Neurocognitive Impairment among HIV-Infected Participants on Methadone for IV-Heroin use in Yunnan, China Relates to AIDS Status and Depression Severity, not Patterns of Substance use

We used a comprehensive and culturally normed battery of Neurocognitive (NC) tests to evaluate NC impairment (NCI) in 406 adults with prior IV heroin use who were in a government-supervised methadone maintenance program in Yunnan province, China. Participants included 202 without HIV infection, 57 with AIDS, and 147 HIV+ without AIDS (“nonAIDS group”). The AIDS group had higher proportions of individuals with global NCI (38.6%) relative to nonAIDS (15.7%) and HIV- participants (17.3%; ps < 0.01). The AIDS group performed worse than the non AIDS group globally (< 0.001), and in the domains of executive functioning (ps = 0.001), learning (ps = 0.035), and speeded information processing (ps = 0.0002). Despite the lack of difference in prevalence of NCI between non AIDS and HIV- groups, the non AIDS group showed impairment in memory and complex motor domains relative to the HIV- group (p = 0.03). In People With HIV (PWH), NCI was associated with more severe depression symptoms and HIV disease characteristics (duration of illness, CD4 nadir, AIDS status). Nearly all participants were HCV infected. Alcohol use disorder diagnoses, non-invasive indications of liver fibrosis, and characteristics of prior heroin use were not associated with NCI. PWH with NCI had worse daily functioning, as indexed by unemployment (ps = 0.016) and reported increased cognitive difficulties in daily life (ps = 0.016). These results highlight the importance of early HIV diagnosis and treatment to avoid HIV disease progression, particularly among IV drug users, with the goal of protecting NC abilities, everyday functioning, and life quality in infected individuals.

The global prevalence of HIV infection has seen a significant increase over the past four decades. The HIV pandemic is thought to have reached China around 1985 in the rural areas of Yunnan Province bordering Myanmar, and was first spread predominately via Intravenous Drug Use (IDU) [1,2] in areas that were involved in heroin production and trafficking [3]. Between 1993 and 1996, occurrences of HIV transmission also were observed among rural, low-income Former Plasma blood Donors (FPDs) due to non-sterile collection techniques [4]. Intravenous (IV) drug use, as well as unsafe sexual practices among Men who have Sex with Men (MSM) and sex workers, continue to be major risk factors for HIV transmission. According to the 2021 UNAIDS Report on the Global AIDS Epidemic, an estimated 1,100,000 individuals in China knew they were living with HIV in 2020 [5].

Despite the growing impact of HIV disease in China, our understanding of its effects on the Central Nervous System (CNS) in Asian populations remains limited. This includes the prevalence, severity, and specific nature of HIV-Associated Neurocognitive Disorders (HAND) and the extent to which they may result in functional impairment [6].

Despite the advancement of Antiretroviral Treatment (ART) over the past few decades, research conducted in Western countries has demonstrated that HAND, particularly in milder forms, remains highly prevalent at all stages of infection [7]. Recent estimates suggest that 30 to 50% of Persons With HIV (PWH) exhibit Neurocognitive Impairment (NCI) [7-9]. The most prominent NC deficits are typically observed in the domains of learning and memory, executive functioning, attention/working memory, and information processing speed, with the prevalence and magnitude of impairment worsening with disease progression [10]. Importantly, HAND has been linked with increased all-cause mortality [11], and adverse outcomes in everyday functioning, such as unemployment [12,13], medication non adherence [14], difficulties performing household [12] and health-related tasks [15], and decreased quality of life [16]. With the growing epidemic of HIV/AIDS in China and the aforementioned adverse HIV-associated CNS effects and functional consequences in Western countries, there is significant concern about the CNS impact of HIV in the Chinese population.

