Antiretroviral Therapy and the Hepatitis C Virus

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)和人类免疫缺陷病毒(HIV)混合感染发生在20%-30%的HIV感染患者中。合并感染丙型肝炎病毒/艾滋病病毒的患者的丙型肝炎病毒载量往往高于对照组。此外，现在有证据表明，开始有效的抗逆转录病毒治疗(ART)可能与丙型肝炎病毒载量的矛盾增加有关。丙型肝炎病毒的暴发可能与影响临床决策的血清转氨酶的升高有关，而不是停止抗逆转录病毒疗法。以前的研究未能以系统、渐进的方式前瞻性地评估这些问题。在有效的免疫重建过程中，导致病毒载量增加的机制也没有经过详细的评估。我们提出了以下具体目标来解决这些问题：1.在接受抗逆转录病毒治疗的丙型肝炎病毒/HIV混合感染者中开发和执行临床干预试验，以表征早期/晚期丙型肝炎病毒动力学以及丙型肝炎病毒载量增加的流行率、意义和发病机制。2.前瞻性评价治疗应答者和无应答者在ART治疗开始后出现丙型肝炎病毒准种的意义和作用。3.明确在免疫重建过程中与丙型肝炎病毒载量增加和/或肝脏损伤相关的免疫学相关因素。我们将测试特定的、假设驱动的问题，以帮助实现我们特定目标中描述的更广泛的目标。为了建立丙型肝炎病毒感染和HIV之间关系的概念框架，我们将使用数学建模、分子流行病学和免疫学的工具来研究病毒的选择、突变和复制。

DESCRIPTION (provided by applicant): Coinfection of hepatitis C virus (HCV) with human immunodeficiency virus (HIV) occurs in 20-30% of HIV infected patients. Patients with HCV/HIV coinfection tend to have higher HCV viral loads than controls. Furthermore, there is now evidence that initiation of effective antiretroviral therapy (ART) may be associated with paradoxical increases in HCV viral load. HCV viral flare may be associated with increases in serum tranaminases which affect clinical decision making, vis a vis discontinuation of ART. Previous studies have failed to prospectively evaluate these issues in a systematic, progressive manner. The mechanisms responsible for viral load increase during effective immune reconstitution have also not undergone detailed evaluation. We propose the following Specific Aims to address these issues: 1. To develop and perform a clinical intervention trial in HCV/HIV coinfected subjects treated with ART in order to characterize early/late HCV viral kinetics as well as the prevalence, significance, and pathogenesis of HCV viral load increase. 2. To prospectively evaluate the significance and role of HCV quasispecies emergence following ART initiation between treatment responders and nonresponders. 3. To define immunologic correlates during immune reconstitution that are associated with development of increased HCV viral load and/or liver injury. We will test specific, hypothesis-driven questions to help achieve the broader goals described within our Specific Aims. In an effort to develop a conceptual framework for the relationship between hepatitis C infection and HIV, we will use the tools of mathematical modeling, molecular epidemiology and immunology to study viral selection, mutation and replication.