Viral kinetic models of HCV clearance in hemophiliacs treated with telaprevir

描述（由申请人提供）： 丙型肝炎病毒感染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一个重要因素，这些感染在这些患者中很常见。目前使用聚乙二醇干扰素α和利巴韦林的治疗方式在反应方面是次优的。靶向抑制HCV复制的新小分子在改善应答率和缩短治疗持续时间方面提供了希望，但尚未评估其在特殊人群（包括血友病和相关疾病患者）中的使用。此外，还没有建立提供高疗效和低水平的病毒对实验药物的耐药性发展的最佳方案。该初步研究将检查特拉匹韦与聚乙二醇干扰素α/利巴韦林联合使用的两种策略的疗效和安全性。使用强大的数学建模技术，我们将探讨第一和第二阶段的动力学反应，治疗遗传性出血性疾病的患者谁是初治或治疗经验丰富（干扰素为基础的HCV治疗）。具体来说，我们的目标是1：开发和实施一项试点临床试验，旨在评估特拉匹韦联合标准治疗在遗传性出血性疾病受试者中的动态动力学反应参数和安全性，2：评估蛋白酶抑制剂类特异性耐药突变的发生率和发生率，并确定突变选择的早期预测因子。本研究将为在完成本文拟定的试验阶段后开展一项大型多中心试验提供信息。

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.