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. Smurzynski 1 , M. Yang 1 , K. Robertson 2 , A.C. Collier 3 , K. Wu 1 , R.J. Bosch 1 , R.J. Ellis 4 1 Harvard School of Public Health, Center for Biostatistics in AIDS Research, Boston 2 University of North Carolina, Neurology, Chapel Hill, 3 University of Washington, Harborview Medical Center, Medicine/Infectious Diseases, Seattle 4 University of California, San Diego, Neurosciences, HIV Neurobehavioral Research Center THAB0106
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M. Smurzynski 1 , M. Yang 1 , K. Robertson 2 , A.C. Collier 3 ,
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. Smurzynski 1 , M. Yang 1 , K. Robertson 2 , A.C. Collier 3 , K . Wu 1 , R.J. Bosch 1 , R.J. Ellis 4 - PowerPoint PPT Presentation
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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/InfectiousDiseases, Seattle
4University of California, San Diego,Neurosciences, HIV Neurobehavioral Research Center
THAB0106
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
ACTGParent Study
ALLRT Enrollment 1st NP Testing 2nd NP Testing
(48 weeks)
Repeat NP Testing - every
48 Weeks
Ascertain risk indicators /predictors: stroke, hepatitis C Serostatus, etc.
Ascertain longitudinal neurocognitive outcomes: NPZ-3 and NPZ-4
16+ wks treatment 2-9 years follow-up
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– 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 39 (32, 45)
Gender male 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:• 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
• Co-authors• ACTG Sites• NIH (NIMH)• HIV+ study participants
Backup Slides
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)