1. Prevalence of HIV-associated neurocognitive disorder in a high-functioning and optimally treated Australian cohort: implications for international neuroHIV research Lucette A. Cysique 1 2 3 4 ; Robert K. Heaton 5 ; Jody Kamminga 2 4 ; Tammy Lane 3 ; Thomas M. Gates 1 4 ; Danielle M. Moore 4 ; Emma Hubner 4 ; Andrew Carr 1,4,6 & Bruce J. Brew 1 3 4 1. University of New South Wales, St. Vincent’s Clinical School, Sydney Australia. 2. Neuroscience Research Australia, Sydney (http://www.neura.edu.au/research/themes/cysique-group). 3. St. Vincent’s Hospital; Neurology & Imaging & HIV Departments Sydney, Australia. 4. St. Vincent’s Hospital Centre for Applied Medical Research, Sydney, Australia 5. HIV Neurobehavioral Research Center (HNRC; http://hnrc.hivresearch.ucsd.edu/), Department of Psychiatry, University of California at San Diego, San Diego, California. 6. St. Vincent’s Hospital; HIV, Immunology and Infectious Diseases Unit Sydney, Australia.

2. No Pre-Existing Cause, Delirium absent Antinori et al., Neurology 2007 HIV-associated Neurocognitive Disorders (HAND)

3. Background The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM) Like other English-speaking countries, Australia mostly relies on U.S. neuropsychological normative standards to detect and determine the prevalence of neurological disorders Whether the U.S. NP normative standards are appropriate in Australian HIV+ MSM has not been established

4. Aims 1.To determine the rate of neuropsychological impairment in Australian HIV- versus HIV+ individuals using U.S. normative standards (U.S. norms) 2.To compare the HIV effects on neuropsychological impairment generated from the U.S. normative standards versus impairment generated from the demographically comparable local HIV- control group (Australian local norms) 3.To determine which HIV and other clinical & laboratory markers predict the degree of impairment and the presence of impairment

5. Demographics in HIV- & HIV+ groups HIV-HIV+P N4990- Age54 ± 656 ± 7ns Age > 60 years old22.4%33.3%ns Education15 ± 214 ± 2ns Gender (% male)100% - Ethnicity (% Anglo-Australian)96%93%ns WAIS-III VIQ 1 111 ± 6110. ± 5ns HIV Risk groups (%MSM)85%86%-

6. Clinical characteristics in HIV+ groups HIV Disease characteristicsHIV+ groupInter-quartile range Estimated HIV duration (Median years) 20.614.6-25.5 % AIDS (CDC 1993) 72.2%- % AIDS Defining Illness46.7%- Nadir CD4 (cells/mL Median) 18060 – 286 Current blood CD4 (cells/mL, Median) 528342 - 721 Current blood CD8 (cells/mL, Median) 805629-1150 % Plasma HIV RNA (< 50 cp/m/L “undetectable”) 98.0%- % CSF HIV RNA (< 50 cp/m/L “undetectable”) 97.4%- Current cART duration (months) 2418-48

7. Neuropsychological Battery 7 Cognitive domains11 Individual neuropsychological measures Executive functionsTrail Making Test B time in seconds Verbal generativity COWAT “Letter Fluency” (Letter FAS) total correct Semantic Verbal Fluency (Animal Category) total correct Verbal learningHVLT-R total Learning (total correct) Verbal memoryHVLT-R delayed Recall (total correct) Motor coordinationGrooved Pegboard dominant & Non-dominant hands in seconds Speed of information processing Trail Making Test A time in seconds WAIS-III Digit-symbol Coding total correct Attention/ working memoryWAIS-III Letter-number sequencing total correct WMS-III Spatial span total correct Battery is in widespread use for NeuroAIDS research in the U.S. (Heaton et al, 2010)

8. Statistical Procedure 1 The raw neuropsychological data were transformed using: 1. U.S. standards as uncorrected scaled scores and demographically-corrected T-scores (US norms, Heaton et al. 2004) 2. Z-scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms) 3. To determine HIV-associated neurocognitive disorder prevalence, we used the Global Deficit Score (GDS) U.S. Global Scaled Score U.S. Global T-scores

9. Statistical Procedure 2 Compared to U.S. norms, the Australian HIV- group performed slightly better on neuropsychological testing than expected for their age (d=0.30) and education (d=0.26)

10. Global impairment rate in Australian HIV- & HIV+ Entire sample15 with Hx HAND excluded Impairment classification (GDS≥0.5) based on the local norms was best at discriminating between the 2 groups

11. HAND ANI is the most frequent HAND category

12. Standard mean difference (HIV- vs. HIV+) between US norms and local norms on neuropsychological performance The two sets of norms generated overall a similar profile. But the magnitude of effect sizes was greater when the local norms were used

13. Clinical and HIV relations to neuropsychological performance HIV Disease characteristicsUS norm-based GDSLocal norm-based GDS HIV duration (years).02 % AIDS (CDC 1993).15.08 % AIDS Defining Illness (yes/no).20 *.06 Nadir CD4 (cells/mL).04.02 Current blood CD4 (cells/mL).01.07 Current CART duration (months).11.10 Cardio-vascular D.A.D. score (high/low risk).02.25 * Significant decrease in independence in daily living.33*.36 ** Depressive symptoms.18 Pearson r are reported *p≤.05; **p≤.01

14. Conclusions: for Australia Population norms are needed in Australia possibly with both education and premorbid abilities corrections to account for especially high and low functioning subgroups U.S. T-score corrections greatly reduce age- and education-effects indicating that U.S. norms are likely to be useful in a more- average-functioning sample Further research is needed to determine whether US norms generalize better to the broader Australian population.

15. Implications for international neuroHIV research Population norms are ideally needed with each country? IS THIS POSSIBLE? IN LOCAL CONTROLS ideal demographic factors would be: High income countries: age, education, sex, pre-morbid index (& socio-historical racial/ethnicity construct when relevant) Low to medium income countries : + rural vs. urban residence; access, quality of education; poverty index… & complex effects (gender*education): work with local researchers The presence of absence of such corrections dramatically change the interpretation of neuropsychological data & any relations to clinical & laboratory markers

16. This study was supported by the National Heath and Medical Research Council of Australia project grant ID568746 (Cysique CIA/PI), the 2009-2012 post-doctoral Brain Science UNSW fellowship (Cysique), 2012 Mercks Sharp Dome (MSD) partial salary support for 2012, the National Heath and Medical Research Council of Australia Career Development Fellowship APP1045400 (Cysique CIA/PI) and the Peter Duncan Neurosciences Unit (Head Prof. Bruce Brew). MSD had no direct participation in the current study design, data analyses and interpretation. We would like to give a special thanks to all our participants for their time and involvement in the project and also special thanks to all our associated research & hospital staff. Acknowledgements