CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

595

Epigenetic Age Advancement Is Associated With Cognition, Frailty, and Mortality in Older PWH Carrie Johnston , Alina P. Pang, Eugenia Siegler, Chelsie Burchett, Charlene Thomas, Mia Crowley, Rochelle O'Brien, Lishomwa Ndhlovu, Marshall Glesby, Michael J. Corley Weill Cornell Medicine, New York, NY, USA Background: DNA methylation (DNAm) patterns indicate a trend towards epigenetic age advancement in older persons with HIV (OPWH), however, data on relationships with phenotypic changes are limited. We investigated associations between phenotypic measures of cognition, frailty, and 7-year survival with epigenetic age estimates derived from the modification of DNAm in a population of OPWH. Methods: OPWH aged 50 and older in clinical care for HIV management at Weill Cornell in NYC, were recruited to participate in a detailed biopsychosocial survey, and those age 55 and older were invited to complete an in-person study visit which included blood draw, Montreal Cognitive Assessment (MoCA) and Fried frailty phenotype testing. Genome-wide DNAm was measured from dried blood spots using the Illumina MethylationEPIC platform and analyzed using PhenoAge epigenetic age. Results: A total of 164 participants enrolled in the study; 158 had available biospecimens for DNAm analysis. Median age was 60 years (IQR 56-64), 52 (33%) identified as female, and 76 (50%) identified as Black, median CD4 T-cell count was 588 cells/mmˆ3 (IQR: 323-811) and 93% were virally suppressed on ART. Epigenetic age analysis indicated an average epigenetic "age advancement" (EAA) of 5.4 years (SD 6.6). Median MoCA score was 24 (21-27) and 67% were pre-frail or frail. There were 17 deaths (10.7% mortality rate) from September 2016-September 2023. EAA was inversely related to chronologic age (ß= -0.31 [95%CI: -0.48, -0.14] (p<0.01)) and was associated with lower CD4 T-cell count (ß= -0.84 [95% CI: -1.14, -0.53] for every 100 CD4+ T-cells (p<0.01)) in an unadjusted linear regression model. EAA was associated with lower MoCA score in a linear regression model adjusted for age, sex and race (p<0.01), and there was a trend towards EAA association with more advanced frailty state in an ordinal logistic regression model adjusted for age, sex and race (p=0.07). Survival differed by EAA, and greater advancement was associated with 7-year mortality in a Cox Proportional Hazard model adjusted for age (HR 1.10 [95%CI: 1.02, 1.18] p=0.01) (Figure 1). Conclusion: In OPWH the average EAA was 5.4 years, as calculated by PhenoAge, and was associated with cognitive dysfunction, more advanced frailty state, as well as 7-year mortality. These results suggest epigenetic clocks are a valuable biomarker of aging-related pathologies in OPWH and warrant further study.

