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Van Wesenbeeck L.,Janssen Infectious Diseases Diagnostics BVBA | Meeuws H.,Janssen Infectious Diseases Diagnostics BVBA | Van Immerseel A.,Janssen Infectious Diseases Diagnostics BVBA | Ispas G.,Janssen Infectious Diseases Diagnostics BVBA | And 4 more authors.
Journal of Clinical Microbiology | Year: 2013

Respiratory tract infections (RTIs) are caused by a plethora of viral and bacterial pathogens. In particular, lower RTIs are a leading cause of hospitalization and mortality. Timely detection of the infecting respiratory pathogens is crucial to optimize treatment and care. In this study, three U.S. Food and Drug Administration-approved molecular multiplex platforms (Prodesse Pro- FLU+/FAST+, FilmArray RP, and Verigene RV+) were evaluated for influenza virus detection in 171 clinical samples collected during the Belgian 2011-2012 influenza season. Sampling was done using mid-turbinate flocked swabs, and the collected samples were stored in universal transport medium. The amount of viral RNA present in the swab samples ranged between 3.07 and 8.82 log10 copies/ml. Sixty samples were concordant influenza A virus positive, and 8 samples were found to be concordant influenza B virus positive. Other respiratory viruses that were detected included human rhinovirus/enterovirus, respiratory syncytial virus, parainfluenza virus type 1, human metapneumovirus, and coronavirus NL63. Twenty-five samples yielded discordant results across the various assays which required further characterization by sequencing. The FilmArray RP and Prodesse Pro- FLU+/FAST+assays were convenient to perform with regard to sensitivity, ease of use, and low percentages of invalid results. Although the limit of sensitivity is of utmost importance, many other factors should be taken into account in selecting the most convenient molecular diagnostic assay for the detection of respiratory pathogens in clinical samples. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Van der Borght K.,Janssen Infectious Diseases Diagnostics BVBA | Van der Borght K.,Catholic University of Leuven | Verbeke G.,Catholic University of Leuven | Verbeke G.,Hasselt University | van Vlijmen H.,Janssen Infectious Diseases Diagnostics BVBA
BMC Bioinformatics | Year: 2014

Background: Different high-dimensional regression methodologies exist for the selection of variables to predict a continuous variable. To improve the variable selection in case clustered observations are present in the training data, an extension towards mixed-effects modeling (MM) is requested, but may not always be straightforward to implement.In this article, we developed such a MM extension (GA-MM-MMI) for the automated variable selection by a linear regression based genetic algorithm (GA) using multi-model inference (MMI). We exemplify our approach by training a linear regression model for prediction of resistance to the integrase inhibitor Raltegravir (RAL) on a genotype-phenotype database, with many integrase mutations as candidate covariates. The genotype-phenotype pairs in this database were derived from a limited number of subjects, with presence of multiple data points from the same subject, and with an intra-class correlation of 0.92.Results: In generation of the RAL model, we took computational efficiency into account by optimizing the GA parameters one by one, and by using tournament selection. To derive the main GA parameters we used 3 times 5-fold cross-validation. The number of integrase mutations to be used as covariates in the mixed effects models was 25 (chrom.size). A GA solution was found when R2 MM > 0.95 (goal.fitness). We tested three different MMI approaches to combine the results of 100 GA solutions into one GA-MM-MMI model. When evaluating the GA-MM-MMI performance on two unseen data sets, a more parsimonious and interpretable model was found (GA-MM-MMI TOP18: mixed-effects model containing the 18 most prevalent mutations in the GA solutions, refitted on the training data) with better predictive accuracy (R2) in comparison to GA-ordinary least squares (GA-OLS) and Least Absolute Shrinkage and Selection Operator (LASSO).Conclusions: We have demonstrated improved performance when using GA-MM-MMI for selection of mutations on a genotype-phenotype data set. As we largely automated setting the GA parameters, the method should be applicable on similar datasets with clustered observations. © 2014 Van der Borght et al.; licensee BioMed Central Ltd.


