Incidence and Nature of Cognitive Decline Over 1 Year Among HIV-infected Former Plasma Donors in China Lucette A. Cysique; Scott L. Letendre; Christopher Ake; Hua Jin; Donald R. Franklin; Saurabh Gupta; Chuan Shi; Xin Yu; Zunyou Wu; Ian S. Abramson; Igor Grant; Robert K. Heaton
Authors and Disclosures
Posted: 05/12/2010; AIDS. 2010;24(7):983-990. ? 2010 Lippincott Williams & Wilkins
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 = 22) had incident impairment, whereas 38% (N
= 20) declined within the impaired range and another 20.7% (N = 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.
Several recent studies have provided prevalence estimates of HIV-associated neurocognitive [2,3]disorders (HAND) in 'nonwestern' regions of the world such as sub-Saharan Africa, India, [5,6]China, and south-east Asia. 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).
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. Several longitudinal cohort studies in western countries have assessed cognitive [9–13]decline and its potential contributing factors in the cART era. Published studies, after varying
follow-up periods, have found that between 22 and 63% of participants on cART demonstrated
[12,13]continuing impairment and at least 21% had incident impairment. 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.
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 or adjunctive treatments that may specifically benefit the CNS).
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 cART era. Our aim was to detect and quantify neuropsychological decline over a 1-year period in 192 individual HIV-positive 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 = 101) of demographically comparable HIV-negative individuals. The [17,18]norms for change were derived using a regression change score approach. Here we propose an
extension of this method by introducing a battery approach to derive a normed summary change score [19,20]for each individual. In addition, we propose an adaptation of the Global Deficit Score method to
estimate follow-up impairment rate corrected for practice effect.
Details regarding participant recruitment procedures and baseline results were published in study by Heaton et al. Briefly, at baseline, 203 HIV-positive and 198 HIV-negative 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 = 101) were reassessed. In addition, all available HIV-
positive participants were reassessed (N = 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 HIV-negative 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 = 107; 55.7%) was being prescribed cART at baseline
consistent with prevailing antiretroviral initiation guidelines in China. HIV duration estimated from self-report averaged 154 months (SD = 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.
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. and Heaton et al. (see also Table e-1 & e-2). Clinical
significance of any neuropsychological impairment or change was examined with standard instruments measuring participants' experience of cognitive difficulties in everyday life (Patient's Assessment of Own Functioning Inventory – PAOFI) and decreases in degree of
independence in activities of daily living [modified version of the Lawton & Brody Instrumental Activities of Daily Living (IADL) scale]. Participants also completed the Beck Depression [23,24]Inventory-II (BDI-II).
To identify individuals who presented with overall neuropsychological change, we used a [17,18]statistical methodology based on the multivariate regression change score approach (see
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).
Our detailed method is available in the supplemental file e-Data 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).
Percentage of neuropsychological change as defined by the summary of
regression change score in the HIV-positive and HIV-negative samples.
Secondary analyses were conducted to clarify the nature of both baseline predictors and follow-up correlates of 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, 2cognitive complaints, IADL, and BDI-II using t-test or χ 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 [6,19,20]median practice effect (see also e-Data analysis, http://links.lww.com/QAD/A35 ).
The baseline demographic characteristics of the HIV-negative 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 r = 0.85 and HIV-positive group's mean scaled score r = 0.84]. tttt
Incidence of neuropsychological decline in the HIV-positive group (27.6%) was significantly greater than that in our reference HIV-negative sample (5%) as defined by the sRCS approach 2[χ = 21.4; P < 0.0001]. We found that 53 HIV-positive individuals were classified as having (1)
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 = 0.06). No
other findings approached statistical significance. Importantly, the decliner and nondecliner groups did not 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.
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 = 0.22) or follow-up (P = 0.60), nor in the difference
between baseline and follow-up (P = 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%;