Transcript Powerpoint

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
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
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
Timeline for ascertainment of study predictors
and outcomes
ACTG
Parent Study
ALLRT
Enrollment
16+ wks treatment
Ascertain risk indicators
/predictors: stroke, hepatitis
C Serostatus, etc.
1st
NP Testing
2nd NP Testing
(48 weeks)
Repeat NP
Testing - every
48 Weeks
2-9 years follow-up
Ascertain longitudinal neurocognitive
outcomes: NPZ-3 and NPZ-4
ALLRT NeuroScreen Tests
• Trailmaking Test - Part A
• Trailmaking Test - Part B
• Digit-Symbol Test
• (Added later: HVLT)
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
Predictors evaluated
• Behavioral risks
– smoking, injection drug use (IDU)
• HIV disease and treatment indicators
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–
–
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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
Representative example of serial NPZ-3 scores for one
participant according to continuous vs binary outcome
Continuous
Discrete
Characteristics at Parent Study Entry
Median (IQR) or N (%)
Age at parent study entry
Gender male
39 (32, 45)
1,312 (82%)
White Non-Hispanic
928 (58%)
Black Non-Hispanic
671 (42%)
Injection drug use ever
124 (8%)
Hepatitis B (HBsAg) +
44 (3%)
Hepatitis C status Positive
116 (7%)
Nadir CD4 (cells/ul)
189 (61, 298)
HIV disease and treatment indicators
Protective: NC decline
less likely
Susceptibility: NC decline
more likely
Comorbidity risks / predictors
Protective: NC decline
less likely
Susceptibility: NC decline
more likely
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:
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•
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•
•
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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
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)
Acknowledgements
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Co-authors
ACTG Sites
NIH (NIMH)
HIV+ study participants
Backup Slides
Study Comparison
ALLRT
CHARTER
1,599
436
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)
naïve before parent enroll
Typically extensive
100%
70%
CD4 nadir – Median (IQR)
189 (IQR 61, 298)
184 (49, 230)
CD4 entry – Median (IQR)
218 (continuing increases)
459 (289, 644)
95% at year 2
58% of those on cART
N
Epoch
Past ART Exposure
Current cART
Virologic suppression
Outcome Measure Repeated NPZ-3 [unimpaired
to impaired]
NP tests
3 tests, 2 domains
Clinically significant decline
by sRCS
15 tests, 7 domains
Training Videos