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1.  Tumefactive demyelination in a patient with human immunodeficiency virus 
Journal of neurovirology  2013;19(3):265-269.
doi:10.1007/s13365-013-0165-y
PMCID: PMC3700605  PMID: 23645348
tumefaction; demyelination; HIV; viral inclusion; leukoencephalopathy
2.  HIV-Associated Neurocognitive Disorders and the Impact of Combination Antiretroviral Therapies 
HIV-associated neurocognitive disorders (HAND) are the most common preventable and treatable cause of dementia. While the incidence of the most severe form of HAND, HIV-associated dementia, has decreased since the introduction of combination antiretroviral therapy (cART), the prevalence of less severe forms of HAND has continued to rise. HAND leads to a subcortical dementia consisting of a triad of cognitive, behavior, and motor dysfunction. No single laboratory test can establish HAND, but ancillary studies including neuropsychological testing, neuroimaging studies, and cerebrospinal fluid (CSF) analysis are useful for supporting or refuting the diagnosis. More recent evidence has suggested that higher central nervous system–penetrating cART may lead to greater suppression of CSF HIV viral loads and improved cognition. Because viral control generally has been successful without eliminating cognitive dysfunction, further clinical studies that assess adjunctive neuroprotective drugs are likely to be required.
PMCID: PMC3932327  PMID: 18957181
3.  PML diagnostic criteria 
Neurology  2013;80(15):1430-1438.
Objective:
To establish criteria for the diagnosis of progressive multifocal leukoencephalopathy (PML).
Methods:
We reviewed available literature to identify various diagnostic criteria employed. Several search strategies employing the terms “progressive multifocal leukoencephalopathy” with or without “JC virus” were performed with PubMed, SCOPUS, and EMBASE search engines. The articles were reviewed by a committee of individuals with expertise in the disorder in order to determine the most useful applicable criteria.
Results:
A consensus statement was developed employing clinical, imaging, pathologic, and virologic evidence in support of the diagnosis of PML. Two separate pathways, histopathologic and clinical, for PML diagnosis are proposed. Diagnostic classification includes certain, probable, possible, and not PML.
Conclusion:
Definitive diagnosis of PML requires neuropathologic demonstration of the typical histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with the techniques to show the presence of JC virus. The presence of clinical and imaging manifestations consistent with the diagnosis and not better explained by other disorders coupled with the demonstration of JC virus by PCR in CSF is also considered diagnostic. Algorithms for establishing the diagnosis have been recommended.
doi:10.1212/WNL.0b013e31828c2fa1
PMCID: PMC3662270  PMID: 23568998
5.  Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration 
Objectives
Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC90).
Methods
Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography–tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir.
Results
Twenty-nine matched CSF–plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma.
Conclusions
Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.
doi:10.1093/jac/dks441
PMCID: PMC3566670  PMID: 23143899
HIV; antiretroviral therapy; central nervous system; protein binding
6.  Continued High Prevalence and Adverse Clinical Impact of Human Immunodeficiency Virus–Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy 
Archives of neurology  2010;67(5):552-558.
Objective
To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era.
Design
Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models.
Setting
Six US academic medical centers.
Patients
One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study.
Main Outcome Measures
The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey.
Results
We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95%confidence interval, 1.8–2.5] per 10 years), lower CD4 nadir (1.2 [1.1–1.2] per 100-cell decrease), current CART use (1.6 [1.3–2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3–2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir.
Conclusions
Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
doi:10.1001/archneurol.2010.76
PMCID: PMC3924778  PMID: 20457954
7.  The Alzheimer Disease-8 and Montreal Cognitive Assessment as Screening Tools for Neurocognitive Impairment in HIV-Infected Persons 
Journal of neurovirology  2013;19(1):109-116.