Hoetelmans R.M.W.,Janssen Infectious Diseases Diagnostics BVBA | Dierynck I.,Janssen Infectious Diseases Diagnostics BVBA | Smyej I.,Janssen Infectious Diseases Diagnostics BVBA | Meyvisch P.,Janssen Infectious Diseases Diagnostics BVBA | And 4 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2014

OBJECTIVES:: To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor. METHODS:: Healthy participants aged 18-55 years with body mass index 18-30 kg/m were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75-2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively. RESULTS:: In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration-time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system. CONCLUSIONS:: TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir. Copyright © 2013 by Lippincott Williams & Wilkins.


Lathouwers E.,Janssen Infectious Diseases Diagnostics BVBA | De La Rosa G.,Janssen Therapeutics | Van De Casteele T.,Janssen Infectious Diseases Diagnostics BVBA | Baeten B.,Janssen Infectious Diseases Diagnostics BVBA | And 3 more authors.
Antiviral Therapy | Year: 2013

Background: The aim of this analysis was to characterize viral resistance in the Phase III, randomized ODIN trial, which demonstrated non-inferiority of once-daily darunavir/ritonavir (DRV/r) 800/100 mg to DRV/r 600/100 mg twice daily, each combined with an optimized background regimen in treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Methods: Virological failure (VF) was defined as never achieving or losing confirmed virological suppression after week 12, with patients being classed as 'never suppressed' (never achieved HIV-1 RNA<50 copies/ml) or 'rebounders' (achieved two consecutive HIV-1 RNA<50 copies/ml but then ≥50 copies/ml). Phenotypes and genotypes of plasma HIV-1 viruses, using populationbased sequencing and Antivirogram®, were determined at screening/baseline and on samples from VFs with HIV-1 RNA≥50 copies/ml. Results: Mean baseline HIV-1 RNA was 4.16 log10 copies/ml and 53.9% of patients were protease inhibitor (PI)-experienced at enrolment. VF rate was similar in both arms. A similar proportion of virologically failing patients in both arms developed PI RAMs (11.7% versus 9.5%, respectively) or nucleoside reverse transcriptase inhibitor RAMs (6.7% versus 7.1%). One patient with VF (once-daily arm) developed four primary PI mutations, three of which were also DRV RAMs. This patient was also the only VF to lose susceptibility to DRV. Loss of susceptibility to other PIs (once daily 3.4%; twice daily 0%) and nucleoside reverse transcriptase inhibitors (once daily 13.6%; twice daily 9.8%) in VF patients was infrequent and comparable between treatment arms. Conclusions: These analyses showed once-daily DRV/r 800/100 mg was associated with similar rates of VF and emergence of resistance as DRV/r 600/100 mg twice daily in treatment-experienced patients with no DRV RAMs. ©2013 International Medical Press.


Ozdemir M.S.,Janssen Pharmaceutical | Marczak M.,Janssen Pharmaceutical | Bohets H.,Octens BVBA | Bonroy K.,Janssen Infectious Diseases Diagnostics BVBA | And 5 more authors.
Analytical Chemistry | Year: 2013

We report here on a new potentiometric biosensing principle for the detection of antibody-antigen interactions at the sensing membrane surface without the need to add a label or a reporter ion to the sample solution. This is accomplished by establishing a steady-state outward flux of a marker ion from the membrane into the contacting solution. The immunobinding event at the sensing surface retards the marker ion, which results in its accumulation at the membrane surface and hence in a potential response. The ion-selective membranes were surface-modified with an antibody against respiratory syncytial virus using click chemistry between biotin molecules functionalized with a triple bond and an azide group on the modified poly (vinyl chloride) group of the membrane. The bioassay sensor was then built up with streptavidin and subsequent biotinylated antibody. A quaternary ammonium ion served as the marker ion. The observed potential was found to be modulated by the presence of respiratory syncytial virus bound on the membrane surface. The sensing architecture was confirmed with quartz crystal microbalance studies, and stir effects confirmed the kinetic nature of the marker release from the membrane. The sensitivity of the model sensor was compared to that of a commercially available point-of-care test, with promising results. © 2013 American Chemical Society.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.3.2-3 | Award Amount: 17.07M | Year: 2010

