HIV -Associated Neurocognitive Disorders (HAND) in Men and Women on C ombined A ntiretroviral T herapy (cART) and

1. HIV-Associated Neurocognitive Disorders (HAND) in Men and Women on Combined Antiretroviral Therapy (cART) and Suppressed Plasma Viral Load: Prospective Results from the OHTN Cohort Study 22nd Annual Canadian Conference on HIV/AIDS Research Vancouver, Canada April 12, 2013 Sean B. Rourke, Ph.D. Professor of Psychiatry, University of Toronto Scientific and Executive Director, Ontario HIV Treatment Network Scientist, Li Ka ShingKnowledge Institute of St. Michael’s Hospital Director, CIHR Centre for REACH in HIV/AIDS and Collaborative CBR Centre Director, Universities Without Walls (CIHR STIHR)

2. I have no conflicts of interest

3. Funding Support

4. Centre for Brain Health in HIV/AIDS Co-Authors M. John Gill (University of Alberta); Anita Rachlis (Sunnybrook Hospital and University of Toronto); Adriana Carvalhal (St. Michael’s Hospital and University of Toronto); Evan Collins (University Health Network and University of Toronto; Gordon Arbess (St. Michael’s Hospital and University of Toronto;Jason Brunetta (Maple Leaf Medical Clinic); Neora Pick (Oak Tree Hospital and University of British Columbia); Jennifer McCombe (University of Alberta); Scott Letendre (University of California, San Diego); Tom Marcotte (University of California, San Diego); Tsegaye Bekele (OHTN); Ann Burchell (OHTN and University of Toronto); Janet Raboud (University Health Network and University of Toronto); Francisco Ibanez-Carrasco (OHTN and University of Toronto); Allen Thornton (Simon Fraser University); Max Silverbrook (OHTN and Queens’s University); Claire Bourgeois (OHTN and Queen’s University); Ron Rosenes (OHTN); Maggie Atkinson (OHTN); Robert Reinhard (OHTN); Paul McPhee (St. Michael's Hospital); Frank McGee (MOHLTC AIDS Bureau)

5. Centre for Brain Health in HIV/AIDS Main Foci Natural history / epidemiology / validation (including screening) of HAND in Canada - building foundational work to support multidisciplinary investigations Understand the “lived experience” of HAND Build and Evaluate Interventions for HAND – Cognitive / Behavioural / Medical (smoking / CVD) / CNS Penetration Build Models of Care for HAND in the Health System Education and KTE – Ensure knowledge and evidence is available in useful ways for decision-making – for patient care, health care providers and policy-makers

6. INTRODUCTION

7. Introduction for Current Study • Approximately 30-50% of people with HIV develop neuropsychological impairments (NPI) - generally in mild / mild to moderate in severity) - Previous work by our group at St. Michael’s Hospital has shown similar rates of neuropsychological impairment by CDC-93 staging • Risk factors for NPIinclude: older age, reduced cognitive reserve, history of immune suppression (low CD4 nadir), and a host of mental heath and medical comorbidities, including HCV • Incidence of NPI in HIVis estimated to be 10-25% in the US • But is this neuropsychological impairment important to assess ? What does it mean to a person’s everyday life ? • YES – increases in NPI related to reduced ability to function in everyday activities (work, managing medications, driving), social functioning, confidence and sense of self, quality of life, and survival.

8. Updated Nosology for HIV-Associated Neurocognitive Disorders Frascati Criteria – 3 Diagnostic HAND Categories 1. Asymptomatic Neurocognitive Impairment (ANI) Presence of NP impairment in at least 2 NP ability domains, but no functional impairment in everyday life. 2. Mild Neurocognitive Disorder (MND) Presence of neurocognitive impairment in at least 2 NP ability domains with mild functional impairment in everyday life. 3. HIV Associated Dementia (HAD) Presence of neurocognitive impairment in at least 2 NP ability domains with marked functional impairment in everyday life. *Antinori et al (2007). Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789 –1799.