The diagnosis of HIV-associated neurocognitive impairment is time-intensive and often omitted in busy outpatient settings. Brief screening tools are needed. The Montreal Cognitive Assessment (MoCA) and the Alzheimer’s disease (AD)-8 have been used in neurodegenerative disorders. We evaluated the sensitivity and specificity of these brief screening tools in HIV-infected persons. The AD-8, MoCA, and formal neuropsychological testing were administered to 200 HIV-infected patients followed at a single institution. Normalized scores on formal neuropsychological testing were used to define neurocognitive impairment. The sensitivity and specificity of the MoCA and AD-8 were assessed to diagnose impairment. Neurocognitive impairment was highly prevalent in this cohort: 127 persons (64%) were diagnosed with neurocognitive impairment based on formal testing. Using the AD-8 and MoCA, 113 (57%) and 101 (51%) persons were identified with neurocognitive impairment, respectively. The sensitivity and specificity of MoCA were 63% and 71%, respectively. The sensitivity and specificity of AD-8 were 61% and 51%, respectively. Our findings highlight that brief screening tools correlate with formal neuropsychological testing. However, the sensitivities of these screening tools are lower than desired. Nevertheless, given their ease in administration, these tools could assist as a first line for identifying individuals who may subsequently require formal neuropsychological testing.
doi:10.1007/s13365-012-0147-5
PMCID: PMC3655767  PMID: 23345074
HIV; Neurocognitive Disorder; MoCA; AD-8; Neuropsychological Testing; Cognition
8.  Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants 
Pharmacogenetics and genomics  2012;22(12):858-867.
Objectives
Prior candidate gene studies have associated CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics.
Materials and methods
Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry.
Results
Among 856 individuals, CYP2B6 516G→T was associated with efavirenz estimated Cmin (P = 8.5 × 10−41). After adjusting for CYP2B6 516G→T, CYP2B6 983T→C was associated (P = 9.9 × 10−11). After adjusting for both CYP2B6 516G→T and 983T→C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P = 4.4 × 10−15). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5× 10−8. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms.
Conclusion
Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization.
doi:10.1097/FPC.0b013e32835a450b
PMCID: PMC3614365  PMID: 23080225
CYP2B6; efavirenz; HIV; pharmacogenomics; pharmacokinetics
9.  Concurrent Classification Accuracy of the HIV Dementia Scale for HIV-associated Neurocognitive Disorders in the CHARTER Cohort 
Background
The HIV Dementia Scale (HDS) was developed to screen for HIV-associated Neurocognitive Disorders (HAND), but concerns have persisted regarding its substandard sensitivity. This study aimed to examine the classification accuracy of the HDS using raw and norm-based cutpoints, and to evaluate the contribution of the HDS subtests to predicting HAND.
Methods
1,580 HIV-infected participants from 6 U.S. sites completed the HDS, and a gold standard neuropsychological battery, on which 51% of participants were impaired. Results: Sensitivity and specificity to HAND using the standard raw HDS cutpoint were 24% and 92%, respectively. The raw HDS subtests of attention, recall, and psychomotor speed significantly contributed to classification of HAND, while visuomotor construction contributed the least. A modified raw cutpoint of 14 yielded sensitivity of 66% and specificity of 61%, with cross-validation. Using norms also significantly improved sensitivity to 69% with a concomitant reduction of specificity to 56%, while the positive predictive value declined from 75% to 62% and negative predictive value improved from 54% to 64%. The HDS showed similarly modest rates of sensitivity and specificity among subpopulations of individuals with minimal comorbidity and successful viral suppression.
Conclusions
Findings indicate that while the HDS is a statistically significant predictor of HAND, particularly when adjusted for demographic factors, its relatively low diagnostic classification accuracy continues to hinder its clinical utility. A raw cutpoint of 14 greatly improved the sensitivity of the previously established raw cutscore, but may be subject to ceiling effects, particularly on repeat assessments.
doi:10.1097/QAI.0b013e318278ffa4
PMCID: PMC3529802  PMID: 23111573
HIV; cognition; HIV-associated neurocognitive disorders; screening measures; HIV dementia scale
10.  Higher HIV-1 Genetic Diversity is Associated with AIDS and Neuropsychological Impairment 
Virology  2012;433(2):498-505.
Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population-based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment.
doi:10.1016/j.virol.2012.08.028
PMCID: PMC3466337  PMID: 22999095
HIV; AIDS; genetic diversity; neuropsychological impairment; viral population dynamics
11.  HIV peripheral neuropathy progression: protection with glucose-lowering drugs? 
Journal of neurovirology  2012;18(5):428-433.
