Incidence and nature of cognitive decline over 1 year
among HIV-infected former plasma donors in China
Lucette A. Cysiquea,g, Scott L. Letendreb, Christopher Akea, Hua Jina,d,
Donald R. Franklina, Saurabh Guptaa, Chuan Shie, Xin Yue,
Zunyou Wuf, Ian S. Abramsonc, Igor Granta, Robert K. Heatona,
and the HIV Neurobehavioral Research Center group
Objective: To quantify and characterize the nature of cognitive change over 1 year in a
cohort of HIV-positive former plasma donors in rural China.
Design: The present study is an observational cohort study.
Methods: One hundred and ninety-two HIV-positive and 101 demographically comparable HIV-negative individuals, all former plasma donors, who lived in a rural part of
China, received comprehensive medical and neuropsychological examinations. At
study entry, 56% of HIV-positive group was on combination antiretroviral treatment and
60.9% at follow-up. Multiple regression change score approach was used with the
HIV-negative sample to develop norms for change that would be then applied to
the HIV-positive participants. Follow-up test scores adjusted for the control group
practice effect.
Results: Fifty-three HIV-positive individuals (27%) developed significant cognitive
decline as compared with five (5%) HIV-negative individuals. Cognitive decline was
predicted at baseline by AIDS status, lower nadir CD4, and worse processing speed; at
follow-up, it was associated with lower current CD4 cell count and failure of viral
suppression on combination antiretroviral treatment. Neuropsychological decline also
was associated with decreased independence in activities of daily living. Using
neuropsychological impairment scores that were corrected for ‘practice’ on repeated
testing, we found that among the decliners, 41.5% (N ¼ 22) had incident impairment,
whereas 38% (N ¼ 20) declined within the impaired range and another 20.7% (N ¼ 11)
declined within the normal range.
Conclusion: The present study demonstrates that despite ongoing combination antiretroviral treatment, cognitive decline in HIV-positive people is common over a 1-year
follow-up. Regression-based norms for change on western neuropsychological tests
can be used to detect disease-related cognitive decline in a developing country.
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2010, 24:983–990
Keywords: antiretroviral therapy, China, highly active, HIV/AIDS, incidence
studies, longitudinal studies, neurocognitive disorders, neuropsychological tests
a
Department of Psychiatry, bDepartment of Medicine, cDepartment of Mathematics, and HIV Neurobehavioral Research Center
(HNRC), University of California at San Diego, dVA San Diego Healthcare System, San Diego, California, USA, eInstitute of Mental
Health, Peking University, fNational Center for AIDS/STD Control & Prevention (NCAIDS), Beijing, China, and gDepartment of
Psychiatry, Brain Sciences, University of New South Wales, Sydney, Australia.
Correspondence to Robert K. Heaton, Department of Psychiatry, University of California San Diego, 9500 Gilman Drive #0603, La
Jolla, CA 92093-0603, USA.
Tel: +1 858 534 4044; fax: +1 858 534 9917; e-mail: rheaton@ucsd.edu
Received: 26 July 2009; revised: 31 August 2009; accepted: 18 September 2009.
DOI:10.1097/QAD.0b013e32833336c8
ISSN 0269-9370 Q 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Introduction
Several recent studies have provided prevalence estimates
of HIV-associated neurocognitive disorders (HAND) [1]
in ‘nonwestern’ regions of the world such as sub-Saharan
Africa [2,3], India [4], China [5,6], and south-east Asia
[7]. Taken together, the findings of these studies have
demonstrated that HAND can be validly assessed in
resource-limited countries, when using appropriate
control samples. HAND prevalence appears to be similar
in these areas of the world to the estimates reported with
western HIV-positive cohorts (i.e., 20–50%, depending
upon disease stages and comorbid conditions [8]).
Combination antiretroviral therapy (cART) has greatly
decreased HIV-associated mortality and medical morbidity, including HIV-associated dementia (HAD), but the
prevalence of milder forms of HAND remains high [8].
Several longitudinal cohort studies in western countries
have assessed cognitive decline and its potential contributing factors in the cART era [9–13]. Published
studies, after varying follow-up periods, have found that
between 22 and 63% of participants on cART demonstrated continuing impairment and at least 21% had
incident impairment [12,13]. Variability in these estimates of cognitive impairment and change probably is
related to methodological factors such as inclusion of
appropriate normative standards for detecting these
outcomes [14].
