McCutchan Ja

HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.

Objectives: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). Methods: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Results: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm3 (30% vs 47% in remaining subgroups). Conclusions: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

Cortical Synaptic Density is Reduced in Mild to Moderate Human Immunodeficiency Virus Neurocognitive Disorder

Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)‐related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante‐mortem levels of cognitive performance in AIDS patients. Three‐dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin‐immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life.

Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy

Objective: To rigorously evaluate the time course of cognitive change in a cohort of individuals with HIV-associated neurocognitive disorders (HAND) initiating combination antiretroviral therapy (CART), and to investigate which demographic, laboratory, and treatment factors are associated with neuropsychological (NP) outcome (or “any NP improvement”). Methods: Study participants included 37 HIV+ individuals with mild to moderate NP impairment who initiated CART and underwent NP testing at 12, 24, 36, and 48 weeks thereafter. NP change was assessed using a regression-based change score that was normed on a separate NP-stable group thereby controlling for regression toward the mean and practice effect. Mixed-effect regression models adjusting for loss to follow-up were used to evaluate the time course of cognitive change and its association with baseline and time-varying predictors. Results: In persons with HAND initiating CART, cognitive improvement happens soon after initiation (13% at week 12), but more often 24, 36, and up to 48 weeks after initiation (up to 41%), with fewer than 5% demonstrating significant worsening. In multivariate analyses, unique predictors of NP improvement included more severe baseline NP impairment and higher CART CNS penetration index. Greater viral load decrease was associated with NP improvement only in univariate analyses. Conclusion: Clinically meaningful neuropsychological improvement seemed to peak around 24–36 weeks after combination antiretroviral therapy initiation and was prolonged over the 1-year study period. This study also provides new evidence that benefit may be maximized by choosing antiretroviral medications that reach therapeutic concentrations in the CNS.

Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources

Objective: To identify the sources of HIV virions in CSF by modeling treatment-associated HIV dynamics. Background: We postulated a model in which cell-free CSF virions originate from two major sources, namely, systemic non-CNS and CNS tissues, the latter including brain parenchyma and meninges. The model predicted that with initiation of antiretroviral therapy, the acute-phase decline in CSF HIV RNA levels would be controlled by the kinetics of the dominant virion source (systemic versus CNS). Based on prior observations, we hypothesized that the dominant source of CSF virions would shift from systemic to CNS in more advanced disease. Methods: Three patient groups were studied: Group 1 (n = 5): nondemented, with early HIV disease (CD4+ lymphocytes ≥ 400/μL) or pleocytosis (CSF leukocytes ≥ 4/μL); Group 2 (n = 5): nondemented, with advanced HIV disease (CD4+ < 400/μL) and no pleocytosis; Group 3 (n = 2): patients with HIV-associated dementia (HAD). All patients began a new, highly active antiretroviral treatment regimen and underwent serial lumbar punctures and phlebotomies. Results: For patients in Group 2, the rate of decline in CSF HIV RNA was slower than in plasma (p < 0.00001). For Group 1, the rate of decline in CSF was not different from plasma (p > 0.25). Patients with HAD showed high CSF HIV RNA after 5 to 6 weeks of treatment despite a 100-fold decrease in plasma HIV RNA. Conclusions: CSF and plasma HIV dynamics became increasingly independent in advanced HIV disease, and the compartmental discrepancy was largest in HAD. Our findings suggest that viral replication in CNS tissues may constitute a major, independent source of CSF HIV RNA. In patients with HAD, brain parenchyma itself may be the principal CNS tissue source, and CNS-targeted treatment strategies may be required to eradicate this infection.

Neuropsychological impairment in human immunodeficiency virus-infection: implications for employment. HNRC Group. HIV Neurobehavioral Research Center.

&NA; Individuals infected with the human immunodeficiency virus‐Type 1 (HIV‐1), are at increased risk for neurobehavioral impairment, particularly in later stages of the disease. Even patients in the medically asymptomatic or minimally symptomatic stages of infection may show mild deficits on comprehensive neuropsychological (NP) test batteries, although the clinical significance of such deficits remains uncertain. The present study used vocational difficulties as markers of clinical significance of NP impairment. In a sample of 289 HIV‐infected, nondemented men, those who evidenced NP impairment had a higher unemployment rate (p < .001) than did their unimpaired counterparts. In HIV‐positive subjects who remained employed, NP impairment was strongly associated with subjective decreases in job‐related abilities. Neither depression nor medical symptoms could explain the relationship between the NP impairment and employment problems. These results are consistent with previous studies investigating other neuropsychiatric disorders, which suggest that even mild NP impairment can interfere with employment status. From this standpoint, such impairment in HIV‐infected persons may be described as “clinically significant.”

