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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  Long-Term Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals (ACTG 5097s) 
HIV clinical trials  2009;10(6):343-355.
Background
Efavirenz (EFV) is an antiretroviral (ARV) drug associated with neuropsychological effects. Limited data describing the long-term impact of EFV-based regimens on neuropsychological performance over more than 3 years are available.
Methods
We enrolled a subset of participants from a large initially EFV placebo-controlled trial of therapies for HIV subjects naïve to ARV treatment (A5095). Clinical follow-up continued for 184 weeks of study. Subjects were assessed with brief neuropsychological testing, a symptom questionnaire of EFV-associated symptoms, the Pittsburgh Sleep Index, Center for Epidemiologic Studies-Depression Scale, and an anxiety rating interview.
Results
Over 184 weeks on EFV, the median NPZ3 score in 86 evaluable patients improved from baseline by +0.5 (p < .01); all components improved, although higher EFV levels were associated with slightly lower responses. Overall symptom scores did not change, while EFV-associated CNS symptoms increased (p = .01). Median change of bad dream sleep scores and anxiety increased from the baseline while global depression score decreased.
Conclusions
In participants who continued EFV-based regimens, neuropsychological performance improvement from baseline was maintained over 3 years. EFV-based treatment was generally well tolerated, but small increases from baseline in EFV-associated symptoms, bad dreams, and anxiety were detected.
doi:10.1310/hct1006-343
PMCID: PMC2958039  PMID: 20133265
anxiety; depression; efavirenz; HIV therapy; neuropsychologic effects; sleep
16.  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
17.  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
18.  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
19.  Lower Than Expected Maraviroc Concentrations in Cerebrospinal Fluid Exceed the Wild-Type CCR5-tropic HIV-1 50% Inhibitory Concentration 
AIDS (London, England)  2012;26(7):890-893.
Objectives
to measure maraviroc total cerebrospinal fluid (CSF) concentrations and compare them with total and unbound plasma concentrations.
Methods
Total maraviroc was measured by reverse phase high performance liquid chromatography with tandem mass spectrometry while ultrafiltration was used for unbound maraviroc.
Results
Maraviroc was detected in all nine CSF/plasma pairs with a median CSF total concentration of 2.4 ng/mL. CSF concentrations exceeded the 50% inhibitory concentration (IC50) of wild-type CCR5-tropic HIV-1 in all specimens.
Conclusions
CSF concentrations are lower than expected based on plasma concentrations and physicochemical characteristics. Unbound maraviroc plasma concentrations may be informative in estimating concentrations in CSF.
doi:10.1097/QAD.0b013e328351f627
PMCID: PMC3454507  PMID: 22313954
cerebrospinal fluid; HIV; 50% inhibitory concentration; maraviroc; pharmacokinetics
20.  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
21.  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
22.  Peripheral neuropathy in HIV: prevalence and risk factors 
AIDS (London, England)  2011;25(7):919-928.
Objectives
To estimate neuropathic sign/symptom rates with initiation of combination antiretroviral therapy (cART) in HIV-infected ART-naive patients, and to investigate risk factors for: peripheral neuropathy and symptomatic peripheral neuropathy (SPN), recovery from peripheral neuropathy/SPN after neurotoxic ART (nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART.
Design
AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial participants who initiated cART in randomized trials for ART-naive patients were annually screened for symptoms/signs of peripheral neuropathy. ART use and disease characteristics were collected longitudinally.
Methods
Peripheral neuropathy was defined as at least mild loss of vibration sensation in both great toes or absent/hypoactive ankle reflexes bilaterally. SPN was defined as peripheral neuropathy and bilateral symptoms. Generalized estimating equation logistic regression was used to estimate associations.
Results
Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/µl. Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus. Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use.
Conclusion
Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN.
doi:10.1097/QAD.0b013e328345889d
PMCID: PMC3196556  PMID: 21330902
aging; antiretroviral therapy; HIV; neurological; peripheral neuropathy; risk factors
23.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
Objectives
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
Methods
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Results
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Conclusions
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
doi:10.1093/jac/dkq434
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
24.  Effects of Central Nervous System Antiretroviral Penetration on Cognitive Functioning in the ALLRT Cohort 
AIDS (London, England)  2011;25(3):357-365.
Objective
Differences in antiretroviral (ARV) distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of ARV therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive subjects with plasma HIV-1 RNA (vRNA) suppression.
Design
Subjects with ≥6 weeks ongoing ARV use and vRNA<50 copies/mL (N=2,636; 83% male, median baseline CD4 T-cells: 244 cells/uL) had ≥1 neuroscreen assessment (Trailmaking A,B, WAIS-R Digit Symbol) at 10,413 neurovisits. Neuroscreen test scores were demographically adjusted and converted to Z-scores (NPZ3: lower scores imply more impairment). CNS penetration-effectiveness (CPE) ranks of 0.0(low), 0.5(medium) or 1.0(high) were assigned to ARVs and summed per regimen, per neurovisit.
Methods
Multivariate linear regression models using generalized estimating equations assessed NPZ3 scores with respect to ARV regimen. Covariates were retained if p≤0.1.
Results
A final model demonstrated that better NPZ3 scores were associated with higher CPE among subjects taking >3 ARVs (+0.07 per one unit increase in CPE score; p=0.004) but not among subjects with ≤3 ARVs in the regimen (+0.01; p=0.5). Results were adjusted for demographics, injection drug use, HCV serostatus, CD4 count (current and nadir), baseline vRNA, ARV experience and years since first ARV use.
Conclusions
Use of ARVs with better estimated CNS penetration may be associated with better neurocognitive functioning; some people may require >3 ARVs to treat HIV in the CNS. Clinically this means ARV regimens could be designed to optimize estimated CNS penetration without sacrificing virologic and immunologic benefits.
doi:10.1097/QAD.0b013e32834171f8
PMCID: PMC3022370  PMID: 21124201
HIV; Antiretroviral Agents; Neurologic Impairment; Central Nervous System; HIV-1 RNA suppression
25.  Role of CD4+ and CD8+ T-Cell Responses against JC Virus in the Outcome of Patients with Progressive Multifocal Leukoencephalopathy (PML) and PML with Immune Reconstitution Inflammatory Syndrome ▿  
Journal of Virology  2011;85(14):7256-7263.
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the brain caused by JC virus (JCV). To assess the role of CD4+ and CD8+ T-cells against JCV in the clinical outcome of PML and PML in the setting of immune reconstitution inflammatory syndrome (IRIS), we tested gamma interferon (IFN-γ) response by enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) in 117 subjects, including 66 PML patients with different clinical outcomes. Both assays were concordant and demonstrated that the cellular immune response against JCV is associated with better clinical outcome. PML survivors had an early CD8+ T-cell response more frequently than PML progressors (100% versus 27.3%; P = 0.001), while only a trend was observed for the early CD4+ T-cell response between these two groups (80% versus 45.5%; P = 0.18). Although IRIS itself was more frequent in the PML survivor group, there was no difference in IFN-γ-producing CD4+ and CD8+ T-cells between IRIS and non-IRIS PML patients, suggesting that T-cells expressing other cytokines likely have a role in the immunopathogenesis of IRIS. ELISpot and ICS assays are useful prognostic markers of PML evolution and may help in the clinical management of these patients.
doi:10.1128/JVI.02506-10
PMCID: PMC3126613  PMID: 21543472

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