Galea C.A.,Monash Institute of Pharmaceutical Sciences |
Galea C.A.,Murdoch Childrens Research Institute |
Huq A.,Murdoch Childrens Research Institute |
Lockhart P.J.,Murdoch Childrens Research Institute |
And 25 more authors.
Annals of Neurology | Year: 2016
Objective Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% of affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA. Methods We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (1) homozygous expansions, and three compound heterozygote groups; (2) null (no frataxin produced); (3) moderate/strong impact; and (4) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses. Results Mutations in the hydrophobic core of frataxin affected stability whereas surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus, compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups. Interpretation In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provide a definitive resource for investigating disease pathogenesis in FRDA. © 2016 American Neurological Association.
PubMed | Besancon University Hospital Center, k Janssen, University of Paris Pantheon Sorbonne, French Institute of Health and Medical Research and 7 more.
Type: Clinical Trial | Journal: Infectious diseases (London, England) | Year: 2016
Etravirine (ETR) was approved in France in September 2008 and is used in combination with a boosted protease inhibitor (bPI) and other anti-retrovirals (ART) in HIV-infected pre-treated patients. This study aimed to report in a real-life setting the efficacy and tolerability of ETR-based regimens and factors associated with virological response.The study population included all treatment-experienced patients who initiated an ETR-based regimen between September 2008 and July 2013 from the French DatAIDS cohort. Analyses were performed in ART-experienced patients starting ETR after virological failure (VF) or as a maintenance therapy (MT), with or without bPI.A total of 2006 patients (VF, n = 1014 (51%); MT, n = 992 (49%)) were included. At M12, the proportion of patients with HIV RNA < 50 copies/ml was 71.7% (72.0% and 71.1% with or without bPI) in the VF group and 90.5% (85.0% and 92.3% with or without bPI) in the MT group, without significant differences regarding the use of bPI. ETR was discontinued in 8.8% of patients for adverse events in 23.9% of cases (21.5% in VF, 29.5% in MT), treatment failure in 15.2% (16.2% in VF, 7.4% in MT) or simplification in 5.4% (4.6% in VF, 7.4% in MT). In the VF group, factors associated with virological response were a longer duration of HIV infection (OR = 2.7; p < 0.001) and baseline HIV RNA < 5 log10 copies/mL (OR = 2.1; p = 0.002).This study shows that in ART-experienced patients ETR is well tolerated with a high efficacy when combined with other active drugs, even when the regimen does not include a bPI.
Achenbach C.J.,Northwestern University |
Assoumou L.,French Institute of Health and Medical Research |
Assoumou L.,University Pierre and Marie Curie |
Deeks S.G.,San Francisco General Hospital |
And 27 more authors.
The Lancet HIV | Year: 2015
Background: Achievement of a cure for HIV infection might need reactivation of latent virus and improvement of HIV-specific immunity. As an initial step, in this trial we assessed the effect of antiretroviral therapy intensification and immune modulation with a DNA prime and recombinant adenovirus 5 (rAd5) boost vaccine. Methods: In this multicentre, randomised, open-label, non-comparative, phase 2 clinical trial, we enrolled eligible adults 18-70 years of age with chronic HIV-1 infection on suppressive antiretroviral therapy with current CD4 count of at least 350 cells per μL and HIV DNA between 10 and 1000 copies per 106 peripheral blood mononuclear cells. After an 8 week lead-in of antiretroviral intensification therapy (standard dose raltegravir and dose-adjusted maraviroc based on baseline antiretroviral therapy), patients were randomly assigned (1:1) to receive antiretroviral therapy intensification alone or intensification plus injections of HIV DNA prime vaccine (4 mg VRC-HIVDNA016-00-VP) at weeks 8, 12, and 16, followed by HIV rAd5 boost vaccine (1010 particle units of VRC-HIVADV014-00-VP) at week 32. Randomisation was computer generated in permuted blocks of six and was stratified by study site. The primary endpoint was a 0·5 log10 or greater decrease in HIV DNA in peripheral blood mononuclear cells at week 56. This study is registered with ClinicalTrials.gov, number NCT00976404. Findings: Between Nov 29, 2010, and Oct 28, 2011, we enrolled 28 eligible patients from three academic HIV clinics in the USA. After the 8 week lead-in of antiretroviral intensification therapy, 14 patients were randomly assigned to continue antiretroviral therapy intensification alone and 14 to intensification plus vaccine. Enrolled participants had median CD4 count of 636 cells per μL, median HIV DNA 170 copies per 106 peripheral blood mononuclear cells, and duration of antiretroviral therapy of 13 years. The