This proposal is for a large scale collaborative project in which we propose both to develop novel microbicides directed against new intracellular targets and to investigate novel combinations of highly active anti-retroviral drugs which may be particularly effective as microbicides. Combinations may enhance efficacy but equally importantly will increase the genetic barrier to the development of resistance. The proposal includes development of both slow release and gel formulations, pharmacokinetic and challenge experiments in macaques as well as human studies including a collaborative study with an EDCTP-funded project to use multiplex and proteomic technologies as well as culture-independent DNA-based analysis of mucosal microbiota to investigate biomarkers and establish a baseline signature from which perturbations can be recognised. This is a large consortium comprising 30 partners from 8 EU countries and from Switzerland, Ukraine, South Africa and the United States.Partners include microbicide developers, IPM and Particle Sciences, and producers, Gilead, Tibotec and Virco. Two SMEs will also participate in RTD aspects. The consortium is multidisciplinary with scientists engaged in basic discovery working with new targets and developing novel chemistry to produce compounds with improved safety and efficacy profiles as well as altered patterns of resistance.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.3.3-1 | Award Amount: 31.38M | Year: 2014

Far from receding, the threats posed by infections with epidemic potential grow ever greater. Although Europe has amongst the best healthcare systems in the world, and also the worlds supreme researchers in this field, we lack co-ordination and linkage between networks that is required to respond fast to new threats. This consortium of consortia will streamline our response, using primary and secondary healthcare to detect cases with pandemic potential and to activate dynamic rapid investigation teams that will deploy shared resources across Europe to mitigate the impact of future pandemics on European health, infrastructure and economic integrity. If funded, PREPARE will transform Europes response to future severe epidemics or pandemics by providing infrastructure, co-ordination and integration of existing clinical research networks, both in community and hospital settings. It represents a new model of collaboration and will provide a one-stop shop for policy makers, public health agencies, regulators and funders of research into pathogens with epidemic potential. It will do this by mounting interepidemic (peace time) patient oriented clinical trials in children and in adults, investigations of the pathogenesis of relevant infectious diseases and facilitate the development of sophisticated state-of-the-art near-patient diagnostics. We will develop pre-emptive solutions to ethical, administrative, regulatory and logistical bottlenecks that prevent a rapid response in the face of new threats. We will provide education and training not only to the members of the network, but also to external opinion leaders, funders and policy makers thereby streamlining our future response. By strengthening and integrating interepidemic research networks, PREPARE will enable the rapid coordinated deployment of Europes elite clinical investigators, resulting in a highly effective response to future outbreaks based on solid scientific advances.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2010-ITN | Award Amount: 4.98M | Year: 2011

Virus infections remain a major cause of disease, with dramatic costs in mortality, morbidity, and economic loss worldwide. There is an unmet need for potent antiviral drugs, in particular against viruses with a (\)RNA genome which include many important pathogens of humans and animals. Antiviral drug development requires a detailed understanding of virus replication and effective translation of this knowledge into drug discovery. Europe needs well-trained experts with multidisciplinary skills to advance this field. However, few, if any, European training institutes have the broad know-how required to provide such a comprehensive training programme. The EUVIRNA partnership aims to fill this gap with the proposed EUVIRNA training programme. The EUVIRNA partnership consists of six outstanding European academic partners and four industrial partners (one pharmaceutical R&D company and three SMEs), and an associated partner (SME specialized in education). All EUVIRNA partners are recognized leaders in their field, ensuring state-of-the-art training possibilities, and their skills are highly complementary. Three Visiting Researchers will complement the expertise of the partners. EUVIRNA aims to introduce 18 ESRs and 2 ERs to state-of-the-art knowledge and technology applied in molecular virology and antiviral therapy, with both local and network-wide training activities. Individual research projects, research training workshops and intersectoral secondments will be supplemented with complementary skills courses to improve career development and perspectives. The industrial partners are actively involved in the entire programme, and will furthermore organize a 1-week industry-oriented conference aimed at further bridging the gap between academia and industry. Thus, EUVIRNA offers talented researchers a multidisciplinary and intersectoral training programme and prepares them for a future leading role in European molecular virology research and antiviral dru


