Neurologic Complications of HIV: Understanding Cognitive Impairment in the Era of Antiretroviral Therapy

1. Neurologic Complications of HIV Victor G. Valcour, MD Professor of Medicine University of California San Francisco San Francisco, California AU Edited: 12/09/15 New Orleans, Louisiana: December 15-17, 2015

2. Learning Objectives • Describe the frequency, severity, and burden of cognitive impairment in HIV in the era of combination antiretroviral therapy • Recognize multiple likes of evidence supporting ongoing HIV-related brain injury despite suppression of plasma HIV RNA to undetectable levels • Describe the role of comorbidity as contributors to cognitive symptoms in the current era After attending this presentation, participants will be able to:

3. Clinical Features of Impairment Cognition Memory loss Concentration Mental slowing Behavior Apathy Depression Agitation, Mania Motor Unsteady gait Poor coordination Tremor

4. HIV-Associated Neurocognitive Disorders (HAND) HAND No HAND HIV Asymptomatic Neurocognitive Impairment Mild Neurocognitive Disorder (MND) HIV-associated Dementia (HAD) HIV infection Neurology 2007 HAND terminology implies that the etiology is HIV; but, likely multifaceted

5. ARS Question 1

6. Prevalence of Cognitive Diagnoses Pre-cART Post-cART HAD MND ANI NL • Lower incidence, but, no change in prevalence • Lesser severity • Most HAND cases are asymptomatic Modified from Nat Rev Neurosci 2007

7. Should we worry about “asymptomatic” neurocognitive impairment? Stephanie Chiao & Lauren Wendelken

8. Cognitive Performance No difference in summary neuropsychological testing scores between those who were asymptomatic (ANI) and those who were symptomatic (MND/HAD) CO HIV-NL ANI SNI HIV neg. HIV+ NL Controls Cognition asymptomatic symptomatic

9. Everyday Function Total NAB Score • Memory • Judgment • Driving (Attention/Executive) • Bill Pay (Language and calculations) • Map (Spatial ability) NAB = Neuropsychological Assessment Battery, a series of everyday function testing

10. Is the Cognitive Impairment Real?DTI measures in HIV vs. controls Human Brain Mapping 2012

11. Asymptomatic Case 79 year old male, brain MRI with broad atrophy including central atrophy and large areas of confluent white matter injury

12. Conversion to Symptomatic Impairment 347 subjects, 90 months of follow-up Conversion to symptomatic From CROI 2012 – Igor Grant - Asymptomatic HIV-associated Neurocognitive Disorder (ANI) Increases Risk for Future Symptomatic Decline: A CHARTER Longitudinal Study Neurology 2014

13. ARS Question 2

14. The Role of Confounding Factors

15. Slide 17 of 49 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration-Effectiveness

16. Slide 18 of 49 2 3 5 4 (a) ARV toxicity (b) poor CPE 1 5 CPE = CNS Penetration-Effectiveness

17. Slide 19 of 49 (a) ARV toxicity (b) poor CPE 1 CPE = CNS Penetration-Effectiveness

18. Evidence of Ongoing Neuronal Injury Despite cART • Neurofilament (NFL) is a major structural element of myelinated fibers • NFL is elevated in cART vs. controls; 85 subjects on cART for > 1 year with plasma HIV RNA < 50 copies Krut et al PlosOne 2014

19. Abnormalities in Diffusion Tensor Imaging • n=56, all but 6 with suppressed plasma HIV RNA, age > 60 • Broad abnormalities in DTI in HIV vs. controls; +: Exacerbated by APOE4 Fractional Anisotropy Nir et al. Human Brain Mapping 2013

20. Elevated sCD163 Associated with Impairment 34 CHARTER (US) participants with suppressed plasma HIV RNA, on cART > 1 year; CD4 > 500 CD163 = scavenger receptor involved in inflammation and secreted from monocytes as sCD163 Burdo et al AIDS 2013

21. Effect of cART on HIV Reservoir Size Before cART 6 months 12 months Differing response in those with dementia vs. those without Valcour et al J Leukocyte Biol 2010

22. Increased Macrophage Staining Despite cART n=10 cART vs. 9 NL Anthony et al J Neuropath Exp Neuro 2005

23. 7 asymptomatic subjects, mean 9 years of HIV • on cART > 3 years, undetectable plasma HIV RNA • PET Scan with 11c-PK1116 PET ligand • Microglial activation noted • signal in corpus callosum, anterior cingulate, posterior cingulate, temporal and frontal lobes • Correlated to poorer executive function Garvey et al AIDS 2014

24. Maraviroc Intensification for HAND Reduction of inflammation Reduction of HIV DNA reservoir Cognitive improvement J Neurovirology 2014

25. Slide 28 of 49 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration-Effectiveness

26. Neuronal Injury linked to Antiretroviral Therapy Schinburg et al JNV 2005

27. Slide 30 of 49 Healthy neurons Neurons treated for 7 days with ARV

28. Cognitive Performance During Treatment Interruption 167 subjects, mean CD4 > 400 before interruption; had been on cART > 4 years Robertson et al, Neurology 2010

29. Slide 32 of 49 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration-Effectiveness

30. Increasing Frequency of Ischemic Stroke in HIV Ovbiageleand Nath 2011 Neurology & Chow et al 2011 JAIDS

31. Metabolic Disorders and Cerebrovascular Disease # CVD risk factors Number of cerebrovascular risk factors and cognitive performance

32. White Matter Injury Subjects over the age of 60 in the US who are living with HIV as a chronic illness

33. ARS Question 3

34. Mild Moderate Severe • Autopsy series in the US between 1999 to 2011 • Associated with PI use; ? Legacy effect 50 % of cases Soontornniyomkij et al AIDS 2014

35. Slide 38 of 49 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration-Effectiveness

36. CNS Escape: Sub-Acute or Acute Neurological Syndromes (Case Series) Canestri et al, CID 2010

38. Projected Proportion of HIV Over 50+ Years Old Projected based on 2008 CDC data Adapted from JAMA 2013

39. Aging with HIV – An International Issue Mills et al NEJM 2012

40. Prevalence of Dementia Prevalence * Comorbidities: HIV infection, Hepatitis C, Cerebrovascular disease, lifestyle factors

41. Considerations • Age and HIV impact cognition, but not synergistically (additive) • Nevertheless, older individuals are more likely to meet a threshold of important amounts of decline • Older patients tend to be more symptomatic • Age is not the most important determinant of cognition in HIV • The variation in age is as great as the variation across ages

42. 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

43. Summary • Cognitive impairment remains frequent despite cART • cART does not control HIV-related contributions • Antiretroviral therapy may contribute to cognitive impairment • Suppression of plasma HIV RNA is essential in the treatment of cognitive impairment • Attention to CNS penetration effectiveness of ARVs is important in select (uncommon) circumstances

44. Summary • The etiology of cognitive impairment is likely heterogeneous • Contributions from cerebrovascular disease • With age, possibly neurodegenerative disorders • Background comorbidity may play a role in the frequency of poor neuropsychological performance in some