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

 描述(由申请人提供)：这项研究将解决在丙型肝炎病毒/艾滋病毒混合感染者的移植领域取得进展的一个主要障碍，即严重的丙型肝炎疾病和肝移植后侵袭性复发的问题。具体地说，这将是一项第二阶段的研究，旨在评估在肝移植前(n=25)或肝移植后(n=25)的丙型肝炎病毒/艾滋病毒混合感染者中，索莫布韦/来地帕斯韦FDC片剂的安全性和有效性，疗程为12周。这种新颖有效的全口服DAA方案被认为是安全、耐受性好的，与传统的基于干扰素的治疗相比，产生更高的持续病毒学应答(SVR)率。机制研究将探索在肝硬变和失代偿性肝病中使用FDC Sofosbuvir/Ledipasvir治疗期间HIV合并感染对丙型肝炎病毒动力学和宿主特异性丙型肝炎免疫的影响，并将其与代偿性肝硬变或早期肝病的类似治疗进行比较。这些信息将是设计未来治疗算法以减少治疗失败的关键。进一步的机制研究将评估药物诱导的免疫抑制和HIV合并感染对肝移植后丙型肝炎复发患者在FDC Sofosbuvir/Ledipasvir治疗期间对丙型肝炎病毒动力学和外周丙型肝炎免疫的影响。生成的数据将使我们能够推断在艾滋病毒合并感染和免疫抑制的情况下，加强免疫以根除丙型肝炎的必要性。该研究计划的总体目标是明确的；消除在丙型肝炎病毒/艾滋病毒混合感染者的肝移植方面取得进展的关键障碍。

 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.