The concomitant use of second-generation antipsychotics and long-term antiretroviral therapy may be associated with increased cardiovascular risk.

To study the effect of concurrent use of second-generation antipsychotics (SGAs) on metabolic syndrome (MetS) components conferring increased cardiovascular risk in a sample of human immunodeficiency virus (HIV)-infected adults taking antiretroviral therapy (ART). A retrospective study of participants consecutively recruited at the UCSD HIV Neurobehavioral Research Program examined effects of combined ART and SGAs on body mass index (BMI), nonfasting serum lipids, diabetes mellitus (DM) incidence, and mean arterial pressure (MAP). Metabolic outcome variables and covariates were compared using t-tests, Chi-squared or Fisher's exact tests. Linear and logistic multivariable models explored metabolic outcomes for participants taking (SGA+) or not taking (SGA-) concomitant SGAs, after controlling for demographic and HIV disease- and ART-related covariates. Of 2229 HIV-infected participants, 12% (N=258) were treated with SGAs. In multivariable models adjusted for relevant covariates, the SGA+ group had significantly higher mean triglycerides, significantly higher odds of DM, significantly higher MAPs and marginally higher BMI. The use of SGAs in HIV-infected adults taking ART was independently associated with worse indicators of MetS and cardiovascular risk. Aggressive monitoring for the metabolic complications from concurrent SGA and ART is indicated in all patients receiving these medication combinations.

HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

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

BACKGROUND: Prior 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: Failure 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.

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.

Relationships among neurocognitive status, medication adherence measured by pharmacy refill records, and virologic suppression in HIV-infected persons.

BACKGROUND: Optimal antiretroviral therapy (ART) effectiveness depends on medication adherence, which is a complex behavior with many contributing factors, including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence. METHODS: A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington. Pharmacy refill records were the primary method to measure ART adherence, indexed to a "sentinel" drug with the highest central nervous system penetration-effectiveness score. Standardized neuromedical, neuropsychological, psychiatric, and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and relationships between adherence and changes in plasma and cerebrospinal fluid HIV RNA concentrations between visits. RESULTS: Among 80 (33 at JHU and 47 at University of Washington) participants, the mean adherence score was 86.4%, with no difference between sites. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV infected for a longer period of time. Worse performance in working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits. CONCLUSIONS: Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support.

Synergistic effects of HIV infection and older age on daily functioning.

OBJECTIVE: To determine whether HIV infection and aging act synergistically to disrupt everyday functioning. DESIGN: Cross-sectional factorial study of everyday functioning in the context of HIV serostatus and age (≤40 years vs. ≥50 years). METHODS: One hundred three HIV+ and 87 HIV- participants were administered several measures of everyday functioning, including self-report indices of health-related quality of life (HRQoL) and instrumental and basic activities of daily living (IADLs and BADLs), and objective measures of functioning, including employment and Karnofsky Performance Scale ratings. RESULTS: Significant interaction effects of HIV and aging were observed for IADL and BADL declines, and for Karnofsky Performance Scale ratings (Ps < 0.05), independent of potentially confounding factors. Follow-up contrasts revealed significantly worse functioning in the older HIV+ group for most functional outcome measures relative to the other study groups (Ps < 0.05). A significant interaction effect was also observed on the emotional functioning HRQoL subscale, and additive effects of both age and HIV were observed for the physical functioning and general health perceptions HRQoL subscales (Ps < 0.05). Significant predictors of poorer functioning in the older HIV+ group included current major depressive disorder for all outcomes, and comorbid medical conditions, lower estimated premorbid functioning, neurocognitive impairment, and nadir CD4 count for selected outcomes. CONCLUSION: Findings suggest that older age may exacerbate the adverse effects of HIV on daily functioning, which highlights the importance of evaluating and monitoring the functional status of older HIV-infected adults. Early detection of functional difficulties could facilitate delivery of compensatory strategies (eg, cognitive remediation) or assistive services.

Health-related quality of life 'well-being' in HIV distal neuropathic pain is more strongly associated with depression severity than with pain intensity.