In 2006, our group began a collaboration with groups of investigators from two Chinese provinces, namely Yunnan and Anhui, known to have high rates of HIV infection. Our goal was to examine the neurological, psychiatric, and NC consequences of HIV among individuals from two of the most prominent risk groups in China: FPD in Anhui and IDU in Yunnan. Our first comprehensive investigation into the NC effects of HIV [17] was conducted in a large sample of FPDs with HIV/AIDS from the rural province of Anhui, China (n = 203). We translated and adapted a comprehensive NC test battery for use in China, and developed demographically corrected Chinese NC norms based on a sample of 198 demographically matched HIV seronegative FPDs from Anhui. Then we observed a high prevalence of NC impairment in the HIV-infected group (35.5%) relative to only 12.7% of the demographically-matched HIV-uninfected comparisons. As expected, a higher rate of NCI was observed in individuals with AIDS relative to those with less advanced disease (approximately 43% versus 29%, respectively) in the PWH sample. Consistent with the aforementioned research in Western countries, we also observed a significant association between NCI and self-reported declines in everyday functioning in the group of FPD individuals with HIV [17].

Our findings highlighted the problem of the HAND in China and the need for a greater understanding of HIV-associated NCI and functional decline across Asia. However, questions remain as to whether there are different risk factors for HAND, and whether the CNS effects of HIV may manifest differently in other PWH in China, which may have significant implications for the identification and treatment of NC deficits in China’s diverse populations. A prior, multicenter cross-sectional study conducted in China [18] examined HAND amongst individuals with HIV disease in Henan (predominately FPDs), Yunnan (predominately IDU and sexual transmission), and Beijing (risk factor was primarily sexual contact among MSM), and found rates of approximately 27%, 44%, and 46%, respectively. Overall, the rate of impairment among the PWH group was approximately 37%, and this proportion increased with advancing disease stage [18]. These numbers may underestimate the true rates of impairment in these groups, given the limited NC test battery that was used to diagnose HAND in that study. Regardless, preliminary data suggest a considerable prevalence of NCI across risk groups, and highlights the need for more detailed investigation.

The role of IV heroin use as the original source of the HIV epidemic in Yunnan in the late 1980s [1] and its current role in HIV transmission in China [19,20] are well documented. Despite this, prior international research on the NC impact of opioid use on HIV-seronegative individuals has produced inconsistent results, largely due to methodological challenges, such as the use of multiple substances by opioid users in the prior studies. Nevertheless, existing research has linked both chronic opioid use and opioid withdrawal to NC deficits across a range of cognitive domains, particularly within the domains of executive functions (e.g., inhibitory control, cognitive flexibility) and attention/working memory [21,22]. Recent evidence from our group examined the potential effects of prior injection heroin use, and associated high rates of HCV infection in a large sample of HIV-seronegative IDU from Yunnan [23], and did not find evidence to suggest adverse effects of the prior heroin use on NC performance. All participants were also on Methadone Maintenance Therapy (MMT) at the time of their evaluations, which may improve NC outcomes in this population [24]. Research on the NC consequences of injection heroin use within HIV positive samples is sparse, though a recent study conducted in the United States did not find support for additional adverse effects of opiate-dependence on NC functioning beyond what could be attributed to HIV infection alone [25]. To our knowledge, there are no prior studies that have examined the NC effects of prior heroin use within the IDU, HIV population in China.

To our knowledge the current study is the first large scale, comprehensive investigation into prevalence and nature of NCI in individuals with HIV disease from the urban province of Yunnan, China, where IV drug use is a primary risk factor for HIV transmission. With prior research demonstrating that NCI increases as the disease progresses, we aimed to investigate prevalence and nature of NCI in PWH, separately for those who had and had not been diagnosed with AIDS, compared to a group of HIV- negative individuals, all of whom were former IDU and currently on MMT. Furthermore, we sought to explore the relationship between HIV-associated NCI and practical concerns such as self-reported experience of cognitive difficulties in everyday functioning and other negative functional outcomes, including unemployment and increased need for assistance in carrying out activities of daily living. Groups in Western countries have been able to improve NC functioning with effective treatment and rehabilitation [26], and a greater understanding of the nature of NC deficits in Chinese individuals may aid in the development of similar interventions aimed at reducing the health-related and day-to-day impact of HIV-related CNS involvement in the Chinese population.

Participants

All participants included in this study were recruited and enrolled as part of a larger research protocol examining the neurobehavioral effects of HIV infection in China. This study was approved by the Institutional Review Boards from the China Center for Disease Control (CDC)/National Center for AIDS (NCAIDS), Peking University, and the University of California at San Diego (UCSD).

