Transcript Slide 1

Slide 1 of 22
Emerging Issues in HIV,
Aging, and Cognition
Victor G. Valcour, MD
Professor of Geriatric Medicine
University of California San Francisco
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
IAS–USA
Slide 2 of 22
HIV-associated Neurocognitive
Disorders (HAND)
Neuropsychological
Testing
Mild Neurocognitive Mild-moderately
Impairment (MND)
impaired in at least two
cognitive domains
Function
Typically mild to
moderate impairment
HIV-associated
Dementia (HAD)
More severely impaired Typically more
in at least two cognitive severe impairment
domains
Asymptomatic
Neurocognitive
Impairment (ANI)
Any degree of
impairment in at least
two cognitive domains
No identified
impairment
Antinori et al Neurology 2007
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 3 of 22
Cognitive Impairment in HIV
HIV-associated
Dementia
(HAD)
Mild
Neurocognitive
Disorder
(MND)
HIV
Asymptomatic
Neurocognitive
Impairment
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
HIV
infection
Slide 4 of 22
Cognitive Diagnoses
Pre-HAART and Post-HAART Eras
Pre-cART
Post-cART
HAD
MND
ANI
NL
•
•
Lower incidence
No change in prevalence
Modified from Ellis et al, Nat Rev Neurosci 2007 and Grant et al., CROI 2009
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 5 of 22
Clinical Features of Impairment
Cognition
Memory loss
Concentration
Mental slowing
Comprehension
Behavior
Apathy
Depression
Agitation, Mania
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Motor
Unsteady gait
Poor coordination
Tremor
Slide 6 of 22
Brain Impairment and HIV
39% Impaired
21% Developed
impairment after
48 weeks of
HAART
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Robertson K, et al. AIDS. 2007
Slide 7 of 22
Cognitive Diagnoses
Pre-HAART and Post-HAART Eras
HAD
MND
NL
ANI
Asymptomatic Neurocognitive Impairment
accounts for about 70% of non-confounded cases
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 8 of 22
Composite neuropsychological
testing performance
CO
HIV-NL
ANI
HAD
HIV-NL
ANI
SNI
NPZComp Scores
2
1
0
-1
-2
-2
-3
-4
CO
HIV Negative Controls (CO), HIV Normal Cognition (HIVNL), asymptomatic impairment (ANI), and symptomatic
impairment (SNI = MND + HAD)
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 9 of 22
Objective Measures of Everyday
Function
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Grant et al CROI 2012
Slide 10 of 22
Is the Cognitive Impairment Real?
DTI measures in HIV vs. controls
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 11 of 22
Imaging
• Corpus Callosum volume and
Fractional Anisotropy (FA) correlate
to functional performance on the
NAB
Top panel: Correlation
between NAB t-scores (yaxis) and corpus callosum
volume as a fraction of ICV.
Bottom panel: Correlation
between NAB t-scores (yaxis) and splenium FA.
0.0015
0.0020
0.0025
2
0
-2
Regions of significant difference in fractional anisotropy
(FA) correlated to NAB z-scores, controlling for age
-4
-6
-8
2
0.4
1
0
-1
-2
-3
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
0.5
0.6
0.7
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Conversion to symptomatic
Conversion to Symptomatic
Impairment
347 subjects, 90 months of follow-up
CROI 2012 – Grant et al CHARTER Cohort
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 13 of 22
Poor Proxy Networks in HIV
Data from the HIV Over 60 Cohort indicates poor
proximity of informants.
Control
28
66 (61-70)
0.0
AD
20
70 (60-80)
0.8
HIV NL
35
64 (59-76)
0.1
HIV ANI
17
63 (60-79)
0.2
MND+HAD
23
65 (60-82)
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%
Sample Size
Mean Age (Range)
CDR mean
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 14 of 22
Age Distribution of HIV in the US
Extrapolation of CDC data through 2008
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 15 of 22
Who are they?
• Mostly aging with HIV
– 11% of new infections among 50+
• Heterogeneity
• Multimorbidity, polypharmacy, +/- frailty
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 16 of 22
HIV Over Age 60
• Nearly 100% adherent – can’t compare to
younger cohorts
• More symptomatic impairment
• Survival tendencies
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 17 of 22
UCSF HIV Over 60 Cohort
Predictors 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
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 18 of 22
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 19 of 22
Diffuse plaques in frontal cortex
as a factor of duration of HIV
In vitro evidence that tat inhibits neprilysin, providing theoretical
evidence for increased accumulation of amyloid
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Rempel, Pulliam et al AIDS 2005
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Apo E4 and Cognition
UCSF HIV Over 60 Cohort
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 21 of 22
Where do we go from here?
Treatment options
• Antiretroviral treatment considerations
• Treatments used for neurodegenerative
disorders?
• Exercise
• Cognitive stimulation
• Treatment of comorbidities
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 22 of 22
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
From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.