Antiviral activity of Peg-IFN alpha in chronic HIV-1

描述(由申请人提供)：这项建议的长期目标是确定聚乙二醇化干扰素-a-2a(Peg-干扰素-A2a)是否可以在感染者缺乏抗逆转录病毒治疗(ART)的情况下维持对HIV-1的抑制。这项研究的短期目标是比较两种不同剂量的罗氏Pegasys(R)Peg-IFN-A2a，每周90和180？g，在HIV感染的受抑患者(VL&lt；50拷贝/毫升)ART中断时开始使用24周或更长时间时保持病毒控制的能力，通过观察在两次连续12周ART中断时获得的病毒设定点(增量病毒载量)的0.5对数差异来确定，仅在第二次ART中断期间使用PEG-干扰素-A2A。初步分析将是“意向治疗”分析，并将解决这样一种假设，即两种不同剂量的聚乙二醇化干扰素A2a(90g/周和180g/周)在抑制病毒复制方面将具有类似的效果，这是根据每个实验组的增量病毒载量之间的0.5对数差来定义的。二级AIMS将评估：(1)安全性、耐受性和剂量依赖、治疗相关的毒性，每周50次，每周180或90克(与ART联合使用，最初2周，随后单独使用48周)；(2)在ART中断后，Peg-IFNa2A介导(直接和免疫介导)抗病毒活性将病毒控制延长48周的可能性；(3)通过监测NK和DC亚群的变化以及维持/增强天然免疫功能(DC分泌反应、NK抗病毒细胞毒反应)的能力，天然免疫结果与Peg-IFNa2A剂量和抗病毒活性相关；(4)获得性免疫结果通过监测T细胞亚群的变化和维持细胞介导的增殖反应和细胞因子对Recall抗原的反应的能力而与Peg-IFNa2A剂量和抗病毒活性相关(HIV-1 Gag P55)。这项提议的完成将解决为慢性艾滋病毒感染开发安全和可耐受的替代治疗策略的需要，并有助于确定由系统Peg-IFNa2A治疗激活的ART重组的先天和适应性免疫效应器的抗逆转录病毒作用。这项多地点随机开放标签临床研究代表了Wistar研究所、乔纳森·拉克斯免疫疾病治疗中心(费城战斗)、宾夕法尼亚大学传染病部门、德雷克塞尔大学医学院艾滋病诊所、马萨诸塞大学生物统计学系、罗氏生物科学公司和格拉德斯通病毒学和免疫学研究所的多学科研究成果。

DESCRIPTION (provided by applicant): The long-range goal of this proposal is to determine if pegylated Interferon-a-2A (Peg-IFN-a2A) can sustain HIV-1 suppression in the absence of Anti-Retroviral Therapy (ART) in infected individuals. The short-range goal of this study is to compare two different doses of Roche Pegasys(r) Peg-IFN-a2A, 90 and 180 ¿g per week, for their ability to maintain viral control when initiated at the time of ART interruption in HIV-infected suppressed patients (VL<50 copies /ml) for 24 weeks or more, as determined by observing >0.5 log difference in viral set-points (delta viral load) obtained at two sequential 12 weeks ART discontinuations, with Peg-IFN-a2A administered only during the second discontinuation. Primary analysis will be an "intent to treat" analysis and will address the hypothesis that two different doses of Peg-IFN a2A (90 and 180 ¿g/week) will be similarly effective at inhibiting viral replication as defined by <0.5 log difference between the delta viral loads of each experimental arm. Secondary aims will evaluate: (1) safety, tolerability and dose-dependent, treatment-associated toxicity, of 50 weekly administrations of Peg-IFN a2A at 180 ¿g or 90 ¿g/week (in association with ART for the initial 2 weeks, followed by 48 weeks of Peg-IFN-a2A, alone); (2) the potential for Peg-IFNa2A-mediated (direct and immune-mediated) antiviral activity to extend viral control over a period of 48 weeks after ART interruption; (3) innate immunity outcomes correlated to Peg-IFNa2A dose and antiviral activity, by monitoring NK and DC subset changes and the ability to maintain/enhance innate immune functions (DC secretory responses, NK antiviral cytotoxic responses); (4) adaptive immunity outcomes correlated to Peg-IFNa2A dose and antiviral activity by monitoring T-cell subsets changes and the ability to maintain cell-mediated proliferative and cytokine responses against recall antigens (HIV-1 gag p55). Completion of this proposal will address the need to develop safe and tolerable alternative therapy strategies for chronic HIV infection, and help determine the anti-retroviral role of ART-reconstituted innate arid adaptive immunity effectors activated by systemic Peg-IFNa2A therapy. This multi-site randomized, open-label clinical study represents a multidisciplinary research effort by the Wistar Institute, The Jonathan Lax Center for the Treatment of Immune Disorders (Philadelphia FIGHT), The Infectious Disease Division for the University of Pennsylvania, The AIDS clinic of Drexel University Medical College, the University of Massachusetts' Department of Biostatistics, BD Biosciences, Roche, Inc. and The Gladstone Institute of Virology and Immunology.