Search

Tenofovir is a nucleotide HIV reverse transcriptase inhibitor whose chemical properties suggest that it may not penetrate into the central nervous system in therapeutic concentrations. The study's objective was to determine tenofovir's penetration into cerebrospinal fluid (CSF).CNS HIV Antiretroviral Therapy Effects Research is a multicenter observational study to determine the effects of antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking tenofovir between October 2003 and March 2007. All samples were assayed by mass spectrometry with a detection limit of 0.9 ng/mL.One hundred eighty-three participants (age 44 ± 8 years; 83 ± 32 kg; 33 females; CSF protein 44 ± 16 mg/dL) had plasma and CSF samples drawn 12.2 ± 6.9 and 11 ± 7.8 hours post dose, respectively. Median plasma and CSF tenofovir concentrations were 96 ng/mL [interquartile range (IQR) 47-153 ng/mL] and 5.5 ng/mL (IQR 2.7-11.3 ng/mL), respectively. Thirty-four of 231 plasma (14.7%) and 9 of 77 CSF samples (11.7%) were below detection. CSF to plasma concentration ratio from paired samples was 0.057 (IQR 0.03-0.1; n = 38). Median CSF to wild-type 50% inhibitory concentration ratio was 0.48 (IQR 0.24-0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type 50% inhibitory concentration. More subjects had detectable CSF HIV with lower (7 ng/mL) versus higher (>7ng/mL) CSF tenofovir concentrations (29% versus 9%; P = 0.05).Tenofovir concentrations in the CSF are only 5% of plasma concentrations, suggesting limited transfer into the CSF, and possibly active transport out of the CSF. CSF tenofovir concentrations may not effectively inhibit viral replication in the CSF. [ABSTRACT FROM AUTHOR]

Objective: Neurocognitive (NC) impairment in people with HIV (PWH) is associated with erythrocyte indices, which may serve as indicators of iron metabolism, inflammation, and related factors. Erythropoiesis requires iron, regulated by a multifaceted system of peptide hormones, including hepcidin. This study postulated that hepcidin might modify the relationship between erythrocyte indices and NC performance in PWH., Methods: Plasma hepcidin and erythrocyte indices were quantified in 88 virally-suppressed PWH who underwent comprehensive NC assessments. Global NC performance was summarized by global T-scores. Associations of global T-scores with anemia and erythrocyte indices were determined in univariable analyses. To examine the influence of hepcidin on the relationship between NC performance and erythrocyte indices, we evaluated interactions between these covariates in relation to global T-scores and then performed stratified analyses., Results: In multivariable analyses, hepcidin detectability interacted with age (p = 0.007) and mean corpuscular volume (MCV) (p = 0.031) in relation to the global T-score. Interactions between anemia and erythrocyte indices on global T-scores were significant (anemia x MCV, p = 0.008; anemia x MCH, p = 0.011). Stratified analyses identified that lower global T-scores were associated with older age (p = 0.001) and higher MCV (p = 0.0046) and mean corpuscular hemoglobin (MCH, p = 0.026) only when hepcidin was undetectable. Among the anemic, worse global T-score was associated with higher MCV (p = 0.001) and MCH (p = 0.002)., Conclusion: Findings suggest that iron-related factors (hepcidin, anemia, MCV, MCH) and age influence neurocognitive health. This cross-sectional study underscores hepcidin as an effect modifier in the associations of erythrocyte indices, anemia, and age with neurocognitive function in PWH., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HIV infection is linked to persistent inflammation despite effective antiretroviral therapy (ART). The Systemic Immune-Inflammation Index (SII) is a marker of inflammation in various conditions., Methods: We compared SII values between PWH and PWoH. Clinical blood laboratory data were used to calculate the SII for each participant using the formula [(Platelet count × Neutrophil count) / Lymphocyte count]. Differences in SII values between the groups were analyzed using the Wilcoxon test, and the impact potential confounders was assessed with multivariable regression models., Results: The study included 343 PWH and 199 PWoH. Age and race did not significantly differ, but sex distribution did (83.1% male in PWH vs. 55.8% in PWoH, P < 0.0001). Among PWH, median [IQR] nadir and current CD4 counts were 199 cells/μL [50, 350] and 650 [461,858], respectively. Nearly all PWH were on ART, with 97.2% achieving viral suppression. PWH had lower SII values than PWoH (327 [224, 444] vs. 484 [335,657], P = 1.35e-14). PWH also had lower neutrophils and platelets (ps < 0.001) and higher lymphocyte counts (P = 0.001). These differences remained significant after adjusting for age, sex, and other potential confounders., Discussion: Contrary to expectations, PWH had lower SII levels, likely due to altered hematologic parameters influenced by HIV and ART. These findings suggest that SII interpretation in PWH requires consideration of unique hematologic profiles and underscore the need for further research to understand the mechanisms and clinical implications of SII in HIV management., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To quantify and characterize the nature of cognitive change over 1 year in a cohort of HIV-positive former plasma donors in rural China., Design: The present study is an observational cohort study., Methods: One hundred and ninety-two HIV-positive and 101 demographically comparable HIV-negative individuals, all former plasma donors, who lived in a rural part of China, received comprehensive medical and neuropsychological examinations. At study entry, 56% of HIV-positive group was on combination antiretroviral treatment and 60.9% at follow-up. Multiple regression change score approach was used with the HIV-negative sample to develop norms for change that would be then applied to the HIV-positive participants. Follow-up test scores adjusted for the control group practice effect., Results: Fifty-three HIV-positive individuals (27%) developed significant cognitive decline as compared with five (5%) HIV-negative individuals. Cognitive decline was predicted at baseline by AIDS status, lower nadir CD4, and worse processing speed; at follow-up, it was associated with lower current CD4 cell count and failure of viral suppression on combination antiretroviral treatment. Neuropsychological decline also was associated with decreased independence in activities of daily living. Using neuropsychological impairment scores that were corrected for 'practice' on repeated testing, we found that among the decliners, 41.5% (N = 22) had incident impairment, whereas 38% (N = 20) declined within the impaired range and another 20.7% (N = 11) declined within the normal range., Conclusion: The present study demonstrates that despite ongoing combination antiretroviral treatment, cognitive decline in HIV-positive people is common over a 1-year follow-up. Regression-based norms for change on western neuropsychological tests can be used to detect disease-related cognitive decline in a developing country.

