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1.  Are Time- and Event-based Prospective Memory Comparably Affected in HIV Infection?† 
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
PMCID: PMC3081684  PMID: 21459901
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
2.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
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.
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).
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.
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.
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
3.  Etravirine in CSF is highly protein bound 
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
4.  Increases in brain white matter abnormalities and subcortical gray matter are linked to CD4 recovery in HIV infection 
Journal of neurovirology  2013;19(4):393-401.
MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T-cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79% initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T-cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.
PMCID: PMC3776609  PMID: 23838849
Antiretroviral therapy; brain; CD4+ T-cell; immune recovery/reconstitution; inflammation; MRI
5.  Concurrent Classification Accuracy of the HIV Dementia Scale for HIV-associated Neurocognitive Disorders in the CHARTER Cohort 
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.
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.
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.
PMCID: PMC3529802  PMID: 23111573
HIV; cognition; HIV-associated neurocognitive disorders; screening measures; HIV dementia scale
6.  Cluster Analysis of the Klein Sexual Orientation Grid in Clinical and Nonclinical Samples: When Bisexuality Is Not Bisexuality 
Journal of bisexuality  2014;14(3-4):349-372.
We used a cluster analysis to empirically address whether sexual orientation is a continuum or can usefully be divided into categories such as heterosexual, homosexual, and bisexual using scores on the Klein Sexual Orientation Grid (KSOG) in three samples: groups of men and women recruited through bisexual groups and the Internet (Main Study men; Main Study women), and men recruited for a clinical study of HIV and the nervous system (HIV Study men). A five-cluster classification was chosen for the Main Study men (n = 212), a four-cluster classification for the Main Study women (n = 120), and a five-cluster classification for the HIV Study men (n = 620).
We calculated means and standard deviations of these 14 clusters on the 21 variables composing the KSOG. Generally, the KSOG’s overtly erotic items (Sexual Fantasies, Sexual Behavior, and Sexual Attraction), as well as the Self Identification items, tended to be more uniform within groups than the more social items were (Emotional Preference, Socialize with, and Lifestyle). The result is a set of objectively identified subgroups of bisexual men and women along with characterizations of the extent to which their KSOG scores describe and differentiate them.
The Bisexual group identified by the cluster analysis of the HIV sample was distinctly different from any of the bisexual groups identified by the clustering process in the Main Sample. Simply put, the HIV sample’s bisexuality is not like bisexuality in general, and attempts to generalize (even cautiously) from this clinical Bisexual group to a larger population would be doomed to failure. This underscores the importance of recruiting non-clinical samples if one wants insight into the nature of bisexuality in the population at large. Although the importance of non-clinical sampling in studies of sexual orientation has been widely and justly asserted, it has rarely been demonstrated by direct comparisons of the type conducted in the present study.
PMCID: PMC4267693  PMID: 25530727
sexual orientation; bisexuality; cluster analysis; Internet; Klein Sexual Orientation Grid
7.  Genetic Variation in Iron Metabolism Is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy 
PLoS ONE  2014;9(8):e103123.
HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP.
PMCID: PMC4140681  PMID: 25144566
8.  Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration 
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).
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.
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.
Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.
PMCID: PMC3566670  PMID: 23143899
HIV; antiretroviral therapy; central nervous system; protein binding
9.  Relationships Among Neurocognitive Status, Medication Adherence Measured by Pharmacy Refill Records, and Virologic Suppression in HIV-infected Persons 
Optimal antiretroviral therapy (ART) effectiveness depends upon medication adherence, which is a complex behavior with many contributing factors including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence.
A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington (UW). Pharmacy refill records were the primary method to measure ART adherence, indexed to a “sentinel” drug with the highest central nervous system penetration effectiveness score.
Standardized neuromedical, neuropsychological, psychiatric and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and the relationships between adherence and change in plasma and cerebrospinal fluid HIV RNA concentrations between visits.
Among 80 (33 JHU, 47 UW) participants, the mean adherence score was 86.4% with no difference by site. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV-infected for a longer time-period. Worse performance on working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits.
Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support.
PMCID: PMC3906725  PMID: 23202813
HIV; adherence; cognitive impairment; pharmacy refill records; HAND; CPE
10.  CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy 
AIDS (London, England)  2011;25(14):10.1097/QAD.0b013e32834a40cd.
Despite immune recovery in individuals on combination antiretroviral therapy (CART), the frequency of HIV-associated neurocognitive disorders (HANDs) remains high. Immune recovery is typically achieved after initiation of ART from the nadir, or the lowest historical CD4. The present study evaluated the probability of neuropsychological impairment (NPI) and HAND as a function of CD4 nadir in an HIV-positive cohort.
One thousand five hundred and twenty-five HIV-positive participants enrolled in CNS HIV Antiretroviral Therapy Effects Research, a multisite, observational study that completed comprehensive neurobehavioral and neuromedical evaluations, including a neurocognitive test battery covering seven cognitive domains. Among impaired individuals, HAND was diagnosed if NPI could not be attributed to comorbidities. CD4 nadir was obtained by self-report or observation. Potential modifiers of the relationship between CD4 nadir and HAND, including demographic and HIV disease characteristics, were assessed in univariate and multivariate analyses.
The median CD4 nadir (cells/μl) was 172, and 52% had NPI. Among impaired participants, 603 (75%) had HAND. Higher CD4 nadirs were associated with lower odds of NPI such that for every 5-unit increase in square-root CD4 nadir, the odds of NPI were reduced by 10%. In 589 virally suppressed participants on ART, higher CD4 nadir was associated with lower odds of NPI after adjusting for demographic and clinical factors.
As the risk of NPI was lowest in patients whose CD4 cell count was never allowed to fall to low levels before CART initiation, our findings suggest that initiation of CART as early as possible might reduce the risk of developing HAND, the most common source of NPI among HIV-infected individuals.
PMCID: PMC3867631  PMID: 21750419
CD4 nadir; combination antiretroviral therapy; HIV-associated; neurocognitive disorders; neurocognitive impairment
11.  Relationship of Medication Management Test-Revised (MMT-R) Performance to Neuropsychological Functioning and Antiretroviral Adherence in Adults with HIV 
AIDS and behavior  2012;16(8):2286-2296.
While performance-based tests of everyday functioning offer promise in facilitating diagnosis and classification of HIV-associated neurocognitive disorders (HAND), there remains a dearth of well-validated instruments. In the present study, clinical correlates of performance on one such measure (i.e., Medication Management Test—Revised; MMT-R) were examined in 448 HIV+ adults who were prescribed antiretroviral therapy. Significant bivariate relationships were found between MMT-R scores and demographics (e.g., education), hepatitis C co-infection, estimated premorbid IQ, neuropsychological functioning, and practical work abilities. MMT-R scores were not related to HIV disease severity, psychiatric factors, or self-reported adherence among participants with a broad range of current health status. However, lower MMT-R scores were strongly and uniquely associated with poorer adherence among participants with CD4 T-cell counts <200. In multivariate analyses, MMT-R scores were predicted by practical work abilities, estimated premorbid functioning, attention/working memory, learning, and education. Findings provide overall mixed support for the construct validity of the MMT-R and are discussed in the context of their clinical and research implications for evaluation of HAND.
PMCID: PMC3575112  PMID: 22722882
HIV; medication management; neuropsychological functioning; adherence; construct validity; instrumental activities of daily living
12.  Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy 
AIDS (London, England)  2011;25(2):F1-F6.
In HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated.
Prospective, comparative, single-center, cross-sectional cohort study.
Clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression.
Of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (≥ 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ≤ 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4–5.5).
Elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.
PMCID: PMC3729045  PMID: 21150557
antiretroviral; HIV; sensory neuropathy; triglyceride
13.  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.
PMCID: PMC3702821  PMID: 21544705
HIV; MRI; Neuroimaging; Immunospupression
14.  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.