We recruited 202 HIV-seronegative and 204 HIV-seropositive, former IDU from government supervised outpatient methadone clinics in Kunming and Gejio City in Yunnan province. There were also people, without HIV or IDU histories, recruited from the general Yunnan community, who’s previously reported data were used to compute demographically corrected NC norms for the Yunnan population [23].

The HIV status for all participants was confirmed by the HIV Quick Test (OraSure Technologies Inc, Bethlehem, PA). HCV status was determined through detection of anti-HCV IgG antibodies using an Enzyme-Linked Immunosorbent Assay (ELISA). Liver fibrosis variables such as FIB-4 and ARPI were added to standard medical blood work for HIV, which included CD4 counts and plasma viral RNA.

Lifetime and current history of major depressive disorder and substance use disorders were assessed using the World Mental Health Composite International Diagnostic Interview (WMH-CIDI) [27]. The Beck Depression Inventory 2 (BDI-II) [28] was used to assess presence and severity of current depressive symptoms. Heroin use characteristics such as age at first use and date of last use were reported by participants. Exclusion criteria for all study participants included head injury with loss of consciousness for more than 30 minutes, a history of severe psychiatric (e.g., schizophrenia) or neurological (e.g., epilepsy, stroke) disorders, or current alcohol or other substance dependence diagnoses within the last 30 days.

Participants provided informed written consent for all procedures administered, including our comprehensive NC and medical evaluations. No participants were receiving treatment for HCV and not all PWH were receiving ART. By 2006, China’s National Center for AIDS/STD Control and Prevention’s National Free Antiretroviral Therapy Program (NFATP) had expanded to all areas of China with 64% of the HIV population being treated; although problems of resource limitations, nonadherence, and hepatoxicity hampered initial results, rates of ART use have since improved [29].

Neurocognitive assessment

Our battery included 17 standardized tests that have been widely used in the U.S. and internationally [7,30,31] for NC studies in PWH. The battery was designed to assess NC domains relevant to HAND, including executive functions, verbal fluency, attention/working memory, learning, delayed recall, speed of information processing, and complex motor skills [32]. All NC tests were translated and modified for use in Chinese samples [33]. Recent publications from our group have demonstrated the reliability and validity of this NC test battery for use in China [17,34].

The cognitive domains and individual tests within in each domain are as follows: 1) Executive functions: Color Trails II (completion time) [35]; Halstead Category Test (total errors) [36], Stroop Color-Word Interference Test (total correct) [37]; 2) Verbal fluency: Animal Fluency (total correct) and Action Fluency (total correct) [38]; 3) Attention/Working Memory: Paced Auditory Serial Addition Test (50-item version)(PASAT-50) [39,40], Wechsler Memory Scale – Third Edition (WMS-III) Spatial Span [41]; 4) Learning: Total learning scores from the Hopkins Verbal Learning Test – Revised (HVLT-R) [41], and the Brief Visuospatial Memory Test - Revised (BVMT-R) [42]; 5) Delayed Recall: Delayed recall scores for the HVLT-R and BVMT-R; 6) Speed of Information Processing (SIP): total correct for the Wechsler Adult Intelligence Scale – III (WAIS-III) Digit Symbol and Symbol Search subtests [43], Trail Making Test Part A (completion time), and Color Trails 1 (completion time) [35]; and 7) Motor Speed/Fine Coordination: completion time for Grooved Pegboard Dominant and Non-Dominant Hand [44] trials.

Raw scores for each of the individual tests were converted to demographically (i.e., age, education, and gender) corrected T-scores using comprehensive test data derived from the HIV-seronegative Chinese samples, separately from our two study sites Anhui and Yunnan [17]. In Yunnan, the community HIV-/IDU- controls performed equivalently to the HIV-/IDU+ in the Methadone Maintenance Program and they were combined for norm development [23]. These T-scores are normally distributed (and have a mean of 50 and standard deviation of 10 in the HIV seronegative controls), and allow for assessment of disease-related impairment in individual Chinese subjects. To derive a summary score that better reflects impairment on the entire test battery, the standardized T-scores for each of the tests were converted to deficit scores according to the following criteria: T > 40 = 0 (normal); T(35-39) = 1 (mild impairment); T(30-34) = 2 (mild to moderate impairment); T(25-29) = 3 (moderate impairment); T(20-24) = 4 (moderate to severe impairment); and T(< 20 ) = 5 (severe impairment). The individual deficit scores were then averaged to derive NC Domain Deficit Scores (DDS) and a Global Deficit Score (GDS), which reflect prevalence and degree of NCI across the comprehensive test battery; this reduces the number of comparisons made across tests and associated risk of Type I error. A standard GDS cut-off score of > 0.5 was used to classify individuals as NC-impaired [17,32,45]; the GDS reflects the number and severity of deficits on the total test battery, and this “global impairment” cutoff requires that, on average, the person was at least mildly impaired on at least half of the test measures in the battery. Impairment on domain deficit scores requires a slightly more conservative cutoff of > 0.5.