Just as it is important to define cross-sectional neuropsychological impairment in individual cases, rather than
relying on group mean comparisons, longitudinal
methods for classifying meaningful neuropsychological
change in individuals also are needed. Advantages of
reliably detecting cognitive change at the individual level
include understanding factors responsible for variable
manifestations and course of HAND, and alerting
clinicians to consider changes in antiretroviral regimens
early (e.g., to include agents with better central nervous
system (CNS) penetration [15] or adjunctive treatments
that may specifically benefit the CNS [16]).
To our knowledge, the current study is the first to assess
long-term neurocognitive outcomes in a large cohort of
HIV-positive persons in China and in the cARTera. Our
aim was to detect and quantify neuropsychological
decline over a 1-year period in 192 individual HIVpositive former plasma donors (FPDs) in the Chinese
province of Anhui. For this, we developed norms for
change using longitudinal data of a fairly large sample
(N ¼ 101) of demographically comparable HIV-negative
individuals. The norms for change were derived using a
regression change score approach [17,18]. Here we
propose an extension of this method by introducing a
battery approach to derive a normed summary change
score for each individual. In addition, we propose an
adaptation of the Global Deficit Score method [19,20] to
estimate follow-up impairment rate corrected for practice
effect.
Methods
Participants
Details regarding participant recruitment procedures and
baseline results were published in study by Heaton et al. [6].
Briefly, at baseline, 203 HIV-positive and 198 HIVnegative participants, virtually all of whom were farmers in
the rural area of Anhui province, were enrolled into the
study at a local hospital in Fuyang city. By design, at
12 months postbaseline, half of the baseline HIV-negative
participants (N ¼ 101) were reassessed. In addition, all
available HIV-positive participants were reassessed
(N ¼ 192), yielding a 5.4% (11/203) attrition rate. The
causes for dropout were one case of cerebral infarct; two
cases of blindness and an additional case of substantial vision
decline precluding valid neuropsychological testing; four
moved away for work; and three deaths. The 101 HIVnegative participants had been randomly selected in order
to compose a sample representative of the total baseline
group with respect to demographic and baseline neuropsychological characteristics. This sample of HIV-negative
participants was followed up at 1 year in order to develop
normative standards for neuropsychological change (see
also e-data analysis, http://links.lww.com/QAD/A35). At
baseline, 106 (55.2%) of the 192 HIV-positive participants
met CDC-1993 criteria for AIDS. Virtually, the same
subgroup (N ¼ 107; 55.7%) was being prescribed cART at
baseline consistent with prevailing antiretroviral initiation
guidelines in China. HIV duration estimated from selfreport averaged 154 months (SD ¼ 42). When they were
retested after 12 months, 20 additional HIV-positive participants had transitioned to AIDS and at that time, 60.9% of
the total group was receiving cART.
Procedure
As in the baseline assessment, participants underwent
comprehensive neurocognitive and neuromedical evaluations, and a structured psychiatric examination, as well as
a self-report assessment of daily functioning. Examinations were performed by the same Chinese psychiatric
staff who had conducted the baseline assessments the
previous year. They had been trained and certified in the
standardized testing procedures by the US research team
(R.K.H., D.F., and H.J.). Prior to starting the second
annual testing phase, the Chinese examiners participated
in another training session in order to review and practice
test administration and test scoring procedures.
Details of the neuropsychological battery selection and
adaptation for use in China are provided in studies by
Cysique et al. [5] and Heaton et al. [6] (see also Table e-1
& e-2). Clinical significance of any neuropsychological
impairment or change was examined with standard
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cognitive decline in HIV infection Cysique et al.
instruments measuring participants’ experience of cognitive difficulties in everyday life (Patient’s Assessment of
Own Functioning Inventory – PAOFI [21]) and
decreases in degree of independence in activities of daily
living [modified version of the Lawton & Brody
Instrumental Activities of Daily Living (IADL) scale
[22]]. Participants also completed the Beck Depression
Inventory-II (BDI-II [23,24]).