PMCID: PMC3299895  PMID: 22217676
tenofovir; CSF; pharmacokinetics
15.  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.
PMCID: PMC3587171  PMID: 23073667
genetics; mitochondria; HIV-related neurological diseases; peripheral neuropathy
16.  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.
PMCID: PMC3572198  PMID: 22528397
HIV; central nervous system; tat; compartmentalization
17.  Lifetime Suicidal Ideation and Attempt is Common Among HIV+ Individuals 
Journal of Affective Disorders  2011;136(3):993-999.
Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART).
Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204).
Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters.
Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt.
High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggests that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.
PMCID: PMC3222733  PMID: 21784531
HIV; depression; suicide
18.  Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy 
AIDS (London, England)  2002;16(7):1019-1029.
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.
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.
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.
PMCID: PMC3548569  PMID: 11953468
HIV leukoencephalopathy; antiretroviral therapy
19.  A double-blinded, randomized controlled trial of zoledronate therapy for HIV-associated osteopenia and osteoporosis 
AIDS (London, England)  2009;23(1):51-57.
To evaluate the efficacy of a single dose of intravenous zoledronate for the treatment of HIV-associated osteopenia and osteoporosis.
A double-blinded, randomized, placebo-controlled, 12 month trial of 5 mg intravenous zoledronate dose to treat 30 HIV-infected men and women with osteopenia and osteoporosis.
Following zoledronate or placebo infusions, participants were followed for 12 months on daily calcium and vitamin D supplements. Lumbar spine and hip bone density was assessed at baseline, 6 and 12 months. Biomarkers of bone metabolism were measured at baseline, 2 weeks, 3, 6, 9, and 12 months. Student’s t-test and repeated measure analyses were used to evaluate bone density and bone marker changes over time.
In the 30 HIV-infected men (27) and women (3) in the trial, median T-scores at entry were -1.7 for the lumbar spine and -1.4 for the hip. Median CD4 count was 461 cells/μL, 93% had HIV-RNA viral loads <400 copies/mL, and 97% were taking antiretroviral medications. Bone density measured either absolutely or as sex-adjusted T-scores significantly improved in zoledronate recipients as compared to minimal changes in those receiving placebo. Bone resorption markers significantly decreased over the study period in the zoledronate recipients as compared to placebo controls. No acute infusion reactions were detected, but one patient developed uveitis, a recognized complication of zoledronate, which responded to therapy.
In this small study, annual zoledronate appears to be a safe and effective therapy for HIV-associated bone loss.
PMCID: PMC3477869  PMID: 19050386
metabolic bone diseases; osteoporosis; zoledronic acid; HIV; bisphosphonates
20.  Neurocognitive Impact of Substance Use in HIV Infection 
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.
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.
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.
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.
PMCID: PMC3183737  PMID: 21725250
Substance use; HIV-associated neurocognitive disorder; cognition
21.  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.
PMCID: PMC3318381  PMID: 22290964
22.  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.
to measure maraviroc total cerebrospinal fluid (CSF) concentrations and compare them with total and unbound plasma concentrations.
Total maraviroc was measured by reverse phase high performance liquid chromatography with tandem mass spectrometry while ultrafiltration was used for unbound maraviroc.
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.
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.
PMCID: PMC3454507  PMID: 22313954
cerebrospinal fluid; HIV; 50% inhibitory concentration; maraviroc; pharmacokinetics
23.  Association of Ongoing Drug and Alcohol Use with Non-Adherence to Antiretroviral Therapy and Higher Risk of AIDS and Death: Results from ACTG 362 
AIDS care  2011;23(6):775-785.