depressive symptoms (BPSP2), mild-to-moderate NCI with severe depressive symptoms and IADL dependence (BPSP3), and mild-to-moderate NCI without depressive symptoms or IADL dependence (BPSP4). Proteins were quantified by the Olink Target-96 Inflammation panel. Linear regression of normalized protein expression values analyzed group differences. Benjamini-Hochberg adjusted alpha was 0.003. Proteins with p<0.10 were next analyzed by multivariable regression adjusting for demographic, disease, and treatment characteristics. Classification accuracy was assessed by discriminant analysis. Results: Cohort characteristics: mean age 45.0 years, 22.8% women, 51.5% Black, median CD4+ T-cells 480/µL, median duration: HIV 10.6 years, ART 5.7 years. An example volcano plot is shown in the Figure A. Across all dimensions, the most frequently associated proteins were CD8 antigen, IL-12B, IL-17C, FGF-21, FGF-23, and TGF-α. Adjusted multivariable models with R2>0.15 were found for global NCI, motor impairment, BDI-II somatic subscale, and all BPSPs (Table B). Among all dimensions, discriminant analysis correctly classified >75% of participants in only BPSP3 and BPSP4. The BPSP3 model included CCL19 and DNER and the BPSP4 model included CD8 antigen, IL-33, CCL3, TNFSF11, and stem cell factor. Conclusion: Data-driven, cross-sectional analyses identified plasma proteins associated with multiple neuropsychiatric dimensions. While the results reinforce the complexity of neuropsychiatric disorders, novel, biologically plausible targets were identified for validation and future investigation. The BPSPs generally performed better in analyses, suggesting that they may be more inflammation-driven than other dimensions. The focus on inflammation is a limitation; future analyses that include other proteins (e.g., neuronal) should provide additional insights. The figure, table, or graphic for this abstract has been removed. Clinical Profiles Predicting Cognitive Decline Over 10 Years Among Older Adults With HIV in Canada Marie-Josée Brouillette 1 , Marianne Harris 2 , graham Smith 3 , Réjean Thomas 4 , Shariq Haider 5 , Scott L. Letendre 6 , Lesley K. Fellows 1 , Nancy E. Mayo 1 1 McGill University, Montreal, Canada, 2 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada, 3 Maple Leaf Medical Clinic, Toronto, Canada, 4 Clinique Médicale l'Actuel, Montreal, Canada, 5 McMaster University, Hamilton, Canada, 6 University of California San Diego, San Diego, CA, USA Background: Correlates of cognitive impairment in older adults with HIV (OAWH) have been identified cross-sectionally, but much less is known about the clinical profiles predicting cognitive decline over several years among ART treated OAWH. Methods: The Positive Brain Health Now cohort included 856 individuals (mean age 53 years) from 5 HIV clinics in Canada between 2013-2016. Comprehensive cognitive and biopsychosocial characterization was conducted every 9-12 months for up to 10 years. Global cognitive ability was measured with the B-CAM, a computerized battery assessing cognitive domains known to be impacted by HIV and optimized to detect change. A longitudinal analysis was carried out on participants with ≥ 5 years of follow-up (n=229, 85% men). Group-based trajectory analysis was applied to centered B-CAM scores to identify distinct groups of individuals with a similar evolution over time. Recursive partitioning was used to identify profiles of participants with a declining trajectory. Results: The sample was educated (70.5% post high-school education), predominantly aviremic (92.4%), had a mean B-CAM at baseline of 57.3/100 (SD: 13.8) and were followed for up to 9.3 years. Three trajectories of cognition emerged: 38.9% flat; 28.8% inverse U shaped; and 32.3% declining. The highest probably of decline was observed with a current CD4 count < 255 cells/μl (n=13, risk 77%). With CD4 count ≥ 255 cells/μl, a high probability of decline (59%) was observed with HDL cholesterol < 1.2 mmol/L plus a HADS-A ≥ 3.0 plus FIB-4 ≥ 1.5. Profiles of participants with lowest probability (18%) of being in the declining group included those with CD4 count ≥ 255 cells/μl, HDL cholesterol ≥ 1.2 mmol/L and HADS-A < 3.0 (very low anxiety). Some factors showed evidence of protection only when combined with others, e.g. CD4/CD8 ≥ 0.73 was protective only when combined with CD4 count ≥ 255 cells/μl. Conclusion: In this cohort of primarily male, ART-treated OALH, cognition declined over 10 years in about one in three participants, who were characterized by low immune function, higher cardiovascular disease risk, and liver fibrosis. Recursive partitioning supported the identification of the interaction of several factors associated with cognitive decline. Early detection and optimal treatment of HIV and interventions to preserve vascular health could potentially prevent cognitive decline. Replication is required in a different sample.

Poster Abstracts

597

596

Plasma Proteomics Identifies Variable Patterns of Association With Neuropsychiatric Dimensions Patricia K Riggs , Ronald J. Ellis, Bin Tang, Jennifer E. Iudicello, Mattia Trunfio, Donald Franklin, Michael Potter, Melanie Crescini, Sara Gianella Weibel, Robert K. Heaton, Scott L. Letendre University of California San Diego, San Diego, CA, USA Background: People with HIV (PWH) can suffer from neuropsychiatric conditions that have complex etiologies. We investigated the plasma proteome in 206 virally suppressed PWH on antiretroviral therapy (ART) and compared the results to multiple dimensions of a comprehensive neuropsychiatric assessment. Methods: Neuropsychiatric dimensions included global and domain-specific neurocognitive impairment (NCI), Beck Depression Inventory (BDI)-II and subscales, and instrumental activities of daily living (IADL) dependence. Based on these and other data, 4 biopsychosocial phenotypes (BPSPs) were previously derived by machine learning analysis: healthy (BPSP1), mild NCI with moderate

CROI 2024 165