Post on 23-Jan-2016
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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)
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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