The purpose of this study is to evaluate risk factors for progression from asymptomatic peripheral neuropathy (APN) to symptomatic peripheral neuropathy (SPN). Antiretroviral therapy (ART)-naïve patients initiating combination ART were followed longitudinally and screened for signs/ symptoms of PN. Having APN was associated with higher odds of future SPN (odds ratio (OR)=1.58, 95 % confidence interval (CI)=(1.08, 2.29), p=0.027). Neurotoxic ART use was associated with increased odds of progression to SPN (OR= 2.16, 95 % CI=(1.21, 3.85), p=0.009) while use of glucose-lowering drugs (non-insulin) was protective (OR=0.12, 95 % CI=(0.02, 0.83), p=0.031). Use of glucose-lowering drugs (non-insulin) may prevent progression from APN to SPN.
doi:10.1007/s13365-012-0119-9
PMCID: PMC3485691  PMID: 22806348
Peripheral neuropathy; Symptomatic peripheral neuropathy; Risk factors; HIV; Glucose-lowering drugs
12.  HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Naïve Patients 
PLoS ONE  2013;8(7):e70164.
Objectives
Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury.
Methods
We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF).
Results
The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions.
Interpretation
Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS.
doi:10.1371/journal.pone.0070164
PMCID: PMC3729685  PMID: 23936155
13.  Global NeuroAIDS Roundtable 
Journal of neurovirology  2013;19(1):1-9.
In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the “Global NeuroAIDS Roundtable” in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the “Global NeuroAIDS Roundtable”, presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.
doi:10.1007/s13365-012-0143-9
PMCID: PMC3713197  PMID: 23354550
Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2); Acquired immunodeficiency syndrome (AIDS); HIV clade; NeuroAIDS; HIV-associated neurocognitive disorders (HAND); Neuropathogenesis
14.  Clinical factors related to brain structure in HIV: the CHARTER study 
Journal of neurovirology  2011;17(3):248-257.
Despite the widening use of combination anti-retroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n=251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.
doi:10.1007/s13365-011-0032-7
PMCID: PMC3702821  PMID: 21544705
HIV; MRI; Neuroimaging; Immunospupression
15.  Health-Related Quality of Life ‘Well-Being’ In HIV Distal Neuropathic Pain Is More Strongly Associated With Depression Severity Than With Pain Intensity 
Psychosomatics  2012;53(4):380-386.
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 US 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.
doi:10.1016/j.psym.2012.05.002
PMCID: PMC3389373  PMID: 22748751
Quality of Life; Depression; HIV-Associated Distal Neuropathic Pain; Pain Intensity
16.  A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes 
Journal of Neurovirology  2013;19:351-358.
Immune reconstitution has improved outcomes for progressive multifocal leukoencephalopathy (PML), a potentially lethal brain disease caused by JC virus (JCV). However, an antiviral treatment to control JCV is needed when immune reconstitution is delayed or not possible. On the basis of in vitro efficacy, this study evaluated the effect of mefloquine on PML and factors that may predict PML outcomes. This 38-week, open-label, randomized, parallel-group, proof-of-concept study compared patients with PML who received standard of care (SOC) with those who received SOC plus mefloquine (250 mg for 3 days, then 250 mg weekly). Patients randomized to SOC could add mefloquine treatment at week 4. The primary endpoint was change from baseline to weeks 4 and 8 in JCV DNA copy number (load) in cerebrospinal fluid (CSF). Exploratory analyses evaluated factors that might correlate with clinical outcome. The majority of enrolled patients were HIV positive. Preplanned interim data analyses suggested that the study was unlikely to successfully demonstrate a significant difference between groups; therefore, the study was terminated prematurely. There was no significant difference between groups in CSF JCV DNA loads or clinical/MRI findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better clinical outcome at 16 weeks, as measured by Karnofsky scores. This study found no evidence of anti-JCV activity by mefloquine. An early decrease of CSF JCV DNA load appears to be associated with a better clinical outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s13365-013-0173-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s13365-013-0173-y
PMCID: PMC3758507  PMID: 23733308
Mefloquine; Leukoencephalopathy; Progressive multifocal; JC virus; Magnetic resonance imaging
17.  Rituximab-Associated Progressive Multifocal Leukoencephalopathy in Rheumatoid Arthritis 
Archives of neurology  2011;68(9):1156-1164.