median amount of HIV DNA did not change significantly between baseline and week 56 in the antiretroviral therapy intensification plus vaccine group. One participant in the antiretroviral therapy intensification alone group reached the primary endpoint, with 0·55 log10 decrease in HIV DNA in peripheral blood mononuclear cells. Both treatments were well tolerated. No severe or systemic reactions to vaccination occurred, and five serious adverse events were recorded during the study, most of which resolved spontaneously or were judged unrelated to study treatments. Interpretation: Antiretroviral therapy intensification followed by DNA prime and rAd5 boost vaccine did not significantly increase HIV expression or reduce the latent HIV reservoir. A multifaceted approach that includes stronger activators of HIV expression and novel immune modulators will probably be needed to reduce the latent HIV reservoir and allow for long-term control in patients off antiretroviral therapy. Funding: Objectif Recherche Vaccin SIDA (ORVACS). © 2015 Elsevier Ltd.
Kirwan J.R.,Royal Infirmary |
Boers M.,VU University Amsterdam |
Hewlett S.,University of the West of England |
Beaton D.,University of Toronto |
And 23 more authors.
Journal of Rheumatology | Year: 2014
Objective. The Outcome Measures in Rheumatology (OMERACT) Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The "Truth" section of the OMERACT Filter presupposes an explicit framework for identifying the relevant core outcomes that are universal to all studies of the effects of intervention effects. There is no published outline for instrument choice or development that is aimed at measuring outcome, was derived from broad consensus over its underlying philosophy, or includes a structured and documented critique. Therefore, a new proposal for defining core areas of measurement ("Filter 2.0 Core Areas of Measurement") was presented at OMERACT 11 to explore areas of consensus and to consider whether already endorsed core outcome sets fit into this newly proposed framework. Methods. Discussion groups critically reviewed the extent to which case studies of current OMERACT Working Groups complied with or negated the proposed framework, whether these observations had a more general application, and what issues remained to be resolved. Results. Although there was broad acceptance of the framework in general, several important areas of construction, presentation, and clarity of the framework were questioned. The discussion groups and subsequent feedback highlighted 20 such issues. Conclusion. These issues will require resolution to reach consensus on accepting the proposed Filter 2.0 framework of Core Areas as the basis for the selection of Core Outcome Domains and hence appropriate Core Outcome Sets for clinical trials. © 2014. All rights reserved.
Avouac B.,Henri Mondor Hospital |
Berenbaum F.,University Pierre and Marie Curie |
Blin O.,Aix - Marseille University |
Bru I.,UCB Pharma |
And 4 more authors.
Journal of Rheumatology | Year: 2011
Objective. To compare the clinical efficacy of certolizumab pegol (CZP) with that of other anticytokine agents indicated for the treatment of rheumatoid arthritis (RA) with identical therapeutic indication (anti-tumor necrosis factor-α, anti-interleukin 1 or 6), with the objective of determining the noninferiority of CZP. Methods. A systematic review was performed to identify randomized controlled trials that assessed the efficacy of anticytokine agents in combination with conventional disease-modifying antirheumatic drugs (DMARD) after 6 months of treatment, using the American College of Rheumatology (ACR) response criteria, in patients with RA who have shown inadequate response to DMARD including methotrexate. Indirect treatment comparisons were carried out by a multiple-treatment Bayesian random-effects metaanalysis. Data were analyzed using the Markov chain Monte Carlo simulation. Noninferiority of CZP was assessed in comparison with a predefined equivalence margin of 5%. Results. Nineteen placebo-controlled studies were identified: 14 evaluated the efficacy of 5 anti-TNF-α agents (infliximab, etanercept, adalimumab, golimumab, CZP) and 5 evaluated efficacy of 2 anti-interleukin agents (anakinra, tocilizumab). Every treatment showed significant efficacy versus placebo in individual studies. The multiple-treatment metaanalysis showed a highest OR for CZP on ACR20 response. Metaanalysis indicates that the efficacy of CZP according to ACR20 response is superior to that of infliximab, adalimumab, and anakinra, and equivalent or superior to that of etanercept, golimumab, and tocilizumab. According to ACR50 response, the efficacy of CZP is equivalent or superior to that of all other anticytokines. Conclusion. Results of this original multiple-treatment Bayesian metaanalysis indicate that certolizumab pegol is at least as efficacious as the preexisting antirheumatic anticytokine biotherapies. The Journal of Rheumatology Copyright © 2011. All rights reserved.
