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: 7418572
• 负责人: Luis J Montaner
• 金额: $ 58.28万
• 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/7418572
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse event; Alternative Therapies; Anti-Retroviral Agents; Antigens; Antiviral Agents; Basic Science; Biometry; Cells; Chronic; Clinic; Clinical; Clinical Research; Communicable Diseases; Data; Dose; Funding; Gagging; Goals; HIV; HIV Infections; HIV-1; Hepatitis C; Immune; Immune System Diseases; Immunity; Immunology; Incidence; Individual; Institutes; Interdisciplinary Study; Interferon-alpha; Interferons; Interruption; Label; Laboratories; Massachusetts; Mediating; Medical; Monitor; Natural Immunity; Outcome; Pathway interactions; Patients; Pennsylvania; Philadelphia; Positioning Attribute; Randomized; Range; Research Design; Roche brand of peginterferon alfa-2a; Role; Safety; Site; Structure; T-Lymphocyte Subsets; Time; Toxic effect; Universities; Upper arm; Viral; Viral Load result; Week; Work; clinical research site; college; cytokine; cytotoxic; data management; experience; fighting; human MPP1 protein; immune function; in vivo; reconstitution; response; therapy outcome; treatment center; virology

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（由申请方提供）：本提案的长期目标是确定在不进行抗逆转录病毒治疗（ART）的情况下，聚乙二醇化干扰素-a-2A（Peg-IFN-a2 A）是否可持续抑制感染个体中的HIV-1。本研究的短期目标是比较两种不同剂量的Roche Pegasys（r）Peg-IFN-a2 A，90和180 μ g。g/周，用于在HIV感染抑制患者中断ART时开始维持病毒控制的能力（VL<50拷贝/ml）持续24周或更长时间，如通过观察病毒设定点的>0.5 log差异所确定的在两次连续的12周ART停药时获得的Δ病毒载量，仅在第二次停药时给予Peg-IFN-α 2A。主要分析将是“意向治疗”分析，并将解决两种不同剂量的Peg-IFN α 2A（90和180 μ g/周）将在抑制病毒复制方面类似地有效，如通过每个实验组的δ病毒载量之间的<0.5 log差异所定义的。（1）每周50次给予180 μ g或90 μ g Peg-IFN α 2A的安全性、耐受性和剂量依赖性、治疗相关毒性。g/周（最初2周与ART联合，随后48周单独使用Peg-IFN-α 2A）;（2）Peg-IFNa 2A介导的（直接和免疫介导的）抗病毒活性，以在ART中断后48周的时间内延长病毒控制;（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，先天免疫结果与Peg-IFNa 2A剂量和抗病毒活性相关（DC分泌反应，NK抗病毒细胞毒性反应）;（4）通过监测T细胞亚群变化和维持细胞免疫的能力，获得与Peg-IFNa 2A剂量和抗病毒活性相关的适应性免疫结果。介导的针对回忆抗原（HIV-1 gag p55）的增殖和细胞因子应答。该提案的完成将解决开发安全和可耐受的慢性HIV感染替代治疗策略的需求，并有助于确定由系统性Peg-IFNa 2A治疗激活的ART重建的先天性和适应性免疫效应物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由Wistar研究所、Jonathan Lax免疫疾病治疗中心（Philadelphia FIGHT）、宾夕法尼亚大学传染病部、德雷克塞尔大学医学院艾滋病诊所、马萨诸塞州大学生物统计学系、BD Biosciences、Roche，Inc.以及格莱斯顿病毒学和免疫学研究所。