Antiviral pharmacology and adherence in drug users

 描述(由申请人提供)： 在所有携带丙型肝炎病毒(丙型肝炎病毒)的美国人中，大约有一半是吸毒者，但他们接受丙型肝炎治疗的可能性最小。吸毒者被推定为不遵守，因此被拒绝接受潜在的拯救生命的治疗。这一假设只能通过在这一人群中进行前瞻性的药理学和依从性研究来证实或消除。通过一种目前在丙型肝炎病毒领域中不存在的客观、定量的依从性衡量标准，这些研究将得到极大的加强。通过这项申请中提出的工作，60名艾滋病毒/丙型肝炎病毒混合感染的吸毒者将接受直接作用抗病毒药物(DAA)治疗，并随机接受直接观察DAA治疗(DOT)与不接受直接观察治疗(NO-DOT)。随机接受非DOT治疗的患者将接受无线观察治疗(WOT)，其中包括使用便携式分药机，该分药机向服务器发送信号，显示分药机打开的日期和时间。在目标1中，将比较随机使用DOT和不使用DOT的患者的DAA浓度。DAA的药代动力学也将被定义，考虑到临床因素，如肝脏损害的程度以及相关娱乐和抗逆转录病毒药物的使用。目标是量化这一人群中的依从性，以及不同依从性对药物浓度的影响。在目标2中，DAA浓度(血浆、细胞、头发)将与使用WOT和DOT确定的黏附模式相联系。目标是确定一种药物浓度生物标记物，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测量与药物浓度)和治愈率之间的关系。目标是确定治愈丙型肝炎所需的依从性程度。这个项目对人类健康很重要，因为它将治疗被忽视的患者群体，利用技术使依从性监测变得方便，评估基于药代动力学的新依从性措施，确定依从性对丙型肝炎病毒治愈可能性的贡献，并产生关于DAA“宽恕”的第一数据。拟议的工作将产生急需的药理学和客观依从性数据，以鼓励吸毒者治疗丙型肝炎病毒。

 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.