1. DACS 272 Neurologic deficits in the years following ART initiation among subjects in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort M. Smurzynski 1, M. Yang 1, K. Robertson 2, A.C. Collier 3, K. Wu 1, R.J. Bosch 1, R.J. Ellis 4 1 Harvard School of Public Health, Center for Biostatistics in AIDS Research, Boston 2 University of North Carolina, Neurology, Chapel Hill, 3 University of Washington, Harborview Medical Center, Medicine/Infectious Diseases, Seattle 4 University of California, San Diego, Neurosciences, HIV Neurobehavioral Research Center THAB0106

2. Background/Objective Previous studies focused on concurrent risk factors for neurocognitive impairment – Lower CD4 nadir, older, comorbidities, vascular risk – ART regimens: PI vs NNRTI; CPE Objective: To identify risk factors for poor neurocognitive outcomes during follow-up on ART

5. Design, Participants Design: Prospective observational cohort Participants: 1,599 HIV+ individuals enrolled in ALLRT and having undergone neuropsychological testing – Antiretroviral naïve prior to parent study entry

6. Timeline for ascertainment of study predictors and outcomes ACTG Parent Study ALLRT Enrollment 1 st NP Testing 2 nd NP Testing (48 weeks) Repeat NP Testing - every 48 Weeks Ascertain risk indicators /predictors: stroke, hepatitis C Serostatus, etc. Ascertain longitudinal neurocognitive outcomes: NPZ-3 and NPZ-4 16+ wks treatment2-9 years follow-up

7. ALLRT NeuroScreen Tests Trailmaking Test - Part A Trailmaking Test - Part B Digit-Symbol Test (Added later: HVLT)

8. Primary Outcome: serial NPZ-3 scores Overall performance: mean z-scores across the 3 tests (NPZ-3) Impairment: ≤ -2.0 SD on one test or ≤ -1.0 on two tests Uni- and multi-variable repeated measures regression models evaluated predictors of NPZ-3 worsening. Variables with p< 0.10 eligible to enter multivariable models

9. Predictors evaluated Behavioral risks – smoking, injection drug use (IDU) HIV disease and treatment indicators – Years since parent entry (surrogate for ART duration) – pre-ART CD4 – ART regimen type – time-updated plasma viral load (PVL) and CD4 Coinfections – hepatitis B surface antigen (HBsAg) – hepatitis C virus (HCV) serostatus Other brain comorbidities – history of stroke

10. Representative example of serial NPZ-3 scores for one participant according to continuous vs binary outcome Continuous Discrete

11. Characteristics at Parent Study Entry Median (IQR) or N (%) Age at parent study entry39 (32, 45) Gender male1,312 (82%) White Non-Hispanic928 (58%) Black Non-Hispanic671 (42%) Injection drug use ever124 (8%) Hepatitis B (HBsAg) +44 (3%) Hepatitis C status Positive116 (7%) Nadir CD4 (cells/ul)189 (61, 298)

12. HIV disease and treatment indicators Protective: NC decline less likely Susceptibility: NC decline more likely

13. Comorbidity risks / predictors Protective: NC decline less likely Susceptibility: NC decline more likely

14. Summary: Multivariable Predictors of Decline Hazard of NP decline reduced with: Longer duration of ART (time since parent entry) Better immune recovery:  time-updated CD4 (>350 vs <50) Hazard of NP decline increased with: History of stroke prior to parent entry Hazard of NP decline not affected by: Age (in this study 32 - 45) CD4 nadir (>200 or 51-200 vs <=50) Virologic suppression on ART (< 200 copies; 95% in years 1-3) ARV drug class (PI/NRTI vs NRTI only, etc) Smoking history at parent entry IDU history Hepatitis B and C seropositivity

15. Summary: During Longitudinal Follow-up… Longer duration of ART protective with respect to neurocognitive function Continuing CD4 recovery linked to protection – Prior studies: Starting ART before prolonged immunosuppression enhances CD4 recovery – Cross-sectionally, CD4 nadir linked to prevalent impairment Specific comorbidities confer increased risk of poor outcomes – Stroke: marker of vascular risk? – Vascular risk factors highly prevalent in aging HIV+ (metabolic syndrome)

16. Acknowledgements Co-authors ACTG Sites NIH (NIMH) HIV+ study participants

17. Backup Slides

18. Study Comparison ALLRTCHARTER N1,599436 Epoch2003-20132006-2013 Years f/u – Median (IQR)6 (2, 9) 3 (1.5-4) Age, years – Median (IQR)39 (32, 45)44 (35, 51) Past ART Exposurenaïve before parent enrollTypically extensive Current cART100%70% CD4 nadir – Median (IQR)189 (IQR 61, 298)184 (49, 230) CD4 entry – Median (IQR)218 (continuing increases)459 (289, 644) Virologic suppression95% at year 258% of those on cART Outcome Measure Repeated NPZ-3 [unimpaired to impaired] Clinically significant decline by sRCS NP tests3 tests, 2 domains15 tests, 7 domains

19. Training Videos