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.
...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).
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.
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.
Background. Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did ...not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery. Methods. We investigated the incidence and predictors of NC change over 16–72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research Cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change. Results. Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001). Conclusions. NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.
Anemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated ...neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown.
We evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4(+) T-cell count, zidovudine use, and comorbid conditions. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments.
HAND, defined according to standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume and mean corpuscular hemoglobin were positively associated with the global deficit score, a continuous measure of neurocognitive impairment (both P < .01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all P < .05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted hazard ratio, 1.55; P < .01).
Anemia and red blood cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons.
Background. Combination antiretroviral (ARV) therapy can reduce human immunodeficiency virus (HIV) RNA levels in cerebrospinal fluid (CSF) and plasma and improve immunocompetence. However, ...HIV-associated neurocognitive disorders persist, possibly because some ARV drugs do not reach therapeutic concentrations in the brain. The primary objective of this study was to determine whether lopinavir plus ritonavir (LPV-rtv) used alone reduced the HIV RNA level in CSF. Methods. The study was an open-label, 24-week trial of sequential ARV therapy. Fifteen subjects were enrolled and received LPV-rtv therapy. Ten subjects reached the primary study end point at week 3, before at least 2 other ARV drugs were added to the treatment regimen. CSF and blood samples were obtained before treatment and after 3, 12, and 24 weeks of treatment. Results. LPV-rtv therapy alone reduced the HIV RNA level in CSF in all subjects (median change in HIV RNA level, -1.42 log10 copies/mL), including 5 who had slower decreases in HIV RNA level in CSF than in plasma—an indicator of autonomous central nervous system infection. Among 9 subjects who completed 12 weeks of LPV-rtv—containing therapy, the HIV RNA level was below quantitation in the CSF samples from 8 subjects and in the plasma samples from 6 subjects. By week 24, HIV RNA levels were below quantitation in samples of both fluids from all 8 subjects. Conclusions. LPV-rtv therapy alone for 3 weeks consistently reduces the HIV RNA level in CSF by at least 10-fold in most individuals, including those likely to have autonomous HIV replication in the central nervous system. Because it penetrates the central nervous system in therapeutic concentrations and appears to reduce HIV replication in the central nervous system, LPV-rtv may benefit subjects who receive a diagnosis of or are at risk for HIV-associated neurocognitive disorders.
To determine the effects of hepatitis C virus (HCV) infection on neuropsychological (NP) performance.
Cross-sectional analysis of a prospectively enrolled cohort.
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).
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-alpha, and soluble TNF receptor II. HCV-seropositive subjects did not appear to have advanced liver disease.
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.
Objectives
A minority of HIV‐infected patients taking an antiretroviral (ARV) regimen containing dideoxynucleosides (d‐drugs) such as stavudine (d4T) and didanosine (DDI) experiences dose‐limiting ...neuropathic pain and paraesthesias, usually within weeks of starting these drugs. Because d‐drugs are among the few affordable options available in developing countries, continuing d‐drug therapy would be a desirable strategy for many HIV‐infected individuals. Therefore, we evaluated the safety of continuing d‐drug therapy.
Methods
In a US cohort, we compared the rates of worsening neuropathic symptoms and signs in HIV‐infected individuals on stable ARV regimens that did (n=252) or did not (n=250) include d‐drugs. Rates of worsening were compared using proportional hazards model and the log‐rank test.
Results
The risk ratios (RR) were not significantly larger for worsening neuropathy signs 0.94; 95% confidence interval (CI) 0.84–1.07 or symptoms (0.99; 95% CI 0.88–1.14) in patients taking d‐drugs continuously compared to those not taking d‐drugs.
Conclusions
Continued d‐drug exposure among patients tolerating an initial trial did not increase the risk of worsening neuropathy compared to non‐d‐drug‐containing regimens. If applicable in developing countries, these findings suggest that in most patients d‐drugs can be continued safely in the long term without increasing the risk of worsening neuropathy.
HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM; "remembering to remember"), conferring risk of daily functioning declines. However, ...self-perceptions of PM functioning are not reliably associated with PM performance in HIV, suggesting a possible deficit in awareness of PM abilities (meta-PM). Our study examined meta-PM in HAND and its correlates using self-predictions of laboratory-based PM performance. Performance-based PM abilities, self-reported prediction of PM performance, and PM complaints in everyday life were assessed in 49 individuals with HAND, 93 HIV+ without HAND (HIV+ noHAND), and 121 seronegative adults (HIV-). After controlling for group-level differences, HAND was associated with a greater number of PM symptoms in everyday life and worse PM performance when compared with both HIV+ noHAND and HIV- samples. Although HAND individuals reported somewhat lower predictions regarding their laboratory PM performance relative to the other study groups, they nevertheless exhibited significantly greater inaccurate overconfidence in time-based PM abilities. Within the HAND group, overconfidence in time-based meta-PM was associated with executive dysfunction and antiretroviral (ARV) nonadherence. HAND individuals evidenced a moderate deficit in awareness of PM functioning characterized by overconfidence in time-based PM abilities. Overconfidence in PM may result in absence of compensatory strategy use, and lead to increased errors in daily functioning (e.g., ARV nonadherence).
Sensory neuropathy is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy. Metabolic syndrome (MetS), a cluster of risk factors for atherosclerosis and ...microvascular disease, is associated with sensory neuropathy in HIV-uninfected (HIV-negative) persons. We examined whether MetS or its components predispose individuals to HIV-associated sensory neuropathy (HIV-SN).
From a prospective multicenter cohort of 1556 HIV-positive patients, a subgroup (n = 130) with fasting laboratory tests and sensory neuropathy assessment was selected.
Sensory neuropathy was defined by symmetrically decreased reflexes or sensation loss in the legs. MetS was defined by presence of at least three risk factors: mean arterial pressure of at least 100 mmHg; triglycerides (TRGs) of at least 150 mg/dl and high-density lipoprotein cholesterol of less than 40 mg/dl for male patients, less than 50 mg/dl for female patients; body mass index of more than 25 kg/m; plasma glucose (GLU) of at least 100 mg/dl and self-reported diabetes mellitus type 2. Multivariate logistic regression examined the association between HIV-SN and MetS.
After controlling for HIV-SN risk factors such as age, CD4 current, length of HIV infection, use of dideoxynucleoside reverse transcriptase inhibitors and protease inhibitors, MetS was not associated with HIV-SN (P = 0.72). However, when each MetS component was assessed, elevated TRG was a significant risk factor for HIV-SN. From the larger cohort, both diabetes mellitus type 2 (odds ratio = 1.4, P < 0.01) and elevated TRG (odds ratio = 1.4, P = 0.01) were risk factors for HIV-SN.
The risk of HIV-SN was increased for diabetes mellitus type 2 and elevated TRG but not for other MetS components. Both increase the risk of sensory neuropathy in HIV-populations, but the mechanism(s) remains unclear.
Chronic use of methamphetamine (MA) is associated with neuropsychological dysfunction and affective distress. Some normalization of function has been reported after abstinence, but little in the way ...of data is available on the possible added benefits of long-term sobriety. To address this, we performed detailed neuropsychological and affective evaluations in 83 MA-dependent individuals at a baseline visit and following an average one-year interval period. Among the 83 MA-dependent participants, 25 remained abstinent, and 58 used MA at least once during the interval period. A total of 38 non-MA-addicted, demographically matched healthy comparison (i.e., HC) participants were also examined. At baseline, both MA-dependent participants who were able to maintain abstinence and those who were not performed significantly worse than the healthy comparison subjects on global neuropsychological functioning and were significantly more distressed. At the one-year follow-up, both the long-term abstainers and healthy comparison groups showed comparable global neuropsychological performance and affective distress levels, whereas the MA-dependent group who continued to use MA were worse than the comparison participants in terms of global neuropsychological functioning and affective distress. An interaction was observed between neuropsychological impairment at baseline, MA abstinence, and cognitive improvement, with abstinent MA-dependent participants who were neuropsychologically impaired at baseline demonstrating significantly and disproportionately greater improvement in processing speed and slightly greater improvement in motor abilities than the other participants. These results suggest partial recovery of neuropsychological functioning and improvement in affective distress upon sustained abstinence from MA that may extend beyond a year or more.
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