Antiviral pharmacology and adherence in drug users

 描述（由申请人提供）： 大约一半的美国丙型肝炎病毒（HCV）感染者是吸毒者，但他们最不可能接受HCV治疗。吸毒者被认为是不依从的，因此被拒绝接受可能挽救生命的治疗。这一假设只能通过该人群的前瞻性药理学和依从性研究来证实或消除。这样的研究将大大加强了一个客观的，定量的措施，坚持目前不存在的HCV领域。通过本申请中提出的工作，60名HIV/HCV合并感染的吸毒者将接受直接作用的抗病毒药物（DAA）治疗，并随机接受直接观察的DAA治疗（DOT）与无直接观察的治疗（no-DOT）。随机分配至无DOT的患者将接受无线观察治疗（WOT），其中涉及使用便携式药物分配器，该分配器在打开分配器时向服务器发送带有日期和时间的信号。在目标1中，将比较随机分配至DOT组与无DOT组的患者的DAA浓度。DAA药代动力学也将根据临床因素（如肝损害程度和伴随使用娱乐性和抗逆转录病毒药物）进行定义。目标是量化该人群的依从性以及依从性变量对药物浓度的影响。在目标2中，DAA浓度（血浆、细胞、毛发）将与使用WOT和DOT识别的粘附模式相关联。目标是确定一种药物浓度生物标志物，预测该人群的依从性。在目标3中，将建立DAA依从性（通过WOT和DOT以及药物浓度测量）与治愈率之间的关系。目标是确定HCV治愈所需的依从性程度。该项目对人类健康很重要，因为它将治疗被忽视的患者群体，使用技术使依从性监测方便，评估新的基于药代动力学的依从性措施，确定依从性对HCV治愈可能性的贡献，并生成关于DAA“宽恕”的第一个数据。这项工作将产生急需的药理学和客观的依从性数据，以鼓励吸毒者治疗HCV。

 DESCRIPTION (provided by applicant): Approximately one half of all Americans living with Hepatitis C virus (HCV) are drug users, yet they are the least likely to receive HCV treatment. Drug users are presumed non-adherent and therefore denied potentially life-saving therapy. This assumption can only be confirmed or dispelled through prospective pharmacologic and adherence studies in this population. Such studies would be greatly enhanced by an objective, quantitative measure of adherence which does not currently exist in the HCV field. Through the work proposed in this application, sixty HIV/HCV co-infected drug users will be treated with direct acting antiviral agents (DAA) and randomized to receive directly observed DAA therapy (DOT) vs. no directly observed therapy (no-DOT). Patients randomized to no-DOT will have wirelessly observed therapy (WOT) which involves use of a portable medication dispenser that sends a signal to a server with the date and time when the dispenser is opened. In Aim 1, DAA concentrations will be compared in those randomized to DOT vs. no-DOT. DAA pharmacokinetics will also be defined accounting for clinical factors like degree of hepatic impairment and use of concomitant recreational and antiretroviral drugs. The goal is to quantify adherence in this population and the effect of variable adherence on drug concentrations. In Aim 2, DAA concentrations (plasma, cellular, hair) will be linked with adherence patterns identified using WOT and DOT. The goal is to identify a drug concentration biomarker that predicts adherence in this population. In Aim 3, the relationship between DAA adherence (as measured by WOT and DOT and drug concentrations) and rate of cure will be established. The goal is to define the degree of adherence needed for HCV cure. This project is important to human health as it will treat a neglected patient population, use technology to make adherence monitoring convenient, evaluate novel, pharmacokinetic-based adherence measures, determine the contribution of adherence to the likelihood of HCV cure, and generate the first data on DAA "forgiveness". The work proposed will generate much needed pharmacology and objective adherence data to encourage the treatment of HCV in drug users.