| Publication Abstract Display | | Type: Poster | | Title: Suppressive ART is key to reduce neurocognitive impairment in aging HIV+ individuals. | | Authors: Yek C, Smith DM, Wagner GA, Morgello S, Letendre S, Grant I, Kosakovsky Pond SL, Gianella S, the CHARTER Study Group | | Date: 02-23-2015 | | Abstract: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 consecutive 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. |
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