Data analysis
To identify individuals who presented with overall
neuropsychological change, we used a statistical methodology based on the multivariate regression change score
approach (see [17,18] for review of this change score
approach). The advantage of the regression-based change
score approach is that it accounts for practice effect,
regression toward the mean, and other factors that may
influence normal test–retest variability in neurologically
stable people (e.g., test–retest interval, demographics, and
overall baseline neuropsychological competence [18]).
Our detailed method is available in the supplemental file eData analysis, http://links.lww.com/QAD/A35. Briefly,
to define neuropsychological decline in the HIV-positive
sample, the 101 HIV-negative individuals were used as
a reference sample to develop normative regression
formulas. The final regression formulas were then applied
to the HIV-positive sample providing a Z-score for each of
17 neuropsychological variables. These Z-scores reflect
how well or poorly the person performed at follow-up,
relative to normal expectation for someone with the same
baseline neuropsychological and other relevant characteristics. The Z-scores were then summed to provide a
summary regression change score (sRCS). We determined
a 90% confidence interval (CI) on the sRCS to define ‘no
change’ on the test battery. That is, the cut-off for the top
5% of the sRCS distribution of the HIV-negative controls
defined the ‘improved’range and the cut-off for the bottom
5% defined the ‘decliners’ range. This was applied to the
HIV-positive sample (Fig. 1).
Secondary analyses were conducted to clarify the nature
of both baseline predictors and follow-up correlates of
100
95%
Overall X
2
(2)
= 21.5; P < 0.0001
90
% Participants
80
72.4%
70
60
50
40
27.6%
30
20
5%
10
0
Stable HIV
(n = 96)
Declined HIV
(n = 5)
Stable HIV+
(n = 139)
Declined HIV+
(n = 53)
Fig. 1. Percentage of neuropsychological change as defined
by the summary of regression change score in the HIVpositive and HIV-negative samples.
cognitive decline in this population. The HIV-positive
decliners and nondecliners (as defined by the sRCS) were
compared on baseline and follow-up demographic, HIV
disease-related laboratory measures, AIDS status, Global
Deficit Score (GDS), and ability domain summary scores
on the neuropsychological test battery, treatment-related
variables, cognitive complaints, IADL, and BDI-II using
t-test or x2 test as appropriate. We also conducted standard
multivariate analyses to define which combination of
baseline factors provided the most robust prediction of
neuropsychological decline (defined by the sRCS).
The GDS and ability domain T-scores at follow-up were
corrected for the HIV-negative sample median practice
effect (see also e-Data analysis, http://links.lww.com/
QAD/A35 [6,19,20]).
Results
The baseline demographic characteristics of the HIVnegative and HIV-positive persons who participated in
the 12-month follow-up assessment are presented in
Table 1. Test–retest correlations on the neuropsychological battery were robust for both groups [HIV-negative
group’s mean scaled score rtt ¼ 0.85 and HIV-positive
group’s mean scaled score rtt ¼ 0.84].
Incidence of neuropsychological decline in the HIVpositive group (27.6%) was significantly greater than that
in our reference HIV-negative sample (5%) as defined by
the sRCS approach [x2 (1) ¼ 21.4; P < 0.0001]. We found
that 53 HIV-positive individuals were classified as having
neuropsychological decline at the 12-month follow-up
(i.e., they performed below the 5% cut-off reference
range that defined the ‘decliners’ in the HIV-negative
sample; CI of 95% one-tailed; see Fig. 1).
When comparing the 53 HIV-positive participants who
were classified as decliners at the 12-month follow-up
with the 139 HIV-positive nondecliners, we found that
decliners tended to be older (P < 0.08), were more likely
to have AIDS at baseline (P < 0.03), and had lower nadir
CD4 count (P < 0.05). At follow-up, they had lower
current CD4 cell count (P < 0.03) and also were more
likely to have detectable virus in plasma when on cART
(P < 0.01; Table 2). To explore further the CD4 cell
count finding at follow-up and take into account any
cART effect, a two-way analysis of variance (ANOVA)
was performed with the CD4 cell count at follow-up as
the outcome variable, and the decliner status as well as the
treatment status at baseline (whether receiving cART or
not at baseline) as predictors, and their interaction. We
found that the follow-up CD4 cell count still tended to
differ between the decliners and nondecliners (P ¼ 0.06).
No other findings approached statistical significance.
Importantly, the decliner and nondecliner groups did not
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Table 1. Baseline characteristics of 101 HIV-negative and 192 HIV-positive participants at 1-year follow-up.
Baseline
Age (years) [mean (SD)]
Education (years) [mean (SD)]
Sex (%) male
AIDS (%)
Plasma HIV RNAa [median (IQR)]
Plasma HIV RNA (%) undetectable
On cART (%)
Current CD4 cell count [median (IQR)]
Nadir CD4 cell count [median (IQR)]
HCV-positive (%)
Follow-up
New AIDS diagnosis (%)
Plasma HIV RNAb [median (IQR)]
Plasma HIV RNA (%) undetectable
On cARTc (%)
Current CD4 cell count [median (IQR)]
HIV-negative (n ¼ 101)
HIV-positive (n ¼ 192)
P
d
40.8 (6.7)
5.8 (2.1)
56%
–
–
–
–
–
40.2 (6.3)
5.5 (2.3)
61%
55%
4.2 (3.5–4.7)
34%
56.3% (N ¼ 107)
346 (204–454)
200 (159–360)
92.7%
0.42
0.15
0.40
–
–
–
–
–
–
<0.0001
0.09
0.13
0.10
–
–
–
–
–
–
0.46
10% (N ¼ 20)
4.2 (3.6–4.8)
39%
60.9% (N ¼ 117)
375 (11–1173)
–
–
–
–
–
–
–
–
–
–
67.3%
–
–
–
–
ART, antiretroviral treatment; d, Cohen’s d; HCV, hepatitis C virus; IQR, interquartile range.
(N ¼ 127 detectable).
b
(N ¼ 117 detectable).
c
At follow-up, among the participants on ART, all were on cART defined as a regimen composed of at least three antiretroviral drugs except for one
patient who was on monotherapy. This is higher than baseline wherein, in this sample, 89% were on cART; 9% on dual therapy, and 2% on
monotherapy. Most commonly prescribed ART drugs were stavudine (N ¼ 103); nevirapine (N ¼ 98); didanosine (N ¼ 77); and lamivudine
(N ¼ 51). Other drugs prescribed less frequently were efavirenz (N ¼ 10); atazanavir (N ¼ 7); and zidovudine (N ¼ 8). The restricted range did not
allow testing central nervous system (CNS) penetration effectiveness [15]. However, it should be noted that overall, the CNS penetration
effectiveness ratings for ART regimens in this cohort are fairly low, suggesting that some individuals may be suboptimally treated for their CNS HIVrelated injury.
a
Table 2. Baseline and follow-up characteristics in HIV-positive persons who declined versus those who did not decline on the
neuropsychological battery.
Age [mean (SD)]
Education [mean (SD)]
Sex (%)
Neuropsychologically impaired [baseline (%)]
Neuropsychologically impaired [follow-up (correcteda) %]
Global Deficit Score baseline [mean (SD)]
Global Deficit Score follow-up [(correcteda) mean (SD)]
HCV-positive (%)
Estimated HIV duration [(months) mean (SD)]
AIDS (%) baseline
AIDS (%) follow-up
New AIDS-defining illnesses (%)
BDI-II baseline (% clinically depressed)b
BDI-II follow-up (% clinically depressed)b
On cART at baseline (Total N ¼ 107; 35 decliners, 72 nondecliners) (%)
On cART at follow-up (Total N ¼ 117; 38 decliners, 79 nondecliners) (%)
cART duration at follow-up [(months) mean (SD)]
Current CD4 cell count at baseline [mean (SD)]
Current CD4 cell count at follow-up [mean (SD)]
CD4 nadir count [mean (SD)]
CD4 nadir count <200%
Percentage of undetectable VL at baseline (<50 copies/ml, total sample %)
Percentage of undetectable VL at follow-up (<50 copies/ml, total sample %)
Percentage of undetectable VL at baseline (<50 copies/ml, on cART at baseline %)
Percentage of undetectable VL at follow-up (<50 copies/ml, on cART at follow-up %)
