Longitudinal bond strength of a universal adhesive and chemical dentin characterization under different acid etching protocols.

OBJECTIVE: This study aimed to analyze the longitudinal bond strength of a universal adhesive and chemically characterize the dentin substrate under different acid etching protocols. METHODOLOGY: Dentin samples were etched with polyacrylic acid 25% (PAA) for 10 seconds (n=3) and phosphoric acid 32% (PA) for 15 seconds (n=3) and analyzed by Fourier transform infrared spectroscopy - attenuated total reflectance (FTIR-ATR) before and after treatment. For collagen degradation, samples (n=12) were divided into 3 groups: PAA, PA, and Deionized water (control), and analyzed by the quantity of solubilized type I collagen C-terminal cross-linked telopeptides and solubilized C-terminal peptide in relation to total protein concentration (ICTPtp and CTXtp) and by their ultimate tensile strength (UTS). For the adhesive interface analysis, dentin samples (n=72) were divided into 3 groups: PAA, PA, and Self-etch (SE), and subdivided into 2 groups: 24 h (baseline) and 1 year. The following tests were performed: microtensile bond strength (µTBS) (n=48), scanning electron microscopy (SEM) (n=12), and nanoleakage (n=12). RESULTS: The FTIR of PAA showed lower reduction of the peaks in the phosphate group when compared to PA. For ICTPtp, PA showed a significantly higher value. For CTXtp, PA and PAA groups failed to statically differ from each other. UTS was significantly lower for PA. For µTBS, storage time significantly affected bond strength. The results were unaffected by the etching protocol. For SEM, after 1 year, PA had little evidence of degradation in the upper third of the adhesive interface in comparison to the other groups. Nanoleakage showed no considerable silver impregnation after 1 year in the SE group. CONCLUSION: The use of PAA prior to a universal adhesive (when compared to PA) represents a less aggressive type of etching to dentin. However, self-etching still seems to be the best option for universal adhesive systems that have functional monomers in their composition.

Longitudinal bond strength of a universal adhesive and chemical dentin characterization under different acid etching protocols

Abstract Objective This study aimed to analyze the longitudinal bond strength of a universal adhesive and chemically characterize the dentin substrate under different acid etching protocols. Methodology Dentin samples were etched with polyacrylic acid 25% (PAA) for 10 seconds (n=3) and phosphoric acid 32% (PA) for 15 seconds (n=3) and analyzed by Fourier transform infrared spectroscopy - attenuated total reflectance (FTIR-ATR) before and after treatment. For collagen degradation, samples (n=12) were divided into 3 groups: PAA, PA, and Deionized water (control), and analyzed by the quantity of solubilized type I collagen C-terminal cross-linked telopeptides and solubilized C-terminal peptide in relation to total protein concentration (ICTPtp and CTXtp) and by their ultimate tensile strength (UTS). For the adhesive interface analysis, dentin samples (n=72) were divided into 3 groups: PAA, PA, and Self-etch (SE), and subdivided into 2 groups: 24 h (baseline) and 1 year. The following tests were performed: microtensile bond strength (μTBS) (n=48), scanning electron microscopy (SEM) (n=12), and nanoleakage (n=12). Results The FTIR of PAA showed lower reduction of the peaks in the phosphate group when compared to PA. For ICTPtp, PA showed a significantly higher value. For CTXtp, PA and PAA groups failed to statically differ from each other. UTS was significantly lower for PA. For μTBS, storage time significantly affected bond strength. The results were unaffected by the etching protocol. For SEM, after 1 year, PA had little evidence of degradation in the upper third of the adhesive interface in comparison to the other groups. Nanoleakage showed no considerable silver impregnation after 1 year in the SE group. Conclusion The use of PAA prior to a universal adhesive (when compared to PA) represents a less aggressive type of etching to dentin. However, self-etching still seems to be the best option for universal adhesive systems that have functional monomers in their composition.

Interaction of epigallocatechin-gallate and chlorhexidine with Streptococcus mutans stimulated odontoblast-like cells: Cytotoxicity, Interleukin-1ß and co-species proteomic analyses.