Objective
To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab.
Design
Case study.
Setting
Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver.
Patients
Four patients developing PML in the setting of rituximab therapy for RA.
Intervention
Rituximab therapy.
Main Outcome Measures
Clinical and pathological observations.
Results
Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease.
Conclusion
These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.
doi:10.1001/archneurol.2011.103
PMCID: PMC3428054  PMID: 21555606
18.  LOW CSF Concentrations of the Nucleotide HIV Reverse Transcriptase Inhibitor, Tenofovir 
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 objective was to determine tenofovir penetration into cerebrospinal fluid (CSF).
CHARTER is a multi-center, observational study to determine 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.
183 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 (IQR 47 – 153) and 5.5 ng/mL (IQR 2.7 – 11.3), respectively. Thirty-four of 231 (14.7%) plasma and 9/77 (11.7%) CSF samples were below detection. CSF/plasma concentration ratio from paired samples was 0.057 (IQR 0.03 – 0.1; n=38). Median CSF/wild-type IC50 ratio was 0.48 (IQR 0.24 – 0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type IC50. More subjects had detectable CSF HIV with lower (≤ 7 ng/mL) versus higher (> 7ng/mL) CSF tenofovir concentrations (29% vs. 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.
doi:10.1097/QAI.0b013e318247ec54
PMCID: PMC3299895  PMID: 22217676
tenofovir; CSF; pharmacokinetics
19.  Performances on the CogState and Standard Neuropsychological Batteries Among HIV Patients Without Dementia 
AIDS and behavior  2011;15(8):1902-1909.
HIV-associated neurocognitive disorders (HAND) remain prevalent but challenging to diagnose particularly among non-demented individuals. To determine whether a brief computerized battery correlates with formal neurocognitive testing, we identified 46 HIV-infected persons who had undergone both formal neurocognitive testing and a brief computerized battery. Simple detection tests correlated best with formal neuropsychological testing. By multivariable regression model, 53% of the variance in the composite Global Deficit Score was accounted for by elements from the brief computerized tool (p<0.01). These data confirm previous correlation data with the computerized battery, yet illustrate remaining challenges for neurocognitive screening.
doi:10.1007/s10461-011-0033-9
PMCID: PMC3594991  PMID: 21877204
20.  Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER 
Journal of neurovirology  2012;18(6):511-520.
HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy (CART) and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. CHARTER is a U.S. based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G (odds ratio [95% confidence interval] = 0.27 [0.11-0.65]; p = 0.004) and T489C (odds ratio [95% confidence interval] = 0.41 [0.21-0.80]; p = 0.009). These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups are associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups (odds ratio [95% confidence interval] = 0.29 [0.12-0.71]; p = 0.007 and odds ratio [95% confidence interval] = 0.42 [0.18-1.0]; p = 0.05, respectively). In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.
doi:10.1007/s13365-012-0133-y
PMCID: PMC3587171  PMID: 23073667
genetics; mitochondria; HIV-related neurological diseases; peripheral neuropathy
21.  Genetic features of cerebrospinal fluid-derived subtype B HIV-1 tat 
Journal of neurovirology  2012;18(2):81-90.
Since HIV-1 Tat has been associated with neurocognitive dysfunction, we investigated 60 HIV-1 subtype B infected individuals who were characterized for neurocognitive functioning and had paired CSF and blood plasma samples available. To avoid issues with repeated sampling, we generated population-based HIV-1 tat sequences from each compartment and evaluated these data using a battery of phylogenetic, statistical and machine learning tools. These analyses identified position HXB2 5905 within the cysteine-rich domain of tat as a signature of CSF-derived HIV-1, and a higher number of mixed bases in CSF, measure of diversity, was associated with HIV-associated neurocognitive disorder. Since identified mutations were synonymous, we evaluated the predicted secondary RNA structures, which showed that this mutation altered secondary structure. As a measure of divergence, the genetic distance between the blood and CSF derived tat was inversely correlated with current and nadir CD4+ T cell counts. These data suggest that specific HIV-1 features of tat influence neurotropism and neurocognitive impairment.
