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

Neurocognitive change in the era of HIV combination antiretroviral therapy: A

CHARTER StudyRK 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

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

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HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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)

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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)

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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

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

Potential Predictors EvaluatedGeneral Medical Health Indicators hematocrit, serum albumin, total protein, LFTsIndicators of HIV disease and treatment success cART status: on vs off (naïve + discontinued) initial and follow-up plasma viral loads, CD4Comorbid Conditions Neurocognitive comorbidities (head trauma,

etc)» Minimal, moderate, severe (Frascati)

Past substance abuse/dependence (e.g., methamphetamine)

Mood disorders - depression (Beck)

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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%

% Caucasian 43%

Comorbidity Status*

Minimal 59%

Moderate 29%

Severe 12%

* Sources of impairment other than HIV

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

HIV Disease and Treatment Indicators

Mean (SD), Median [IQR], or %

AIDS 60%

Nadir CD4 184 [49-230]

Current CD4 459 [289-644]

Currently on cART 70%

Duration of Current Regimen (mos) 18.0 (21.2)

Prior cART only 12%

ART Naive 18%

Undetectable HIV in Plasma (n=436) 41% (58% on cART)

Entry Neurocognitive Impairment 46%

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

NP Change Status in CHARTER Sample with ≥ 4 visits (n=436)

Decline (n=99) Stable (n=265) Improve (n=72)0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

22.7%

60.8%

16.5%

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

Sustained viremia associated with neurocognitive decline

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

Always Det Sometimes Det Always Undet

Always Det > Sometimes Det, Always Undet

Sum

mar

y N

P C

hang

e S

core

(F

irst

visi

t to

Las

t vi

sit)

13

p= .005

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

Significant Multivariable Time-Dependent Predictors of Time to Neurocognitive Decline

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Predictor Risk ReferenceRelative

Risk 95% CI

HIV Disease/Treatment Indicators

cART Status Off On 1.9 1.3 - 3.0

Overall Medical Health Indicators

Albumin Lower 1 unit 1.6 1.0 - 2.5

Hematocrit Lower 1 unit 1.1 1.0 - 1.1

Comorbid Conditions

Neurocognitive Comorbidities Severe Minimal 2.1 1.2 - 3.6

Past Methamphetamine Abuse Yes No 2.1 1.3 - 3.3

Worse Depression (Beck) Higher 1 unit 1.02 1.00 - 1.04

Multivariable Cox Regression Model p <0.0001

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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

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Predictor Risk ReferenceRelative

Risk 95% CI

Cognitive Reserve

Premorbid IQ Higher 1 unit lower 1.02 1.00 - 1.04

Overall Medical Heatlh

Total Protein Lower 1 unit 1.85 1.3 - 2.6

Aspartate Aminotransferase Lower 1 unit 1.01 1.00 - 1.03

Comorbid conditions

Lifetime Major Depression Absent Present 2.09 1.3 - 3.5

Multivariable Cox Regression Model p <0.0001

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

SummaryIn 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

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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

HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS 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 GelmanNational Institutes of

Health Mental Health Neurological Disorders and

Stroke

Thanks to all our Study VolunteersAnd to Collaborating Investigators and Sponsors

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

Study Comparison  ALLRT CHARTER

N 1,599 436

Epoch 2003-2013 2006-2013

Years f/u – Median (IQR) 6 (2, 9) 3 (1.5-4)

Age, years – Median (IQR) 39 (32, 45) 44 (35, 51)

Past ART Exposure naïve before parent enroll Typically extensive

Current cART 100% 70%

CD4 nadir – Median (IQR) 189 (IQR 61, 298) 184 (49, 230)

CD4 entry – Median (IQR) 218 (continuing increases) 459 (289, 644)

Virologic suppression 95% at year 2 58% of those on cART

Outcome Measure 

Repeated NPZ-3 [unimpaired to impaired]

Clinically significant decline by sRCS

NP tests 3 tests, 2 domains 15 tests, 7 domains

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

Backup Slides

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

Global Mean T at Baseline and Last Visit by NP Change Status

Baseline Last Visit40

42

44

46

48

50

52

54

Decline Stable Improve

Baseline: No Differences Last Visit: Decline > Stable, Improve

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

Time Dependent Univariable Predictors of Earlier NC Improvement (Survival Analysis*)

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Predictor Risk Reference Relative Risk P-value

Education Higher 1 year 1.10 .0534

Premorbid IQ Higher 1 unit 1.02 .0473

Higher Plasma VL Lower 1 log10 1.27 .0295

Plamsa VL Det/Undet Undetectable Detectable 1.53 .0876

Higher CSF VL Lower 1 log10 1.47 .0476

CSF VL Det/Undet Undetectable Detectable 1.73 .0952

* Univariable predictors with p < .10 chosen for inclusion multivariable model