1. The Double-Edged Sword: Long-Term Complications of ART and HIV Out of sight out of mind: Brain Impairment and HIV Victor Valcour MD Associate Professor Memory and Aging Center University of California – San Francisco/ USA

2. The Double-Edged Sword: Long-Term Complications of ART and HIV Brain Impairment and HIV Cognitive impairment remain frequent despite HAART Causes of brain: 1)Current treatment approaches do not clear reservoirs 2)Co-existing factors (treatment complications/side effects, other diseases, non-HIV related issues) Aging with HIV –Should we be worried about neurological degenerative disorders (Alzheimer’s? Parkinson's?)

3. The Double-Edged Sword: Long-Term Complications of ART and HIV 17% Moderately Impaired 22% Mildly Impaired 21% Developed impairment after 48 weeks of HAART Brain Impairment and HIV Robertson K, et al. AIDS. 2007 39% Impaired

4. The Double-Edged Sword: Long-Term Complications of ART and HIV Cognitive Impairment despite HAART Pre- ARV Pre-HAART HAART Grant et al. 2009 Conference on Retroviruses and Opportunistic Infections

5. The Double-Edged Sword: Long-Term Complications of ART and HIV HIV infection without cognitive impairment HIV Asymptomatic Neurocognitive Impairment Mild Neurocognitive Disorder HIV- associated Dementia Neuropsychological Impairment in the era of HAART (2007) Consensus Working Group, Neurology 2007

6. The Double-Edged Sword: Long-Term Complications of ART and HIV Clinical Features Cognition Memory loss Concentration Mental slowing Comprehension Behavior Apathy Depression Agitation, mania Motor Unsteady gait Poor coordination Tremor

7. The Double-Edged Sword: Long-Term Complications of ART and HIV Functional consequences of cognitive impairment in HIV Heaton et al JINS 2004

8. The Double-Edged Sword: Long-Term Complications of ART and HIV The Case of Mr. B 79 year old male, high school degree, held miscellaneous jobs Referred for research project studying aging –“would be a good control subject…has no cognitive problems” Participant -asymptomatic –“I like opera and I used to be able to name all the singers…a lot of it escapes me now”

9. The Double-Edged Sword: Long-Term Complications of ART and HIV Mr. B’s HIV history HIV+ since 1985 Asymptomatic for decades but eventually started HAART in 2001 with CD4~200 No opportunistic infections; mild neuropathy Currently plasma HIV RNA level – undetectable Current CD4 ~ 250 Has not had detectable viral load or CD4 less than 200 since 2001

10. The Double-Edged Sword: Long-Term Complications of ART and HIV Mr. B’s other medical issues Past Medical History –hepatitis A (1960); occasional vertigo, intermittent illicit drug use including methamphetamine (last use at 75 years old) Neurological exam abnormal –Increased reflexes, slowed finger tapping, distal symmetric neuropathy, abnormal eye movements –Neuropsychological deficits broadly and severe

11. The Double-Edged Sword: Long-Term Complications of ART and HIV Mr. B’s Brain Imaging

12. The Double-Edged Sword: Long-Term Complications of ART and HIV Why is this occurring? (1)Is HAART sufficient? (2)What is the role of coexisting morbidity?

13. The Double-Edged Sword: Long-Term Complications of ART and HIV Blood Brain Barrier Capillary lumen (5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ (3) Impacts brain cells leading to cognitive dysfunction (2) Transfer of HIV into the brain - infection establishment in perivascular macrophages (1) HIV-infected monocytes, some activated HIV (4) Neuronal dysfunction and death Pathology demonstrates multinucleated infected cells (perivascular monocytes), little neuronal infection, but dysfunctional neurons with decreased arborization and damaged synaptic function HAART

14. The Double-Edged Sword: Long-Term Complications of ART and HIV Peripheral monocyte infection correlates to HIV dementia Valcour Neurology 2009 Poorer cognitive performance

15. The Double-Edged Sword: Long-Term Complications of ART and HIV Failure of HAART to eradicate virus in circulating monocytes Valcour et al, J Leukocyte Biology 2010

16. The Double-Edged Sword: Long-Term Complications of ART and HIV Correlation between HIV DNA and cognition in treated subjects Not Impaired Impaired Shiramizu, et al 2005 AIDS All IndividualsIndividuals with undetectable plasma HIV RNA

17. The Double-Edged Sword: Long-Term Complications of ART and HIV CD68 expression in hippocampus Elevated despite viral control with HAART Anthony, Bell, et al. J Neuropath Exp Neurol 2005

18. The Double-Edged Sword: Long-Term Complications of ART and HIV Blood Brain Barrier Capillary lumen (5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ (3) Impacts brain cells leading to cognitive dysfunction (2) Transfer of HIV into the brain - infection establishment in perivascular macrophages (4) Neuronal dysfunction and death (1) HIV-infected monocytes, some activated HAART ?

