The Role Of Interleukin-2 In The Management Of HIV

IL-2 在 HIV 治疗中的作用

• 批准号: 7212389
• 负责人: JOSEPH A KOVACS
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7212389
• 关键词: AIDS therapy; CD4 molecule; HIV infections; antiAIDS agent; antiviral agents; clinical trials; combination chemotherapy; corticosteroids; drug administration rate /duration; drug administration routes; drug adverse effect; drug tolerance; human immunodeficiency virus; human subject; human therapy evaluation; immunomodulators; immunotherapy; interleukin 2; leukocyte count; patient oriented research; virus load

Interleukin-2 (IL-2) is a cytokine with important regulatory properties for both T and B cells. The current studies were undertaken to evaluate IL-2 in the treatment of HIV infection. Our studies initially focused on patients with CD4 counts above 200 cells/mm3, administering IL-2 for 5 days approximately every 2 months at doses ranging from 6 to 18 million units/d. The courses of IL-2 were well-tolerated, although most of the patients required dosage reductions due to IL-2 related adverse effects. Sustained improvement in CD4 number was seen primarily in patients with greater than 200 CD4 cells/mm3. There also was a transient increase in viral load as measured by the bDNA assay seen at day 6 to day 8 following initiation of IL-2 therapy. Responses in CD4 number were less common in patients with lower baseline CD4 counts. Based on the preliminary results seen in our open trial, we undertook a randomized trial to evaluate IL-2 therapy in patients with CD4 counts above 200 cells/mm in combination with currently approved antiretroviral therapies. The study opened in April 1993 and was completed in February of 1995, with 60 patients enrolling. This study also showed in a controlled setting that intermittent therapy with IL-2 can lead to a substantial and sustained increase in CD4 cell counts without leading to an increase in plasma viral load. More recently, we have focused on improving the tolerance of IL-2, by decreasing the dose and duration of therapy, and by evaluating alternative methods of administering IL-2. We had enrolled patients in an extension phase of ongoing studies to determine whether administration of corticosteroids with IL-2 can lead to improved tolerance of IL-2 without interfering with the immunomodulatory effects. This phase has been discontinued due to the occurrence of avascular necrosis of the hip in some patients receiving prednisone. We continue to follow patients receiving IL-2 to determine the long term side effects and immunologic activity of IL-2. In addition, in combination with labeling studies, we are investigating the mechanisms leading to the profound CD4 cell increases seen with intermittent IL-2 therapy. These studies are potentially important because they are the first ones to suggest that immunomodulating agents combined with antiretroviral agents may have a benefit in patients with HIV infection.

白介素 2 (IL-2) 是一种对 T 细胞和 B 细胞具有重要调节特性的细胞因子。目前的研究是为了评估 IL-2 在 HIV 感染治疗中的作用。我们的研究最初集中于 CD4 计数高于 200 个细胞/mm3 的患者，大约每 2 个月施用 IL-2 5 天，剂量范围为 6 至 1800 万单位/天。尽管大多数患者由于 IL-2 相关的不良反应而需要减少剂量，但 IL-2 的疗程耐受性良好。 CD4 细胞数持续改善主要见于 CD4 细胞/mm3 大于 200 个的患者。在开始 IL-2 治疗后第 6 天至第 8 天，通过 bDNA 测定观察到病毒载量也出现短暂增加。在基线 CD4 计数较低的患者中，CD4 数量的反应不太常见。根据我们公开试验中的初步结果，我们进行了一项随机试验，以评估 IL-2 疗法与目前批准的抗逆转录病毒疗法联合治疗 CD4 计数高于 200 个细胞/mm 的患者。该研究于 1993 年 4 月开始，于 1995 年 2 月完成，共有 60 名患者入组。这项研究还表明，在对照环境中，IL-2 间歇性治疗可导致 CD4 细胞计数大幅持续增加，而不会导致血浆病毒载量增加。最近，我们致力于通过减少治疗剂量和持续时间以及评估 IL-2 的替代给药方法来提高 IL-2 的耐受性。我们已将患者纳入正在进行的研究的扩展阶段，以确定皮质类固醇与 IL-2 联合给药是否可以改善 IL-2 的耐受性，而不干扰免疫调节作用。由于一些接受泼尼松治疗的患者发生髋部缺血性坏死，该阶段已终止。我们继续跟踪接受 IL-2 治疗的患者，以确定 IL-2 的长期副作用和免疫活性。此外，结合标记研究，我们正在研究导致间歇性 IL-2 治疗中 CD4 细胞显着增加的机制。这些研究具有潜在的重要意义，因为它们是第一个表明免疫调节剂与抗逆转录病毒药物联合使用可能对 HIV 感染患者有益的研究。