HCV Disease Management in HIV-HCV Coinfected IDUs

描述(申请人提供)：该研究项目由R01DA16065资助，重点研究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疗法(ART)降低了艾滋病毒感染的DU的总死亡率，但丙型肝炎病毒疾病是发病率和死亡率的主要原因。然而，与有效的抗逆转录病毒治疗一样，导致持续病毒学应答(SVR或治愈)的丙型肝炎病毒治疗可能会降低终末期肝病(ESLD)、肝细胞癌(HCC)和合并感染者死亡的风险。基于干扰素的丙型肝炎病毒治疗一直没有效果，因为治疗摄取率低，在接受治疗的患者中，SVR的发生率低，不良反应发生率高。然而，随着省去聚乙二醇干扰素的口服直接作用抗病毒药物(DAAs)的出现，丙型肝炎病毒的治疗正在迅速改善。与基于聚乙二醇干扰素的方案相比，口服DAA疗法在临床试验中导致了更高的SVR发生率，更好的安全性和耐受性，以及更短的治疗持续时间。DAA疗法在有望治疗混合感染的同时，也提出了与丙型肝炎病毒治疗相关的突出临床问题：丙型肝炎病毒治疗是否为个人和人群带来临床益处？治疗丙型肝炎的哪些行为障碍将持续存在于DAA，这些障碍能否通过DAA交付的创新战略来克服？哪些生物学障碍将持续存在于DAA中，这些障碍是否会受到HIV合并感染的影响？在下一个资金周期中，我们计划通过一系列综合的临床和翻译研究来回答这些和其他与艾滋病毒感染者慢性丙型肝炎管理有关的问题，这些研究扩展了我们和其他人在过去十年中开发的丙型肝炎疾病自然病史和丙型肝炎治疗的模型。具体目标如下：目标1验证有效的丙型肝炎病毒治疗、抗逆转录病毒治疗可降低终末期肝病、肝细胞癌和艾滋病毒/丙型肝炎混合感染者死亡风险的假设。目的2是验证这样一种假设，即新的干预措施--同行指导和或有经济激励--将促进旨在通过增加丙型肝炎病毒治疗的启动和对口服DAA的坚持以及通过减少饮酒来降低混合感染者中丙型肝炎病毒疾病风险的健康行为。目的3验证一种假设，即与单一感染的丙型肝炎病毒患者相比，HIV/丙型肝炎病毒混合感染患者在用不含干扰素的口服DAAs治疗丙型肝炎病毒的过程中，血清和肝脏内的丙型肝炎病毒RNA和免疫反应动力学将受到损害。拟议的研究将确定使用新型DAA治疗丙型肝炎对丙型肝炎疾病自然病史的影响，指导有效实施DAA以克服治愈丙型肝炎的行为障碍的策略，并通过机制研究了解HIV合并感染对DAA应答的影响和消除丙型肝炎病毒以克服治愈丙型肝炎的生物障碍。

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.