Review of HIV and Neurocognitive Impairment

1. Review of HIV and Neurocognitive Impairment Scott Letendre, MD Joss de Wet, MD

2. Metabolic Risk Factors for Neurocognitive Impairment Multivariate regression of NCI as a function of demographic, medical and metabolic predictors of interest including both BMI and WC (n=55) Adapted from McCutchan A. et al. Role of Central Obesity, Diabetes, and Metabolic Variables in HIV-associated Neurocognitive Disorder CROI 2012 Paper #490

3. Vascular Risk Factors and Cognitive Dysfunction Predictors of poor performance on tests of psychomotor speed among HIV-infected individuals only Predictors of poor performance on delayed verbal and nonverbal memory among HIV-infected individuals only Odds ratio and p values are taken from model 2 (the final significant model) IMT=intima-media thickness; GFR=glomerular filtration rate; LDL= low-density lipoprotein; CAC = coronary artery calcium Adapted from Becker JT et al. Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men. Neurology. 2009 Oct 20;73(16):1292-9.

4. 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. Effect of ART on Neurocognitive Variables in Primary HIV Young A et al. Progressive Changes in Cerebral Metabolites and Effect of ART in Primary HIV-1 Infection: A Magnetic Resonance Spectroscopy Study CROI 2012 Paper #79 Peterson J. et al. Changes in Neurocognitive Performance from Early HIV-1 Infection to Initiation of ART . CROI 2012 Paper #80

5. Earlier Initiation of Antiretroviral Therapy Results in Better Neurocognitive Functioning Mean scaled scores in Treated and Untreated groups, stratified by high and low baseline mean scaled score Marcotte T. et al. Earlier Initiation of ART Results in Better Neurocognitive Functioning . CROI 2012 Paper #485

6. Low NCI Risk in an Early Treated Military Cohort Crum-Cianflon N. et al. An Early Diagnosed and Treated HIV Cohort Shows Low Rates of Neurocognitive Impairment. CROI 2012 Paper #500

7. European AIDS Clinical Guidelines (EACS) Available at: http://www.europeanaidsclinicalsociety.org

8. The Montreal Cognitive Assessment Available at http://www.mocatest.org/

9. The Relationship Between CPE and Detectable CSF Viral Load Letendre S. et al. Longitudinal Correlates of HIV RNA Levels in 2207 Cerebrospinal Fluid Specimens. CROI 2012 Paper #473

10. The Relationship Between CPE Scores and Cognitive Function 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 * * Rourke S. et al. CNS Penetration Effectiveness of cART and Neuropsychological Outcomes: Cross-sectional Results from the OHTN Cohort Study . CROI 2012 Paper #484

11. Trends, But No Clear Benefit, To Using Rivastigmine for HAND Current Effect F(1,13)=5.57, p=0.035 Current Effect F(1,13)=3.94, p=0.07 CANTAB Spatial Working Memory Strategy Trail Making Test A Placebo Treatment Placebo Treatment Current Effect F[1,13]=2.71, p=0.12 Cognitive Function (MOS-HIV) Placebo Treatment 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

12. 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 in HIV+ Adults . CROI 2012 Paper #506

13. CMV Antibodies & Risk Factors for Neurocognitive Impairment Nadir CD4 Count CSF HIV RNA Neurocog 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 HIV Disease . CROI 2012 Paper #466

14. 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