Everyday functioning assessment

Participants also were administered standard self-report questionnaires designed to assess a) experience of everyday cognitive difficulties, b) changes in the independence with which they perform activities of daily living, and c) employment status. These measures were developed in the U.S., translated into Mandarin, and validated for use in Chinese samples through prior studies [17,34]. The Patient’s Assessment of Own Functioning Inventory (PAOFI) [46] is a 33-item self-report questionnaire designed to assess the frequency with which cognitive difficulties are experienced by participants in their daily lives. PAOFI items ask about frequency of experienced problems within the domains of memory, language/communication, higher level cognitive and intellectual functioning, sensory-perceptual ability, and motor function, using a 6-point Likert-type scale that ranges from 1, “almost never” to 6 “almost always.” A PAOFI Total Score was derived for each participant by summing the total number of items that were rated as difficulties encountered “fairly often,” “very often,” or “almost always” [46].

Participants also completed a modified version of the Lawton and Brody Activities of Daily Living (ADL) scale [47] adapted for use in Chinese individuals [17,33], which queried their current and best level of independence with regard to performing fourteen common activities of daily living: walking, eating, dressing, laundry, bathing, combing hair/brushing teeth, using a toilet, making a phone call, doing housework, taking medicine, using transportation, preparing a meal, handling bills, and shopping. A dichotomous ADL variable was derived by classifying individuals as “ADL Dependent” if they reported current need for increased assistance in two or more of the 14 functional domains.

Lastly, employment information was derived from a question regarding current employment status on the PAOFI and through the extended demographic interview, which also gathered sociodemographic information such as monthly household income, family/household size, and marital status.

Statistical analyses

Differences in demographic, medical, psychiatric, neurocognitive, and everyday functioning characteristics across the study groups (HIV-, HIV+ non AIDS, and HIV+ AIDS) and by NCI status (Impaired versus Unimpaired) in the PWH were evaluated using ANOVAs, t-tests, Wilcoxon signed rank sums tests, Fisher’s exact tests, or chi-square tests as appropriate. Statistical analyses were performed using JMP Pro version 14.0.0 (SAS Institute Inc., Cary, NC, 1989-2007).

Similar analyses were conducted within the PWH group to examine associations between global neurocognitive impairment (NCI vs unimpaired) and HIV disease characteristics (e.g., duration of infection, CD4+ T-cells and nadir CD4+ T-cells), non-invasive indices of liver fibrosis severity (e.g., AST-to-Platelet Ratio [APRI]), heroin use variables (i.e., age at first use, days since last use), depressive symptoms and history of DSM-IV diagnosis of major depressive disorder, and everyday functioning characteristics, including cognitive symptoms, self-reported declines in daily activities, dependence in activities of daily living, and employment status.

Demographic and disease characteristics for the three IDU study groups are displayed in table 1. The HIV seronegative (i.e., “HIV-”), PWH without AIDS (i.e., “nonAIDS”), and PWH with AIDS (i.e., “AIDS”) groups were similar in age, education, gender, marital status (i.e., % married vs not married), household size, employment, and household monthly income (ps > 0.10).

As mentioned above, all of these study participants were recruited from a government-supervised methadone clinic and had a history of intravenous drug (i.e., heroin) use. Most of our study subjects were infected with HCV: 80.2% of the HIV- group, 98.6% of the non AIDS group, and 98.1% of the AIDS group.

