58 research outputs found

    Randomised clinical trial: Alisporivir combined with peginterferon and ribavirin in treatment-naĂŻve patients with chronic HCV genotype 1 infection (ESSENTIAL II)

    No full text
    Background Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. Aim To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naĂŻve patients with chronic HCV genotype 1 infection. Methods Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≄12 weeks and 20% had received ≄24 weeks of ALV/PR triple therapy. Results A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. Conclusions Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naĂŻve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens

    Randomised clinical trial: Alisporivir combined with peginterferon and ribavirin in treatment-na\uefve patients with chronic HCV genotype 1 infection (ESSENTIAL II)

    No full text
    BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-\u3b12a and ribavirin (PR) in treatment-na\uefve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received 6512 weeks and 20% had received 6524 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-na\uefve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens

    Marked Markovian Arrivals in a Tandem G-Network with Blocking

    No full text
    Queueing networks with blocking have broad applications in computer modelling and manufacturing. The present paper focusses on the MMAP[2]/M/1/ aaEuro parts per thousand a dagger'center dot/M/1/K + 1 G-queue with blocking. This network consists of a sequence of two single-server stations with an infinite queue allowed before the first server and an intermediate queue of finite capacity K a parts per thousand yenaEuro parts per thousand 0 allowed between servers. This restriction results in the blocking of the first server whenever a unit having completed its service in Station 1 cannot enter into Station 2 due to K + 1 units are accommodated into Station 2. There are two types of arrivals, called units and signals, which are modelled by a single Markovian arrival process with marked transitions. Each unit is served at Stations 1 and 2 in that order, and then it exits of the network. A signal induces the last unit in queue or in service, if there is one, to leave the network instantly, and it has no effect otherwise. Our purpose is to study the influence of the dependence between units and signals on the performance evaluation of the continuous-time Markov chain describing the state of the network at arbitrary times, which constitutes a quasi-birth-and-death process. We present tractable formulas for a variety of probabilistic descriptors, with special emphasis on the distribution of inter-departure times

    The CDF Run IIb silicon detector: Design, preproduction, and performance

    No full text
    A new silicon microstrip detector was designed by the CDF collaboration for the proposed high-luminosity operation of the Tevatron p (p) over bar collider (Run IIb). The detector is radiation-tolerant and will still be functional after exposure to particle fluences of 10(14) 1-MeV equivalent neutrons/cm(2) and radiation doses of 20 MRad. The detector will maintain or exceed the performance of the current CDF silicon detector throughout Run IIb. It is based on an innovative silicon "supermodule" design. Critical detector components like the custom radiation-hard SVX4 readout chip, the beryllia hybrids and mini-port (repeater) cards, and the silicon sensors fulfill their specifications and were produced with high yields. The design goals and solutions of the CDF Run IIb silicon detector are described, and the performance of preproduction modules is presented in detail. Results relevant for the development of future silicon systems are emphasized. Crown Copyright (c) 2005 Published by Elsevier B.V. All rights reserved

    Immunopathogenesis of Hepatitis C Virus Infection: Multifaceted Strategies Subverting Innate and Adaptive Immunity

    No full text

    The CDF Run IIb silicon detector: Design, preproduction, and performance

    Get PDF
    A new silicon microstrip detector was designed by the CDF collaboration for the proposed high-luminosity operation of the Tevatron p (p) over bar collider (Run IIb). The detector is radiation-tolerant and will still be functional after exposure to particle fluences of 10(14) 1-MeV equivalent neutrons/cm(2) and radiation doses of 20 MRad. The detector will maintain or exceed the performance of the current CDF silicon detector throughout Run IIb. It is based on an innovative silicon supermodule design. Critical detector components like the custom radiation-hard SVX4 readout chip, the beryllia hybrids and mini-port (repeater) cards, and the silicon sensors fulfill their specifications and were produced with high yields. The design goals and solutions of the CDF Run IIb silicon detector are described, and the performance of preproduction modules is presented in detail. Results relevant for the development of future silicon systems are emphasized. Crown Copyright (c) 2005 Published by Elsevier B.V. All rights reserved

    Development of radiation tolerant semiconductor detectors for the Super-LHC.