9. PUBMED RESULTS (APRIL 2013) BY YEAR - Hits with “HAND” = 217 PubMed Search Results on “HAND” = 217 Hits (April 10, 2013)Publication Date from January 2006 to present

10. Rehabilitation Context Weber, Blackstone and Woods, 2013

11. Introduction and Rationale for Current Study Canada lacks data on the population level on all HAND Categories: • Asymptomatic Neuropsychological Impairment • Mild Neurocognitive Disorder • HIV-Associated Dementia Current study provides 1st look at HAND in Canada

12. METHODS

13. OHTN Cohort Study (OCS) Ongoing observational, open dynamic cohort of HIV-positive persons in care in Ontario HIV Ontario Observational Database (1994-1999) HIV Infrastructure Information Program (2000-2006) Renamed OCS in 2007 Over 5,900 participants recruited from 11 specialized HIV clinics & primary care practices throughout Ontario Neuropsychological assessments are conducted at two sites in Toronto (since October 2007) Rourke et al , 2012 Cohort Profile: The Ontario HIV Treatment Network Cohort Study (OCS). International Journal of Epidemiology, 2012

14. Study Sample with Exclusion Criteria Completed Baseline NP* test N=938 Completed 2nd NP test at 1 yr N=631 • Exclusions (baseline) • Not on ARV therapy (n=104) or on < 3 ARVs (n=21) • No recent VL data (n=14)** • Had detectable VL (n=71) On cART and with supressed VL at baseline N=421 (67%) • Exclusions (at follow up) • On < 3 ARVs (n=8) • No recent VL data (n=16)** or detectable VL (n=22) On cART and with suppressed VL at baseline and 1-year follow up n=375 (59%) *NP = Neuropsychological; **Within 90 days prior/after NP assessment

15. Measures • Brief NP test battery administered (baseline and 1-year follow up): WMS-III Spatial Span, Third Edition (Wechsler, 1997) WAIS-R Digit Symbol Test (Heaton et al,2002; The Psychological Corporation, 1997) Grooved Pegboard Test (Klove, 1963) Hopkins Verbal Learning Test – Revised (HVLT–R; Benedict et al , 1998) • Self-reported cognitive complaints were assessed with the 4-item version of the Medical Outcomes Study (MOS) Cognitive Functioning scale (Wu et al, 1991; Stewart et al, 1992) • Adherence to ARVs (past 4 days) was assessed using one item from the Adults AIDS Clinical Trials Group (AACTG) Adherence Follow Up Questionnaire (Chesney et al, 2000) • Clinical / medical data (e.g., CD4 count) obtained from clinical charts • Determinants of health data - Other non-clinical data obtained through interviewer-administered quantitative questionnaire that included measures for mental health status (CES-D), alcohol use (AUDIT-10) and drug use (DAST-20)

16. Methods – Generating NP Status and HAND Categories • Conversions - Participants’ raw NP scores on each test were first converted into scaled scores and then into z-scores. Z-scores of ability domains were computed by averaging z-scores of individual tests • Corrections for demographics - Published age/gender/education/race norms were used to convert raw scores into T-scores(Heaton et al, 2002; Heaton et al, 2004; Norman et al, 2011) • Calculating NP Impairment - Global Deficit Scores (GDS) were computed from T-scores using previously published cut-off scores; “Normal” NP functioning GDS < 0.5; “Impaired” NP ≥ 0.05 (Carey et al, 2004). • Following the Antinori et al., criteria, GDS score and self-reported cognitive complaints were used to determine HAND status.

17. RESULTS

18. Prevalence of HAND at Baseline and 1-year Follow Up (N=375) Overall – 58% have Neuropsychological Impairment (NPI); Approximately 60% of persons with NPI have ANI % with Neuropsychological Impairment Estimating HAND in Canada: ANI = 22,750 persons; MND / HAD = Each 7,800 persons

19. Sample Characteristics – By HAND Group

20. Sample Characteristics – By HAND Group *p<0.05

21. Change in HAND Group Over 1-year Period HAND status remained stable (n=219, 58%) HAND status improved (n=76, 20%) HAND status worsened (n=80, 22%) ANI , Asymptomatic Neurocognitive Impairment MND, Mild Neurocognitive Disorder HAD, HIV-associated Dementia

22. Change in HAND Status Comparable to US CHARTER Study * Heaton et al, 2012. Prevalence and Predictors of Neurocognitive Decline over 18 to 42 Months: A CHARTER Longitudinal Study (Abstract). 19th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, March 5-8, 2012.