With regard to psychiatric characteristics, all three of the IDU groups reported elevated current depressive symptoms on the BDI-II, though they did not significantly differ from each other (Table 1). The AIDS group had the highest proportion of individuals who met criteria for Major Depressive Disorder (MDD) in their lifetime (10.4%), yet this proportion did not differ significantly from the non AIDS group (8.2%) or the HIV- group (6.4%; ps > 0.10). The three study groups also did not differ in the proportions of individuals diagnosed with a lifetime alcohol use disorder (i.e., abuse or dependence; p > 0.10), which was relatively low in all three (range 15.8-19.3%).

PWH within both the AIDS and non AIDS groups were, on average, slightly younger when they first used heroin, relative to the group without HIV. At the time of their NC evaluations, the AIDS and non AIDS groups reported comparable periods of abstinence from heroin, whereas the HIV- were abstinent from heroin for a slightly (still not significantly) shorter time than the PWH groups, table 1. Relative to the non AIDS group, the AIDS group had longer estimated durations of HIV infection, and lower nadir and current CD4+ T-cell counts (ps < 0.01). At the time the study was performed, factors including AIDS defining illness, CD4+ T-cell levels, risk of nonadherence, and risk of hepatotoxicity, determined whether a participant was receiving ART. The AIDS group had a higher proportion of individuals taking antiretroviral therapy relative to the non AIDS group (57.9% vs 11.0%), and a higher proportion of participants with current CD4+ T-cell counts below 350 cells/uL (59.7% vs 11.6%; ps <0.001). Consistent with differences in ART status, the total AIDS group had lower plasma viral loads (p = 0.05) and was less likely to have detectable virus in plasma relative to the total non AIDS group (p < 0.001). Among participants currently on ART, plasma viral loads and the proportion of participants with detectable virus did not differ significantly between the AIDS and non AIDS groups; however, high rates of detectable virus were observed amongst those not on ART within both the AIDS and non AIDS groups (91.7% and 90.7% detectable, respectively; ps > 0.10).

Neurocognitive performance among MMT participants in Yunnan, China

Neurocognitive results are presented in table 2. There was a significant overall group effect for prevalence of NCI (ps < 0.01), which was indexed by the standard GDS cutpoint for impairment (i.e., GDS ≥ 0.50). The AIDS group had a significantly higher proportion of NCI (38.6%) relative to both HIV-IV+ group and the non AIDS group (ps < 0.001). Overall proportions of NCI between the HIV- and non AIDS group did not differ significantly from each other. However, in the non AIDS group, the continuous domain deficit scores were significantly worse in memory and motor skills, compared to the HIV- group. In the AIDS group, executive functioning, working memory, learning, memory, motor skills, and speeded information were each significantly impacted.

Among the individuals with HIV who were classified as having NCI (22.1% overall; n = 45), the most prominent NC domain impairment (as indexed by NC domain deficit score > 0.50) was observed in speeded information processing (77.8%), followed by learning (64.4%), memory (60.0%), motor (57.8%), working memory (48.9%), and executive functions (44.4%). Few PWH with global NCI demonstrated impairment within the verbal fluency domain (17.8%).

Associations between neurocognitive impairment and HIV disease and treatment characteristics within the overall PWH sample (n = 204)

When looking at factors associated with global NCI (i.e., as indexed by the GDS ≥ 0.5) among PWH, HIV disease characteristics revealed the most significant relationships. Specifically, PWH with NCI were more likely to have AIDS (p = 0.001) and a history of severe immunosuppression (i.e., nadir CD4+ T cell count less than 200 cells/uL; p < 0.001) and had longer estimated durations of HIV infection (p = 0.039) (Table 3). No significant associations were found between NCI and current CD4+ T-cell count, or proportions of individuals currently using ART, or with detectable HIV viral load (ps > 0.10). A history of severe immunosuppression (nadir CD4+ T-cell count < 200) was associated with NCI regardless of ART status. For participants currently on ART at the time of assessment, trend level associations were found between NCI and AIDS status, estimated duration of infection, and current CD4+ T-cell counts (ps < 0.10). For those not currently on ART at the time of assessment, NCI was significantly associated with AIDS status (p=0.008), nadir CD4+ T-cell counts as a continuous variable (p = 0.021), history of CD4 < 200 (p = 0.002), and current CD4+ T-cell count < 200 (p = 0.070). A trend level association was found between NCI and detectable viral load in untreated participants (p = 0.074).

