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.
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.
HIV-associated Neurocognitive Disorders (HAND)
Acquired
Impairment in ≥2
Cognitive Abilities
Interferes
with Daily
Functioning
Asymptomatic
Neurocognitive
Impairment (ANI)
YES
NO
Mild Neurocognitive
Disorder (MND)
YES
MILD
MARKED
MARKED
HIV-Associated
Dementia (HAD)
No Pre-Existing Cause, Delirium absent
Antinori et al., Neurology 2007
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
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
Demographics in HIV- & HIV+ groups
HIV-
HIV+
P
N
49
90
-
Age
54 ± 6
56 ± 7
ns
Age > 60 years old
22.4%
33.3%
ns
Education
15 ± 2
14 ± 2
ns
Gender (% male)
100%
100%
-
Ethnicity (% Anglo-Australian)
96%
93%
ns
WAIS-III VIQ 1
111 ± 6
110. ± 5
ns
HIV Risk groups (%MSM)
85%
86%
-
Clinical characteristics in HIV+ groups
HIV Disease characteristics
HIV+ group
Inter-quartile range
Estimated HIV duration (Median years)
20.6
14.6-25.5
% AIDS (CDC 1993)
72.2%
-
% AIDS Defining Illness
46.7%
-
Nadir CD4 (cells/mL Median)
180
60 – 286
Current blood CD4 (cells/mL, Median)
528
342 - 721
Current blood CD8 (cells/mL , Median)
805
629-1150
% Plasma HIV RNA (< 50 cp/m/L “undetectable”)
98.0%
-
% CSF HIV RNA (< 50 cp/m/L “undetectable”)
97.4%
-
Current cART duration (months)
24
18-48
Neuropsychological Battery
7 Cognitive domains
11 Individual neuropsychological measures
Executive functions
Trail Making Test B time in seconds
Verbal generativity
COWAT “Letter Fluency” (Letter FAS) total correct
Semantic Verbal Fluency (Animal Category) total correct
Verbal learning
HVLT-R total Learning (total correct)
Verbal memory
HVLT-R delayed Recall (total correct)
Motor coordination
Grooved 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 memory
WAIS-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)
Statistical Procedure 1
U.S. Global Scaled Score
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 T-scores
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)
Global impairment rate in Australian HIV- & HIV+
70.0
70.0
Entire sample
15 with Hx HAND excluded
p<.0001
60.0
60.0
p<.0001
57.8%
50.0
50.0
40.0
40.0
30.0
30.0
53.3%
p<.03
20.0
20.0
p=.06
17.8%
14.3%
10.0
0.0
14.3%
4.1%
4.1%
U.S. norm-based GDS
14.7%
10.0
0.0
HIV-
HIV+
Local-norm-based GDS
Local-norm-based GDS
U.S. norm-based GDS
HIV-
HIV+
Impairment classification (GDS≥0.5) based on the local norms was best at
discriminating between the 2 groups
HAND
ANI is the most frequent HAND category
90.0
80.0
82.2
70.0
60.0
50.0
40.0
42.2
37.8
30.0
20.0
14.5
10.0
8.8
0.0
NP-normal
ANI
US norms based GDS
4.6
MND
Local norms based GDS
4.4
5.5
HAD
Standard mean difference (HIV- vs. HIV+) between US
norms and local norms on neuropsychological performance
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
Verbal genera vity Execu ve Func ons
Learning
Delayed Recall
Local norms
Speed Processing
Working Memory Motor-coordina on Global mean score
U.S. norms
The two sets of norms generated overall a similar profile. But the magnitude of
effect sizes was greater when the local norms were used
Clinical and HIV relations to neuropsychological performance
HIV Disease characteristics
US norm-based GDS
Local norm-based GDS
HIV duration (years)
.02
.02
% AIDS (CDC 1993)
.15
.08
.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
.18
% AIDS Defining Illness (yes/no)
Pearson r are reported *p≤.05; **p≤.01
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 ageand education-effects indicating that U.S.
norms are likely to be useful in a moreaverage-functioning sample
•
Further research is needed to determine
whether US norms generalize better to the
broader Australian population.
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
Acknowledgements
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.