Declined
(N ¼ 53)
Did not decline
(N ¼ 139)
P
d
41.6 (6.6)
5.2 (2.4)
60.4%
37.7%
79.2%
0.52 (0.4)
0.91 (0.5)
94.3%
161 (36)
68.0%
71.1%
9.4%
26.4%
20.7%
66.0%
71.7%
139 (58)
324 (186)
352 (184)
233 (159)
62.3%
33.9%
32.1%
40% (14/35)
39.5% (15/38)
39.6 (6.2)
5.6 (2.2)
61.9%
36.7%
28.8%
0.49 (0.5)
0.40 (0.4)
92.1%
152 (44)
50.4%
63.8%
10.1%
25.2%
8.6%
52.5%
56.8%
124 (70)
365 (203)
422 (225)
268 (156)
46.0%
33.8%
41.2%
55.5% (40/72)
64.5% (51/79)
<0.08
0.34
0.85
0.89
<0.0001
0.65
<0.0001
0.59
0.13
<0.03
0.30
0.89
0.86
0.02
0.09
0.06
0.22
0.19
<0.03
0.17
<0.05
0.98
0.22
0.13
<0.01
0.32
0.17
0.03
0.02
1.2
0.06
1.2
0.08
0.21
0.36
0.17
0.03
0.02
0.32
0.27
0.32
0.22
0.20
0.32
0.22
0.33
0.01
0.20
0.24
0.42
ART, antiretroviral treatment; d, Cohen’s d; HCV, hepatitis C virus; VL, viral load. Test–retest interval did not differ between the decliners and
nondecliners (333 37 versus 331 45; P ¼ 0.79). Level of adherence was high in this sample and there were no significant differences between
decliners and nondecliners at baseline: 100% of decliners on ART reported that they took their medication ‘Almost all of the time’ and 98.5% of
nondecliners on ART reported that they took their medication ‘Almost all of the time’. At follow-up, 94.7% of decliners on ART reported that they
took their medication ‘Almost all of the time’ and 98.8% of nondecliners on ART reported that they took their medication ‘Almost all of the time’.
There were no significant differences in baseline demographics (age, P ¼ 0.44; education, P ¼ 0.86; sex, P ¼ 0.10) and baseline overall
neuropsychological performance (P ¼ 0.35) between the five HIV-negative decliners and 96 HIV-nondecliners.
a
The Global Deficit Score was based on T-scores corrected for HIV-negative median practice effect.
b
BDI-II: Beck Depression Inventory-II; (a score 17 reflects threshold for clinical level of depressive complaints).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cognitive decline in HIV infection Cysique et al.
Table 3. Mean and domain T-scores in HIV-positive persons who declined versus those who did not decline.
Declined (N ¼ 53)
Mean T-score baseline [mean (SD)]
Executive baseline [mean (SD)]
Verbal baseline [mean (SD)]
Attention/WM baseline [mean (SD)]
Learning baseline [mean (SD)]
Memory baseline [mean (SD)]
Motor baseline [mean (SD)]
SIP baseline [mean (SD)]
Mean T-score follow-up a [mean (SD)]
Executive follow-up a [mean (SD)]
Verbal follow-up a [mean (SD)]
Attention/WM follow-up a [mean (SD)]
Learning follow-up a [mean (SD)]
Memory follow-up a [mean (SD)]
Motor follow-up a [mean (SD)]
SIP follow-up a [mean (SD)]
44.5
45.1
46.3
45.1
45.2
44.2
46.5
42.5
40.2
40.6
42.3
42.4
39.4
37.2
42.4
38.6
(5.2)
(8.8)
(7.2)
(7.3)
(7.8)
(7.2)
(8.6)
(5.7)
(3.9)
(8.2)
(7.4)
(6.0)
(6.5)
(7.1)
(9.1)
(5.0)
Did not decline (N ¼ 139)
46.1
45.9
46.6
47.2
46.0
45.8
45.2
46.0
46.9
46.1
47.4
48.4
46.9
45.8
47.9
46.2
(6.1)
(9.3)
(8.1)
(8.4)
(8.9)
(8.3)
(10.3)
(7.2)
(5.4)
(7.9)
(8.1)
(8.4)
(8.4)
(8.3)
(9.4)
(6.7)
P
d
0.08
0.57
0.81
0.09
0.52
0.18
0.37
0.0005
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.002
<0.0001
0.27
0.09
0.04
0.26
0.06
0.20
0.13
0.51
1.31
0.68
0.64
0.76
0.93
1.06
0.58
1.19
SIP, speed of information processing; WM, working memory.