Objectives: To characterize HIV-1 env compartmentalization between cerebrospinal fluid (CSF) and peripheral blood plasma over all stages of the HIV-1 disease course, and to determine the relationship between the extent of CSF HIV-1 env compartmentalization and clinical neurologic disease status., Design: Paired blood plasma and CSF specimens were collected from 66 HIV-infected patients cross-sectionally representing all major clinical stages relating to HIV-associated neurologic disease, including primary infection, asymptomatic chronic infection, chronic infection with minor global impairment, and immune deficiency with HIV-associated dementia., Methods: Heteroduplex tracking assays and bulk sequence analysis targeting the V1/V2, C2-V3, and V4/V5 regions of env were performed to characterize the genetic makeup of complex HIV-1 populations in the cross-sectional blood plasma and CSF specimens. The levels of blood plasma/CSF env compartmentalization were quantified and compared across the different clinical stages of HIV-1 neurologic disease., Results: Blood plasma/CSF env compartmentalization levels varied considerably by disease stage and were generally consistent across all three regions of env characterized. Little or no compartmentalization was observed in non-impaired individuals with primary HIV-1 infection. Compartmentalization levels were elevated in chronically infected patients, but were not significantly different between mildly impaired and non-impaired patients. Patients with HIV-associated dementia showed significantly greater blood plasma/CSF env compartmentalization relative to other groups., Conclusion: : Increased CSF compartmentalization of the HIV-1 env gene, which may reflect independent HIV-1 replication and evolution within the central nervous system, is specifically associated with HIV-associated dementia and not the less severe forms of HIV-1 neurologic disease.

Objective: Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF)., Design: Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005., Methods: Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml., Results: One hundred and seventeen participants (43 +/- 7.7 years, 79% men, 81 +/- 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10 (5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml., Conclusion: Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.

Objective: To determine the effects of low-dose oral lithium on the neuropsychological performance of individuals diagnosed with HIV-associated neurocognitive impairment., Design and Methods: The project was a single-arm, open-label, 12-week pilot study at a university-based tertiary care center. The participants were adults who had been diagnosed with HIV-associated neurocognitive impairment and had been on stable antiretroviral therapy for at least 12 weeks. Conditions that could affect cognition, worsen adherence to study procedures, or increase the risk of lithium adverse reactions were excluded. Twenty-one individuals were screened and eight were enrolled, all of whom completed the study. Oral lithium was initiated at 300 mg daily and was titrated to maintain 12-h trough concentrations between 0.4 and 0.8 mEq/l. Global neuropsychological performance was assessed by the global deficit score., Results: At baseline, all participants had impaired neuropsychological performance and most had reduced CD4 cell counts (median 292 cells/microl), and HIV RNA levels in plasma below 400 copies/mL (seven of eight). Titrated lithium doses ranged between 600 and 1200 mg/day. Performance improved in all eight individuals after 12 weeks, and became unimpaired in six. The study treatment was well tolerated with no grade 3 or 4 adverse events and no premature discontinuations., Conclusions: Lithium resulted in improved neuropsychological performance in antiretroviral-treated, impaired individuals in this small, open-label study. Based on published in vitro data, lithium may exert this effect by inhibiting neuronal glycogen synthase kinase-3beta.

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-alpha, 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.

Objectives: To describe a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy (HAART), its relationship to clinical and neuroimaging findings, and suggest hypotheses regarding pathogenesis., Design and Methods: AIDS patients who failed HAART and displayed severe leukoencephalopathy were included. All cases had detailed neuromedical, neuropsychological, neuroimaging and postmortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses., Results: Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein-Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis., Conclusions: Taken together, our findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals.