Sean B. Rourke, Ph.D. University of Toronto, Toronto, Canada Ontario HIV Treatment Network St. Michael’s Hospital

1. Examining the impact of CNS penetration effectiveness (CPE) of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living with HIV: Findings from the Ontario HIV Treatment Network (OHTN) Cohort Study Sean B. Rourke, Ph.D. University of Toronto, Toronto, Canada Ontario HIV Treatment Network St. Michael’s Hospital

2. CONFLICT OF INTEREST DISCLOSURE I have the following potential conflicts of interest: Advisory Board/ Publications/ Honoraria: Abbott Laboratories Research Funding: Canadian Institute for Health Research Public Health Agency of Canada The Ontario HIV Treatment Network

3. INVESTIGATOR TEAM • Co-Principal Investigators: • Dr. Sean B. Rourke • OHTN, St. Michael’s Hospital, University of Toronto • Dr. Adriana Carvalhal • McMaster University, Psychiatry and BehavioralNeurosciences • Co-Investigators: • Amy R. Zipursky OHTN, St. Michael’s Hospital • Tsegaye Bekele OHTN • Dr. Jen McCombeUnivAlberta, Univ Calgary, Department of Medicine • Dr. Anita Rachlis University of Toronto, Sunnybrook Health Sciences Center • Dr. Evan Collins University of Toronto, Psychiatry • Dr. M. John Gill University of Calgary, Department of Medicine • Dr. Janet RaboudUniversity Health Network, University of Toronto • Dr. Ann Burchell OHTN, McGill University, Oncology

4. BACKGROUND

5. THE ISSUE • HIV enters CNS shortly after infection • HIV Associated Neurocognitive Disorder (HAND): Antinori et al. • Asymptomatic neurocognitive impairment (ANI) • HIV-associated mild neurocognitive disorder (MND) • HIV-associated dementia (HAD) • Introduction of cARThas decreased incidence of HAD, but there is evidence of an increased prevalence of MND and ANI • Detrimental effect of mild neuropsychological deficits in HIV • Can affect job functioning and decreased performance in those working • Can affect ability to carry out complex tasks • Shown to affect medication adherence • Associated with increased mortality rates

6. THE ISSUE • cARTcan improve NP functioning (but not complete recovery) • Different ARVs have different abilities to penetrate the CNS • Letendre et al., (2006, 2010) developed a system to evaluate the CNS penetration of antiretroviral drugs with respect to neurological outcomes • What we know so far: (1) Increased CNS penetration of ARVs is associated with decreased CNS viral load (most consistent in prospective studies); (2) the relationship between CPE of ARVs and neuropsychological outcomes is more equivocal (potentially because further downstream in effect)

7. CURRENT LITERATURE REVIEW

8. MAJOr Objective To assess the association of CNS penetration of ARV regimen and neuropsychological functioning in people living with HIV in Ontario Hypothesis: Individuals on antiretroviral regimens with higher CPE rankings will perform better overall on measures of neuropsychological functioning (global, domains)

9. METHODS

10. Participants and testing • 834 participants were recruited from two hospital-based clinics in Toronto, Canada that are part of the Ontario HIV Treatment Network Cohort Study (OCS), a longitudinal cohort of 5,000 people living with HIV collected at 10 sites across the province • Neuropsychological tests were administered as part of the annual data collection of the OCS • Medical information retrieved by chart abstraction • Sample is restricted to participants with both neuropsychological and medical information available. Frequency of neuropsychological assessments: • Time 1: 338 • Time 2: 271 • Time 3: 218 • Time 4: 007

11. Sample Completed Neuropsychological Tests Sample Size=834 Observations=1,562 Excluded ARV Naïve, N=211 Suboptimal ARV, N=94 Final Sample Sample=529 Observations=864

12. Sample – Comparison included and excluded a – difference between those on >=3 ARVs and on suboptimal ARVs is significant (p<0.05) b - difference between those on >=3 ARVs and Not on ARVs is significant (p<0.05) c - difference between those on suboptimal ARVs and Not on ARVs is significant (p<0.05)

13. Computation of neuropsychological scores • Raw scores were converted into demographically corrected T-scores (corrected for Age, gender, education, race/ethnicity). 6 NP tests were categorized into 3 domains • T-scores were converted below into deficit scores for each test using Carey et al (2004) algorithm • NP Deficit Scores: 5 Impairment levels were collapsed into 2 categories (i.e., NP normal v NP impaired) Carey, C.L., Woods, S.P., Gonzalez, R., Conover, E., Marcotte, T.D., Grant, I., Heaton, R.K., & the HNRC Group (2004). Predictive Validity of Global Deficit Scores in Detecting Neuropsychological Impairment in HIV Infection. Journal of Clinical and Experiment Neuropsychology, 26, 307-319.

14. Methods to calculate Impairment Two major ways to evaluate neurocognitive impairment: Global Neuropsychological (NP) Impairment Rating, Heaton et al (1991): at least mild neuropsychological impairment on 2 or more ability domains Global NP Deficit Score, Carey et al (2004): total sum of deficits scores for all tests were ≥0.50 cut-off

15. CPE Ranking System 2006 LetendreS, et al. 13th CROI, Denver 2006, Abstract #74

16. CPE Ranking System 2010 LetendreS, et al. 17th CROI, San Francisco CA 2010, Oral #172

17. Comparison of CPE Ranking Systems 2006 and 2010 Letendre S, et al. 17th CROI, San Francisco CA 2010, Oral #172

18. Dichotomized CPE Scores 2006 Letendre, S., Marquie-Beck, J., Capparelli, E., Best, B., Clifford, D., Collier, A. C. et al. (2008). Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch.Neurol., 65, 65-70.