OBJECTIVES: The dentin therapeutic agent chlorhexidine has inflammatory and cytotoxic characteristics urging investigation of alternatives like the natural compound epigallocatechin-gallate. The aim is to verify the effect of epigallocatechin-gallate and chlorhexidine on viability, interleukin-1ß (IL-1ß) and differential protein expression of MDPC-23 odontoblast-like cells stimulated by Streptococcus mutans. DESIGN: Cells were stimulated with heat-killed S. mutans at multiplicity of infection (MOI) of 100-1000 and subsequently treated with 100-1 µM of epigallocatechin-gallate. Cells with no treatment or chlorhexidine were controls. Combined stimulated/treated cells were tested for cytotoxicity (Alamar-Blue, N = 3, n = 3), total protein (N = 3, n = 3), IL-1ß (ELISA, N = 3, n = 3), and differential protein expression by liquid chromatography-tandem mass spectrometry (LC-MS/MS, n = 2). RESULTS: Cells stimulated at MOI 100/1000 and treated with 10 µM epigallocatechin-gallate and chlorhexidine did not present cytotoxicity. IL-1ß significantly increased in both un-stimulated and stimulated chlorhexidine 10 µM groups when compared to un-treated control (p < 0.05). MOI 100 chlorhexidine 10 µM group significantly increased IL-1ß compared to un-stimulated chlorhexidine 10 µM and epigallocatechin-gallate 10 µM groups, as well as to MOI 100 epigallocatechin-gallate 10 µM group (p < 0.05). LC-MS/MS revealed S. mutans and mammalian proteins, with tooth-specific proteins exhibiting different abundance levels, depending on the tested condition. CONCLUSIONS: Odontoblast-like cells stimulated with S. mutans at different MOI combined with epigallocatechin-gallate treatment did not cause cytotoxicity. S. mutans stimulation combined with chlorhexidine 100 µM treatment decreased cell viability, while treatment with chlorhexidine 10 µM concentration significantly increased IL-1ß. S. mutans stimulation and treatment of cells resulted in varied protein expression.

Analysis of permeability and biological properties of dentin treated with experimental bioactive glasses.

OBJECTIVES: To evaluate obliterating capability and biological performance of desensitizing agents. METHODS: 50 dentin blocks were distributed according to the desensitizing agent used (n = 10): Control (Artificial saliva); Ultra EZ (Ultradent); Desensibilize Nano P (FGM); T5-OH Bioactive Glass (Experimental solution); F18 Bioactive Glass (Experimental solution). Desensitizing treatments were performed for 15 days. In addition, specimens were subjected to acid challenge to simulate oral environment demineralizing conditions. Samples were subjected to permeability analysis before and after desensitizing procedures and acid challenge. Cytotoxicity analysis was performed by using Alamar Blue assay and complemented by total protein quantification by Pierce Bicinchoninic Acid assay at 15 min, 24-h and 48-h time points. Scanning electron microscopy and energy dispersion X-ray spectroscopy were performed for qualitative analysis. Data of dentin permeability was analyzed by two-way repeated measures ANOVA and Tukey's test. For cytotoxicity, Kruskal-Wallis and Newman-Keuls tests. RESULTS: for dentin permeability there was no significant difference among desensitizing agents after treatment, but control group presented highest values (0.131 ± 0.076 Lp). After acid challenge, control group maintained highest values (0.044 ± 0.014 Lp) with significant difference to other groups, except for Desensibilize Nano P (0.037 ± 0.019 Lp). For cytotoxicity, there were no significant differences among groups. CONCLUSION: Bioglass-based desensitizers caused similar effects to commercially available products, regarding permeability and dentin biological properties. CLINICAL SIGNIFICANCE: There is no gold standard protocol for dentin sensitivity. The study of novel desensitizing agents that can obliterate dentinal tubules in a faster-acting and long-lasting way may help meet this clinical need.

Functionalized epigallocatechin gallate copolymer inhibit dentin matrices degradation: Mechanical, solubilized telopeptide and proteomic assays.

OBJECTIVES: We investigated the biostability of dentin organic matrices treated with epigallocatechin gallate (EGCG) in comparison to chlorhexidine (CHX), both extracted from functionalized copolymers. METHODS: Copolymers were prepared with bis-GMA:TEGDMA and incorporated with 1% of EGCG or CHX (w/w). Blank copolymers were used as control. Copolymer samples were individually stored in 1mL deionized water to produce copolymer extracts. Dentin matrices were obtained by demineralization of dentin disks in 10% phosphoric acid solution. Matrices were individually treated with 1mL of the copolymer extracts or distilled water for 48h. Collected extracts were analyzed by high-performance liquid chromatography (HPLC) for the presence and quantification of EGCG, CHX, and copolymer by-products. Treated dentin matrices were tested for ultimate tensile strength, gravimetric changes, and swelling ratio. The treatment media were tested for total protein concentration, and dentin protease activity through solubilized telopeptide (ICTP- and CTX-ELISA) assays. The treatment media were also submitted to proteomic analysis. RESULTS: HPLC identified released unreacted copolymer species and showed higher release of CHX compared to EGCG from respective copolymer extracts. EGCG extract inhibited activity of dentin proteolytic enzymes and promoted collagen biomodification observed by the telopeptide assays and in the changes to dentin matrix properties. The proteomic results showed less collagenous peptide hits in the EGCG extract media compared to CHX, and suggest compound-specific dentin protein binding interactions. SIGNIFICANCE: This study demonstrates specific antiproteolytic effect and protein interactions of EGCG copolymer extract directly on dentin. This represents an advancement in dental materials which can impact the clinical procedures.

