Zunyou Wu

Neurobehavioral effects of human immunodeficiency virus infection among former plasma donors in rural China.

The human immunodeficiency virus (HIV) epidemic in China has expanded rapidly in recent years, but little is known about the prevalence and features of HIV-associated neurocognitive disorders (HANDs) in this part of the world. We administered a comprehensive Western neuropsychological (NP) test battery to 203 HIV+ and 198 HIV − former plasma donors in the rural area of Anhui province. They found that 26% of the HIV − samples, and 46% of the HIV+ samples, were infected with hepatitis C virus (HCV), which can also have central nervous system (CNS) effects. To classify NP impairment, we developed demographically corrected test norms based upon individuals free of both infections (N=141). Using a global summary score, NP impairment was found in 34.2% of the HIV-monoinfected group and 39.7% of the coinfected group, as compared to 12.7% of the uninfected controls (P <.001). HIV+ participants with acquired immunodeficiency syndrome (AIDS) were more likely to be impaired (43%) than non-AIDS individuals (29%; P <.05). Lastly, when all infection groups were combined, participants with NP impairment reported more cognitive complaints (P <.01) and increased dependence in everyday functioning (P=.01). In sum, NP impairment in this large rural Chinese sample was associated with both HIV and HCV infections, and the impairment’s prevalence, severity, and pattern were similar to those reported by Western studies. Clinical significance of NP impairment in this population is suggested by the participants’ reports of reduced everyday functioning. These findings indicate that HAND is likely to be an important feature of HIV infection in developing countries, underscoring the need for international efforts to develop CNS-relevant treatments.

Neurobehavioral effects of HIV-1 infection in China and the United States: A pilot study

The HIV epidemic in China has been increasing exponentially, yet there have been no studies of the neurobehavioral effects of HIV infection in that country. Most neuroAIDS research has been conducted in Western countries using Western neuropsychological (NP) methods, and it is unclear whether these testing methods are appropriate for use in China. Twenty-eight HIV seropositive (HIV+) and twenty-three HIV seronegative (HIV-) individuals with comparable gender, age, and education distributions were recruited in Beijing and the rural Anhui province in China. Thirty-nine HIV+ and thirty-one HIV- individuals were selected from a larger U.S. cohort recruited at the HIV Neurobehavioral Research Center, in San Diego, to be matched to the Chinese sample for age, disease status, and treatment variables. The NP test battery used with the U.S. and China cohorts included instruments widely used to study HIV infection in the United States. It consisted of 14 individual test measures, each assigned to one of seven ability areas thought to be especially vulnerable to effects of HIV on the brain (i.e., verbal fluency, abstraction/executive function, speed of information processing, working memory, learning, delayed recall, and motor function). To explore the cross-cultural equivalence and validity of the NP measures, we compared our Chinese and U.S. samples on the individual tests, as well as mean scaled scores for the total battery and seven ability domains. On each NP test measure, the mean of the Chinese HIV+ group was worse than that of the HIV- group. A series of 2x2 analyses of variance involving HIV+ and HIV- groups from both countries revealed highly significant HIV effects on the Global and all Domain mean scaled scores. Country effects appeared on two of the individual ability areas, at least partly due to education differences between the two countries. Importantly, the absence of HIV-by-Country interactions suggests that the NP effects of HIV are similar in the two countries. The NP test battery that was chosen and adapted for use in this study of HIV in China appears to have good cross-cultural equivalence, but appropriate Chinese norms will be needed to identify disease-related impairment in individual Chinese people. To inform the development of such norms, a much larger study of demographic effects will be needed, especially considering the wide range of education in that country.

Incidence and nature of cognitive decline over 1 year among HIV-infected former plasma donors in China.

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.

APOE ε4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors

Background:Host genetic factors are important determinants for risk of HIV-1 infection and disease progression. This study examined associations of host genetic variants and neurocognitive impairment in Chinese individuals infected through contaminated blood products. Methods:Two hundred and one HIV-infected patients from Anhui, China, had neuropsychological tests at baseline and 12 months. DNA was genotyped for APOE ϵ2, ϵ3 and ϵ4 alleles; MBL2-A/O; CCR5-wt/Δ32; CCR5-59029-G/A; CCR2-180-G/A; SDF-1-G/A; IL4-589-C/T; MCP-1-2518-A/G; CX3CR1-745-G/A; −849-C/T polymorphisms and CCL3L1 copy number variants using real-time PCR. Univariate and multivariate analyses were performed. Results:The cohort included 61% men, with mean education 5.5 years, AIDS diagnosis 113 (55%), on antiretrovirals 114 (56%), mean baseline CD4+ cell count 349 cells/μl and mean log10 RNA 4.09. At baseline, 37% had global neuropsychological impairment increasing to 44% after 12 months. Of 43 patients with the APOE ϵ4 allele, 58% were cognitively impaired compared with 31% without the ϵ4 allele (P = 0.001, odds ratio 3.09, 95% confidence interval 1.54–6.18). The mean global deficit score (GDS) for ϵ4-positive participants on antiretrovirals for 12 months was 0.88 (0.55) compared with 0.63 (0.54) for ϵ4-negative participants (P = 0.053, 95% confidence interval −0.004 to 0.51). For MBL2, 52% of patients with the O/O genotype declined in cognitive function over 12 months compared with 23% with A/A (odds ratio 3.62, 95% confidence interval 1.46–9.03, P = 0.004). No associations were observed for the other genetic variants. Conclusion:The APOE ϵ4 allele was associated with increased risk for cognitive deficits, whereas the MBL2 O/O genotype was associated with increased risk for progressive cognitive decline in Chinese individuals infected with HIV through contaminated blood products.

