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

描述（由申请人提供）：本提案的长期目标是确定聚乙二醇化干扰素-a- 2a （Peg-IFN-a2A）是否可以在没有抗逆转录病毒治疗（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Pegasys(r) Peg-IFN-a2A，每周90和180¿g，在hiv感染抑制患者（VL<50拷贝/ml）中断抗逆转录病毒治疗时开始24周或更长时间内维持病毒控制的能力，通过观察两次连续12周抗逆转录病毒治疗中断时获得的病毒设定点（δ病毒载量）的>.5 log差异来确定。Peg-IFN-a2A仅在第二次停药期间使用。初步分析将是“治疗意图”分析，并将解决以下假设：两种不同剂量的Peg-IFN a2A（90和180¿g/周）在抑制病毒复制方面同样有效，定义为每个实验组的δ病毒载量之间的差异<0.5 log。次要目标将评估：(1)每周给药50次，180克或90克/周的Peg-IFN a2A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，随后48周单独给药Peg-IFN-a2A）；(2) peg - ifna2a介导的（直接和免疫介导的）抗病毒活性在ART中断后48周内延长病毒控制的潜力；(3)先天免疫结果与Peg-IFNa2A剂量和抗病毒活性相关，通过监测NK和DC亚群的变化以及维持/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）；(4)适应性免疫结果与Peg-IFNa2A剂量和抗病毒活性相关，通过监测t细胞亚群的变化和维持细胞介导的增殖和细胞因子对召回抗原的反应的能力（HIV-1 gag p55）。这一建议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-IFNa2A治疗激活的art重组先天免疫和适应性免疫效应物的抗逆转录病毒作用。这项多地点随机、开放标签的临床研究代表了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科、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、BD生物科学、罗氏公司和格莱斯顿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.