19. Dichotomized CPE Scores - PRESENT • For the Present Investigation: • Breakdown of sample: • 1) CPE rank 2006 • Mean CPE= 1.57, Median=1.50 • Group 1 (CPE <=1.5:52.9%) • Group 2 (CPE>1.5:47.1%) • * Same as Letendre et al., 2008 dichotomized scores • 2) CPE rank 2010 • Mean CPE= 7.08, Median=7.00 • Group 1 (CPE <=7:40.0%) • Group 2 (CPE>7:60.0%)

20. RESULTS

21. Baseline characteristics of participants (N=834) Global deficit score is computed as the average of Spatial Span, Digit Symbol, Grooved Pegboard, and HVLT tests deficit scores following Carey et al’s (2004) algorithm

22. Global Deficit Score ≥ 0.5 by CPE 2006 (N=834, p=0.06)

23. Global Deficit Score ≥ 0.5 by CPE 2010 (N=834, p=0.41)

24. Neuropsychological Impairment by CPE 2006 (n=529)

25. Neuropsychological Impairment by Domain (n=529) – CPE 2006

26. Neuropsychological Impairment Classifications (n=529) – CPE 2006

27. Generalized estimating equation (gee) • Dependent Variable • Neuropsychological Outcomes • Covariates • Age at interview (Years) • Race (White / Black/ Other) • Gender (Male / Female) • Education (Years) • HCV Diagnosis (Yes/No) • Current CD4 count (< 500 / >= 500) • Dichotomized ARV CPE (High/Low) • Time HIV positive (Years) • Closest viral load value from interview date (log) • CD4 nadir (< 200/ >=200) • Drug Use Last Six Months (Yes/No) • Depressive Symptoms (CES-D total score)

28. Generalized estimating equation RESULTS • NOTE: Numbers reported are Odds Ratio (95% CI) from GEE models • * CPE > 7 vs. CPE <=7 • ** CPE > 1.5 vs. CPE <= 1.5

29. Generalized estimating equation • NOTE: Numbers reported are unstandardized regression coefficients from linear GEE models • * CPE > 7 vs. CPE <=7 • ** CPE > 1.5 vs. CPE <= 1.5 Observations=864

30. Significant covariates – Full Sample (obs=864)

31. Neuropsychological Impairment among participants who completed two NP evaluations (N=218)

32. Neuropsychological Impairment among participants who completed two NP evaluations and were on >=3 ARVs at baseline (N=127) NOTE: 2006 CPE ranking was used.

33. CONCLUSIONS

34. CONCLUSIONS • No effect of CPE scores on overall neuropsychological (NP) outcomes but specific effect were seen on individual domains using Letendre 2006 criteria (but not using the 2010 criteria): (1) negative effect on motor functioning (2) positive effect on spatial working memory • Our results are consistent with other neuropsychological studies of CPE (Smurzyinski et al., 2011; Starace et al., 2010, Cysiqueet al., 2009; and Tozziet al., 2009; however, our results need to be replicated prospectively, and we need to identify why our results were not consistent across both criteria • NP outcomes are downstream effects – we will need to explore other ARV effects (timing / length), methodological issues (better matching) and confounding comorbidities (e.g., HCV)

35. NEUROTOXICITY Igor G, Canada Presentation, 2011, http://hnrc.hivresearch.ucsd.edu/

36. Thank You Examining the impact of CNS penetration effectiveness (CPE) of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living with HIV: Findings from the Ontario HIV Treatment Network (OHTN) Cohort Study Sean B. Rourke, Ph.D. (sean.rourke@utoronto.ca) University of Toronto, Toronto, Canada St. Michael’s Hospital Ontario HIV Treatment Network

37. EXTRA: Sample Info Geographic region of birth of Foreign-born participants (N=358)

38. Baseline characteristics of participants by place of birth (N=834)

39. Baseline characteristics of NP Impaired (GDS > 0.5) participants by place of birth (N=470)

40. Generalized estimating equation- GDS >=0.5 only • NOTE: Numbers reported are unstandardized regression coefficients from linear GEE models • * CPE > 7 vs. CPE <=7 • ** CPE > 1.5 vs. CPE <= 1.5 Observations=483

41. Generalized estimating equation • NOTE: Numbers reported are unstandardized regression coefficients from linear GEE models • * CPE > 7 vs. CPE <=7 • ** CPE > 1.5 vs. CPE <= 1.5

42. Generalized estimating equation • NOTE: Numbers reported are Odds Ratio (95% CI) from GEE models • * CPE > 7 vs. CPE <=7 • ** CPE > 1.5 vs. CPE <= 1.5

43. Generalized estimating equation • NOTE: Numbers reported are Odds Ratio (95% CI) from GEE models • * CPE > 7 vs. CPE <=7 • ** CPE > 1.5 vs. CPE <= 1.5