HCV Disease Management in HIV-HCV Coinfected IDUs

描述（由申请人提供）：该研究项目由R 01 DA 16065资助，重点关注HIV感染的吸毒者（DU）中的慢性丙型肝炎病毒（HCV）感染。虽然有效的抗逆转录病毒治疗（ART）降低了HIV感染DU的总体死亡率，但HCV疾病是发病率和死亡率的主要原因。然而，像有效的ART一样，HCV治疗导致持续的病毒学应答（SVR或治愈）可能会降低合并感染个体的终末期肝病（ESLD），肝细胞癌（HCC）和死亡的风险。基于干扰素的HCV治疗由于治疗吸收低而无效，并且在接受治疗的患者中，SVR率低且不良反应率高。然而，随着聚乙二醇干扰素保留的直接作用抗病毒药物（DAA）口服方案的出现，HCV治疗正在迅速改善。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更高的SVR率、改善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，但也提出了与该人群中HCV治愈相关的突出临床问题：HCV治愈是否会为个人和人群带来临床益处？HCV治愈的哪些行为障碍将持续使用DAA，这些障碍可以通过DAA交付的创新策略来克服吗？HCV治愈的生物学障碍将持续与DAA和这些受HIV合并感染的影响？在下一个资助周期中，我们计划通过一系列综合临床和转化研究来回答这些和其他与HIV感染者慢性HCV管理相关的问题，这些研究扩展了我们和其他人在过去十年中开发的HCV疾病自然史和HCV治疗模型。具体目的如下：目的1是检验有效的HCV治疗抗逆转录病毒治疗可降低HIV/HCV合并感染者终末期肝病、肝细胞癌和死亡风险的假设。目的2是检验一种假设，即新的干预措施-同伴指导和应急财政激励-将促进健康行为，旨在减少合并感染者的HCV疾病的风险，增加HCV治疗的启动和坚持口服DAA和减少饮酒。目的3是检验以下假设，即与HCV单一感染患者相比，HIV/HCV合并感染患者在用无IFN的口服DAA治疗HCV期间将具有受损的血清和肝内HCV RNA和免疫应答动力学。拟议的研究将确定HCV治疗与新的DAA对HCV疾病的自然史的影响，指导策略的有效交付的DAA，以克服行为障碍的HCV治愈，并通过机制研究了解艾滋病毒合并感染的影响对DAA和HCV根除的反应，以克服生物学障碍的HCV治愈。

DESCRIPTION (provided by applicant): The research program, funded by R01DA16065, is focused on chronic hepatitis C virus (HCV) infection in HIV- infected drug 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.