    No full text
    The envisaged upgrade of the Large Hadron Collider (LHC) at CERN towards the Super-LHC (SLHC) with a 10 times increased luminosity of 1035 cm−2 s−1 will present severe challenges for the tracking detectors of the SLHC experiments. Unprecedented high radiation levels and track densities and a reduced bunch crossing time in the order of 10 ns as well as the need for cost effective detectors have called for an intensive R&D program. The CERN RD50 collaboration “Development of Radiation Hard Semiconductor Devices for Very High Luminosity Colliders” is working on the development of semiconductor sensors matching the requirements of the SLHC. Sensors based on defect engineered silicon like Czochralski, epitaxial and oxygen enriched silicon have been developed. With 3D, Semi-3D and thin detectors new detector concepts have been evaluated and a study on the use of standard and oxygen enriched p-type silicon detectors revealed a promising approach for radiation tolerant cost effective devices. These and other most recent advancements of the RD50 collaboration are presented

    Radiation-hard semiconductor detectors for SuperLHC.

    No full text
    An option of increasing the luminosity of the Large Hadron Collider (LHC) at CERN to 1035 cm−2 s−1 has been envisaged to extend the physics reach of the machine. An efficient tracking down to a few centimetres from the interaction point will be required to exploit the physics potential of the upgraded LHC. As a consequence, the semiconductor detectors close to the interaction region will receive severe doses of fast hadron irradiation and the inner tracker detectors will need to survive fast hadron fluences of up to above 1016 cm−2. The CERN-RD50 project “Development of Radiation Hard Semiconductor Devices for Very High Luminosity Colliders” has been established in 2002 to explore detector materials and technologies that will allow to operate devices up to, or beyond, this limit. The strategies followed by RD50 to enhance the radiation tolerance include the development of new or defect engineered detector materials (SiC, GaN, Czochralski and epitaxial silicon, oxygen enriched Float Zone silicon), the improvement of present detector designs and the understanding of the microscopic defects causing the degradation of the irradiated detectors. The latest advancements within the RD50 collaboration on radiation hard semiconductor detectors will be reviewed and discussed in this work

    Blocking of interleukin-10 receptor - A novel approach to stimulate T-helper cell type 1 responses to hepatitis C virus

    No full text
    Chronic hepatitis C virus (HCV) infection is associated with weak CD4+ T-helper type 1 reactivity and enhanced interleukin-10 production to HCV antigens. Here we demonstrate in vitro that monoclonal antibody-induced blockade of IL-10 receptor (IL-10R) generates a favorable balance of CD4+ T-cell responses to HCV. The addition of anti-IL-10R to mononuclear cells leads to a dose-dependent increase of T-cell proliferative response to HCV core, non-structural proteins 3 and 4. In competition experiments, anti-IL-10R reversed the inhibitory effect of IL-10 on HCV-specific T-cell proliferation. Furthermore, the blockade of IL-10R altered the balance towards type 1 antiviral T-cell reactivity with an increased frequency of HCV-specific IFN-γ producing T-cells and IFN-γ secretion. The impact of IL-10R blockade on T-cell reactivity to HCV demonstrates the major role of IL-10 in suppressing antiviral T-cell responses. Blocking IL-10 activity may be a useful immunotherapy approach to enhance the efficacy of antiviral treatment in chronic hepatitis C. © 2005 Elsevier Inc. All rights reserved

    Recent advancements in the development of radiation hard semiconductor detectors for S-LHC

    No full text
    The proposed luminosity upgrade of the Large Hadron Collider (S-LHC) at CERN will demand the innermost layers of the vertex detectors to sustain fluences of about 1016 hadrons/cm2. Due to the high multiplicity of tracks, the required spatial resolution and the extremely harsh radiation field new detector concepts and semiconductor materials have to be explored for a possible solution of this challenge. The CERN RD50 collaboration “Development of Radiation Hard Semiconductor Devices for Very High Luminosity Colliders” has started in 2002 an R&D program for the development of detector technologies that will fulfill the requirements of the S-LHC. Different strategies are followed by RD50 to improve the radiation tolerance. These include the development of defect engineered silicon like Czochralski, epitaxial and oxygen-enriched silicon and of other semiconductor materials like SiC and GaN as well as extensive studies of the microscopic defects responsible for the degradation of irradiated sensors. Further, with 3D, Semi-3D and thin devices new detector concepts have been evaluated. These and other recent advancements of the RD50 collaboration are presented and discussed
    • 

    corecore