Review of HIV and Neurocognitive Impairment
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Review of HIV and Neurocognitive Impairment
Scott Letendre, MDJoss de Wet, MD
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Metabolic Risk Factors for Neurocognitive Impairment
Adapted from McCutchan A. et al.Role of Central Obesity, Diabetes, and Metabolic Variables inHIV-associated Neurocognitive DisorderCROI 2012 Paper #490
Multivariate regression of NCI as a function of demographic, medicaland metabolic predictors of interest including both BMI and WC (n=55)
Variable Odds ratio 95% CI p- value
AIDS 49.57 2.26, 1089 0.013
Diabetes 17.6 0.76, 409 0.07
BMI, kg/m2 0.69 0.49, 0.98 0.038
Waist circumference, cm
1.34 1.13, 1.60 0.001
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Vascular Risk Factors and Cognitive Dysfunction
Adapted from Becker JT et al. Vascular risk factors, HIV serostatus, and cognitive dysfunction ingay and bisexual men. Neurology. 2009 Oct 20;73(16):1292-9.
IMT=intima-media thickness; GFR=glomerular filtration rate; LDL= low-density lipoprotein; CAC = coronary artery calcium
Variable Unadjusted model OR (95% CI)
Adjusted model OR (95% CI), p*
Modèle 1 Race 5.45 (3.59-8.29) 5.2 (3.14-8.73), <0.001
Depression 1.99 (1.27-3.09) 2.2 (1.27-3.92), 0.005
Education 5.09 (2.93-8.85) 0.56 (0.340-0.939), 0.028
Model 2 (added to above)
Carotid IMT 1.95 (1.22-3.13) 1.8 (1.03-3.24), 0.040
Hypertension 1.09 (0.738-1.62)
Diabetes 1.32 (0.645-2.72)
GFR 1.07 (0.657-1.75)
Hémoglobin A1c 1.65 (0.921-2.96)
Glucose 0.689 (0.464-1.02) 0.59 (0.36-0.97), 0.037
Metabolic syndrome 0.746 (0.445-1.25)
LDL 0.318 (0.135-0.754)
Total cholesterol 0.753 (0.409-1.39)
CAC 1.23 (0.390-3.88)
BMI 1.06 (0.584-1.91)
Model 3 (added to above)
AIDS 0.740 (0.397-1.36)
Detectable virus 1.53 (1.04-2.26)
CD4+ cell count 1.02 (0.852-3.07)
Odds ratio and p values are taken from model 2 (the final significant model)
Predictors of poor performance on tests of psychomotor speed among HIV-infected individuals only
Predictors of poor performance on delayed verbal and nonverbalmemory among HIV-infected individuals only
Variable Ratio de cotes non ajusté (IC 95%)
Modèle ajusté de ratio de cotes (IC
95%), p*
Model 1 Race 4.79 (3.17-7.25) 3.1 (1.92-5.17), <0.001
Depression 1.68 (1.08-2.61) 1.5 (0.884-2.66), 0.128
Education 5.38 (3.01-9.46) 0.35 (0.211-0.582), <0.001
Model 2 (added to above)
GFR 1.71 (0.956-3.07)
Carotid IMT 1.24 90.774-1.98)
Hypertension 1.39 90.934-2.06)
Diabetes 1.63 (0.800-3.31)
GFR 1.08 (0.662-1.77)
Hémoglobin A1c 1.71 (0.956-3.07)
Glucose 0.687 (0.462-1.02)
Metabolic syndrome 0.718 (0.426-1.21)
LDL 0.295 (0.119-0.733)
Total cholesterol 0.460 (0.236-0.895)
CAC 0.973 90.304-3.12)
Model 3 (added to above)
BMI 0.871 (0.479-1.58)
CD4+ cell count 1.44 (0.763-2.74)
Detectable virus 2.62 (1.78-3.89) 2.1 (1.30-3.45), 0.003
AIDS 0.804 (0.433-1.49)
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Effect of ART on Neurocognitive Variables in Primary HIV
Neurocognitive Performance
• 20% of male subjects during primary HIV infection performed >1 standard deviation below norm means on 2 or more of the 4 NPZ4 tests at baseline.
• In the absence of ART, parallel declines were observed:
– NPZ4 (per 10 weeks: slope = –0.015, p = 0.027),
– Composite motor domain (slope = –0.020, p = 0.012).
• With ART there was stabilization in performance
– NPZ4 slope = 0.0009, p = 0.86– Composite motor domain slope = –0.0026,
p = 0.68
Imaging Studies(Proton Magnetic Resonance Spectroscopy)
• Without ART, increases in cerebral metabolite ratios per 10 weeks were observed for:
– Cho/Cr (slope = 0.035, p = 0.007) and mI/Cr (slope = 0.012, p = 0.035) in frontal white matter (FW)
– mI/Cr in parietal grey matter (PG) (slope = 0.009, p = 0.030).
