Higher HDL, better brain Higher HDL, better brain? Higher HDL cholesterol is associated with better cognition in a cohort of older persons living with HIV infection Akintomiwa Makanjuola1, Kunling Wu2, Katherine Tassiopoulos2, Baiba Berzins3, Kwang-Youn Kim3, Adesola Ogunniyi1, Kevin Robertson4, Babafemi Taiwo3, Felicia Chow5 1University of Ibadan, 2Harvard T.H. Chan School of Public Health, 3Northwestern University, 4University of North Carolina, Chapel Hill, 5University of California, San Francisco The A5322 (HAILO) Study

Disclosures None

Objective and methods Investigate the association of cardiovascular (CV) risk factors with prevalent neurocognitive impairment in middle-aged and older PLWH (age >40 years) at entry into the ACTG A5322 Study (HIV, Aging and Immune Function Long-Term Observational [HAILO] study). Primary neurocognitive outcomes 1. NPZ-4, mean z-scores of the 4 tests in the neurocognitive screen 2. Neurocognitive impairment, defined as >1 SD below the mean on 2 or more tests or >2 SD below the mean on 1 test Linear and logistic regression models to evaluate the association between CV risk factors and the two primary neurocognitive outcomes. Neurocognitive impairment remains prevalent in persons living with HIV (PLWH) and in several studies, CVD has been shown to be a risk factor for cognitive impairment in PLWH. Understanding when CVD may contribute to the development of CI is key to designing trials to test impact of interventions that address CVD on CI in HIV Digit symbol measures processing speed, working memory, visuospatial processing and attention. Trails A: processing speed Trails B: executive function HVLT: verbal learning and memory All HAILO participants (n=1035, all >40 years) were assigned to randomized initial ART regimens through ACTG interventional trials and were previously followed long-term in the ACTG Longitudinal Linked Randomized Trial (ALLRT) study after randomized trial participation ended. HAILO enrollment occurred in 2013-2014; ongoing visits occur every 6 months. All participants who underwent a brief neurocognitive screen (Trailmaking Tests A and B, Hopkins Verbal Learning Test-Revised [HVLT-R], and Digit Symbol) at entry into HAILO were eligible (n=988). We used linear and logistic regression models to determine the association between cardiovascular (CV) risk factors and the two primary outcomes. Candidate variables with p <0.10 in demographics and education-adjusted models were included in multivariable models.

HAILO participant characteristics N (%), unless indicated n=988 Age (years), mean (SD) 52 (8) Women 195 (20) Race/ethnicity: Black Hispanic/Latino 299 (30) 204 (21) Education: Undergraduate degree Graduate school 480 (49) 135 (14) CD4 count (cells/mm3), mean (SD) 661 (308) HIV RNA <40 copies/ml 894 (90) ART duration (years), median (IQR) 8 (4, 11) ART use: PI NNRTI Integrase inhibitor Abacavir use Efavirenz use 409 (41) 396 (40) 219 (22) 154 (16) 323 (33) Anti-hypertensive use 359 (36) Statin use 267 (27) Diabetes mellitus 125 (13) Prior stroke 23 (2) Total cholesterol (mg/dL), mean (SD) 188 (44) HDL cholesterol (mg/dL), mean (SD) 49 (16) BMI (kg/m2), mean (SD) 28 (6) Waist circumference (cm), mean (SD) 97 (14) Anti-depressant medication use 212 (21) Hepatitis C infection 123 (12) Current smoker Prior smoker 252 (26) 321 (33) Current IVDU Prior IVDU 1 (0.1) 70 (7) Of 1035 HAILO participants, 988 underwent the brief neurocognitive screen at entry and thus were included in this study Education (years), median (IQR): 14 (12, 16) Nadir mean (SD) 205 (164) Hgb A1c 5.7 (1), eGFR 90 (19) Afib, prior MI and CHF few LDL 109 (39) SBP/DBP 126/78

Risk factors associated with cognitive impairment HDL >50 mg/dL  odds of cognitive impairment by 35% (p=0.013) and HDL >60 mg/dL  odds by 45% (p=0.004) independent of demographics, CV and HIV-related risk factors Older age, female sex, Hispanic/Latino ethnicity, anti-depressant use, integrase inhibitor use, shorter duration of ART, and hepatitis C were associated with lower NPZ-4. In a multivariable model including both CV and HIV-related risk factors, we observed a trend toward an association between higher HDL and higher NPZ-4, while all other CV risk factors were no longer significantly associated with NPZ-4. DM and a1c a/w CI but effect no longer significant after adjusting for age and sex Statin use like HDL a/w significantly better cognition in demographics adjusted model but no longer statistically significant when other CV risk factors added to model Smoking also a/w worse cognition but this was no longer significant after use of antidepressant meds added to model. In demographics and education-adjusted models, HDL was the only CV risk factor associated with cognitive impairment, with higher HDL associated with lower odds of cognitive impairment. In a multivariable model, we observed a trend toward higher HDL protecting against cognitive impairment (OR 0.89 for every +10 mg/dL HDL, p=0.073) HDL>60 45% lower chance of CI (0.004); HDL>50 lowered chance by 35% (0.013); HDL >60 a/w ; continuous HDL>60 a/w 0.17 higher NPZ4 score (0.022) and 0.13 (0.048) Odds ratio

Implications and next steps Can mid-life CV risk factors, including HDL, predict later cognitive impairment and cognitive decline? Can CV risk prediction scores (FRS-CVD and Pooled Cohort Equations) help to identify PLWH at high risk for cognitive impairment and cognitive decline? Can interventions that raise HDL improve or protect cognitive function in PLWH?

Acknowledgments Participants in AIDS Clinical Trials Group A5322/HAILO Study NIH/Fogarty D43TW009608 CV risk prediction scores a/w prevalent cognitive impairment and longitudinal cognitive decline The A5322 (HAILO) Study