Associations between neurocognitive impairment and medical/psychiatric characteristics among PWH

While almost universal HCV coinfection in the PWH group precluded direct examination of the independent effects of HCV on NCI within that group, we did examine APRI and FIB-4 values available for a subset of the PWH sample, and did not observe any significant associations between NCI and either index of liver fibrosis severity (Table 3) APRI and FIB-4 values; ps > 0.10). The majority (87.6%) of the HIV- group also had HCV infection without correlation to NCI (p > 0.10), which is consistent with our previous, comprehensive investigation into the impact of HCV in Chinese individuals without HIV infection (see Gupta S, et al. [23] for more detail).

Within the PWH group, NCI was significantly associated with current depression symptoms as measured by the BDI-II (p = 0.001), though the association between NCI and lifetime MDD diagnoses only reached trend-level significance (p = 0.092). There was no significant association between NCI and lifetime alcohol use disorders (i.e., abuse or dependence; p > 0.10). Of note, since the entire PWH sample also were IDU, we could not examine the potential influence of IDU on NCI in this group. However, in the PWH sample, NCI was not associated with heroin use characteristics, including age at first use, and days since last use of heroin (ps > 0.10). Also of note, IDU status within our combined HIV- group from Yunnan (HIV-/IDU+ and HIV-/IDU-) was not significantly associated with NCI (P > 0.10; See Gupta S, et al. [23] for more detail regarding the HIV-/IDU- group).

Everyday functioning among PWH with and without AIDS from Yunnan, China

The everyday functioning characteristics for the three study groups also are presented in table 2, Evaluation of overall differences across the three study groups for indices of daily functioning revealed significant overall effects. The AIDS group reported more ADL dependence (ps = < 0.001) than the non AIDS group. Both the AIDS and non AIDS groups had high rates of unemployment (72.4% and 69.7% respectively), though they did not differ from each other (p > 0.10).

Within the total PWH group, NCI was significantly associated with a higher number of self-reported cognitive difficulties in everyday life (PAOFI Total Score; ps = 0.013), and higher proportions of unemployment (ps = 0.016). PWH with NCI also had higher proportions of individuals who met criteria for ADL Dependence though this difference did not reach statistical significance (p = 0.129) (Table 3).

This study examined the prevalence and nature of NCI in Chinese HIV infected and uninfected individuals with a history of IV heroin use, using a comprehensive battery of NC tests and normative data from a large sample of HIV-seronegative, comparison subjects from the same region. Consistent with prior prevalence estimates in China [17,18] our results demonstrated increased proportions of NCI in our PWH sample relative to 202 demographically matched HIV-seronegative IDU comparison subjects, which was driven by a higher proportion of impairment in the PWH subgroup with more advanced HIV disease (i.e., AIDS; 38.6%). Among the PWH classified with global NCI, the most prominent NC deficits were observed in the domains of speeded information processing, learning and memory, complex motor skills, attention/working memory, and executive functions. This is broadly consistent with the profile of impairment in our Chinese PWH cohort of FPDs from Anhui [17,33] and other cohorts of PWH in China [18].

There were lower rates of verbal fluency impairment as well as global NCI in Yunnan relative to our Anhui FPD sample. A probable reason for this discrepancy is that the PWH participants in Anhui had been infected for a much longer period than those in Yunnan (average 11.8 versus 5.1 years; ps < 0.001). In addition, all PWH in Yunnan were participating in a government supervised, methadone maintenance program, and recent evidence suggests the possibility of neuroprotective effects of methadone in IDU populations [6,23].

Current symptoms of depression were significantly associated with NCI in this study, a relationship that has been described and explored in other populations as well [48,49]. While our neurocognitive tests were culturally normed, our measure of depression, the Beck Depression Inventory, was developed in a different cultural milieu.

Our results also suggest an association between NCI and HIV disease characteristics, particularly those related AIDS diagnoses and a history of severe immunosuppression (CD4 nadir below 200). As mentioned before, our AIDS sample had the highest rate of NCI relative to the other IDU groups.

Among all PWH, although NCI was associated with a history of severe immune suppression (nadir CD4 count < 200), it was not significantly related to either current CD4 count or plasma HIV viral load. This evidence is consistent with research in both Western countries [50,51] and in China [17,18], and provides support for the notion that historical (legacy) markers of disease progression may be more strongly predictive of neurocognitive functioning, rather than markers of current disease status [7,52]. This emphasizes the importance of early treatment for individuals with PWH, that may help prevent NCI.