Profiling cytokine levels in chlorhexidine and EGCG-treated odontoblast-like cells.

OBJECTIVE: To screen the effect of two compounds, chlorhexidine diacetate (CHX) and epigallocatechin-gallate (EGCG), on the levels of cytokines produced by odontoblast-like cells (MDPC-23). METHODS: Cells were seeded at 24h and 48h with serial dilution of the compounds to determine cell metabolic activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (n=3). Cells with no compound treatment were used as control (Ctr). For the highest equal non-cytotoxic compound dilution tested at 48h cell treatment, total protein concentration was measured using a Pierce bicinchoninic acid (BCA) assay (n=3), and expression of 23 cytokines was analyzed using the Bio-Plex cytokine assay (n=2). Data were analyzed by one-way ANOVA and Tukey's test (α=5%). RESULTS: The MTT assay revealed that at 24h and 48h, CHX and EGCG did not reduce cell metabolic activity at concentrations of 2.5-20µM (CHX) and 2.5-160µM (EGCG), respectively (p>0.05). At 48h, total protein levels were consistent across all groups for 20µM compound dilution (Ctr: 1.04mg/mL; CHX: 0.98mg/mL; and EGCG: 1.06mg/mL). At 20µM dilution, both CHX and EGCG significantly increased the secretion of IL-1ß, IL-10, IL-12, KC, MIP-1α, IFN-γ and IL-6 (p<0.05). Treatment with CHX significantly increased secretion of IL-4 and RANTES (p<0.05). TREATMENT: with EGCG significantly increased Eotaxin secretion (p<0.05). Both CHX and EGCG significantly decreased secretion of IL-17 (p<0.05). GM-CSF and TNF-α did not present significant change in secretion after treatment with either CHX or EGCG (p>0.05). SIGNIFICANCE: Both CHX and EGCG modulate secretion of various inflammatory and anti-inflammatory mediators in odontoblastic cells.

The effects of antiretroviral treatment initiation on cognition in HIV-infected individuals with advanced disease in Pune, India.

There has been a reduction in the most severe cases of HIV-associated neurocognitive disorders (HAND) with advances in antiretroviral treatment (ART). But the prevalence of milder forms of HAND still remains high. Data from systematically conducted studies on the effects of ART on cognition are scanty in India, where HIV-1 clade C is prevalent. The purpose of the present study was to assess the effect of antiretroviral therapy in HIV-seropositive (HIV+) individuals (n = 92) with CD4 cell counts <200 cells/mm(3). The overall and domain-specific levels of cognitive functioning were determined using a locally recruited normative sample, and a change in neurocognitive functioning at the 1-year follow-up visit was analyzed. Results revealed cognitive impairment in 44.6 % of the HIV+ group at baseline. At the 1-year follow-up, the group showed significant improvement in the Learning domain (p < 0.05). HIV+ individuals showing improvement in the global cognitive scores had a significantly lower baseline CD4 cell count compared to others. Overall, the degree of improvement associated with the magnitude of rise in CD4 suggests the possibility that early, mild subclinical deficits may also benefit from treatment.

Neurocognitive functioning in a Romanian cohort of young adults with parenterally-acquired HIV-infection during childhood.

The Romanian cohort can provide valuable information about the effect of chronic HIV-infection and exposure to combined antiretroviral therapy (cART) on the developing brain, based on its unique characteristics: young adults infected parenterally with HIV clade F in the late 1980s and exposed to cART for a decade. We conducted a prospective study using a neuropsychological test battery validated in other international HIV cohorts, in order to evaluate the rate and severity of neurocognitive impairment in a group of young Romanian adults. The 49 HIV-infected (HIV+) participants and the 20 HIV negative (HIV-) controls were similar for age and gender, although the HIV- group tended to be more educated. We found higher cognitive impairment prevalence in the HIV+ group (59.1 %) versus the HIV- group (10 %), and the impairment rate remained significantly higher even when the groups were matched based on the educational level (38.7 % for the HIV+ group vs. 10.0 % for the HIV- controls; p = 0.025). The nadir CD4 count was <200 in 71.4 % of patients, but at the time of neurocognitive assessment, 89.5 % of patients had normal immunological status and 81.8 % undetectable HIV load. Among the HIV-impaired group, 26 % of the participants had syndromic impairment while the other 74 % had asymptomatic neurocognitive impairment. We found a high prevalence of neurocognitive dysfunction in the Romanian young adults growing-up with HIV. The greatest HIV-related cognitive deficits were in the domains of executive and motor functioning, consistent with a frontosubcortical pattern.

HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

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 cut points and to evaluate the contribution of the HDS subtests to predicting HAND. METHODS: A total of 1580 HIV-infected participants from 6 US 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 cut point were 24% and 92%, respectively. The raw HDS subtests of attention, recall, and psychomotor speed significantly contributed to classification of HAND, whereas visuomotor construction contributed the least. A modified raw cut point 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%, whereas 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 cut point of 14 greatly improved the sensitivity of the previously established raw cut score, but may be subject to ceiling effects, particularly on repeat assessments.

Relationships among neurocognitive status, medication adherence measured by pharmacy refill records, and virologic suppression in HIV-infected persons.

BACKGROUND: Optimal antiretroviral therapy (ART) effectiveness depends on 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. METHODS: 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. 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 relationships between adherence and changes in plasma and cerebrospinal fluid HIV RNA concentrations between visits. RESULTS: Among 80 (33 at JHU and 47 at University of Washington) participants, the mean adherence score was 86.4%, with no difference between sites. 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 period of time. Worse performance in working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits. CONCLUSIONS: 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.

Effects of Marathi-Hindi bilingualism on neuropsychological performance.

The present study aimed to examine if bilingualism affects executive functions and verbal fluency in Marathi and Hindi, two major languages in India, with a considerable cognate (e.g., activity is actividad in Spanish) overlap. A total of 174 native Marathi speakers from Pune, India, with varying levels of Hindi proficiency were administered tests of executive functioning and verbal performance in Marathi. A bilingualism index was generated using self-reported Hindi and Marathi proficiency. After controlling for demographic variables, the association between bilingualism and cognitive performance was examined. Degree of bilingualism predicted better performance on the switching (Color Trails-2) and inhibition (Stroop Color-Word) components of executive functioning; but not for the abstraction component (Halstead Category Test). In the verbal domain, bilingualism was more closely associated with noun generation (where the languages share many cognates) than verb generation (which are more disparate across these languages), as predicted. However, contrary to our hypothesis that the bilingualism "disadvantage" would be attenuated on noun generation, bilingualism was associated with an advantage on these measures. These findings suggest distinct patterns of bilingualism effects on cognition for this previously unexamined language pair, and that the rate of cognates may modulate the association between bilingualism and verbal performance on neuropsychological tests.

Incidence of post-dural puncture headache in research volunteers.

OBJECTIVE: To determine the frequency and risk factors of post-dural puncture headache (PDPH) in research volunteers. BACKGROUND: Despite increasing interest in measuring cerebrospinal fluid (CSF) biomarkers to investigate disease pathogenesis and diagnosis, previous case series have evaluated lumbar puncture (LP) safety only in clinical care. PDPH is a common complication after LP. METHODS: We determined the frequency of PDPH in neurologically unselected HIV seropositive and seronegative adults volunteering for research, as well as the variables associated with the development of PDPH. Variables studied were body mass index (BMI), HIV serostatus, volume of CSF removed, number of previous LPs, use of pre-medication, LP position, lumbar space, number of needle passes, whether or not aspiration was used, CSF white blood cell counts, CSF red blood cell counts, CD4 count, CD4 nadir, CSF HIV viral load, plasma HIV viral load, and race. RESULTS: Of 675 LPs performed over 1 year, headache developed in 38 (5.6%; 95% CI 4.2, 7.1). Most PDPH (92%) resolved spontaneously or with conservative medical management; 3 required epidural blood patch. Greater headache risk was associated with lower BMI (BMI ≤25 vs >25) (OR 3.3; CI 95% 1.5, 7.0; P = .001) and less prior LP experience (previous LPs ≤2 vs >2) (OR 2.1; CI 95% 1.1, 4.1; P = .03). PDPH was not significantly (P > .05) related to HIV serostatus, CSF volume, or gender. CONCLUSION: In this study, where tolerance to risk was low because LPs were done for research rather than clinical purposes and healthy controls were included, adverse effects were mild and self-limited.

Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study.

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.

Role of metabolic syndrome components in human immunodeficiency virus-associated stroke.

Metabolic syndrome (MetS) is a cluster of risk factors, including elevated mean arterial pressure (MAP), atherogenic dyslipidemia (elevated triglycerides [TRG]), abdominal obesity (increased body mass index [BMI]), glucose intolerance (elevated glucose [GLU]), and prothrombotic/inflammatory state (increases in uric acid [UA]), that are associated with increased risk of cerebrovascular disease. We studied if an association existed between MetS components and human immunodeficiency virus (HIV)-associated cryptogenic strokes-those not caused by HIV complications, endocarditis, or stimulant abuse. We performed a retrospective case-control study. Eleven cryptogenic strokes were identified from 2346 HIV-infected (HIV+) participants. Each case was matched by age, sex, and date of stroke diagnosis to five HIV+ controls without stroke. Nonparametric stratified Wilcoxon ranked sum tests with subsequent mixed effect logistic regression determined the influence of each MetS component on HIV-associated cryptogenic stroke. Although each MetS component appeared higher for HIV+ cases with cryptogenic strokes than HIV+ controls, only MAP (odds ratio [OR] = 5.70, 95% confidence interval [CI] = 1.15-28.3) and UA (OR = 1.88, 95% CI = 1.06-3.32) were statistically different. A significantly higher percentage of HIV-associated cryptogenic stroke cases met criteria for MetS (4/11 = 36%) compared to HIV+ controls (6/55 = 11%). This observational study suggests a possible role for MetS components in HIV+ cryptogenic stroke cases. Although MetS is defined as a constellation of disorders, elevated hypertension and hyperuricemia may be involved in stroke pathogenesis. Reducing MetS component levels in HIV+ patients could therefore protect them from subsequent stroke.

Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy.

OBJECTIVE: Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long-term use in highly active ARV therapy. METHODS: We evaluated current and past exposure to PIs as a risk factor for DSPN in 1,159 HIV-infected individuals enrolled in a large, prospective, observational, multicenter study. Signs of DSPN were ascertained by neurological examination. Subjects were grouped into categories according to past and current exposure to any ARV and to PIs. We included disease indicators such as nadir CD4, plasma viral load, and duration of HIV infection, as well as advancing age and exposure to dideoxynucleoside ARVs in multivariate models. RESULTS: In univariate analyses, both past and current PI exposure significantly increased the risk for DSPN. However, after adjusting for previously validated concomitant risk factors in multivariate models, none of the PI exposure groups was more likely to have DSPN than ARV naive subjects. A secondary evaluation of duration of PI use and exposure to individual PI drugs was similarly nonsignificant in multivariate models, except for small effects of amprenavir and lopinavir. INTERPRETATION: Evaluation of concomitant risks for HIV DSPN suggests that the independent risk attributable to PIs, if any, is small. This risk must be weighed against the important role of PIs in modern ARV therapy regimens.

Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders.

Effective combination antiretroviral therapies (ART) have markedly lengthened survival among HIV infected individuals. In this long-surviving cohort, both psychiatric comorbidities and HIV-associated neurocognitive disorders (HAND) remain common. Even mild neurocognitive impairment can significantly disrupt of activities of daily living and reduce quality of life. Persistence of HAND might reflect incomplete containment of HIV within the central nervous system (CNS) due to the limited penetration of most antiretrovirals (ARVs) across the blood-brain barrier. Recent data support that certain medications used to treat psychiatric comorbidities in HIV-infected individuals may also protect the brain from toxic byproducts of HIV replication and neuroinflammation. Two drug classes in particular, glycogen synthase kinase-3 beta (GSK-3b) inhibitors and serotonin reuptake inhibitors (SRIs), may benefit individuals with HAND. Valproic acid (VPA) and lithium are potentially beneficial GSK-3b inhibitors. While the mechanism of benefit of SRIs in HAND remains unknown, evidence supports some benefit of citalopram and paroxetine. The present brief review focuses on these drugs and assesses their possible adjunct roles in the treatment of HIV-infected individuals.

The role of cohort studies in drug development: clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system.

BACKGROUND: Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. METHODS: Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. RESULTS: SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p = 0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or "antiviral" SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p = 0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p = 0.01). "Antiviral" SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p = 0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p < 0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p < 0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of "antiviral" SRIs-but not statins-was associated with undetectable HIV RNA levels in CSF and better NP performance. CONCLUSIONS: SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs-supporting differences in antiviral efficacy between drugs-in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.