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.3.2-1 | Award Amount: 3.90M | Year: 2008

Standard therapy of infection with the human immunodeficiency virus type 1 (HIV-1) is based on potent cocktails of drugs targeting viral proteins. This treatment is associated with severe side effects and is almost unaffordable for the patients living in sub-Saharan Africa. Incomplete suppression of HIV replication results in drug-resistance. Therefore, a continued research effort is required to develop more potent, cheaper and less toxic antivirals. The insight has grown that HIV requires cellular proteins to serve as co-factors for viral replication. Our over-all objective is to develop novel drugs by targeting co-factors required for HIV replication. The virus will find it difficult to develop antiviral resistance against drugs targeting interaction between invariable cellular proteins and conserved viral protein domains. We will focus on the cellular proteins that mediate HIV trafficking, nuclear import and integration, such as Lens Epithelium Derived Growth Factor (LEDGF/p75), a novel cofactor of HIV-1 integration. THINC is composed of 3 virologists, 2 medicinal chemists, 1 virologist from South Africa, 1 structural biologist, 1 pharmaceutical company. Our first objective is to identify and validate novel co-factors of HIV trafficking, nuclear import and integration as novel targets for anti-HIV therapy. The second objective is to develop new drugs against the validated cellular target LEDGF/p75. The third objective is to perform this work in the perspective of those who will benefit most: the HIV infected people all over the world. The initial steps of target validation and hit identification will mainly be taken by academic groups, while optimization and (pre)clinical development of drugs requires the participation of Tibotec, a European company devoted to the development of antiviral drugs. The project will also increase our generic understanding of protein-protein interactions (PPI).


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.3.2-7 | Award Amount: 13.02M | Year: 2009

CHAIN is a large scale integrating project aimed to effectively and durably combat new and existing anti-HIV drug resistance in clinical settings, with a special emphasis on Eastern Europe and in heavily affected resource-poor regions in Africa. This will be achieved through our pan-European network of surveillance and basic research activities, the involvement of all main actors in the field of HIV and anti-HIV drug resistance, monitoring how resistances develop and evolve, improved understanding of mechanisms of resistance development, performing molecular epidemiology studies, providing improved and new strategies to evaluate and limit the emergence and transmission of HIV drug resistance, setting up training and dissemination activities and supporting evidence-based public health policy and action. CHAIN brings together Europes leading internationally recognised scientific expertise in basic science, molecular epidemiology, bioinformatics and surveillance of HIV and HIV resistance including the WHO, strong links to Eastern Europe through the existing FP6 funded cohort network Europe HIVresistance and strategic links to relevant pan-European cohort networks and national cohort networks (PENTA/ECS, CASCADE, EuroSIDA, COHERE, ICoNa, UK-CHIC, SHCS). Our balanced programme of work is informed by optimising the synergistic skills represented by the applicants, and also through harmonising with existing initiatives, that ensures lack of duplication, but rather maximises the impact of European activities. Thus, our African and Eastern European work will be linked to WHO policy, our European surveillance studies will be guided by ECDC (through our advisory board), and our clinical research will generate questions best addressed through the NEAT clinical trial network. Finally, our partnership with the key biotechnology companies in HIV resistance will ensure maximal impact of our basis research activities.

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