T-scores corrected for HIV-negative median practice effect.
a
differ in education and sex characteristics, or for
prevalence of hepatitis C virus (HCV) infection or
cART duration. They also did not differ in overall
baseline neuropsychological performance (GDS) or
prevalence of baseline neuropsychological impairment.
estimates in the HIV-negative controls also dropped from
an expected 14% to only 2% (P ¼ 0.0004). There is no
known biological reason for such change; this result
should, therefore, be considered as evidence for error due
to failure to correct for practice.
About one quarter of both the decliners and nondecliners
evidenced clinically significant level of depressive
symptoms (BDI-II 17) at baseline (26.4 versus
25.2%). At follow-up, neither group showed an increase
in rates of depression, but the nondecliners improved
somewhat more (see Table 2). Decliners and nondecliners
did not differ in their numbers of reported cognitive
problems either at baseline (P ¼ 0.22) or follow-up
(P ¼ 0.60), nor in the difference between baseline and
follow-up (P ¼ 0.13). Results remain comparable when
the BDI-II was entered as a covariate. However, decliners
were more likely to have significant decrease in IADL
independence at follow-up (9.4 versus 1.4%; P < 0.007;
significant decrease in IADL was defined as decrease in
dependence in at least two everyday functioning areas
[22]).
Although overall neuropsychological performance at
baseline did not differ between decliners and nondecliners, we did find that speed of information processing
(SIP) at baseline was significantly lower in the HIVpositive who would go on to decline as compared with
the nondecliners (medium effect size, d ¼ 0.51 – see
Table 3). At follow-up and using the practice effect
corrected neuropsychological scores to derive demographically corrected ability domain T-scores, we found
that the decliners demonstrated significantly lower
performance in all domains when compared with the
nondecliners, with the greatest difference found in
learning, memory, and SIP (all large effect sizes; d > 0.8).
Although neuropsychological impairment rates for the
decliners and nondecliners were almost identical at
baseline (37.7 versus 36.7%, respectively), not surprisingly, a much higher prevalence of impairment was seen
in the decliners at follow-up (79.25 versus 28.78%;
P < 0.0001). Overall impairment rate in the HIV-positive
group at follow-up was 42.71% (82/192), which was just
slightly higher than that at baseline (36.9%; 71/192).
When using the follow-up scores that were uncorrected
for practice effect, 51% of decliners and 15.1% of
nondecliners would be classified neuropsychologically
impaired at follow-up (and only 25% in the total HIVpositive group – see also Table e-2 e-Data analysis,
http://links.lww.com/QAD/A35). Importantly, without
correction for practice effect, impairment prevalence
We found that among the 53 HIV-positive decliners, 22
(41.5%) showed incident impairment on the corrected
GDS at follow-up. Eleven (20.7%) declined within the
normal range and another 20 (38%) declined within the
impaired range. These subgroups did not statistically
differ on the sRCS.
Finally, we tested predictors of cognitive change using a
stagewise regression approach. First, in a multivariate
model with the sRCS as the outcome and including the
predictors that were found (P < 0.10) to be different
between HIV-positive decliners and nondecliners at
baseline (see Table 2), we found that SIP (P ¼ 0.004) and
AIDS at baseline (trending at P ¼ 0.06) remained unique
contributors to the model (R2 ¼ 0.10; P ¼ 0.007; baseline
age did not uniquely predict change). Second, in a final
two-covariate logistic regression model that predicted
decliners’ status, baseline SIP mean T-score had an odds
ratio of 1.07 (CI 1.03–1.13) for a one-unit decrease and
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2010, Vol 24 No 7
baseline AIDS had an odds ratio of 1.94 (CI 0.98–3.84)
relative to baseline non-AIDS.
Discussion
The present study demonstrated that performance on the
neuropsychological tests originally developed in western
regions of the world was quite reliable over time in both
the infected and uninfected rural Chinese participants.
