M. Smurzynski 1 , M. Yang 1 , K. Robertson 2 , A.C. Collier 3 ,

1. THAB0106 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. Smurzynski1, M. Yang1, K. Robertson2, A.C. Collier3, K. Wu1, R.J. Bosch1, R.J. Ellis4 1Harvard School of Public Health, Center for Biostatistics in AIDS Research, Boston 2University of North Carolina, Neurology, Chapel Hill, 3University of Washington, Harborview Medical Center, Medicine/Infectious Diseases, Seattle 4University of California, San Diego, Neurosciences, HIV Neurobehavioral Research Center

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 16+ wks treatment 2-9 years follow-up Ascertain risk indicators /predictors: stroke, hepatitis C Serostatus, etc. Ascertain longitudinal neurocognitive outcomes: NPZ-3 and NPZ-4

7. ALLRT NeuroScreenTests • 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

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

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

19. Training Videos