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

Peg-IFN α 对慢性 HIV-1 的抗病毒活性

• 批准号: 7074762
• 负责人: Luis J Montaner
• 金额: $ 57.61万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074762
• 关键词: Antiviral; activity; Peg; IFN; alpha

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.

描述（由申请人提供）：该提案的长期目标是确定聚乙二醇化干扰素-a-2A (Peg-IFN-a2A) 在感染个体中是否可以在缺乏抗逆转录病毒治疗 (ART) 的情况下维持 HIV-1 抑制。本研究的短期目标是比较两种不同剂量的罗氏派罗欣 (R) Peg-IFN-a2A（每周 90 克和 180 克），在 HIV 感染抑制患者 (VL<50 拷贝/ml) 的 ART 中断时启动 24 周或更长时间，以观察其维持病毒控制的能力，这是通过观察病毒设定值 >0.5 对数差异（δ 病毒）来确定的。 负荷）在连续两次 12 周 ART 停药时获得，仅在第二次停药期间施用 Peg-IFN-a2A。主要分析将是“治疗意向”分析，并将解决以下假设：两种不同剂量的 Peg-IFN a2A（90 和 180 µg/周）在抑制病毒复制方面具有相似的效果，定义为每个实验组的 delta 病毒载量之间的差异 <0.5 log 差异。次要目标将评估：(1) 每周 180 µg 或 90 µg/周的 Peg-IFN a2A 给药 50 周的安全性、耐受性和剂量依赖性、治疗相关毒性（最初 2 周与 ART 联合使用，随后单独使用 Peg-IFN-a2A 48 周）； (2) Peg-IFNa2A 介导的（直接和免疫介导的）抗病毒活性有可能在 ART 中断后将病毒控制延长至 48 周； (3) 通过监测 NK 和 DC 亚群变化以及维持/增强先天免疫功能的能力（DC 分泌反应、NK 抗病毒细胞毒性反应），了解与 Peg-IFNa2A 剂量和抗病毒活性相关的先天免疫结果； (4) 通过监测 T 细胞亚群变化以及维持细胞介导的针对记忆抗原 (HIV-1 gag p55) 的增殖和细胞因子反应的能力，将适应性免疫结果与 Peg-IFNa2A 剂量和抗病毒活性相关。该提案的完成将解决针对慢性 HIV 感染开发安全且可耐受的替代治疗策略的需求，并有助于确定由系统性 Peg-IFNa2A 疗法激活的 ART 重建的先天性和适应性免疫效应器的抗逆转录病毒作用。这项多中心随机、开放标签临床研究代表了 Wistar 研究所、Jonathan Lax 免疫性疾病治疗中心（费城 FIGHT）、宾夕法尼亚大学传染病部、德雷塞尔大学医学院艾滋病诊所、马萨诸塞大学生物统计学系、BD Biosciences、罗氏公司、 Inc.和格拉德斯通病毒学和免疫学研究所。