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.

Impact of long-term treatment with neurotoxic dideoxynucleoside antiretrovirals: implications for clinical care in resource-limited settings.

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.

Low CSF leptin levels are associated with worse learning and memory performance in HIV-infected men.

OBJECTIVE: The main objective of this study was to investigate the association between human CSF leptin levels and neuropsychological (NP) performance in the setting of HIV infection. We hypothesized that human CSF leptin levels positively correlate with NP performance. BACKGROUND: Leptin is an adipocyte-derived hormone that influences brain development and function, particularly learning and memory, in the mouse model. The extent to which leptin contributes to neurocognitive functioning in humans is less clear. METHOD: A cross-sectional evaluation of CSF leptin and NP performance was performed. Leptin levels in CSF and serum samples from 59 HIV-positive men were measured by ELISA. Comprehensive, standardized NP testing was used to determine impairment status in global and specific domains. RESULTS: Lower CSF leptin levels and reduced leptin uptake into the central nervous system (CNS) correlated with impaired learning and memory performance in both univariate and multivariate analyses. In multivariate analyses, lower CSF leptin levels and reduced CNS leptin uptake were associated with worse NP performance in learning and memory, adjusting for CD4 nadir, antiretroviral treatment exposure, and HIV RNA levels in CSF. CONCLUSIONS: Low CSF leptin levels are associated with poorer performance in learning and memory among HIV-infected men adjusting for usual predictors of HIV-associated neurocognitive impairment. This association is consistent with prior in vitro and animal data suggesting leptin has a trophic or facilitatory role in the hippocampus, above and beyond its role in hypothalamic regulation.

Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine.

OBJECTIVE: To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence. METHODS: Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits. RESULTS: Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency. CONCLUSION: Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.

Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy.

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.