Together with the earlier finding of greater baseline
impairment associated with HIV and HCV infections
and associations of neuropsychological impairment with
both HIV disease severity and indications of decreases
in everyday functioning [6], this suggests that neuropsychological tests standardized and widely used in western
regions of the world (here historically and geographically
defined as Europe, Australia, and North America)
generalize to people having very different cultural,
linguistic, and educational backgrounds. It may be,
therefore, that the abilities assessed by most or all of these
tests capture some universal features of cognition.
Moreover, using the regression change score approach
that has been validated mainly in non-HIV populations in
the United States, we found that we could detect
cognitive decline in 27.6% of the HIV-positive participants after a 1-year interval. This greatly exceeded the
expected 5% normative cut-off of the HIV-negative
sample. Even though our infected sample remained
relatively healthy from a general medical point of view
(average immune status improved and few participants
had new AIDS-defining illnesses) and reported excellent
adherence to their cART (Table 2), many evidenced
worsening of their neurocognitive status and slightly
fewer than expected showed any improvement. Thus,
though cART has dramatically improved the mortality
and medical morbidity associated with HIV disease, such
treatment appears less effective in alleviating or reversing
CNS compromise that has been observed since the
beginning of the HIV epidemic [25].
The minimal 12-month dropout rate (5%) for our
HIV-positive FPDs is remarkable and reflects high levels
of cooperation and dedication of the Chinese participants and examiners. Of the 11 baseline HIV-positive
patients who could not be retested, seven were
presumed to be due to HIV disease phenomena (three
deaths, one stroke, three with recent severe visual
impairment), so their loss to follow-up may have slightly
underestimated rates of HIV-related neuropsychological decline.
Similar to prior longitudinal neuropsychological findings
in western studies [26–29], test–retest interval in our
rural Chinese population was not a significant predictor of
variability in cognitive performance. Still, the variation in
retest interval was restricted by design (actual range 237–
494 days) and it is possible that more discrepant test–retest
intervals may have yielded different results. Also similar to
results in western studies, we found that the most robust
predictors of follow-up neuropsychological scores were
baseline scores on the same tests, as well as overall
neuropsychological competence at baseline [18,27,28,
30,31], and to a lesser extent age [27] (see also e-Data
analysis, http://links.lww.com/QAD/A35).
Supporting the current method for classifying change is
the fact that neuropsychological decline was associated
with markers of advanced HIV disease such as AIDS at
baseline and lower nadir CD4 count. The same diseaserelated predictors were associated with neuropsychological impairment at baseline [6]. Worse immune recovery,
as reflected by lower current CD4 cell counts at followup, also was associated with cognitive decline. Even
though both groups’ CD4 cell counts improved at followup, immune recovery was slightly worse for the decliners.
Although cART use and duration did not differ between
the groups, the cARTof the decliners was less likely to be
effective (they were more likely to have detectable viral
loads at follow-up, suggesting more treatment failure in
the decliner group).
Altogether, our findings would imply that current
virological response to cART and past immune injury
are important factors for HAND prognosis. Lower nadir
CD4 cell counts may reflect prior HIV-related brain
injury, representing a neuropathogenic process that may
persist despite partial immune recovery, whereas current
viral load detection would reflect ineffective cART. In
any event, our results regarding long-lasting effects of
earlier immunosuppression are consistent with several
reports in western regions [10,13,32–34] as are findings
suggesting that successful cART is an important factor for
maintaining stable cognitive functions [9]. Together, these
findings strengthen the hypothesis that effective cART
initiated earlier in HIV disease may be more efficient at
preventing HAND [35].
As has been noted in relation to studies of NeuroAIDS
in the west, the precise timing and nature of the
neuropathological mechanisms occurring in Chinese
HIV-positive persons with stable or incident HAND
are not well understood [36]. Coinfection with HCV,
though associated with somewhat increased risk of
neuropsychological impairment in this population at
baseline, was unrelated to further cognitive decline over
the next year. One explanation for this observation is that
any brain injury that was previously linked to HCV had
already occurred and was static and nonprogressive.
