Viral kinetic models of HCV clearance in hemophiliacs treated with telaprevir

描述(由申请人提供)： 感染丙型肝炎病毒是血友病和其他遗传性出血性疾病患者发病率和死亡率的重要因素，在这些人中，这种感染很常见。就疗效而言，目前使用聚乙二醇化干扰素α和利巴韦林的治疗方式并不理想。以抑制丙型肝炎病毒复制为目标的新小分子在提高应答率和缩短治疗持续时间方面提供了希望，但它们的使用尚未在特殊人群中进行评估，包括血友病和相关疾病的人群。此外，提供高疗效和低水平对试验剂的病毒耐药性的最佳方案尚未建立。这项先导性研究将检验两种策略的有效性和安全性，这些策略将与聚乙二醇化干扰素α/利巴韦林联合使用。使用强大的数学建模技术，我们将探索遗传性出血疾病患者治疗的第一和第二阶段动力学反应，这些患者要么接受治疗，要么接受治疗(基于干扰素的丙型肝炎治疗)。我们的具体目标是：1：开发和实施一项试验性临床试验，旨在评估遗传性出血障碍患者的动态动力学反应参数和替拉维韦与标准护理治疗相结合的安全性；2：评估特定类别对蛋白酶抑制剂的耐药性突变的发生率和出现率，并确定突变选择的早期预测因素。这项研究将为大型多中心试验的发展提供信息，该试验将在本文建议的试验阶段完成后进行。

DESCRIPTION (provided by applicant): Infection with the hepatitis C virus is an important contributor to morbidity and mortality among those with hemophilia and other inherited bleeding disorders in whom such infections are common. Current treatment modalities using pegylated-interferon alfa and ribavirin are suboptimal in terms of response. New small molecules targeted to inhibition of HCV replication offer promise in terms of improved response rates, and shorter durations of therapy, but their use has not been assessed in special populations, including those with hemophilia and related disorders. Furthermore, the optimal regimen which provides high efficacy with low levels of development of viral resistance to the experimental agent has not been established. This pilot study will examine the efficacy and safety of two strategies utilizing telaprevir in combination with pegylated- interferon alfa/ribavirin. Using powerful mathematical modeling techniques we will explore first and second phase kinetic responses to treatment in patients with inherited bleeding disorders who are either treatment na¿ve or treatment experienced (interferon-based HCV treatment). Specifically our aims are 1: Development and implementation of a pilot clinical trial designed to assess dynamic kinetic response parameters and safety of telaprevir combined with standard of care therapy in subjects with inherited bleeding disorders, and 2: To evaluate prevalence and rate of emergence of class-specific resistance mutations to protease inhibitors and to identify early predictors of mutational selection. This study will inform development of a large, multicenter trial that would follow completion of the pilot phase proposed herein.