Risks and predictors of current suicidality in HIV-infected heroin users in treatment in Yunnan, China: a controlled study.

Objective:Suicide is an important public health problem in China. Elsewhere, injection drug use and HIV infection have independently been associated with suicidality, but research has often overlooked these high-risk groups in China. We determined the frequency and predictors of suicidal ideas in Chinese HIV-infected (HIV+) and HIV-uninfected (HIV−) heroin injection drug users (IDUs) in treatment and a control sample. We hypothesized that rates of suicidal ideas would be significantly higher among IDUs compared with controls and highest among HIV+ IDUs. Method:We assessed suicidal ideas within the past 2 weeks in HIV+ (n = 204) and HIV− (n = 202) heroin IDUs in methadone treatment in Yunnan, a province at the intersection of the heroin and HIV epidemics, and in demographically matched HIV− non–drug-using controls (n = 201). Results:Rates of suicidality were higher in IDUs than controls, but there was no additive effect of HIV infection (HIV+ IDU: 43.1%; HIV− IDU: 37.1%; controls: 8.5%). Among HIV+ IDUs, suicidality was associated most strongly with a combination of prior history of major depression, low perceived social support, and experience of HIV-relevant stress, but not with AIDS diagnosis. Among HIV− IDUs, suicidality was associated with prior history of major depressive or alcohol use disorder. Less than 25% of IDUs with suicidality had histories of mood or alcohol use diagnoses. Conclusion:Because suicidal ideation is frequent in IDUs in China, regardless of HIV status, and is not fully accounted for by past psychiatric history, additional research may be warranted.

Neuropsychological performance in mainland china: the effect of urban/rural residence and self-reported daily academic skill use.

Age, education, and gender are the most common covariates used to define normative standards against which neuropsychological (NP) performance is interpreted, but influences of other demographic factors have begun to be appreciated. In developing nations, urban versus rural residence may differentially affect numerous factors that could influence cognitive test performances, including quality of both formal and informal educational experiences and employment opportunities. Such disparities may necessitate corrections for urban/rural (U/R) status in NP norms. Prior investigations of the U/R effect on NP performance typically have been confounded by differences in educational attainment. We addressed in this by comparing the NP performance of large, Chinese urban (Yunnan Province, n = 201) and rural (Anhui Province, n = 141) cohorts of healthy adults, while controlling for other demographic differences. Although the groups did not differ in global NP scores, a more complex pattern was observed within specific NP ability domains and tests. Urban participants showed better performance in select measures of processing speed and executive functions, verbal fluency, and verbal learning. Self-reported daily use of academic skills was predictive of many U/R differences. Controlling for academic skill use abrogated most U/R differences but revealed rural advantages in select measures of visual reasoning and motor dexterity.

Psychiatric context of human immunodeficiency virus infection among former plasma donors in rural China.

BACKGROUNDnChinas HIV epidemic commenced in its agrarian provinces through contaminated commercial plasma donation centers and is now becoming a public health concern nationwide. Little is known of the psychiatric and substance use disorder characteristics of this population, or their impact on everyday function, employment, and life quality.nnnMETHODSnHIV-infected (HIV+) former plasma donors (N=203) and HIV-negative (HIV-) donor controls (N=198) completed the World Mental Health Survey Composite International Diagnostic Interview to determine lifetime major depressive disorder (MDD), substance use disorders, and suicidality. Current mood and suicidality were assessed with the Beck Depression Inventory-II. Everyday function was measured by an Activity of Daily Living questionnaire; life quality was evaluated by the Medical Outcomes Study-HIV.nnnRESULTSnHIV+ participants had known their infected status for 2 years on average. Most were taking antiretroviral treatment and had frank AIDS. Rates of current MDD were similar across groups (1-2%), but HIV+ had a higher frequency of lifetime MDD (14% vs. 5%, p<.05). Its onset preceded date of known infection in one-third of cases. Alcoholism was the only substance use disorder detected; HIV+ had a higher proportion of lifetime substance use diagnoses (14% vs. 6%, p<.05). Depression and AIDS independently predicted worse daily functioning and life quality, and unemployment.nnnLIMITATIONSnThe epicenter of China HIV has moved into urban injection drug users, limiting the representativeness of this sample.nnnCONCLUSIONSnHigh rates of MDD and its impact suggest that in China, as elsewhere, comprehensive care requires detection and treatment of mood disorder.

