1. Slide 1 of 22 IAS–USA Victor G. Valcour, MD Professor 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.

2. 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

3. 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)

4. 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

5. Slide 5 of 22 From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA. Clinical Features of Impairment Cognition Memory loss Concentration Mental slowing Comprehension Behavior Apathy Depression Agitation, Mania Motor Unsteady gait Poor coordination Tremor

6. 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

7. 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

8. 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) COHIV-NLANISNI

9. 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

10. 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

11. 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 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

12. 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-up CROI 2012 – Grant et al CHARTER Cohort Conversion to symptomatic

13. 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.

14. 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

15. 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

16. 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

17. Slide 17 of 22 From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA. 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

18. Slide 18 of 22 From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

19. 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

20. Slide 20 of 22 From VG Valcour, MD, at Atlanta, GA: April 10, 2013, IAS-USA. Apo E4 and Cognition UCSF HIV Over 60 Cohort

21. 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

22. 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