doi:10.1007/s13365-011-0059-9
PMCID: PMC3572198  PMID: 22528397
HIV; central nervous system; tat; compartmentalization
22.  HIV Associated Neurocognitive Disorder (HAND) is Not Associated with Increased Fibrillar Amyloid Deposits Using 11C-PiB in Middle-Aged HIV+ Participants 
Archives of neurology  2012;69(1):72-77.
Objectives
Diagnostic challenges exist for differentiating HIV associated neurocognitive disorders (HAND) from symptomatic Alzheimer’s disease (AD) in HIV+ participants. Both disorders have cerebral amyloid containing plaques associated with abnormalities in amyloid beta protein 1–42 (Aβ42) metabolism. We evaluated if the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB) could discriminate AD from HAND in middle-aged HIV+ participants.
Design
11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. χ2 and t-tests assessed differences in clinical and demographic variables between HIV+ participants and community-living individuals followed by Alzheimer Disease Research Center (ADRC). An analysis of variance (ANOVA) assessed for regional differences in Aβ42 using 11C-PiB.
Setting
ADRC and HIV clinic
Participants
16 HIV+ participants (11 cognitively normal, 5 with HAND) and 19 ADRC participants (8 cognitively normal, 11 with symptomatic AD).
Main Outcome Measure(s)
Mean and regional 11C-PiB binding potentials
Results
Symptomatic AD were older (p < 0.001), had lower CSF Aβ42 (p < 0.001), and had higher CSF tau levels (p < 0.001) than other groups. Regardless of degree of impairment, HIV+ participants did not have increased 11C-PiB. Mean and regional binding potentials were elevated for symptomatic AD participants (p <0.0001).
Conclusions
Middle-aged HIV+ participants, even with HAND, do not exhibit increased 11C-PiB while symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV+ participants. Future cross sectional and longitudinal studies are required to assess utility of 11C-PiB in older HAND individuals.
doi:10.1001/archneurol.2011.761
PMCID: PMC3536500  PMID: 22232345
HIV; Pittsburgh compound B (PIB); amyloid; HIV associated neurocognitive disorders; Alzheimer’s disease
23.  John Cunningham Virus Antibody and Viremia as Predictors of Progressive Multifocal Leukoencephalopathy in Human Immunodeficiency Virus-1–Infected Individuals 
We examined whether prediagnostic John Cunningham virus (JCV) antibodies and viremia are predictors of progressive multifocal leukoencephalopathy (PML) in 83 PML cases and 240 human immunodeficiency virus (HIV) disease-matched controls. JCV viremia was not predictive of PML, but some patients showed higher anti-JCV immunoglobulin G (IgG) responses 6 months prior to diagnosis.
doi:10.1093/cid/cir507
PMCID: PMC3166351  PMID: 21852452
24.  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 CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study.
METHODS
After excluding cases with behavioral evidence of acute intoxication and histories of factors that independently could account for NCI (e.g., 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 DSM-IV diagnosis, self-report of marked lifetime SU, or positive urine toxicology (UTOX). Participants were divided into three groups: no SU (N = 134), Non-syndromic SU (N = 131), syndromic SU (N = 134) and matched on literacy level, nadir CD4, and depressive symptoms.
RESULTS
While approximately 50% of the participants were diagnosed with HAND, a MANCOVA of neurocogntive summary scores, covarying for UTOX, revealed no significant effect of SU status. Correlational analyses indicated weak associations between lifetime heroin dosage and poor recall and working memory, as well as 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.
doi:10.1097/QAI.0b013e318229ba41
PMCID: PMC3183737  PMID: 21725250
Substance use; HIV-associated neurocognitive disorder; cognition
25.  Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid 
Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = −0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC50 for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.
doi:10.1128/AAC.05098-11
PMCID: PMC3318381  PMID: 22290964

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