Absence of neurocognitive impairment in a large Chinese sample of HCV-infected injection drug users receiving methadone treatment

BACKGROUNDnPrior research has demonstrated neuropsychological (NP) impairment in persons with histories of injection drug use (IDU), hepatitis C virus (HCV) infection, and methadone maintenance treatment (MMT), individually, but little is known about the NP effects of these three risk factors in combination. This issue is particularly important in China, which is addressing its highly HCV-comorbid IDU epidemic with widespread government sponsored MMT, especially in light of recent evidence suggesting that methadone may be neuroprotective in some circumstances.nnnMETHODSnWe administered a comprehensive NP test battery to 195 Chinese heroin IDU individuals taking MMT (IDU+ group), the majority of whom were also HCV+ (87%; n=169), and compared their NP performance to that of 198 demographically comparable, non-IDU Chinese controls (IDU- group). All participants in both groups tested negative for HIV infection, which is also a common comorbidity in the Chinese IDU population.nnnRESULTSnThe IDU+ group did not have an increased rate of global NP impairment, or perform significantly worse on any individual NP test measure. Within the IDU+ group, liver disease characteristics and reported details of heroin use were not significantly associated with NP performance.nnnCONCLUSIONnFailure to detect NP impairment in IDU+ subjects with or without HCV infection was surprising, particularly considering the previously demonstrated sensitivity of our NP battery to neurocognitive disorders associated with HIV infection in China. One possible explanation, which should be explored in future research, is the potential neuroprotective effect of methadone in the context of HCV infection and/or heroin withdrawal.

The influence of HLA on HIV-associated neurocognitive impairment in Anhui, China.

Background HLA-DR*04 was identified as a predictor of HIV-Associated neurocognitive disorder (HAND), low CD4 T-cell responses to HIV, and low plasma HIV RNA levels in a U.S. cohort. We hypothesized that low CD4 T-cell activation leads to poor immune control of HIV in the CNS, predisposing to HAND, but also provided fewer target (activated CD4 T-cells) for HIV replication. To assess the consistency of these HLA Class II associations in a new cohort and extend analysis to HLA Class I, HLA types, neurocognitive, and virologic status were examined in a cohort of former plasma donors in China. Methods 178 HIV infected individuals in Anhui China, were HLA typed and underwent neurocognitive evaluations (using locally standardized norms), neuromedical, treatment and virologic assessments at baseline and at 12 months. Results HLA DR*04 was associated with a higher rate of baseline neurocognitive impairment (pu200a=u200a0.04), neurocognitive decline (pu200a=u200a0.04), and lower levels of HIV RNA in plasma (pu200a=u200a0.05). HLA Class I alleles (B*27,57,58,A*03,33) that specify a CD8 T-cell response to conserved HIV sequences were neuroprotective, associated with less impairment at baseline (pu200a=u200a0.037), at month 012 (pu200a=u200a0.013) and less neurocognitive decline (pu200a=u200a0.023) in the interval. Consistent with the theory that effective CD8 T-cell responses require CD4 T-cell support, the HLA DR*04 allele reduced the neuroprotective effect of the Class I alleles. The presence of HLA-DR*04 and the Alzheimer associated allele ApoE4 in the same individual had a synergistic negative effect on cognition (pu200a=u200a0.003). Conclusions Despite major background differences between U.S. and Anhui China cohorts, HLA DR*04 predicted neurocognitive impairment and lower plasma HIV RNA levels in both populations. HLA Class I alleles associated with CD8 T-cell control of HIV were associated with protection from HAND, but protection was reduced in the presence of HLA-DR*04.

Subtype associations with HIV-associated neurocognitive disorder in China

Factors associated with HIV-associated neurocognitive disorders (HAND) include CD4+ nadir and count, HIV RNA level, and HIV-1 subtype. Here, we investigated demographical and clinical markers with respect to HAND in a homogenous Chinese population. Individuals with HAND (global deficit score ≥0.5) had lower nadir (pu2009<u20090.01) and CD4+ counts (pu2009=u20090.03). HAND was also associated with AIDS (pu2009<u20090.01), but subtype was not (pu2009=u20090.198). Furthermore, worse impairment correlated with higher viral diversity (ru2009=u20090.16, pu2009<u20090.01), lower nadir (ru2009=u2009−0.17, pu2009<u20090.01), and CD4+ counts (ru2009=u2009−0.11, pu2009=u20090.01). These remained significant even when correcting for subtype. Our findings suggest that subtype does not have a major impact on HAND.