impairment, and factors that affected the “closeness” of an individual to one of the canonical trajectories Methods: The Multicenter AIDS Cohort Study (MACS) is a four-site longitudinal study of the natural and treated history of HIV Disease among gay and bisexual men. Using data from 3,892 men (both HIV-infected and uninfected) enrolled in the neuropsychology substudy of the MACS, a Mixed Membership Trajectory Model (MMTM) was applied to capture the pathways from normal cognitive function to mild impairment to severe impairment. MMTMs allow the data to identify canonical pathways and to model the effects of risk factors on an individual’s “closeness” to these trajectories. Results: We identified three canonical trajectories - a “normal aging” profile with relatively low probability of even mild impairment until well into middle age (60% of sample), a “premature aging” profile with a probability of mild impairment climbing at age 45-50 (21% of sample); and, an “unhealthy” profile with a high probability of mild impairment even at a very young age (19% of sample). The premature aging profile was characterized as including men who were from the original study cohort (1984-1991), had HIV Disease and had AIDS, with 11%with HCV infection. The unhealthy profile was characterized by men from the latest enrollment cohort (2001-2003), HCV infection, and other medical confounds. We tested the effects of seven time invariant predictors on the “closeness” of individuals to each of these profiles. HCV infection, HIV, AIDS, recruitment cohort, confounding conditions, depression, and the interaction between cohort and race have a significant effect on the closeness of individuals to these profiles.

Poster Abstracts

329

CROI 2015