Importantly, and consistent with findings from numerous studies in Western countries [11,12], our study found associations between NCI and poorer everyday functioning outcomes, including a greater number of self-reported cognitive difficulties in everyday functioning and unemployment. This also is consistent with our findings from Anhui [17], with the exception that the association between NCI and unemployment was observed among our PWH sample from Yunnan, but not in Anhui. One potential explanation for this difference is that in general, the more typical occupations in Yunnan and other urban areas in China may be more neurocognitively demanding relative to the primary farming-related occupations in rural areas such as Anhui. This disparity across groups in rural vs. urban settings in China could worsen as individuals tend to migrate from rural to urban areas in search of more economic opportunities. Future research is needed to explore the relationship between NCI and these functional outcomes in greater detail. For example, a number of Western studies have linked HAND to poor performance on standardized work samples [11] as well as poor medication adherence [12]; in turn, poor medication adherence can have important clinical implications as it can lead to further NC decline along with reduced immunological competence [53,54]. In addition, future research should explore the relationships between NCI and HIV transmission risk behaviors (e.g., risky sexual practices and/or drug use behaviors, poor decision making) that contribute to the continued growth of the HIV epidemic [55], in order to determine whether transmission rates may be improved to some degree with early identification and treatment with ART in PWH and/or individuals at risk for HIV.

Several limitations of this study are worth noting. First, because nearly the entire PWH sample from Yunnan had HCV coinfection, we were unable to conduct analyses to isolate the potential adverse additive effects that these conditions may have had on NC functioning within the PWH group, and particularly amongst those with AIDS. This is of concern, as our previous work in Anhui found the highest rates of impairment within the sample of PWH who had both HCV and AIDS [17]. Similar findings suggesting that the risk of HCV-associated NCI may increase with advancing HIV disease have also been observed in Western studies [56,57]. Given this collective evidence, it is possible that the higher proportions of NCI in our AIDS sample may also reflect adverse effects of HCV and IDU to some extent. However, we detected no increase in NCI in our HIV-, IDU+, HCV+ group as compared to the community group lacking a history of IDU, HIV, or HCV (p > 0.5). We were able to examine some heroin use characteristics and did not find any significant associations with NCI. We also obtained HCV disease characteristics (i.e., indices of liver fibrosis severity) in a subsample of our PWH group, and again did not find any significant associations with NCI. This is consistent with another study from our group [23], in which we examined the effects of HCV in a large sample of Chinese HIV-seronegative individuals from Yunnan (n = 169), all of whom also had histories of IDU, relative to HIV-seronegative individuals without either HCV or any history of IDU, and did not find evidence to suggest adverse effects of liver fibrosis or heroin use characteristics on NC performance. Of note, only a small proportion of both these samples and the PWH group from the current study had evidence of significant liver fibrosis; therefore additional research is needed to clarify whether individuals at later stages of HCV disease or who have more severe liver fibrosis may be more vulnerable to cognitive impairment or decline.

Strengths of this study include the use of a thorough medical assessment, standardized psychiatric evaluation, and a comprehensive, well-validated NC test battery known to be sensitive to effects of HIV infection, with demographically corrected normative data based on a large sample of HIV-seronegative individuals who had similar backgrounds and risk factors. This promotes more accurate classification of HAND within the PWH groups, and more interpretable findings regarding the association between HAND and everyday functional outcomes. Overall, the results of this study about the prevalence, nature, and everyday functioning consequences of HAND in China may provide insight into the development of early identification and prevention efforts aimed at avoiding NCI or preventing further cognitive decline and subsequent problems in everyday life. In addition, the observed association between NCI and depressed mood (Table 3) among PWH in this study suggests that intervention to reduce depression in this population may have beneficial effects on both cognitive and everyday functioning (Figure 1).

Figure 1: Pattern of NC impairment across individual domains (% DDS > 0.5) in HIV+ with Global NCI (n = 45)

This study was funded by 5R01 MH073433: Neurobehavioral Effects of HIV and Host Genetics in China. The HIV Neurobehavioral Research Center is funded public funding from the National Institutes of Health (NIH) (NIMH Award Number P30MH062512).

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