Genetic Composition of Human Immunodeficiency Virus Type 1 in Cerebrospinal Fluid and Blood without Treatment and during Failing Antiretroviral Therapy

ABSTRACT Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance (P = 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits (P = 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns (P = 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS.

Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline

Objective: While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline). Methods: A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7–63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood. Results: The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1–3.6; p = 0.02) for SR, 5.8 (CI 3.2–10.7; p < 0.0001) for PB, and 3.2 (CI 2.0–5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not. Conclusions: This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.

The effects of hepatitis C, HIV, and methamphetamine dependence on neuropsychological performance : biological correlates of disease

Objective:To determine the effects of hepatitis C virus (HCV) infection on neuropsychological (NP) performance. Design:Cross-sectional analysis of a prospectively enrolled cohort. Methods:A total of 239 HIV-seropositive and 287 HIV-seronegative subjects enrolled in prospective cohort studies at a single center. Subjects underwent standardized assessments, including comprehensive neuropsychological testing, substance use inventory neuromedical examination, venipuncture, and lumbar puncture. HCV antibody was measured in serum. In seropositive individuals, HCV RNA was measured in plasma and cerebrospinal fluid (CSF). Results:HCV-seropositive subjects performed worse on neuropsychological testing and were almost twice as likely to be diagnosed as globally impaired, compared with those who were HCV seronegative. In a multivariate analysis, HCV, HIV, and methamphetamine dependence were independently associated with worse performance, even after adjusting for Centers for Disease Control stage and antiretroviral use. HCV-RNA levels in plasma were higher in those with memory, but not global, impairment. In cerebrospinal fluid, HCV RNA was below 100 copies/ml in all specimens. In HIV-infected subjects, HCV was associated with higher levels of HIV RNA in CSF, but not in plasma. HCV was also associated with higher levels of monocyte chemotactic protein 1, TNF-α, and soluble TNF receptor II. HCV-seropositive subjects did not appear to have advanced liver disease. Conclusions:HIV, HCV, and methamphetamine independently injure the central nervous system, leading to global neuropsychological impairment. HCV may injure the brain by viral or immune-mediated mechanisms. HCV-associated brain injury may be preventable or reversible because HCV infection is potentially curable.

Validity of the Quality of Well-being Scale for Persons With Human Immunodeficiency Virus Infection

To evaluate the validity of the Quality of Well-Being Scale (QWB) for studies of patients with human immunodeficiency virus (HIV) disease, 514 men were studied who were divided among four categories: Centers for Disease Control and Prevention (CDC) Group A (N = 272), CDC-B (N = 81), CDC-C (N = 47), and uninfected male controls (N = 114). The QWB and a variety of medical, neuropsychological, and biochemical measures were administered to all participants. When QWB scores were broken down by HIV grouping, the CDC-C group was significantly lower (.614) than the CDC-B (.679), CDC-A (.754), or control group (.801). The difference between Groups CDC-C and CDC-A was about.14 units of well-being, which suggests that individuals lose one-seventh equivalents of 1 well year of life for each year they are in Group CDC-C in comparison to the asymptomatic group (Group CDC-A). In comparison to the controls, this would equal a 1-year of life loss for each seven infected individuals. The QWB was shown to be significantly associated with CD4+ lymphocytes (p <.001), clinician ratings of neuropsychological impairment (p <.04), neurologists ratings of dysfunction (p <.001), and all subscales of the Profile of Mood States. Baseline QWB scores were significant prospective predictors of death over a median follow-up time of 30 months. Multivariate models demonstrated high covariation between predictors of QWB. It was concluded that the QWB is a significant correlate of biological, neuropsychological, neurological, psychiatric, and mortality outcomes for male HIV-infected patients.

Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder

Objective: To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study. Methods: In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, 130 HIV+ participants provided fasting blood samples. Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined. Demographics, biomarkers of HIV disease, metabolic variables, combination antiretroviral therapy (CART) history, other drug exposures, and self-reported diabetes were examined in multivariate models predicting NCI. Separate models were used for body mass index (BMI) alone (n = 90) and BMI and waist circumference (WC) together (n = 55). Results: NCI (global impairment rating ≥5) was diagnosed in 40%. In univariate analyses, age, longer duration of HIV infection, obesity, and WC, but not BMI, were associated with NCI. Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort. Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for. Conclusions: As in HIV-uninfected persons, central obesity, but not more generalized increases in body mass (BMI), was associated with a higher prevalence of NCI in HIV+ persons. Diabetes appeared to be associated with NCI only in older patients. Avoidance of antiretroviral drugs that induce central obesity might protect from or help to reverse neurocognitive impairment in HIV-infected persons.