Slide 1 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA. 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 Washington, DC: June 18, 2013, IAS-USA.

Slide 2 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 3 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Cognitive Impairment in HIV

HIV infection

HIV Asymptomatic Neurocognitive

Impairment

Mild Neurocognitive

Disorder (MND)

HIV-associated Dementia

(HAD)

Slide 4 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 5 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Clinical Features if Impairment

CognitionMemory loss

ConcentrationMental slowingComprehension

BehaviorApathy

DepressionAgitation, Mania

MotorUnsteady gait

Poor coordinationTremor

Slide 6 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA. Antinori 2007 Neurology

Fluctuation in Cognitive Status

HIV-

HIV+

Slide 7 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Brain Impairment and HIV

21% Developed impairment after 48 weeks of HAART

Robertson K, et al. AIDS. 2007

39% Impaired

Slide 8 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 9 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 10 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Neuropsychological Assessment Battery (NAB)

1. Memory

2. Judgment

3. Driving (Attention/Executive)

4. Bill Pay (Language and calculations)

5. Map (Spatial ability)

Slide 11 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Total NAB Performance

Total NAB across groups

Control NL ANI MND0

20

40

60

80

100P

erce

nti

le

ANI did not differ from MND, but both ANI and MND performed more than 2 SD below controls.

Slide 12 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Is the Cognitive Impairment Real?DTI measures in HIV vs. controls

Slide 13 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 14 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 15 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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%

Slide 16 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Age Distribution of HIV in the US

Extrapolation of CDC data through 2008

Slide 17 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Aging Worldwide HIV Prevalence in age > 50

HIV and aging – Preparing for the Challenges Ahead, NEJM 2012

Slide 18 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Who are they?

• Mostly aging with HIV

– 11% of new infections among 50+

• Heterogeneity

• Multimorbidity, polypharmacy, +/- frailty

Slide 19 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

HIV Over Age 60

• Nearly 100% adherent – can’t compare to younger cohorts

• More symptomatic impairment• Survival tendencies

Slide 20 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 21 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Slide 22 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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

Slide 23 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Apo E4 and CognitionUCSF HIV Over 60 Cohort

Slide 24 of 25

From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

Where do we go from here?Treatment options

• Antiretroviral treatment considerations• Treatments for neurodegenerative disorders?• Exercise• Cognitive stimulation• Treatment of morbidities• Safety in the home/ advanced planning

Slide 25 of 25

From VG Valcour, MD, at Washington, DC: June 18, 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