1. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Neurocognitive change in the era of HIV combination antiretroviral therapy: A CHARTER Study RK Heaton, Ph.D., DR Franklin, Jr., B.S., R Deutsch, Ph.D., SL Letendre, M.D., RJ Ellis, M.D., Ph.D., K Casaletto, M.S., MJ Marquine, Ph.D., SP Woods, Psy.D., F Vaida, Ph.D., JH Atkinson, M.D., TD Marcotte, Ph.D., JA McCutchan, M.D., AC Collier, M.D.,CM Marra, M.D., DB Clifford, M.D., BB Gelman, M.D., Ph.D., JC McArthur, M.B.B.S., S Morgello, M.D., DM Simpson, M.D., I Abramson, Ph.D., A Gamst, Ph.D., C Fennema-Notestine, Ph.D., DM Smith, M.D., and I Grant, M.D. for the CHARTER Group CNS HIV Anti-Retroviral Therapy Effects Research Supported by NIMH and NINDS | N01 MH22005 / HHSN271201000036C / HHSN271201000030C

2. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO 2

3. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Background  HIV-associated neurocognitive disorders (HAND) common (30% - 50%) despite effective cART »Common source of disability; amplified other disabilities by hampering compensatory strategies and treatment adherence  HAND diagnoses can evolve - variable clinical trajectories  Most longitudinal studies limited follow-up duration (6-12 months) or in the context of clinical trial

4. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Objective  Evaluate predictors of neurocognitive change over long-term follow-up in PLWHA  Long-term goal: identify interventions to prevent decline and enhance improvement

5. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER)  HIV+ participants from 6 sites followed longitudinally »Johns Hopkins University (PI: Justin McArthur) »Mount Sinai School of Medicine (PI: Susan Morgello, David Simpson) »University of California San Diego (PI: J. Allen McCutchan) »University of Texas Medical Branch (PI: Benjamin Gelman) »University of Washington Seattle (PI: Ann Collier, Christina Marra) »Washington University, St. Louis (PI: David Clifford)

6. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO CHARTER Neurocognitive Battery 15 tests assessing 7 domains  Verbal Fluency  Speed of Information Proc.  Attention/Working Memory  Motor  Abstraction/Executive  Learning  Memory (delayed recall) Overall performance summarized as a global deficit score (GDS)

7. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Primary Outcome: Reliable NP Change  Multivariate regressions predicting FU scores  Observed – Predicted FU scores/ SD residual = z=score  Average Z-scores on battery = sRCS  Use 90% CI for sRCS to classify changes in individuals over time  Separately, used results of these cohorts (median test- retest differences) to correct for practice effect in classifying impairment at follow-up visits 7

8. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Potential Predictors Evaluated General Medical Health Indicators  hematocrit, serum albumin, total protein, LFTs Indicators of HIV disease and treatment success  cART status: on vs off (naïve + discontinued)  initial and follow-up plasma viral loads, CD4 Comorbid Conditions  Neurocognitive comorbidities (head trauma, etc) »Minimal, moderate, severe (Frascati)  Past substance abuse/dependence (e.g., methamphetamine)  Mood disorders - depression (Beck)

9. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Cox Regression Analysis  Time to NC decline  Time to NC improvement  Univariable predictors with p <.10 eligible for inclusion multivariable model  Selected variables combined into a Cox time-dependent multivariable model »backward elimination with minimal Akaike Information Criterion (AIC) to reduce

10. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Baseline Demographics Mean (SD), Median [IQR], or % Age (years)43.9 (8.4) Education (years)12.9 (2.5) Gender (Male)80% % Caucasian43% Comorbidity Status* Minimal59% Moderate29% Severe12% * Sources of impairment other than HIV

11. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO HIV Disease and Treatment Indicators Mean (SD), Median [IQR], or % AIDS60% Nadir CD4184 [49-230] Current CD4459 [289-644] Currently on cART70% Duration of Current Regimen (mos)18.0 (21.2) Prior cART only12% ART Naive18% Undetectable HIV in Plasma (n=436)41% (58% on cART) Entry Neurocognitive Impairment46%

12. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO NP Change Status in CHARTER Sample with ≥ 4 visits (n=436) 12

13. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Sustained viremia associated with neurocognitive decline 13 p=.005

14. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Significant Multivariable Time-Dependent Predictors of Time to Neurocognitive Decline 14 PredictorRiskReference Relative Risk95% CI HIV Disease/Treatment Indicators cART StatusOffOn1.91.3 - 3.0 Overall Medical Health Indicators AlbuminLower1 unit1.61.0 - 2.5 HematocritLower1 unit1.11.0 - 1.1 Comorbid Conditions Neurocognitive ComorbiditiesSevereMinimal2.11.2 - 3.6 Past Methamphetamine AbuseYesNo2.11.3 - 3.3 Worse Depression (Beck)Higher1 unit1.021.00 - 1.04 Multivariable Cox Regression Model p <0.0001

15. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Multivariable Cox Regression Model with Time-Dependent Predictors to Estimate Time to Neurocognitive Improvement 15 PredictorRiskReference Relative Risk95% CI Cognitive Reserve Premorbid IQHigher1 unit lower1.021.00 - 1.04 Overall Medical Heatlh Total ProteinLower1 unit1.851.3 - 2.6 Aspartate AminotransferaseLower1 unit1.011.00 - 1.03 Comorbid conditions Lifetime Major DepressionAbsentPresent2.091.3 - 3.5 Multivariable Cox Regression Model p <0.0001

16. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Summary In this broadly representative sample of PLWHA in the U.S., most with extensive ARV-exposure:  Over median 3 years follow-up, 22.7% declined, 16.5% improved neurocognitively  Predictors of earlier neurocognitive decline: off cART, poor general medical health indicators (albumin, hematocrit), severe neurocognitive comorbidity (not HAND eligible), neuropsychiatric comorbidity (past substance use, ongoing depression)  Predictors of earlier neurocognitive improvement: greater cognitive reserve (pre-morbid IQ), good general medical health indicators (serum protein, AST), absence of lifetime major depressive disorder

17. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Conclusions and Future Directions  Enhancing neurocognitive function in PLWHA needs attention not only to optimizing cART, but also to comorbidities, particularly substance use and depression, as well as general medical health  Future studies should be designed to assess the impact of treatment of comorbid neuropsychiatric disorders with respect to improved antiretroviral adherence, with positive feedback on overall health  Unexplained variance in long-term NC change: develop surrogate biomarkers (e.g., imaging) of improvement that might be used to accelerate testing of new treatments

18. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Acknowledgements CHARTER Coordinating Center  Igor Grant  Ron Ellis  Scott Letendre  Robert Heaton  Thomas Marcotte  Christine Fennema-Notesine  David Smith  Florin Vaida  J Allen McCutchan  J Hampton Atkinson CHARTER Sites  David Clifford  Justin McArthur  Ann Collier  Christina Marra  Susan Morgello  David Simpson  Ben Gelman National Institutes of Health  Mental Health  Neurological Disorders and Stroke Thanks to all our Study Volunteers And to Collaborating Investigators and Sponsors

19. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO 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

20. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Backup Slides

21. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Global Mean T at Baseline and Last Visit by NP Change Status Baseline: No Differences Last Visit: Decline > Stable, Improve

22. HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGO CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO Time Dependent Univariable Predictors of Earlier NC Improvement (Survival Analysis*) 22 PredictorRiskReferenceRelative RiskP-value EducationHigher1 year1.10.0534 Premorbid IQHigher1 unit1.02.0473 Higher Plasma VLLower1 log 10 1.27.0295 Plamsa VL Det/UndetUndetectableDetectable1.53.0876 Higher CSF VLLower1 log 10 1.47.0476 CSF VL Det/UndetUndetectableDetectable1.73.0952 * Univariable predictors with p <.10 chosen for inclusion multivariable model