23. Predictors of neurocognitive decline with haart – CHARTER Results • Examined neurocognitive changes over 18 to 42 months (N=436) • Changes in NP Status: • 23 % declined (n=98) • 61 % stable (n=266) • 17 % improved (n=72) • NP Decline predicted by: • neurological comorbidities • Lower CD4 count • being off ART • Clinical Implications: • benefit of ART and management of CNS complications Heaton et al. (2012) CROI

24. Sociodemographic and clinical differences

25. Sociodemographic and clinical differences

26. Multivariate Predictors of Change in HANDS Status *p<0.05

27. CONCLUSIONS

28. Summary of Findings – HAND Study • Despite being on cART treatment and having suppressed plasma viral load, 58% of sample had neuropsychological impairment (NPI) • In those with NPI, approximately 60% were classified as having Asymptomatic Neuropsychological Impairment, while about 20% had Mild Neurocognitive Disorder, and 20% had HIV-Associated Dementia. • Over the 1 year follow up period: • 58% remained stable • 22% declined (in all NP domains) • 20% improved (in all NP domains) • Gender differences found – need more focus – see Poster by Claire Bourgeois • Changes in women, but stability in men • Predictors of NP improvement or decline: • Gender • ARV adherence • Duration since HIV diagnosis • Further examination of risk factors for NPI / decline underway – to examine contributions of mental health, addiction and medical comorbidities

29. Limitations of Current Study • We used a brief neuropsychological test battery (and not the “gold standard” assessment), assessed functional abilities using only self-report measures (and these were limited as well) as opposed objective functional ones that have already been validated. This significantly limited our ability to examine the“Asymptomatic Neuropsychological Impairment” group in any great detail or to assess its stability / change over time. • The neuropsychological test measures also were not adjusted for practice effects. As such, our estimates may have underestimated the prevalence of impairment at follow-up, and the real magnitude of change of HAND over the follow up period. • Due to lack of data, we were not able to control for comorbidities that may have contributed to increased rates of HAND (particularly HIV-associated dementia) and/or changes in HAND status over 1 year

30. Progression of Neurocognitive impairment Heaton et al. (2012). CROI

31. Progression of Neurocognitive impairment • Examined risk of NP decline according to HAND (N= 347) • ANI predicts decline • Relative risk of 3-5 for development of HAND compared to those persons who are neurocognitively normal • ANI remained significant predictor after controlling education, reading score, comorbidity status • Implication: Evidence for risk of progression of HAND Heaton et al. (2012) - CROI

32. Some Important Factors to Push the Field Forward • Selection and use of “gold standard” neuropsychological test batteries for assessment / monitoring of HAND • Standardization / harmonization of neuropsychological test batteries across research studies to detect and document HAND but also to pool across studies and centres • Development and validation of new screening tools for milder forms of HAND – and to make sure that these tools do not replace proper assessment for HAND to help persons with HIV better manage HAND related complications • Further development and validation of appropriate functional measures that could be used in wider-scale studies to study the stability of HAND, and its impact of everyday functioning.

33. Systematic Review of Screening Tools for HAND Study funded by the Ontario Ministry of Health and Long-term Care

35. Systematic Review of Screening Tests for HAND • Results: Search Review and Evaluation • Title and abstract review of 1,696 articles – 1,368 were excluded because not relevant to research questions • Full article appraisal completed on 316 papers - 265 of these did not meet full inclusion criteria) • 51 studies met inclusion criteria and fell into 2 categories: • (1) studies evaluating screening tools by comparing them to a reference or “gold” standard (31 of 51 or 61%); and • (2) studies that evaluated screening tools by other methods • Our review focused on those compared to reference standardin (1)

36. Systematic Review of Screening Tests for HAND • Results: Main Findings • Most studies focused on “neurocognitive impairments” or “deficits” (55%) or screening for HIV-Associated Dementia (35%); Few studies focused on milder forms of HAND (ANI or MND) • Only 23% used gold standard battery of NP tests as criterion • Functional status assessed in minority of studies (< 30%) • Quality appraisal – some key aspects rated as poor in quality • 15 of 31 studies had adequate sensitivity (≥ 0.75): HIV Dementia Scale; Cogstate; Hopkins Verbal Learning Test / Grooved Pegboard or WAIS-III Digit Symbol; Screening Algorithm

37. Meta-Analysis of HIV Dementia Scale

38. Evaluation of Screening Tools for HAND: Preliminary Results Study funded by the Canadian Institutes of Health Research

39. HAND Screening Evaluation Study (Toronto, Canada) • PURPOSE: To examine the clinical utility of four short screening tools in detecting HAND. • The 5 tools are: • HIV Dementia Scale (HDS); • Montreal Cognitive Assessment (MoCA); • (3) Combination of Hopkins Verbal Learning Test /WAIS-III Digit Symbol, • (4) Computer Assessment of Mild Cognitive Impairment (CAMCI), and (5) Cogstate • METHODS: • Participants (n=500) will complete the “gold standard” of neuropsychological testing (3-4 hours), functional status battery, and the 5 short screening tools, and then be classified according the HAND (ANI, MND, and HAD) according to Antinori et al., 2007.