Autran B.,University Pierre and Marie Curie |
Autran B.,AP HP Pitie Salpetriere Hospital |
Descours B.,University Pierre and Marie Curie |
Avettand-Fenoel V.,University of Paris Descartes |
And 3 more authors.
Current Opinion in HIV and AIDS | Year: 2011
Purpose of review: The limitations of life-long antiretroviral therapies for the HIV infection lead to a novel concept of a functional cure developing innovative therapeutic strategies to generate a long-term remission of HIV replication without treatment. This concept requires an understanding of the mechanisms by which HIV is controlled in conditions of undetectable virus replication, before developing ambitious therapies blocking durably viral replication - and ultimately eradicating HIV. Recent findings: Recent literature shows that the exceptional elite controller status is usually not driven by virus gross genetic defects, despite some virus attenuation resulting from immune selective pressure, but is frequently determined by host's genetic factors permitting robust cell-mediated immunity to control the virus replication and reservoirs. Lack of immunity and immune deficiency can however limit this model in some cases and only a subgroup in whom both the virus and the immune deficiency are controlled, that is the elite long-term controllers, might represent the best current model for a functional cure. Summary: This review examines whether the exceptional HIV-infected elite controllers, who spontaneously and durably maintain extremely low virus replication, might be considered as a model for a functional cure and whether the mechanisms identified in these exceptional individuals might serve to identify therapeutic or vaccine strategies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
PubMed | Murdoch Childrens Research Institute, University of California at Los Angeles, Children's Hospital of Philadelphia, University of Melbourne and 4 more.
Type: Journal Article | Journal: Annals of neurology | Year: 2016
Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% of affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA.We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (1) homozygous expansions, and three compound heterozygote groups; (2) null (no frataxin produced); (3) moderate/strong impact; and (4) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses.Mutations in the hydrophobic core of frataxin affected stability whereas surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus, compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups.In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provide a definitive resource for investigating disease pathogenesis in FRDA.
Finsterer J.,Krankenanstalt Rudolfstiftung |
Wahbi K.,Cochin Hospital |
Wahbi K.,University of Paris Descartes |
Wahbi K.,AP HP Pitie Salpetriere Hospital
Acta Cardiologica | Year: 2016
There are a number of acute central nervous system (CNS) disorders, which trigger an acute cardiac reaction (brain-heart disorders). Both the brain and the heart may be previously normal or affected by chronic hereditary or acquired disease. The most common of these acute CNS disorders include subarachanoid bleeding, epilepsy, ischaemic stroke, intracerebral bleeding, infectious meningitis/encephalitis, immune-encephalitis, posterior reversible encephalopathy syndrome, migraine, central sleep apnoea syndrome, restless leg syndrome, and traumatic brain injury. Affection of the heart caused by these CNS abnormalities includes takotsubo syndrome, arrhythmias, heart failure or systolic/diastolic dysfunction, myocardial infarction, arterial hypertension, or pulmonary hypertension of which takotsubo syndrome, arrhythmias, or heart failure are the most frequent. Arrhythmias triggered by acute CNS disease include supraventricular or ventricular arrhythmias, including sudden cardiac death. Cardiologists and neurologists must be aware of acute CNS disorders triggering acute cardiac disease not only to overlook appropriate neurological treatment but also in terms of optimizing prophylactic management of possible cardiac disease. © 2016, Acta Cardiologica. All rights reserved.