HCV Disease Management in HIV-HCV Coinfected IDUs

项目摘要和相关性 该研究项目由R 01 DA 16065资助，重点关注HIV-1感染者中的慢性丙型肝炎病毒（HCV）感染。 受感染的地毯使用者（DU）。虽然有效的抗逆转录病毒疗法（ART）降低了艾滋病毒感染者的总体死亡率， 在受感染的DU中，HCV疾病是发病率和死亡率的主要原因。然而，与有效的ART一样，HCV 导致持续病毒学应答（SVR或治愈）的治疗可降低终末期肝病的风险 （ESLD）、肝细胞癌（HCC）和合并感染个体的死亡。基于干扰素的HCV治疗 由于治疗吸收率低，在接受治疗的患者中，SVR率低， 不良反应率。然而，随着聚乙二醇干扰素保留的出现，HCV治疗正在迅速改善， 直接作用抗病毒药物（DAA）的口服方案。与基于聚乙二醇干扰素的方案相比，口服DAA治疗 在临床试验中导致了更高的SVR率、更高的安全性和耐受性以及更短的治疗持续时间。 虽然DAA疗法有望治疗合并感染的DU，但也提出了与以下相关的突出临床问题： 在这一人群中的HCV治愈：HCV治愈是否会为个人和人群带来临床益处？ HCV治愈的行为障碍将持续与DAA，这些障碍可以克服与 DAA交付的创新策略？HCV治愈的生物学障碍将持续与DAA， 受艾滋病毒合并感染的影响？ 在下一个供资周期，我们计划回答这些问题和其他与慢性病管理有关的问题。 通过一系列综合临床和转化研究， 我们和其他人在过去开发的HCV疾病自然史和HCV治疗模型 十年具体目标如下： 目的1是验证有效的HCV治疗抗逆转录病毒治疗降低终末期风险的假设。 肝病、肝细胞癌和HIV/HCV合并感染者的死亡。 目的2是检验新的干预措施--同伴指导和应急经济激励--的假设， 将促进健康行为，旨在减少合并感染者的HCV疾病风险， HCV治疗开始和坚持口服DAA和减少饮酒。 目的3是检验假设，与HCV单一感染患者相比，HIV/HCV患者 在HCV感染期间，合并感染将使血清和肝内HCV RNA以及免疫应答动力学受损。 用不含IFN的口服DAA治疗。 拟议的研究将确定用新型DAA治疗HCV对HCV疾病自然史的影响， 指导有效提供DAA的策略，以克服HCV治愈的行为障碍， 通过机制研究了解HIV合并感染对DAA和HCV应答的影响 根除以克服HCV治愈的生物学障碍。

Project summary and relevance The research program, funded by R01DA16065, is focused on chronic hepatitis C virus (HCV) infection in HIV- infected rug users (DUs). While effective antiretroviral therapy (ART) has reduced overall mortality in HIV- infected DUs, HCV disease is a leading cause of morbidity and mortality. However, like effective ART, HCV treatment leading to sustained virologic response (SVR or cure) may reduce the risk of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC) and death in coinfected individuals. Interferon-based HCV treatments have not been effective due to low treatment uptake and, among those treated, low rates of SVR and high rates of adverse effects. However, HCV treatment is improving rapidly with the advent of peginterferon-sparing, oral regimens of direct acting antivirals (DAAs). Compared to peginterferon based regimens, oral DAA therapy has led to higher SVR rates, improved safety and tolerability, and shorter treatment durations in clinical trials. While promising for the treatment of coinfected DUs, DAA therapy also raises salient clinical questions related to HCV cure in this population: Does HCV cure lead to clinical benefit for individuals and for the population? What behavioral barriers to HCV cure will persist with DAAs and can these barriers be overcome with innovative strategies for DAA delivery? What biological barriers to HCV cure will persist with DAAs and are these impacted by HIV coinfection? In the next funding cycle, we plan to answer these and other questions related to the management of chronic HCV in HIV-infected persons through a series of integrated clinical and translational studies that extend the models of HCV disease natural history and HCV treatment that we and others have developed over the past decade. The specific aims are as follows: Aim 1 is to test the hypothesis that effective HCV treatment antiretroviral therapy reduces the risk of end-stage liver disease, hepatocellular cancer, and death in HIV/HCV coinfected persons. Aim 2 is to test the hypothesis that novel interventions - peer mentoring and contingent financial incentives - will promote health behaviors aimed at reducing the risk of HCV disease in coinfected persons by increasing HCV treatment initiation and adherence to oral DAAs and by decreasing alcohol use. Aim 3 is to test the hypothesis that, compared to patients with HCV monoinfection, patients with HIV/HCV coinfection will have impaired serum and intrahepatic HCV RNA and immune response kinetics during HCV treatment with IFN-free, oral DAAs. The proposed studies will define the impact of HCV treatment with novel DAAs on HCV disease natural history, guide strategies for the effective delivery of the DAAs to overcome behavioral barriers to HCV cure, and, through mechanistic studies understand the impact to HIV coinfection on response to DAAs and HCV eradication to overcome biologic barriers to HCV cure.