Sofosbuvir and Ledipasvir in HIV/HCV Coinfected Pre and Post Liver Transplant

 描述（由申请方提供）：本研究将解决HCV/HIV合并感染受试者移植领域进展的主要障碍，即肝移植后严重HCV疾病和侵袭性复发的问题。具体而言，这将是一项II期研究，旨在评价索非布韦/ledipasvir FDC片剂在肝移植前（n=25）或肝移植后（n = 25）HCV/HIV合并感染受试者中治疗12周的安全性和疗效。这种新的和有效的所有口服DAA方案被假设为是安全的，耐受性良好，并产生更高的持续病毒学应答率（SVR）相比，传统的干扰素为基础的治疗。机制研究将探讨在肝硬化和失代偿性肝病背景下使用FDC sofosbuvir/ledipasvir治疗期间HIV合并感染对HCV病毒动力学和宿主特异性HCV免疫的影响，并将其与代偿性肝硬化或早期肝病的类似治疗进行比较。这些信息将在设计未来的治疗算法，以减少治疗失败的关键。进一步的机制研究将评价在肝移植后复发性HCV患者中使用FDC索非布韦/ledipasvir治疗期间，药物诱导的免疫抑制和HIV合并感染对HCV病毒动力学和外周HCV免疫的影响。所产生的数据将使我们能够推断在HIV合并感染和免疫抑制的情况下增强免疫力以根除HCV的必要性。研究计划的总体目标很简单：消除HCV/HIV合并感染者肝移植进展的关键障碍。

 DESCRIPTION (provided by applicant): The study will address a major barrier to progress in the field of transplantation in HCV/HIV coinfected subjects, namely the issue of severe HCV disease and aggressive recurrence following liver transplantation. Specifically, this will be a phase 2 study designed to evaluate the safety and efficacy of sofosbuvir/ledipasvir FDC tablet, for treatment duration of 12 weeks, in HCV/HIV coinfected subjects pre (n=25) or post (n=25) liver transplant. This novel and efficacious all oral DAA regimen is hypothesized to be safe, well-tolerated and yield higher rates of a sustained virologic response (SVR) compared to traditional interferon based therapy. Mechanistic studies will explore the impact of HIV coinfection on HCV viral kinetics and host-specific HCV immunity during therapy with FDC sofosbuvir/ledipasvir in the setting of cirrhosis and decompensated liver disease, and compare this to similar treatment in compensated cirrhosis or early liver disease. This information will be critical in designing future treatment algorithms to reduce treatment failures. Further mechanistic studies will evaluate the impact of medication induced immune suppression and HIV coinfection on HCV viral kinetic and peripheral HCV immunity during treatment with FDC sofosbuvir/ledipasvir in patients with recurrent HCV post- liver transplant. The generated data will allow us to infer the necessity of augmentation of immunity for HCV eradication in the setting of HIV coinfection and immunosuppression. The overarching goal of the research plan is straightforward; remove critical barriers to progress in liver transplantation of HCV/HIV coinfected people.