Le Touquet – Paris-Plage, France
Le Touquet – Paris-Plage, France

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Heller S.,University of Sheffield | Buse J.,University of North Carolina at Chapel Hill | Fisher M.,Royal Infirmary | Garg S.,Barbara Davis Center for Childhood Diabetes | And 9 more authors.
The Lancet | Year: 2012

Background Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes. Methods In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged =18 years) with type 1 diabetes (glycated haemoglobin [HbA 1c] =10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computergenerated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA 1c after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228. Findings Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA 1c had fallen by 0•40% points (SE 0•03) and 0•39% points (0•07), respectively, with insulin degludec and insulin glargine (estimated treatment diff erence -0•01% points [95% CI -0•14 to 0•11]; p<0•0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA 1c of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3•1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42•54 vs 40•18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1•07 [0•89 to 1•28]; p=0•48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4•41 vs 5•86 episodes per patient-year of exposure; 0•75 [0•59 to 0•96]; p=0•021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups. Interpretation Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides eff ective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy.


Mariette X.,University Paris - Sud | Baron G.,University of Paris Descartes | Tubach F.,Hopital Bichat Claude Bernard | Liote F.,University Paris Diderot | And 9 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Background: The recommendations for detecting latent tuberculosis infection (LTBI) before antitumour necrosis factor (anti-TNF) therapy are based on the tuberculin skin test (TST), which lacks both specificity and sensitivity and can lead to unnecessary treatment with antibiotics. A study was undertaken to investigate the effect of replacing TST with interferon γ (IFNγ) release assays (IGRA) in screening for LTBI and deciding to begin prophylactic antituberculosis (TB) antibiotics before anti-TNF therapy in immune-mediated inflammatory diseases. Methods: In 15 tertiary care hospitals, consecutive patients with rheumatoid arthritis, spondylarthropathies or Crohn's disease were screened for LTBI before anti-TNF therapy with TST, QuantiFERON TB Gold in tube (QTF-Gold IT) and T-SPOT.TB at the same time. The potential diagnosis of LTBI and the effect on the decision to begin antibiotic prophylaxis were assessed. Results: Among 429 patients, 392 had results for the three tests. The results for TST, T-SPOT.TB and QTF Gold IT were positive for 35.2%, 15.1% and 9.9% of patients, respectively (p<0.0001). Antibiotics were required for 177 patients (45.2%) if positive TST results were included in the LTBI definition, 107 patients (27.3%) if TST results were replaced with results from one of the IGRA tests and 84 patients (21.4%) if TST results were replaced with QTF-Gold IT results (p<0.0001). The decision on the use of antibiotic prophylaxis was changed for 113 patients (28.8%, 95% CI 24.4% to 33.6%) if TST results were replaced with QTF-Gold IT results. Conclusions: Replacing TST with IGRA for determining LTBI allowed the proportion of patients with immune-mediated inflammatory diseases needing prophylactic anti-TB antibiotics before beginning anti-TNF agents to be reduced by half.


Mehran R.,Mount Sinai School of Medicine | Baber U.,Mount Sinai School of Medicine | Steg P.G.,Hopital Bichat Claude Bernard | Ariti C.,London School of Hygiene and Tropical Medicine | And 20 more authors.
The Lancet | Year: 2013

