NEW TREATMENTS FOR AIDS AND AIDS-RELATED INFECTIONS

艾滋病和艾滋病相关感染的新疗法

• 批准号: 3546957
• 负责人: HENRY W. MURRAY
• 金额: $ 52.35万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1992-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3546957
• 关键词: AIDS; human subject; human therapy evaluation; microorganism disease chemotherapy; opportunistic infections

The objective of this proposal is to establish an AIDS Clinical Study Group (CSG) to unify and maximize the effectiveness of the future AIDS clinical research carried out at The New York Hospital-Cornell Medical Center. The emphasis in this application is on new and improved treatments for AIDS and AIDS-related opportunistic infections (OI), and our principal focus will be to determine if immune reconstitution with gamma interferon (IFN-gamma) can act synergistically with anti-HIV chemotherapy (azidiothymidine (AZT), ribavirin) to prevent (a) new OI in AIDS patients or (b) progression to AIDS and OI in immunodeficient ARC patients. Our studies have demonstrated that IFN-gamma is a key T4+ cell-derived lymphokine critical for successful activation of mononuclear phagocytes to exert enhanced antimicrobial activity. In addition, we have established that T4+ cells from AIDS patients with OI fail to secrete antigen- induced IFN-gamma, a state which renders them vulnerable to and unable to control opportunistic pathogens. In parallel, we have also demonstrated, however, that the AIDS peripheral blood monocyte, monocyte-derived macrophage, and tissue (alveolar) macrophages is fully responsive to activation by exogenous IFN- gamma in vitro, and in a recent in vivo trial, showed that AIDS monocytes respond to intravenous recombinant (Tau) IFN-gamma with clear evidence of activation and enhanced antimicrobial capacity. In an on-going prospective study of patients at high risk for AIDS conducted in our well-established Immune Deficiency Research Unit (IDRU), we have also reported that the capacity to secrete antigen-stimulated IFN-gamma is an accurate predictor of the risk of progressing to AIDS and developing an OI. We now propose to extend our work using several specific aims: (1) Continue and expand our IDRU longitudinal study of at-risk patients. (2) Determine in two trials, if combination immunotherapy (IFN-gamma) plus antiviral therapy (AZT) is superior to AZT alone in the treatment of AIDS patients with a prior OI in (a) decreasing the occurrence of new OI and (b) permitting a reduction in AZT dose to diminish toxicity while preserving clinical efficacy. (3) Determine if rIFN-gamma plus ribavirin is superior to ribavirin alone in preventing the progression of ARC to AIDS. And (4) Determine the efficacy of new treatments for OI: (a) spiramycin in cryptosporidiosis, (b) Fansidar prophylaxis in reactivated toxoplasmosis, and (c) fluconazole in cryptococcosis. The morbidity and mortality of AIDS-related OI clearly rationale the need for new experimental approaches.

该提案的目标是建立艾滋病临床中心 研究组 (CSG) 旨在统一并最大限度地提高各研究小组的有效性 未来艾滋病临床研究将在纽约进行 医院-康奈尔医学中心。 这其中强调的 申请是针对艾滋病的新的和改进的治疗方法 艾滋病相关的机会性感染 (OI) 以及我们的主要关注点 将确定是否用伽玛进行免疫重建 干扰素 (IFN-gamma) 可以与抗 HIV 药物协同作用 化疗（叠氮胸苷 (AZT)、利巴韦林）以预防 (a) 艾滋病患者出现新的成骨不全症或 (b) 进展为艾滋病和成骨不全症 免疫缺陷的 ARC 患者。 我们的研究表明 IFN-γ 是一种关键的 T4+ 细胞衍生的淋巴因子，对于 成功激活单核吞噬细胞发挥作用 增强抗菌活性。 此外，我们还设立了 来自 AIDS 成骨不全症患者的 T4+ 细胞无法分泌抗原 诱导的 IFN-γ，这种状态使它们容易受到和 无法控制机会致病菌。 与此同时，我们有 然而，也证明艾滋病的外周血 单核细胞、单核细胞衍生的巨噬细胞和组织（肺泡） 巨噬细胞对外源性 IFN- 的激活完全敏感 体外试验和最近的体内试验表明，艾滋病 单核细胞对静脉注射重组 (Tau) IFN-γ 作出反应 具有明显的激活证据和增强的抗菌能力 容量。 在一项正在进行的高危患者前瞻性研究中 在我们既定的免疫缺陷中进行的艾滋病治疗 研究单位（IDRU），我们还报告了 分泌抗原刺激的 IFN-γ 是准确的预测因子 发展为艾滋病和成骨不全症的风险。 我们现在建议通过几个具体目标来扩展我们的工作： (1) 继续并扩大我们对高危人群的 IDRU 纵向研究 患者。 (2) 两次试验确定是否组合 免疫治疗（IFN-γ）加抗病毒治疗（AZT） 治疗艾滋病患者的疗效优于单独使用 AZT (a) 减少新的成骨不全的发生和 (b) 允许减少 AZT 剂量以减少毒性，同时 保持临床疗效。 (3) 判断rIFN-gamma是否加 利巴韦林在预防感染方面优于单独使用利巴韦林 ARC 进展为 AIDS。 (4) 确定功效 成骨不全症的新疗法：(a) 螺旋霉素治疗隐孢子虫病，(b) Fansidar 预防弓形虫病再激活，以及 (c) 氟康唑治疗隐球菌病。 发病率和死亡率 艾滋病相关的成骨不全症显然需要新的实验 接近。