Studies On The Role Of Interleukin-2 In The Management Of HIV Infection

IL-2 在 HIV 感染治疗中作用的研究

• 批准号: 7593007
• 负责人: JOSEPH A KOVACS
• 金额: $ 4.36万
• 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/7593007
• 关键词: Adrenal Cortex Hormones; Adverse effects; Anti-Retroviral Agents; B-Lymphocytes; Branched DNA Signal Amplification Assay; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cells; Dose; Enrollment; HIV Infections; Hip region structure; Immunologics; Interleukin-2; Label; Lead; Measures; Methods; Necrosis; Numbers; Patients; Personal Satisfaction; Phase; Plasma; Prednisone; Property; Randomized Controlled Clinical Trials; Range; Role; Viral Load result; antiretroviral therapy; base; cytokine; day; dosage; improved; response; therapy duration

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 60 patient 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.

我们的研究最初集中于CD4计数以上200细胞/mm3的患者，每2个月大约每2个月施用5天的IL-2，范围为6至1800万单位/d。 IL-2的课程耐受性良好，尽管大多数患者由于IL-2相关的不良反应而需要降低剂量。 CD4数量的持续改善主要是在大于200 CD4细胞/mm3的患者中。通过IL-2治疗开始后的第6到第8天，病毒载量也瞬时增加。在较低的基线CD4计数患者中，CD4数量的反应不太常见。根据我们在开放试验中看到的初步结果，我们进行了60例患者随机试验，以评估CD4计数超过200细胞/mm的患者的IL-2治疗，并结合当前批准的抗逆转录病毒疗法。这项研究于1993年4月开放，于1995年2月完成，有60名患者参加。这项研究还表明，在受控的环境中，使用IL-2进行间歇性治疗会导致CD4细胞计数的大幅增长，而不会导致血浆病毒载量增加。最近，我们通过减少治疗的剂量和持续时间以及评估施用IL-2的替代方法来提高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IL-2的皮质类固醇是否会导致IL-2的耐受性提高而不会干扰免疫调节作用。由于一些接受泼尼松的患者的髋关节血管坏死的发生，因此该阶段已经停止。我们继续跟随接受IL-2的患者确定IL-2的长期副作用和免疫学活性。此外，与标签研究结合使用，我们正在研究导致间歇性IL-2治疗所见的CD4细胞增加的机制。这些研究可能很重要，因为它们是第一个表明与抗逆转录病毒药物结合的免疫调节剂可能对HIV感染患者有好处的研究。