Review of HIV and Neurocognitive Impairment

Scott Letendre, MDJoss de Wet, MD

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

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)

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

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

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

European AIDS Clinical Guidelines (EACS)

Available at:http://www.europeanaidsclinicalsociety.org

The Montreal Cognitive Assessment

Available at http://www.mocatest.org/

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

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

*

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

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ing

Test

A

Cogn

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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

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Placebo Treatment

Placebo Treatment

Placebo Treatment

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

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

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