Antiretroviral Therapy and the Hepatitis C Virus

描述（由申请人提供）：丙型肝炎病毒（HCV）与人类免疫缺陷病毒（HIV）合并感染发生在20-30%的HIV感染患者中。HCV/HIV合并感染的患者往往比对照组有更高的HCV病毒载量。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HCV病毒载量的矛盾增加有关。丙型肝炎病毒爆发可能与血清转氨酶升高有关，而血清转氨酶升高会影响临床决策，不利于停止抗逆转录病毒治疗。以往的研究未能以系统的、渐进的方式前瞻性地评价这些问题。在有效的免疫重建过程中，病毒载量增加的机制也没有经过详细的评估。针对这些问题，我们提出以下具体目标：在接受抗逆转录病毒治疗的HCV/HIV共感染受试者中开展临床干预试验，以表征早期/晚期HCV病毒动力学以及HCV病毒载量增加的患病率、意义和发病机制。2. 前瞻性评价抗逆转录病毒治疗应答者和无应答者开始抗逆转录病毒治疗后HCV准种出现的意义和作用。3. 定义免疫重建过程中与HCV病毒载量增加和/或肝损伤相关的免疫相关因素。我们将测试具体的，假设驱动的问题，以帮助实现我们的具体目标中描述的更广泛的目标。为了建立丙型肝炎感染与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.