Drug and alcohol use have been associated with a worse prognosis in short-term and cross-sectional analyses of HIV-infected populations, but longitudinal effects on adherence to antiretroviral therapy (ART) and clinical outcomes in advanced AIDS are less well characterized. We assessed self-reported drug and alcohol use in AIDS patients, and examined their association with non-adherence and death or disease progression in a multicenter observational study. We defined non-adherence as reporting missed ART doses in the 48 hours before study visits. The association between drug use and ART non-adherence was evaluated using repeated measures generalized estimating equation (GEE) models. The association between drug and alcohol use and time to new AIDS diagnosis or death was evaluated via Cox regression models, controlling for covariates including ART adherence. Of 643 participants enrolled between 1997–1999 and followed through 2007, at entry 39% reported ever using cocaine, 24% amphetamines, and 10% heroin. Ongoing drug use during study follow-up was reported by 9% using cocaine, 4% amphetamines, and 1% heroin. Hard drug (cocaine, amphetamines, or heroin) users had 2.1 times higher odds (p=0.001) of ART non-adherence in GEE models and 2.5 times higher risk (p=0.04) of AIDS progression or death in Cox models. Use of hard drugs was attenuated as a risk factor for AIDS progression or death after controlling for non-adherence during follow-up (HR=2.11, p=0.08), but was still suggestive of a possible adherence-independent mechanism of harm. This study highlights the need to continuously screen and treat patients for drug use as a part of ongoing HIV care.
PMCID: PMC3095689  PMID: 21293986
Substance use; drug use; alcohol use; HIV/AIDS; Outcomes; Adherence; Antiretroviral Therapy; Mortality
24.  Normative data and validation of a regression based summary score for assessing meaningful neuropsychological change 
Reliable detection and quantification of longitudinal cognitive change are of considerable importance in many neurological disorders, particularly to monitor central nervous system effects of disease progression and treatment. In the current study, we developed normative data for repeated neuropsychological (NP) assessments (6 testings) using a modified Standard Regression-Based (SRB) approach in a sample that includes both HIV-uninfected (HIV−, N=172) and neuromedically stable HIV-infected (HIV+, N=124) individuals. Prior analyzes indicated no differences in NP change between the infected and uninfected participants. The norms for change included correction for factors found to significantly affect follow-up performance, using hierarchical regression. The most robust and consistent predictors of follow-up performance were the prior performance on the same test (which contributed in all models) and a measure of prior overall NP competence (predictor in 97% of all models). Demographic variables were predictors in 10%-46% of all models and in small amounts; while test retest interval contributed in only 6% of all models. Based on the regression equations, standardized change scores (z-scores) were computed for each test measure at each interval; these z scores were then averaged to create a total battery change score. An independent sample of HIV− participants who had completed 8 of the 15 tests was used to validate an abridged summary change score. The normative data are available in an electronic format by email request to the first author. Correction for practice effects based on normative data improved the consistency of NP impairment classification in a clinically stable longitudinal cohort after baseline.
PMCID: PMC3151558  PMID: 21391011
Normative data; longitudinal studies; regression; regression change score; SRB; practice effect
25.  Family History of Dementia Predicts Worse Neuropsychological Functioning Among HIV Infected Persons 
HIV-negative individuals with a family history of dementia (FHD) are more likely to develop dementia than those without a FHD. Whether FHD increases risk for neuropsychological (NP) impairment in HIV+ persons is unknown. As part of a multi-site study into HIV-Associated Neurocognitive Disorders (HAND), we captured FHD with a free-response, self-report question, and assessed NP performance with a comprehensive battery of tests. We examined HIV+ persons with (n=190) and without (n=916) self-reported FHD. Despite the fact that the FHD group had factors typically associated with better NP performance (e.g., higher CD4 counts and estimated verbal IQ [VIQ]), persons with FHD had significantly worse NP ability than those without FHD as measured by a Global Deficit Score (GDS) (FHD mean=0.66; No FHD mean=0.55; p<0.05). Thus, FHD appears to be a risk factor for HAND; the mechanism(s) underlying how FHD contributes to NP impairment among HIV+ persons warrants study.
PMCID: PMC3279193  PMID: 21948893
HIV; AIDS; Cognition; Aging; Dementia

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