Safety and Effectiveness of a Nurse-Led Outreach Program for Assessment and Treatment of Chronic Hepatitis C in the Custodial Setting.

Safety and Effectiveness of a Nurse-Led Outreach Program for Assessment and Treatment of Chronic Hepatitis C in the Custodial Setting.

Filed under: Drug and Alcohol Rehabilitation

Clin Infect Dis. 2013 Jan 29;
Lloyd AR, Clegg J, Lange J, Stevenson A, Post JJ, Lloyd D, Rudge G, Boonwaat L, Forrest G, Douglas J, Monkley D

Background.?The global burden of disease attributable to chronic hepatitis C virus (HCV) is very large, yet the uptake of curative antiviral therapies remains very low, reflecting the marginalized patient population and the arduous nature of current treatments.Methods.?The safety and effectiveness of a nurse-led model of care of inmates with chronic HCV was evaluated in 3 Australian correctional centers. The model featured protocol-driven assessment, triage, and management of antiviral therapy by specifically trained nurses, with specialist physician support utilizing telemedicine. Outcomes were evaluated qualitatively with key informant interviews, and quantitatively with patient numbers completing key clinical milestones and adverse events.Results.?A total of 391 patients with chronic HCV infection were enrolled, of whom 141 (36%) completed the clinical and laboratory evaluations for eligibility for antiviral therapy over 24 months. Treatment was initiated in 108 patients (28%), including 85 (79%) triaged for specialist review conducted by telemedicine only. The demographic and clinical characteristics of the patients who entered the model and completed workup and those who initiated treatment featured a high prevalence of individuals of indigenous background, injection drug users, and those with psychiatric disorder. Serious adverse events occurred in 13 of 108 treated patients (12%) with discontinuation in 8 (7%). The sustained virologic response rate among those with complete follow-up data (n = 68) was 69%, and by intention-to treat analysis was 44%.Conclusions.?This nurse-led and specialist-supported assessment and treatment model for inmates with chronic HCV offers potential to substantively increase treatment uptake and reduce the burden of disease.
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Association of Human Leukocyte Antigen Alleles and Nevirapine Hypersensitivity in a Malawian HIV-Infected Population.

Filed under: Drug and Alcohol Rehabilitation

Clin Infect Dis. 2013 Jan 29;
Carr DF, Chaponda M, Jorgensen A, Castro EC, van Oosterhout JJ, Khoo S, Lalloo DG, Heyderman RS, Alfirevic A, Pirmohamed M

Introduction.?The non-nucleoside reverse transcriptase inhibitor nevirapine is the cornerstone of treatment for human immunodeficiency virus (HIV) in many sub-Saharan African countries. However, nevirapine is associated with a 6-10% risk of developing a hypersensitivity reaction, with different phenotypes, including the blistering conditions Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). Our aim was to identify predictive HLA markers that are associated with nevirapine hypersensitivity.Methods.?We identified 117 HIV-infected Malawian adults with nevirapine hypersensitivity (15 drug-induced liver injury (DILI), 33 SJS/TEN, 20 hypersensitivity syndrome (HSS) and 46 nevirapine-induced rash (NIR) plus 3 with both DILI and SJS phenotype) and 155 age-, gender- and ethnicity-matched nevirapine-exposed controls. HLA typing for 5 loci (A, B, C, DRB1 and DQB1) was undertaken using a sequence based high-resolution protocol. Logistic regression analysis included CD4+ cell count as a covariate.Results.?HLA-C*04:01 was found to markedly increase the risk for SJS (OR=17.52, 3.31-92.80) and all hypersensitivity phenotypes (OR=2.64, 1.13-6.18) when compared to the base rare allele group in a binary logistic regression model. The odds ratio for absolute risk of SJS/TEN associated with carriage of HLA-C*04:01 was 5.17 (2.39-11.18). Positive predictive value was 2.6% and negative predictive value was 99.2%. In addition, a number of alleles within the HLA-DQB1 loci protected against nevirapine-induced hypersensitivity phenotypesConclusions.?Our study has identified HLA-C*04:01 carriage as a risk factor for nevirapine-induced SJS/TEN in a Malawian HIV cohort. Validation of these findings in a larger cohort of patients and mechanistic investigation of the pathogenesis is required.
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Sialylneolacto-N-tetraose c (LSTc)-bearing liposomal decoys capture influenza A virus.

Filed under: Drug and Alcohol Rehabilitation

J Biol Chem. 2013 Jan 28;
Hendricks GL, Weirich KL, Viswanathan K, Li J, Shriver ZH, Ashour J, Ploegh HL, Kurt-Jones EA, Fygenson DK, Finberg RW, Comolli JC, Wang JP

Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand-binding interactions for a high-avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza, but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, while control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains.
HubMed – drug

 

Vemurafenib Potently Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in BRAFV600E Melanoma Cells.

Filed under: Drug and Alcohol Rehabilitation

Sci Signal. 2013; 6(260): ra7
Beck D, Niessner H, Smalley KS, Flaherty K, Paraiso KH, Busch C, Sinnberg T, Vasseur S, Iovanna JL, Drießen S, Stork B, Wesselborg S, Schaller M, Biedermann T, Bauer J, Lasithiotakis K, Weide B, Eberle J, Schittek B, Schadendorf D, Garbe C, Kulms D, Meier F

The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway. Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance. We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis. Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis. Consistent with an ER stress-induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2? (which would be expected to inhibit protein synthesis), and induced the expression of ER stress-related genes. Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis. Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo. In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis. Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance.
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