BACKGROUND: Despite modern antiretroviral treatment, HIV-associated distal neuropathic pain (DNP) remains one of the most prevalent and debilitating complications of HIV disease. Neuropathic pain is often accompanied by depressed mood, and both pain and depression have been associated with decreased health-related quality of life (HRQOL) well-being. The relative contribution of depression and pain to worse life quality has not been addressed, however, even though a better understanding might sharpen intervention strategies. METHODS: We used the Medical Outcomes Study HIV (MOS-HIV) Health Survey and the Beck depression inventory-II and linear regression models to investigate HRQOL well-being in HIV-infected patients with DNP (n = 397) participating in an observational cohort study at six U.S. sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). RESULTS: For this sample of patients with HIV DNP, severity of depressed mood was more highly correlated with HRQOL well-being than was pain intensity. CONCLUSIONS: These results suggest that interventions to improve HRQOL well-being in individuals with HIV-associated DNP may need to address not only pain intensity but mood state as well.

Plasma proteomic profiling in HIV-1 infected methamphetamine abusers.

We wanted to determine whether methamphetamine use affects a subset of plasma proteins in HIV-infected persons. Plasma samples from two visits were identified for subjects from four groups: HIV+, ongoing, persistent METH use; HIV+, short-term METH abstinent; HIV+, long term METH abstinence; HIV negative, no history of METH use. Among 390 proteins identified, 28 showed significant changes in expression in the HIV+/persistent METH+ group over the two visits, which were not attributable to HIV itself. These proteins were involved in complement, coagulation pathways and oxidative stress. Continuous METH use is an unstable condition, altering levels of a number of plasma proteins.

Working memory deficits affect risky decision-making in methamphetamine users with attention-deficit/hyperactivity disorder.

Methamphetamine (MA) use and Attention-Deficit/Hyperactivity Disorder (ADHD) commonly co-occur and are independently associated with dysregulation of frontostriatal loops and risky decision-making; however, whether their comorbidity exacerbates risky decision-making is not known. This study evaluated 23 participants with histories of MA dependence and ADHD (MA+ADHD+), 25 subjects with MA dependence alone (MA+ADHD-), and 22 healthy adults (MA-ADHD-), who completed the Iowa Gambling Task (IGT) as part of a larger neuropsychiatric research evaluation. Results showed a significant interaction between ADHD, MA, and working memory, such that individuals with working memory deficits in the MA+ADHD+ cohort demonstrated the strongest propensity to select cards from "disadvantageous" versus "advantageous" decks on the IGT. This effect was not better explained by other psychiatric, substance use, neuromedical, or cognitive factors. Findings suggest that working memory deficits may moderate the expression of risky decision-making in MA users with ADHD.

Lifetime suicidal ideation and attempt are common among HIV+ individuals.

BACKGROUND: Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART). METHOD: Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204). RESULTS: Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters. LIMITATIONS: Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt. CONCLUSIONS: High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggest that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.

Neurocognitive impact of substance use in HIV infection.

BACKGROUND: : To determine how serious a confound substance use (SU) might be in studies on HIV-associated neurocognitive disorder (HAND), we examined the relationship of SU history to neurocognitive impairment (NCI) in participants enrolled in the Central Nervous System HIV Antiretroviral Therapy Effects Research study. METHODS: : After excluding cases with behavioral evidence of acute intoxication and histories of factors that independently could account for NCI (eg, stroke), baseline demographic, medical, SU, and neurocognitive data were analyzed from 399 participants. Potential SU risk for NCI was determined by the following criteria: lifetime SU Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis, self-report of marked lifetime SU, or positive urine toxicology. Participants were divided into 3 groups as follows: no SU (n = 134), nonsyndromic SU (n = 131), syndromic SU (n = 134) and matched on literacy level, nadir CD4, and depressive symptoms. RESULTS: : Although approximately 50% of the participants were diagnosed with HAND, a multivariate analysis of covariance of neurocogntive summary scores, covarying for urine toxicology, revealed no significant effect of SU status. Correlational analyses indicated weak associations between lifetime heroin dosage and poor recall and working memory and between cannabis and cocaine use and better verbal fluency. CONCLUSIONS: : These data indicate that HIV neurocognitive effects are seen at about the same frequency in those with and without historic substance abuse in cases that are equated on other factors that might contribute to NCI. Therefore, studies on neuroAIDS and its treatment need not exclude such cases. However, the effects of acute SU and current SU disorders on HAND require further study.

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

BACKGROUND: China's 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. METHODS: HIV-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. RESULTS: HIV+ 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. LIMITATIONS: The epicenter of China HIV has moved into urban injection drug users, limiting the representativeness of this sample. CONCLUSIONS: High rates of MDD and its impact suggest that in China, as elsewhere, comprehensive care requires detection and treatment of mood disorder.

HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors.

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV-) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV - participants from the pre-CART era (1988-1995; N = 857) and CART era (2000-2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.