• Initiation of ART attenuated the increase in inflammatory biomarkers resulting in non-significant net slopes:
– Cho/Cr in FW (0.001, p = 0.092), mI/Cr in FW (0.005, p = 0.14),
– mI/Cr in PG (0.002, p = 0.36).• Pre-ART Glu/Cr increased in PG (slope = 0.008, p
= 0.039), but was reduced by ART to a near zero net slope (slope = 0.0005, p = 0.81).
• Metabolite changes in basal ganglia and anterior cingulate were non-significant.
Young A et al. Progressive Changes in Cerebral Metabolites and Effect of ART in Primary HIV-1Infection: A Magnetic Resonance Spectroscopy Study CROI 2012 Paper #79Peterson J. et al. Changes in Neurocognitive Performance from Early HIV-1 Infection to Initiationof ART . CROI 2012 Paper #80
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Earlier Initiation of Antiretroviral Therapy Results in Better Neurocognitive Functioning
Marcotte T. et al. Earlier Initiation of ART Results in Better Neurocognitive Functioning .CROI 2012 Paper #485
Mean scaled scores in Treated and Untreated groups, stratified byhigh and low baseline mean scaled score
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Low NCI Risk in an Early Treated Military Cohort
Crum-Cianflon N. et al. An Early Diagnosed and Treated HIV Cohort Shows Low Rates ofNeurocognitive Impairment. CROI 2012 Paper #500
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European AIDS Clinical Guidelines (EACS)
Available at:http://www.europeanaidsclinicalsociety.org
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The Montreal Cognitive Assessment
Available at http://www.mocatest.org/
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The Relationship Between CPE and Detectable CSF Viral Load
Letendre S. et al. Longitudinal Correlates of HIV RNA Levels in 2207 Cerebrospinal FluidSpecimens. CROI 2012 Paper #473
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The Relationship Between CPE Scores and Cognitive Function
Rourke S. et al. CNS Penetration Effectiveness of cART and Neuropsychological Outcomes:Cross-sectional Results from the OHTN Cohort Study . CROI 2012 Paper #484
Motor Efficiency domain T-score by 2010 CPE ranking among individuals on 3 ARVs n=428
*
Verbal Learning and Memory domain T-score by 2010 CPE ranking among individuals on 3 ARVs n=428
*
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Trends, But No Clear Benefit, To Using Rivastigmine for HAND
Simioni S. et al. Rivastigmine for the Treatment of HIV-associated Neurocognitive Disorders:A Randomized, Double-blind, Placebo-controlled, Crossover Pilot Study . CROI 2012 Paper #482
Trai
l Mak
ing
Test
A
Cogn
itive
Fun
ction
(MO
S-H
IV)
Current Effect F(1,13)=5.57, p=0.035 Current Effect F(1,13)=3.94, p=0.07
Current Effect F[1,13]=2.71, p=0.12
CAN
TAB
Spati
al W
orki
ng M
emor
y St
rate
gy
Placebo Treatment
Placebo Treatment
Placebo Treatment
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Behavioral Interventions for HIV+ Individuals with Memory Impairment• Experiment 1 – Paired Word Associates (Didactic vs.
Self Generated)– Patients learned, recalled, and recognized significantly
more words in the self-generated condition than in the the didactic condition (all ps <0.001).
• Experiment 2 – RCT of Mental Imagery and Visualization. – Patients in the mental imagery condition were over 4
times more likely to accurately perform the delayed prospective memory task than HIV+ controls (p <0.05, odds ratio = 4.75, 95%CI 1.1 to 21.4).
Weber E. et al. Brief Cognitive Neurorehabilitation Interventions Improve Memory Functioning inHIV+ Adults . CROI 2012 Paper #506
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CMV Antibodies & Risk Factors for Neurocognitive Impairment
Letendre S. et al. Higher Cytomegalovirus Antibody Concentrations Are Associated with Older Age,Lower Nadir CD4+ Cell Counts, and Worse Global Neurocognitive Functioning in People with HIVDisease . CROI 2012 Paper #466
Nadir CD4 Count CSF HIV RNA Neurocog Impairment
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Aging Associated with Higher ART Levels in CSF
• Tenofovir – CSF concentrations increased more steeply with age (n = 40, r = 0.28,
p = 0.056) than plasma (n = 44, r = 0.08, p = 0.64). • Efavirenz
– CSF concentrations increased markedly in subjects over 55 (n = 71, adjusted R2 for overall generalized additive models = 0.18, p = 0.004)
– Plasma concentrations increased less steeply and steadier (n = 61, r = 0.26, p = 0.05)
• Atazanavir – CSF concentrations increased with age (n = 45, r = 0.29, p = 0.05)– Plasma concentrations did not change with age (n = 98, r = 0.02, p =
0.86)
Croteau D. et al. Older Age Is Associated with Higher ARV Concentrations in CSF in HIV+ Individuals.CROI 2012 Paper #592