Background Dual antiplatelet therapy (DAPT) cessation increases the risk of adverse events after percutaneous coronary intervention (PCI). Whether risk changes over time, depends on the underlying reason for DAPT cessation, or both is unknown. We assessed associations between diff erent modes of DAPT cessation and cardiovascular risk after PCI. Methods The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, 2010. Adult patients (aged 18 years or older) undergoing successful stent implantation in one or more native coronary artery and discharged on DAPT were eligible for enrolment. Patients were followed up at months 1, 6, 12, and 24 after implantation. Prespecifi ed categories for DAPT cessation included physicianrecommended discontinuation, brief interruption (for surgery), or disruption (non-compliance or because of bleeding). All adverse events and episodes of DAPT cessation were independently adjudicated. Using Cox models with time-varying covariates, we examined the eff ect of DAPT cessation on major adverse events (MACE [composite of cardiac death, defi nite or probable stent thrombosis, myocardial infarction, or target-lesion revascularisation]). Incidence rates for DAPT cessation and adverse events were calculated as Kaplan-Meier estimates of time to the fi rst event. This study is registered with ClinicalTrials.gov, number NCT00998127. Findings We enrolled 5031 patients undergoing PCI, including 5018 in the fi nal study population. Over 2 years, the overall incidence of any DAPT cessation was 57•3%. Rate of any discontinuation was 40•8%, of interruption was 10•5%, and of disruption was 14•4%. The corresponding overall 2 year MACE rate was 11•5%, most of which (74%) occurred while patients were taking DAPT. Compared with those on DAPT, the adjusted hazard ratio (HR) for MACE due to interruption was 1•41 (95% CI 0•94-2•12; p=0•10) and to disruption was 1•50 (1•14-1.97; p=0•004). Within 7 days, 8-30 days, and more than 30 days after disruption, adjusted HRs were 7•04 (3•31-14•95), 2•17 (0•97-4•88), and 1•3 (0•97-1•76), respectively. By contrast with patients who remained on DAPT, those who discontinued had lower MACE risk (0•63 [0•46- 0•86]). Results were similar after excluding patients receiving bare metal stents and using an alternative MACE defi nition that did not include target lesion revascularisation. Interpretation In a real-world setting, for patients undergoing PCI and discharged on DAPT, cardiac events after DAPT cessation depend on the clinical circumstance and reason for cessation and attenuates over time. While most events after PCI occur in patients on DAPT, early risk for events due to disruption is substantial irrespective of stent type.


Meinzer U.,CEREMAI | Quartier P.,Hopital Necker Enfants Malades | Alexandra J.-F.,Hopital Bichat Claude Bernard | Hentgen V.,CEREMAI | Kone-Paut I.,CEREMAI
Seminars in Arthritis and Rheumatism | Year: 2011

Objectives: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disorder common in Mediterranean populations. FMF is associated with mutations of the MEFV gene, which encodes pyrin. Functional studies suggest that pyrin is implicated in the maturation and secretion of IL-1. The IL-1 receptor antagonist or anti-IL1 monoclonal antibody may therefore represent a new approach to treat FMF. The aim of this report was to evaluate and discuss treatment of FMF with interleukin-1 targeting drugs. Methods: Electronic mailing lists of French pediatric and adult rheumatologist associations were used to call for FMF patients treated with interleukin-1 antagonists. A search for published FMF patients treated with interleukin-1 targeting drugs was performed by screening PubMed. Results: Here, we report 7 cases of FMF patients treated with anakinra and/or canakinumab and discuss the clinical situations that may indicate the use of IL-1 blocking agents in FMF. The use of interleukin-1 targeting drugs was beneficial to all patients. The reasons for using interleukin-1 targeting drugs in FMF patients were as follows: (1) incomplete control of disease activity despite colchicine treatment; (2) high serum amyloid A levels despite colchicine treatment; (3) impossibility to use colchicine treatment because of severe side effects; (4) FMF in association with vasculitis. Conclusions: Interleukin-1 targeting drugs may be good candidates when looking for an alternative or supplementary treatment to colchicine. These observations highlight the need for controlled trials to further evaluate the safety and efficacy of interleukin-1 antagonists in FMF patients. © 2011 Elsevier Inc.


Thompson M.A.,AIDS Research Consortium of Atlanta | Aberg J.A.,New York University | Cahn P.,University of Buenos Aires | Montaner J.S.G.,University of British Columbia | And 12 more authors.
JAMA - Journal of the American Medical Association | Year: 2010

Context: Recent data regarding the consequences of untreated human immunodeficiency virus (HIV) infection and the expansion of treatment choices for antiretroviral-naive and antiretroviral-experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adults with HIV infection. Objectives: To provide updated recommendations for management of HIV-infected adults, using antiretroviral drugs and laboratory monitoring tools available in the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing. Data Sources and Study Selection: A panel with expertise in HIV research and clinical care reviewed relevant data published or presented at selected scientific conferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiretroviral drug manufacturers for updated clinical trials and adverse event data. Data Extraction and Synthesis: New evidence was reviewed by the panel. Recommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recommendations were made by full panel consensus. Conclusions: Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count ≤500/μL, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count >500/μL. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits. ©2010 American Medical Association. All rights reserved.


