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Port-Saint-Louis-du-Rhône, France

Goutell S.,Service Pharmaceutique Groupement Hospitalier Of Geriatrie | Goutell S.,University Claude Bernard Lyon 1 | Goutell S.,CNRS Biometry and Evolutionary Biology Laboratory | Baudry T.,Service de Maladies Infectieuses et Tropicales | And 14 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h-1; P = 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24], 10.3 ± 2.1 versus 22.4 ± 11.2mg·h·liter-1; P = 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy. Copyright © 2013, American Society for Microbiology. All Rights Reserved. Source


De Fontbrune F.S.,Service dHematologie greffe | Moignet A.,Hopital University Of Rennes | Moignet A.,French Institute of Health and Medical Research | Beaupain B.,Service dHematologie P Ediatrique | And 22 more authors.
Blood | Year: 2015

Severe chronic primary neutropenia (CPN) is a rare entity, and long-term outcome and risk factors for infections in severe CPN adults have not been described to date.We report the characteristics and outcomes of 108 severe adult CPN patients enrolled in a multiinstitutional observational study. SevereCPNadultsweremostly female (78%), andmedian age at diagnosis was 28.3 years. Diagnosis was fortuitous in 62% of cases. The median absolute neutrophil count (ANC) at diagnosis was 0.4 × 109/L, and median ANC without granulocyte colony-stimulating factor (G-CSF) during follow-up was 0.5 × 109/L. Twentythree of 66 (34.8%) evaluable patients had neutrophil autoantibodies, and 6 of 47 (12.8%) a T-cell clone. The presence of neutrophil autoantibodies orT-cell clonewas not associated with any specific clinical or biological characteristics. No death or hematologic malignancies occurred, and 44 severe bacterial infectionswere reported in 27 patients with amedian follow-up of 8.3 years. Fifty patients received G-CSF either sporadically (n = 24) or continuously (n = 26) and responded (96%). Nineteen patients received immunosuppressive therapies: overall response (OR) was 41%, and median duration of response was 3 months. At diagnosis, the only predictive factor for the occurrence of severe bacterial infections was an ANC count below 0.2 × 109/L (OR, 0.76). Severe CPN in adults is characterized by a female predominance and a benign outcome with a low rate of severe bacterial infections and no secondary malignancies. G-CSF is efficient and well tolerated but is not required in a majority of patients. © 2015 by The American Society of Hemetology. Source


Lambotte O.,Service de Medecine Interne | Lambotte O.,University Paris - Sud | Neven B.,NSERM | Neven B.,University of Paris Descartes | And 15 more authors.
Haematologica | Year: 2013

A diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency during adulthood is unusual. We analyzed 17 cases of autoimmune lymphoproliferative syndrome caused by FAS deficiency diagnosed during adulthood in French reference centers for hereditary immunodeficiencies and for immune cytopenias. Twelve of the 17 patients had developed their first symptoms during childhood. The diagnosis of autoimmune lymphoproliferative syndrome had been delayed for a variety of reasons, including unusual clinical manifestations, late referral to a reference center, and the occurrence of somatic FAS mutations. The 5 other patients presented their first symptoms after the age of 16 years. In these patients, three germline heterozygous FAS mutations were predicted to be associated with haploinsufficiency and a somatic event on the second FAS allele was observed in 2 cases. Autoimmune lymphoproliferative syndrome may well be diagnosed in adulthood. The occurrence of additional genetic events may account for the delayed disease onset. © 2013 Ferrata Storti Foundation. Source


Carriere M.,Service dImmunologie Clinique | Carriere M.,University Paris Est Creteil | Lacabaratz C.,Service dImmunologie Clinique | Lacabaratz C.,University Paris Est Creteil | And 14 more authors.
Journal of Infectious Diseases | Year: 2014

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by chronic immune activation and suppressed T-lymphocyte functions. Here we report that CD73, both a coactivator molecule of T cells and an immunosuppressive ecto-enzyme through adenosine production, is only weakly expressed by CD8 + T cells of HIV-infected patients and only partially restored after successful antiviral treatment. CD73 expression on CD8+ T cells correlates inversely with cell activation both ex vivo and in vitro. However, CD8+ T cells from HIV controllers (HICs), which spontaneously control HIV replication, express CD73 strongly, despite residual immune activation. Finally, we demonstrate that CD73 is involved in the HIV-specific CD8 + T-cell expansion. Thus, we show that CD73 is central to the functionality of HIV-specific CD8+ T cells and that the preservation of HIV-specific CD73+CD8+ T cells is a characteristic of HICs. These observations reveal a novel mechanism involved in the control of viral replication. © The Author 2013. Source


Bouillet L.,University Hospital | Launay D.,University of Lille Nord de France | Fain O.,University of Paris 13 | Boccon-Gibod I.,University Hospital | And 7 more authors.
Annals of Allergy, Asthma and Immunology | Year: 2013

Background Hereditary angioedema (HAE) is a rare and potentially life-threatening disease. New specific treatments are available. Objective To identify patients' features and patients' best therapeutic option. Methods A 1-year, multicenter, retrospective study was performed. The primary objective was to examine the clinical presentation of HAE. Secondary objectives included patient characteristics, management of HAE over 12 months, and health-related quality of life using the SF-36v2 questionnaire. Results One hundred ninety-three patients were included, and 69.4% were women. In the 12-month period, the mean number of HAE attacks was 7.6. Among the 568 reported attacks, localizations were the abdomen (57.1%), peripheral limbs (42.5%), upper airway (7.9%), and face (6.9%); 31.6% of attacks were severe and occurred statistically more often in women (P <.02). Compared with a population of allergic patients, all age- and sex-adjusted scores were significantly lower in patients with HAE (P <.05) except for the physical component summary. Health-related quality of life negatively correlated with the annual number of attacks and was markedly altered for patients having more than 5 attacks per year (P <.05 for all dimensions). Conclusion HAE is a severe disease that places a heavy burden on quality of life. © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. Source

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