1. Slide 1 of 25 From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA. 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 Washington, DC: June 18, 2013, IAS-USA.

2. 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

3. 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)

4. 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

5. Slide 5 of 25 From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA. Clinical Features if Impairment Cognition Memory loss Concentration Mental slowing Comprehension Behavior Apathy Depression Agitation, Mania Motor Unsteady gait Poor coordination Tremor

6. 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+

7. 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

8. 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

9. 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) COHIV-NLANISNI

10. 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)

11. Slide 11 of 25 From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA. Total NAB Performance Total NAB across groups ANI did not differ from MND, but both ANI and MND performed more than 2 SD below controls.

12. 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

13. 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 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

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

15. 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.

16. 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

17. 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

18. 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

19. 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

20. Slide 20 of 25 From VG Valcour, MD, at Washington, DC: June 18, 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

21. Slide 21 of 25 From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA.

22. 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

23. Slide 23 of 25 From VG Valcour, MD, at Washington, DC: June 18, 2013, IAS-USA. Apo E4 and Cognition UCSF HIV Over 60 Cohort

24. 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

25. 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