Hylek E.M.,Boston University | Held C.,Uppsala University | Alexander J.H.,Duke University | Lopes R.D.,Duke University | And 9 more authors.
Journal of the American College of Cardiology | Year: 2014

Objectives This study sought to characterize major bleeding on the basis of the components of the major bleeding definition, to explore major bleeding by location, to define 30-day mortality after a major bleeding event, and to identify factors associated with major bleeding. Background Apixaban was shown to reduce the risk of major hemorrhage among patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods All patients who received at least 1 dose of a study drug were included. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. Factors associated with major hemorrhage were identified using a multivariable Cox model. Results The on-treatment safety population included 18,140 patients. The rate of major hemorrhage among patients in the apixaban group was 2.13% per year compared with 3.09% per year in the warfarin group (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.60 to 0.80; p < 0.001). Compared with warfarin, major extracranial hemorrhage associated with apixaban led to reduced hospitalization, medical or surgical intervention, transfusion, or change in antithrombotic therapy. Major hemorrhage followed by mortality within 30 days occurred half as often in apixaban-treated patients than in those receiving warfarin (HR 0.50, 95% CI: 0.33 to 0.74; p < 0.001). Older age, prior hemorrhage, prior stroke or transient ischemic attack, diabetes, lower creatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal anti-inflammatory drugs were independently associated with an increased risk. Conclusions Apixaban, compared with warfarin, was associated with fewer intracranial hemorrhages, less adverse consequences following extracranial hemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of major hemorrhage. © © 2014 by the American College of Cardiology Foundation Published by Elsevier Inc.


Hurtado-Nedelec M.,University Paris - Sud | Chollet-Martin S.,University Paris - Sud | Chapeton D.,Hopital Bichat Claude Bernard | Hugot J.-P.,Service de Genetique | And 2 more authors.
Journal of Rheumatology | Year: 2010

Objective. The SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare disorder that mainly affects bone and skin. Chronic multifocal osteitis is the main diagnostic feature. Genetic studies of HLA genes have shown no role for these class II antigens, whereas studies of 2 mouse models (cmo and Lupo) point to a role of the PSTPIP2 gene.We analyzed the PSTPIP2 gene in patients with SAPHO syndrome. Methods. In a cohort of 38 patients with SAPHO we analyzed PSTPIP2 and 2 other candidate genes, NOD2/CARD15 (Crohn's disease occurs in about 10% of SAPHO patients), and LPIN2 (clinical similarities of SAPHO with Majeed syndrome). Results. Rare variants of the 3 genes observed in patients with SAPHO were not specific or were not found more frequently compared to controls, suggesting no major pathogenetic role of these genes in the SAPHO syndrome. Conclusion.We found no association between PSTPIP2, NOD2, and LPIN2 variants and the SAPHO syndrome. The Journal of Rheumatology Copyright © 2010. All rights reserved.


Rockstroh J.K.,University of Bonn | Dejesus E.,Orlando Immunology Center | Lennox J.L.,Emory University | Yazdanpanah Y.,Hopital Bichat Claude Bernard | And 10 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2013