Another is that some individuals who tested positive for
HCV antibodies at baseline no longer had active HCV
viral replication, though this hypothesis was not tested in
this study. Future longitudinal research with coinfected
(and HCV-monoinfected) samples should determine
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cognitive decline in HIV infection Cysique et al.
whether detectable HCV in plasma confers an increased
risk for neuropsychological decline over time.
Another confirmatory finding with the previous literature in NeuroAIDS is that lower SIP performance was
predictive of future neuropsychological decline [37].
Impairment of this ability appears to be a common and
possibly early feature of both HAND and HAND
progression. If so, the presence of even fairly isolated
deficiencies in information processing speed may suggest
the possibility of an evolving process. Studies in other
countries should be undertaken to see whether this is a
generalizable feature of HAND, independently of the
cultural context.
We showed that our estimate of cognitive decline was
associated with decreased independence in activities of
daily living, but not change in cognitive complaints or
depressive symptoms. Independence in everyday life serves
as an important benchmark to distinguish asymptomatic
from symptomatic forms of HAND [1]. We had previously
demonstrated that neuropsychological criteria for HAND
could be effectively adapted to the Chinese rural context
cross-sectionally [6] and that neuropsychological impairment was associated with reported decrease in performance
of IADL. This longitudinal finding is the first to be
reported in a Chinese HIV-positive cohort and supports
our definition of neuropsychological change and its clinical
meaningfulness.
In conclusion, this study demonstrates that despite
ongoing cART, cognitive decline in HIV-positive people
is common over a 1-year follow-up. Regression-based
norms for change on western neuropsychological tests
can be used to detect disease-related cognitive decline in a
developing country.
Acknowledgements
The present study was supported by the NIMH grant 5
R01 MH073433-04 (R.K.H., PI).
The HIV Neurobehavioral Research Center (HNRC) is
supported by Center award MH 62512 from NIMH. The
authors would like to thank Fuyang city CDC and
Psychiatric Hospital for providing staff support and the
examiners for the study.
The San Diego HIV Neurobehavioral Research Center
(HNRC) group is affiliated with the University of
California, San Diego, the Naval Hospital, San Diego,
and the Veterans Affairs San Diego Healthcare System,
and includes the following members: Director: Igor
Grant, MD; Co-Directors: J. Hampton Atkinson, MD,
Ronald J. Ellis, MD, PhD, and J. Allen McCutchan, MD;
Center Manager: Thomas D. Marcotte, PhD; Naval
Hospital San Diego: Braden R. Hale, MD, MPH (PI);
Neuromedical Component: Ronald J. Ellis, MD, PhD
(PI), J. Allen McCutchan, MD, Scott Letendre, MD,
Edmund Capparelli, Pharm D, Rachel Schrier, PhD;
Neurobehavioral Component: Robert K. Heaton, PhD
(PI), Mariana Cherner, PhD, Steven Paul Woods, Psy D;
Neuroimaging Component: Terry Jernigan, PhD (PI),
Christine Fennema-Notestine, PhD, Sarah L., Archibald,
M.A., John Hesselink, MD, Jacopo Annese, PhD,
Michael J. Taylor, PhD, Neurobiology Component:
Eliezer Masliah, MD (PI), Ian Everall, FRCPsych.,
FRCPath., PhD,Cristian Achim, MD, PhD; Neurovirology Component: Douglas Richman, MD, (PI), David
M. Smith, MD; International Component: J. Allen
McCutchan, MD, (PI); Developmental Component: Ian
Everall, FRCPsych., FRCPath., PhD (PI), Stuart Lipton,
MD, PhD; Clinical Trials Component: J. Allen
McCutchan, MD, J. Hampton Atkinson, MD, Ronald
J. Ellis, MD, PhD, Scott Letendre, MD; Participant
Accrual and Retention Unit: J. Hampton Atkinson, MD
(PI), Rodney von Jaeger, MPH; Data Management Unit:
Anthony C. Gamst, PhD (PI), Clint Cushman, BA, (Data
Systems Manager), Daniel R. Masys, MD (Senior
Consultant); Statistics Unit: Ian Abramson, PhD (PI),
Christopher Ake, PhD, Reena Deutsch, PhD, Florin
Vaida, PhD.
The views expressed in this article are those of the authors
and do not reflect the official policy or position of the
Department of the Navy, Department of Defense, or the
United States Government.
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