19. The Double-Edged Sword: Long-Term Complications of ART and HIV CPE and CSF viral load Letendre et al 2008 Arch Neurol Proportion with detectable virus in CSF HAART with higher BBB penetration

20. The Double-Edged Sword: Long-Term Complications of ART and HIV Non-HIV specific Contributors to Cognitive Impairment in HIV

21. The Double-Edged Sword: Long-Term Complications of ART and HIV Cerebrovascular risks Younger Older 43% 47% 12% 26% 2% 7% JNC7 Hypertensio n Smoking Younger Older 21% 42% Diabetes Younger Older FG 100-125 15% 25% FG > 125 or DM 3% 22% Deaths in the Hawaii Aging with HIV Cohort Cardiovascular 21.05% Cancer 21.05% AIDS-related 10.53% Liver failure 5.26% Drug overdose 10.53% Undetermined 21.05% HAART related lactic acidosis 10.53%

22. The Double-Edged Sword: Long-Term Complications of ART and HIV Cognitive performance worse with greater number of cerebrovascular risk factors

23. The Double-Edged Sword: Long-Term Complications of ART and HIV The role of Co-existing Morbidity Cerebrovascular disease –Carotid Intimal Medial Thickness correlates to cognitive performance in the Multicenter AIDS Cohort Study (MACS) Other non-HIV specific factors –Illicit drug use –Co-infections, particularly Hepatitis C –Depression and other psychiatric conditions Becker 2010 Neurology and Valcour 2005 JAIDS

24. The Double-Edged Sword: Long-Term Complications of ART and HIV Aging with HIV infection The New York Times January 2007 The Honolulu Advertiser 2003

25. The Double-Edged Sword: Long-Term Complications of ART and HIV Prevalence of Dementia % of population

26. The Double-Edged Sword: Long-Term Complications of ART and HIV Prevalence of Dementia % of population

27. The Double-Edged Sword: Long-Term Complications of ART and HIV Amyloid deposition in HIV Amyloid accumulationAmyloid degradation

28. The Double-Edged Sword: Long-Term Complications of ART and HIV Amyloid deposition in HIV Amyloid accumulationAmyloid degradation –Inflammation (Alisky 2007) –Metabolic syndrome (Giunta 2008) –IFNg, TNFa (Liao 2004, Cu 2008) –Ubiquitin proteosome dysfunction due to HAART (Clifford 2007) –Gamma secretase impairment due to immune activation (Brew 2005) –Increased APP as an acute phase reactant (Xu 2008) –GP41 inhibitions of protein kinase C ((Ikezu 2008) –Tat inhibition of micoglial uptake of amyloid beta (Giunta 2008) –Tat interactions with low density lipoprotein receptor inhibiting uptake of amyloid (Liu 2000) –Protease inhibitor down-regulation of insulin degradation enzyme which degrades amyloid –Tat interactions with neprolysin, inhibiting amyloid degradation (Rempel & Pulliam, 2005) –TNFa stimulated BACE1 suppressing amyloid beta degradation in microglia (Xu 2008) –Sub-lethal HIV mediated NMDA excitations leading to alpha secretase inhibition (Xu 2008)

29. The Double-Edged Sword: Long-Term Complications of ART and HIV Clifford et al, Neurology 2009

30. The Double-Edged Sword: Long-Term Complications of ART and HIV Good news No evidence for increased fibrillary amyloid plaque in well-controlled HIV Ances, Clifford 2010 Damage to neuron synapses and decreased arborization of neurons appears to be reversible Ellis, Masliah, 2008

31. The Double-Edged Sword: Long-Term Complications of ART and HIV UCSF HIV Over 60 Cohort Abstract # 11302, IAS 2010

32. The Double-Edged Sword: Long-Term Complications of ART and HIV Where do we go from here? HIV cognitive impairment remains a silent epidemic –Although dementia is rare, milder levels of impairment are frequent and impact function –Many patients adopt compensatory means of getting by Work is needed to detect and treat these issues

33. The Double-Edged Sword: Long-Term Complications of ART and HIV Where do we go from here? HIV appears to be inadequately treated within current treatment approaches –Sequestered reservoirs are inadequately treated – monocytes –Not all antiretroviral medications adequately get into the brain More information is needed, but early data suggest this is a problem for some patients Work is needed to address treatment of reservoirs

34. The Double-Edged Sword: Long-Term Complications of ART and HIV Where do we go from here? Confounding factors are likely to emerge as important treatable aspects of cognitive impairment –Illicit drug use, cerebrovascular risk factors, hepatitis C, medication effects, sleep apnea, others Patients and doctors should address these issues aggressively Patients should remain physically and socially engaged

35. The Double-Edged Sword: Long-Term Complications of ART and HIV Where do we go from here? There are theoretical concerns for the emergence of increased risk for neurodegenerative disorders in older HIV patients It is too early to make firm conclusions at this time More research is needed

36. The Double-Edged Sword: Long-Term Complications of ART and HIV Thank you Research support R01 NS061696 (Monocyte HIV DNA and HIV Dementia) K23AG032872 (Brain Impact of Aging with HIV) R21-MH086341 (Neurological Complications of Acute HIV Infection) UCSF AIDS Research Institute (NeuroImaging Correlates to Dementia in HIV over 60) UCSF-Gladstone Center for AIDS Research (NeuroImaging Correlates to Dementia in HIV over 60) Hillblom Foundation (Cognitive Impact of Insulin Resistance in Aging HIV Patients) Disclosures: Dr. Valcour has provided consultative services to GlaxoSmithKline, Merck, and Abbott Special Thanks: Bruce Miller and the Memory and Aging Center Cecilia Shikuma, Bruce Shiramizu and the Hawaii Center for AIDS Jintanat Ananworanich and the Southeast Asia Research Collaboration with Hawaii (SEARCH, www.SEARCHThailand.org) Our research subjects in California, Hawaii and Thailand