40. Pilot / Preliminary Results: Evaluation of HAND Screening Tools Performance of HAND Screening Tests to Detect Neuropsychological Impairment Using Comprehensive NP Testing and Clinical Diagnosis (Antinori et al., 2007) *Comorbid conditions – based on Frascati criteria: “Contributing”: 005 (daily marijuana use); 006 (learning disability); 007 (traumatic brain injury) “Confounding”: 008 (cerebral event) HDS – Adjusted – Morgan et al., J Clin Exp Neuropsychology (2008) – Age and education adjustments to HDS

41. Pilot / Preliminary Results: Evaluation of HAND Screening Tools Performance of HAND Screening Tests to Detect Neuropsychological Impairment Using Comprehensive NP Testing and Clinical Diagnosis (Antinori et al., 2007) HDS – Adjusted – Morgan et al., J Clin Exp Neuropsychology (2008) – Age and education adjustments to HDS

42. Pilot / Preliminary Results: Evaluation of HAND Screening Tools Using “Gold Standard” – Classification of “NPNormal” vs. “NP Impaired / HAND” (n=20) HIV Dementia Scale – Adjusted: Used Morgan et al., 2008 (J Clin Exp Neuropsych) to adjust HDS scores for age and education

43. Pilot / Preliminary Results: Evaluation of HAND Screening Tools Using “Gold Standard” – Classification of “NP-normal” vs. “ANI or MND” (n=18) Using “Gold Standard” – Classification of “NP-normal” vs. “ANI” (n=7) Using “Gold Standard” – Classification of “NP-normal” vs. “MND” (n=14)

44. Centre for Brain Health in HIV/AIDS Main Foci Natural history / epidemiology / validation (including screening) of HAND in Canada - building foundational work to support multidisciplinary investigations Understand the “lived experience” of HAND Build and Evaluate Interventions for HAND – Cognitive / Behavioural / Medical (smoking / CVD) / CNS Penetration Build Models of Care for HAND in the Health System Education and KTE – Ensure knowledge and evidence is available in useful ways for decision-making – for patient care, health care providers and policy-makers

45. Cognitive Interventions for HAND Underway in Toronto

46. Potential Behavioural Interventions for HAND Mindfulness-Based Cognitive Behaviour Treatment Pilot Study (To Start in May 2013) Led by Drs. Evan Collins and Pat Rockman

47. Helpful Resource – CID 2013; 56(7): 1004-1017

48. Acknowledgements OCS participants and the interviewers, data collectors, research associates and coordinators, nurses and physicians who provide support for data collection OCS Research Team Sean B Rourke (PI) Ann N Burchell (Co-PI) Ahmed M BayoumiJohn Cairney Jeffrey Cohen Curtis Cooper Fred CrouzatSandra Gardner Kevin Gough Don Kilby Mona LoutfyNicole Mittmann Janet Raboud Anita Rachlis Edward Ralph Sergio Rueda Irving E Salit Roger Sandre MarekSmiejaWendy Wobeser OCS Governance Committee Patrick Cupido(Chair) Adrian Betts Evan Collins Tracey Conway Tony DiPede Brian Finch Michael Hamilton Clemon George Troy Grennan Claire Kendall Rick Kennedy Ken King Nathan Lachowsky Joanne Lindsay John MacTavish Carol Major Shari Margolese Colleen Price Lori Stoltz Anita Benoit Brian Huskins Leslie Bowman HlaHla (Rosie) Thein OCS/OHTN Staff Kevin Challacombe Brooke Ellis Mark Fisher Robert Hudder Lucia Light Michael Manno Veronika Moravan Nahid Quereshi Samantha Robinson Data Linkage Public Health Laboratories, Public Health Ontario Funding OCS is funded by the AIDS Bureau of the Ontario Ministry of Health and Long-Term Care

49. Thank you Sean.rourke@utoronto.ca 22nd Annual Canadian Conference on HIV/AIDS Research Vancouver, Canada April 12, 2013 Sean B. Rourke, Ph.D. Professor of Psychiatry, University of Toronto Scientific and Executive Director, Ontario HIV Treatment Network Scientist, Li Ka ShingKnowledge Institute of St. Michael’s Hospital Director, CIHR Centre for REACH in HIV/AIDS and Collaborative CBR Centre Director, Universities Without Walls (CIHR STIHR)