1. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Detecting HIV-Associated Neurocognitive Disorder in South Africa: The need for culturally valid screening tools Reuben N. Robbins, Ph.D. June 30 th, 2011 HIV Center Grand Rounds

2. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University What is HAND? (HIV-Associated Neurocognitive Disorder) HIV has affinity for CNS and crosses blood brain barrier  Cortical and subcortical brain regions affected 1,2  Neurotoxic effects and inflammatory response Disrupts neurocognitive functions 3,4 :  Attention and concentration  Motor speed and coordination  Learning/Memory  Planning and organization Neurocognitive impairment disrupts activities of daily living 5-9  Adherence  Finance management  Employment  Driving

3. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University What is HAND? Manifests as HAND 10  Asymptomatic Neuropsychological Impairment (ANI)  Minor Neurocognitive Disorder (MND)  HIV-Associated Dementia (HAD) HAND highly prevalent among PLWH in developed countries 11-13  Up to 60% have some form (typically milder form)  HAD 1% - 10% Milder HAND associated with mortality and progression to HAD 14,15 Becoming more important as PLWH live longer

4. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University HAND in South Africa Little known about prevalence and impact of HAND in South Africa  Yet, SA hardest hit by HIV with 5.5 million PLWH Recent study by Joska et al. (2010) 16  70% of younger adults with later stage HIV commencing ART had HAND (N=283)  25% HAD; 45% MND

5. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University How is HAND detected/diagnosed? Neuropsychological tests that assess deficits in neurocognitive function  Do not detect disease, but rather pattern of impairment typical of the disease  Require stimulus books, forms, stopwatches, etc  Numerous tests and batteries available  Administration must be exact  Performance compared to normative sample Current gold-standard diagnosis requires multi-hour neuropsychological and neurological exam

6. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University How is HAND detected/diagnosed? Screening for HAND not routine, 17,18 but could help:  Track and monitor  Make most appropriate referrals  Determine when to start ART Current screening tools just for HAD  HIV Dementia Scale (HDS) 19  International HIV Dementia Scale (IHDS) 20  Recent study used Montreal Cognitive Assessment (MoCA) 21 to screen for less severe HAND 22 Need for easy-to-use screening tools in South Africa:  Few neurologists and neuropsychologists, and other experts  Many undetected with HAND  Shift screening demands to lay personnel

7. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University How is HAND Detected? From International HIV Dementia Scale

8. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Montreal Cognitive Assessment (MoCA): highest score = 30, ≤25 = mild impairment Multi-hour neuropsychological exam would include many more items like the MoCA, as well as timed tests of processing speed and motor function

9. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Detecting HAND in South Africa Neurocognitive screening challenging in South Africa  Few tools culturally validated with culturally appropriate norms Neuropsychological test performance negatively influenced by 23-26  Low education  Low literacy  Culture differences  Limited test-taking experience  All very common in South Africa International HIV-Dementia Scale and HIV-Dementia Scale validated for use in South Africa 27-29

10. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Screening in South Africa Dr. Remien’s R34 adherence study (Masivukeni)  Neurocognitive screening tool component  IHDS  Montreal Cognitive Assessment (MoCA)  Grooved Pegboard Recent findings from our research  IHDS suggested 80% of adults on ART likely have HAD (N=65) Abnormalities on the MoCA  Cannot draw cube  Difficulty naming rhinoceros, etc

11. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Pilot Study Grant through Mount Sinai Institute of NeuroAIDS Disparities  Examine suitability of screening tools in South Africa Methods:  39 demographically matched HIV- and HIV+  Psychiatric screening  Neurocognitive screening  IHDS, MoCA, and Grooved Pegboard  Slight modifications to MoCA, cut-off score ≤23 (not 25)  All assessments available in Xhosa and English  Compare performance on MoCA (total, domain, and item)  Compare HIV- group to MoCA published norms

12. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Demographics N= 78  39 HIV+ and 39 demographically matched HIV- All Xhosa- and/or English-speaking Black South Africans from townships Age: 29.62 (SD=5.75) Education: 10.81 (SD=1.38) Gender: 70% (n=55) Some Employment: 22% (n=17)

13. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Results MoCA Domain Score Comparisons Table 2. Between groups Comparison on the MoCA HIV- (n=39)HIV+ (n=39) MeanSDMeanSDtp Total Score (unadjusted for education)21.672.0018.624.393.95.000 Visuospatial/Executive3.82.642.621.504.62.000 Naming2.33.741.791.082.57.012 a Attention4.181.213.361.462.70.009 a Semantic Fluency (Animal Naming)16.923.3311.924.595.42.000 Abstraction.93.42.78.621.47.147 Delayed Recall3.72.973.921.46-.73.467 Orientation5.69.525.69.66.711.00 a Bonferonni Corrected (p<.005)

14. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Results MoCA Individual Item Comparisons Table 3. Between Groups Comparison of Correct Responses on Individual MoCA items HIV- (n=39)HIV+ (n=39) %N%Nχ2χ2 p Visuospatial/Executive Trail Making90%3551%2013.87.000 Cube Copy21%813%5.83.362 Clock Contour100%3982%327.69.006 a Clock Numbers87%3464%255.64.018 a Clock Hands85%3351%209.95.002 Object Naming Lion100%3980%318.91.003 a Rhinoceros49%1938%15.83.361 Camel85%3362%245.28.022 a Attention Digits Forward69%2772%28.06.804 Digits Backward72%2849%194.34.037 a Tapping92%3692%3601.00 Serial 7’s b 31%1210%45.03.025 LanguageAnimal Fluency100%3949%1926.90.000 Abstraction Train-Bicycle87%3464%255.64.018 a Watch-Ruler5%210%4.72.395 Total Score ≤23Education Adjusted54%2180%315.77.016 a a Bonferoni Corrected

15. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Results Comparison to MoCA Norms* Table 4. Comparison of HIV- performance to MoCA published norms MoCA Published Norms HIV- (n=39) Normal Controls (n=90) Mild Cognitive Impairment (n=94) Alzheimer’s (n=93) MeanSDMeanSDMeanSDMeanSD Trail Making.90.31.87.34.56.50.27.45 Cube b.21.41.71.46.50.25.43 Clock2.72.512.65.652.16.821.56.98 Naming b 2.33.742.88.362.64.582.19.82 Memory3.72.973.731.271.171.47.521.03 Digits Span b 1.41.681.82.441.83.431.49.62 Tapping.92.27.97.18.93.26.67.47 Serial 7’s b 1.85.902.89.412.65.651.821.12 Abstraction b.92.421.83.431.43.68.99.80 Orientation c 5.69.525.99.115.52.843.921.73 *MoCA norms from North American older adults

16. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Conclusion MoCA has some potential  Some items discriminate  Some appear to be biased  Norms and cut-off score may not be appropriate Implications  Use “as is” will lead to inaccurate and inflated rates of HAND  Need to make item modifications, develop norms, and determine most accurate cut-off score Future research  Compare against gold standard  Compare expert to lay personnel administration

17. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University The Future Future project  Develop neurocognitive screening tool for mobile technology (e.g., smartphones and tablets)  To address lack of culturally valid screening tools, and increase capacity for ease of screening by lay personnel  Currently have prototype developed  Completely self-contained: do not need timing device, paper, pencils, etc.  Reduce administration errors: automatically scored  Highly portable  Instant results

18. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University Acknowledgements Robert Remien, PhD – Scientific Mentor  The Masivukeni Team Mount Sinai Institute of NeuroAIDS Disparities Scholar Grant (PI: Susan Morgello, MD) John Joska, MD – University of Cape Town  Corne Robertson  Teboho Linda HIV Center T32 Postdoctoral Training Fellowship (PI: Theo Sandfort, PhD)  International Elective HIV Center (PI: Anke Ehrhardt, PhD)

19. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University References 1. Wiley, C. A., Masliah, E., Morey, M., Lemere, C., DeTeresa, R., Grafe, M., et al. (1991). Neocortical damage during HIV infection. Annals of Neurology, 29(6), 651-657. doi: 10.1002/ana.410290613 2. Nottet, H. S. L. M., & Gendelman, H. E. (1995). Unraveling the neuroimmune mechanisms for the HIV-1-associated cognitive/motor complex. Immunology Today, 16(9), 441-448. doi: 10.1016/0167-5699(95)80022-0 3. Grant, I. (2008). Neurocognitive disturbances in HIV. International Review of Psychiatry, 20(1), 33-47. doi: doi:10.1080/09540260701877894 4. Heaton, R. K., Grant, I., Butters, N., White, D. A., & et al. (1995). The HNRC 500: Neuropsychology of HIV infection at different disease stages. Journal of the International Neuropsychological Society, 1(3), 231-251. 5. Gorman, A., Foley, J., Ettenhofer, M., Hinkin, C., & van Gorp, W. (2009). Functional Consequences of HIV-Associated Neuropsychological Impairment. Neuropsychology Review, 19(2), 186-203. doi: 10.1007/s11065-009-9095-0 6. Heaton, R. K., Marcotte, T. D., Mindt, M. R., Sadek, J., Moore, D. J., Bentley, H., et al. (2004). The impact of HIV-associated neuropsychological impairment on everyday functioning. Journal of the International Neuropsychological Society, 10(3), 317-331. 7. Hinkin, C. H., Castellon, S. A., Durvasula, R. S., Hardy, D. J., Lam, M. N., Mason, K. I., et al. (2002). Medication adherence among HIV+ adults: Effects of cognitive dysfunction and regimen complexity. Neurology, 59(12), 1944-1950.

20. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University References 8. Marcotte, T. D., Wolfson, T., Rosenthal, T. J., Heaton, R. K., Gonzalez, R., Ellis, R. J., et al. (2004). A multimodal assessment of driving performance in HIV infection. Neurology, 63(8), 1417-1422. doi: 10.1212/01.wnl.0000141920.33580.5d 9. van Gorp, W. G., Rabkin, J. G., Ferrando, S. J., Mintz, J., Ryan, E., Borkowski, T., et al. (2007). Neuropsychiatric predictors of return to work in HIV/AIDS. Journal of the International Neuropsychological Society, 13(1), 80-89. doi: http://dx.doi.org/10.1017/S1355617707070117 http://dx.doi.org/10.1017/S1355617707070117 10. Antinori, A., Arendt, G., Becker, J. T., Brew, B. J., Byrd, D. A., Cherner, M., et al. (2007). Updated research nosology for HIVassociated neurocognitive disorders. Neurology, 69, 1789-1799. 11. Dore, G. J., McDonald, A., Li, Y., Kaldor, J. M., & Brew, B. J. (2003). Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS, 17(10), 1539-1545. doi: http://dx.doi.org/10.1097/00002030-200307040-00015 12. Sacktor, N., Lyles, R. H., Skolasky, R., Kleeberger, C., Selnes, O. A., Miller, E. N., et al. (2001). HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990-1998. Neurology, 56(2), 257-260. 13. Simioni, S., Cavassini, M., Annoni, J.-M., Rimbault Abraham, A., Bourquin, I., Schiffer, V., et al. (2010). Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS, 24(9), 1243-1250 1210.1097/QAD.1240b1013e3283354a3283357b. 14. Ellis, R., Langford, D., & Masliah, E. (2007). HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci, 8(1), 33-44.

21. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University References 15. Vivithanaporn, P., Heo, G., Gamble, J., Krentz, H. B., Hoke, A., Gill, M. J., et al. (2010). Neurologic disease burden in treated HIV/AIDS predicts survival. Neurology, 75(13), 1150- 1158. doi: 10.1212/WNL.0b013e3181f4d5bb 16. Joska, J., Westgarth-Taylor, J., Myer, L., Hoare, J., Thomas, K., Combrinck, M., et al. (2010). Characterization of HIV-Associated Neurocognitive Disorders Among Individuals Starting Antiretroviral Therapy in South Africa. AIDS and Behavior, 1-7. doi: 10.1007/s10461-010-9744-6 17. Robertson, K. R., Nakasujja, N., Wong, M., Musisi, S., Katabira, E., Parsons, T. D., et al. (2007). Pattern of neuropsychological performance among HIV positive patients in Uganda. BMC Neurology, 7, 8. 18. McArthur, J. C., & Brew, B. J. (2010). HIV-associated neurocognitive disorders: is there a hidden epidemic? AIDS, 24(9), 1367-1370 1310.1097/QAD.1360b1013e3283391d3283356. 19. Power, C., Selnes, O. A., Grim, J. A., & McArthur, J. C. (1995). HIV Dementia Scale: A Rapid Screening Test. JAIDS Journal of Acquired Immune Deficiency Syndromes, 8(3), 273-278. 20. Sacktor, N. C., Wong, M., Nakasujja, N., Skolasky, R. L., Selnes, O. A., Musisi, S., et al. (2005). The International HIV Dementia Scale: A new rapid screening test for HIV dementia. AIDS, 19(13), 1367-1374.

22. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University References 21. Nasreddine, Z. S., Phillips, N. A., Bedirian, V., Charbonneau, S., Whitehead, V., Collin, I., et al. (2005). The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment. Journal of the American Geriatrics Society, 53(4), 695-699. doi: http://dx.doi.org/10.1111/j.1532-5415.2005.53221.x http://dx.doi.org/10.1111/j.1532-5415.2005.53221.x 22. Koski, L., Brouillette, M. J., Lalonde, R., Hello, B., Wong, E., Tsuchida, A., et al. (2011). Computerized testing augments pencil-and-paper tasks in measuring HIV-associated mild cognitive impairment*. HIV Medicine, no-no. doi: 10.1111/j.1468-1293.2010.00910.x 23. Manly, J. J., Byrd, D. A., Touradji, P., & Stern, Y. (2004). Acculturation, reading level, and neuropsychological test performance among African American elders. Applied Neuropsychology, 11(1), 37-46. 24. Manly, J. J., & Espino, D. V. (2004). Cultural influences on dementia recognition and management. Clinics in Geriatric Medicine, 20(1), 93-119. 25. Manly, J. J., Jacobs, D. M., Touradji, P., Small, S. A., & Stern, Y. (2002). Reading level attenuates differences in neuropsychological test performance between African American and White elders.[erratum appears in J Int Neuropsychol Soc 2002 May;8(4):605]. Journal of the International Neuropsychological Society, 8(3), 341-348. 26. Manly, J. J., Touradji, P., Tang, M. X., & Stern, Y. (2003). Literacy and memory decline among ethnically diverse elders. Journal of Clinical & Experimental Neuropsychology, 25(5), 680-690.

23. HIV CENTER for Clinical and Behavioral Studies at NY State Psychiatric Institute and Columbia University References 27. Joska, J. A., Westgarth-Taylor, J., Hoare, J., Thomas, K. G. F., Paul, R., Myer, L., et al. (2011). Validity of the International HIV Dementia Scale in South Africa. AIDS Patient Care and STDs, 25(2), 95-101. doi: doi:10.1089/apc.2010.0292 28. Singh, D., Sunpath, H., John, S., Eastham, L., & Gouden, R. (2008). The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts- a preliminary report. African Journal of Psychiatry, 11(4), 282-286. 29. Ganasen, K. A., Fincham, D., Smit, J., Seedat, S., & Stein, D. (2008). Utility of the HIV Dementia Scale (HDS) in identifying HIV dementia in a South African sample. Journal of the Neurological Sciences, 269(1-2), 62-64.

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