BACKGROUND: STARTMRK, a phase III noninferiority trial of raltegravir-based versus efavirenz-based therapy in treatment-naive patients, remained blinded until its conclusion at 5 years. We now report the final study results. METHODS: Previously untreated patients without baseline resistance to efavirenz, tenofovir, or emtricitabine were eligible for a randomized study of tenofovir/emtricitabine plus either raltegravir or efavirenz. Yearly analyses were planned, with primary and secondary end points stipulated at weeks 48 and 96, respectively. The primary efficacy outcome was the percentage of patients with viral RNA (vRNA) levels <50 copies per milliliter counting noncompleters as failures (NC=F). Changes from baseline CD4 count were computed using an observed-failure approach to missing data. No formal hypotheses were formulated for testing at week 240. RESULTS: Overall, 71 of 281 raltegravir recipients (25%) and 98 of 282 efavirenz recipients (35%) discontinued the study; discontinuations due to adverse events occurred in 14 (5%) and 28 (10%) patients in the respective groups. In the primary NC=F efficacy analysis at week 240, 198 of 279 (71.0%) raltegravir recipients and 171 of 279 (61.3%) efavirenz recipients had vRNA levels <50 copies per milliliter, yielding a treatment difference {[INCREMENT] [95% confidence interval (CI)] = 9.5 (1.7 to 17.3)}. Generally comparable between-treatment differences were seen in both the protocol-stipulated sensitivity analyses and the prespecified subgroup analyses. The mean (95% CI) increments in baseline CD4 counts at week 240 were 374 and 312 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [[INCREMENT] (95% CI) = 62 (22 to 102)]. Overall, significantly fewer raltegravir than efavirenz recipients experienced neuropsychiatric side effects (39.1% vs 64.2%, P < 0.001) or drug-related clinical adverse events (52.0% vs 80.1%, P < 0.001). CONCLUSIONS: In this exploratory analysis of combination therapy with tenofovir/emtricitabine in treatment-naive patients at week 240, vRNA suppression rates and increases in baseline CD4 counts were significantly higher in raltegravir than efavirenz recipients. Over the entire study, fewer patients experienced neuropsychiatric and drug-related adverse events in the raltegravir group than in the efavirenz group. Based on better virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/ emtricitabine seemed to have superior efficacy compared with efavirenz/tenofovir/emtricitabine. Copyright © 2013 by Lippincott Williams & Wilkins.


Heidenreich B.,German Cancer Research Center | Nagore E.,University of Valencia | Rachakonda P.S.,German Cancer Research Center | Garcia-Casado Z.,Instituto Valenciano Of Oncologia | And 6 more authors.
Nature communications | Year: 2014

We previously reported a disease segregating causal germline mutation in a melanoma family and recurrent somatic mutations in metastasized tumours from unrelated patients in the core promoter region of the telomerase reverse transcriptase (TERT) gene. Here we show that the TERT promoter mutations, besides causing an increased gene expression, associate with increased patient age, increased Breslow thickness and tumour ulceration in 287 primary melanomas. The mutations are more frequent at both intermittently and chronically sun-exposed sites than non-exposed sites and tend to co-occur with BRAF and CDKN2A alterations. The association with parameters generally connected with poor outcome, coupled with high recurrence and mechanistic relevance, raises the possibility of the eventual use of TERT promoter mutations in the disease management.


Joly V.,Hopital Bichat Claude Bernard | Jidar K.,Hopital Bichat Claude Bernard | Tatay M.,Hopital Bichat Claude Bernard | Yeni P.,Hopital Bichat Claude Bernard
Expert Opinion on Pharmacotherapy | Year: 2010

Importance of the field: Drug resistance is a major challenge in the treatment of HIV infection. Enfuvirtide is the first entry inhibitor to have been approved for clinical use. Areas covered in this review: Relevant information through searches of MEDLINE (1998 to June 2010) and meeting abstracts of major HIV/AIDS conferences (2003 June 2010) using the search terms 'enfuvirtide', 'T-20' and 'fusion inhibitor'. What the reader will gain: Enfuvirtide blocks HIV fusion to host cells. It works against the different HIV-1 variants but is not active against HIV-2. The recommended dosage of enfuvirtide is 90 mg b.i.d. subcutaneously. The two large Phase III pivotal clinical trials TORO 1 and 2 showed that enfuvirtide is an effective therapeutic option as rescue therapy in combination with other active antiretroviral drugs. Resistance to enfuvirtide is conferred by mutations in the HR1 region of gp41. Single and double mutations have been shown to result in high-level resistance to enfuvirtide. Postmarketing studies have been helpful to define more precisely the place of enfuvirtide in the sequence of antiretroviral therapy. Take home message: The emergence of new compounds and new classes of drugs, highly active against multiresistant virus but more convenient to administer than enfuvirtide, will probably prevent the extensive use of enfuvirtide. This drug remains attractive in some subgroups of patients because of its excellent systemic tolerance and the lack of interactions with the major cytochrome P450 isoenzymes. © 2010 Informa UK, Ltd.

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