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Slide 1 of 22
IAS–USA
Victor G. Valcour, MDProfessor of Geriatric Medicine
University of California San Francisco
Emerging Issues in HIV,Aging, and Cognition
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
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Slide 2 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
HIV-associated Neurocognitive Disorders (HAND)
Neuropsychological Testing
Function
Mild Neurocognitive Impairment (MND)
Mild-moderately impaired in at least two cognitive domains
Typically mild to moderate impairment
HIV-associated Dementia (HAD)
More severely impaired in at least two cognitive domains
Typically more severe impairment
Asymptomatic Neurocognitive Impairment (ANI)
Any degree of impairment in at least two cognitive domains
No identified impairment
Antinori et al Neurology 2007
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Slide 3 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Cognitive Impairment in HIV
HIV infection
HIV Asymptomatic Neurocognitive
Impairment
Mild Neurocognitive
Disorder (MND)
HIV-associated Dementia
(HAD)
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Slide 4 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Cognitive Diagnoses Pre-HAART and Post-HAART Eras
Modified from Ellis et al, Nat Rev Neurosci 2007 and Grant et al., CROI 2009
• Lower incidence• No change in prevalence
Pre-cART Post-cART
HAD
MND
ANI
NL
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Slide 5 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Clinical Features of Impairment
CognitionMemory loss
ConcentrationMental slowingComprehension
BehaviorApathy
DepressionAgitation, Mania
MotorUnsteady gait
Poor coordinationTremor
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Slide 6 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Brain Impairment and HIV
21% Developed impairment after 48 weeks of HAART
Robertson K, et al. AIDS. 2007
39% Impaired
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Slide 7 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Cognitive Diagnoses Pre-HAART and Post-HAART Eras
Asymptomatic Neurocognitive Impairment accounts for about 70% of non-confounded cases
NL ANI
HAD
MND
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Slide 8 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Composite neuropsychological testing performance
HIV Negative Controls (CO), HIV Normal Cognition (HIV-NL), asymptomatic impairment (ANI), and symptomatic impairment (SNI = MND + HAD)
-4
-3
-2-2
-1
0
1
2
NP
ZC
om
p S
co
res
CO HIV-NL ANI SNI
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Slide 9 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Objective Measures of Everyday Function
Grant et al CROI 2012
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Slide 10 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Is the Cognitive Impairment Real?DTI measures in HIV vs. controls
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Slide 11 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Imaging
Regions of significant difference in fractional anisotropy (FA) correlated to NAB z-scores, controlling for age
0.0015 0.0020 0.0025
-8
-6
-4
-2
0
2
0.4 0.5 0.6 0.7
-3
-2
-1
0
1
2
Top panel: Correlation between NAB t-scores (y-axis) and corpus callosum volume as a fraction of ICV.
Bottom panel: Correlation between NAB t-scores (y-axis) and splenium FA.
• Corpus Callosum volume and Fractional Anisotropy (FA) correlate to functional performance on the NAB
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Slide 12 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Conversion to Symptomatic Impairment
347 subjects, 90 months of follow-upCROI 2012 – Grant et al CHARTER Cohort
Con
vers
ion
to s
ympt
om
atic
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Slide 13 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Poor Proxy Networks in HIV
Data from the HIV Over 60 Cohort indicates poor proximity of informants.
Control AD HIV NL HIV ANI MND+HAD Sample Size 28 20 35 17 23
Mean Age (Range) 66 (61-70) 70 (60-80) 64 (59-76) 63 (60-79) 65 (60-82)
CDR mean 0.0 0.8 0.1 0.2 0.5
Unable to contact informant
0% 0% 14% 18% 9%
Informant is relative or spouse
86% 95% 40% 24% 43%
Informant lives with subject
75% 70% 40% 18% 39%
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Slide 14 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Age Distribution of HIV in the US
Extrapolation of CDC data through 2008
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Slide 15 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Who are they?
• Mostly aging with HIV
– 11% of new infections among 50+
• Heterogeneity
• Multimorbidity, polypharmacy, +/- frailty
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Slide 16 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
HIV Over Age 60
• Nearly 100% adherent – can’t compare to younger cohorts
• More symptomatic impairment• Survival tendencies
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Slide 17 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
UCSF HIV Over 60 CohortPredictors of Cognitive
Impairment
Correlated to CI
• CD4 T-lymphocyte nadir*
• Diabetes *• Apo E4 genotype• Monocyte
effectiveness (ME) score
NOT Correlated to CI
• Age and duration of HIV• Current CD4 T-lymphocyte
count• Plasma Viral load• Non-diabetes CVD risk
factors• CNS penetration
effectiveness score (CPE)
CI = Cognitive Impairment, CVD= cardiovascular disease *p<0.10
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Slide 18 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
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Slide 19 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Diffuse plaques in frontal cortex as a factor of duration of HIV
Rempel, Pulliam et al AIDS 2005
In vitro evidence that tat inhibits neprilysin, providing theoretical evidence for increased accumulation of amyloid
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Slide 20 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Apo E4 and CognitionUCSF HIV Over 60 Cohort
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Slide 21 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Where do we go from here?Treatment options
• Antiretroviral treatment considerations
• Treatments used for neurodegenerative disorders?
• Exercise
• Cognitive stimulation
• Treatment of comorbidities
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Slide 22 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Conclusions
• HAND remains frequent despite cART• Asymptomatic impairment may not be that
asymptomatic• Comorbid illnesses are important
contributors to impairment, particularly in older age
• There are not enough data to determine if older HIV+ patients will be at increased risk for Alzheimer’s disease