COMBINATION ANTIRETROVIRAL THERAPY & THYMUS TRANSPLANTATION IN HIV INFECTION

联合抗逆转录病毒治疗

• 批准号: 6273999
• 负责人: CHARLES B HICKS
• 金额: $ 2.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6273999
• 关键词: AIDS therapy; CD4 molecule; HIV infections; T lymphocyte; antiAIDS agent; biopsy; clinical research; clinical trials; combination therapy; flow cytometry; human subject; human therapy evaluation; lamivudine; protease inhibitor; thymus transplantation; zidovudine

In HIV seropositive adults, highly active antiretroviral combination therapy leads to dramatic drops in plasma HIV RNA and increases in CD4 T cell counts. The purpose of this study was to address the question: Does the increase in CD4 T cell counts represent an increase in numbers of T cells or does it also represent an increase in CD4 T cell function? Our concern arises because, in HIV infection, with the death of CD4 T cells, the T cell repertoire becomes restricted. When patients who have restricted T cell repertoires are treated with combination antiretroviral therapy, we want to know whether the T cells which develop just represent more cells with the same restricted repertoire or whether the T cell repertoire has expanded. As we addressed this question, we also want to determine whether thymic transplantation would help restore T cell function in these patients. The thymus is the organ which creates the original broad repertoire of T cells. The thymus is damaged in HIV infection. We do not know whether the lack of functional thymus prevents development of a broad T cell repertoire in HIV patients. We are addressing this issue by transplanting thymic tissue into HIV patients and then following T cell function. Of pivotal importance in this study, therefore, is our assessment of CD4 T cell function. We assess T cell function by testing the ability of T cells to respond to the neoantigen Keyhole limpet hemocyanin, KLH. This aspect of the study is novel, we have an IND to do these immunizations. We are assessing the function of the thymic transplants directly by biopsy at 2 and 6 months. The study called to for 16 HIV-seropositive patients with 200-500 CD4 T cells, who have had less than 6 months of monotherapy. They do not have any protease inhibitor therapy. (We have enrolled 8 patients.) During screening, baseline studies are conducted including flow cytometry, T cell proliferative studies, and plasma HIV RNA. A lymph node biopsy is done to assess tissue HIV RNA. After screening, the patients are started on ritonavir, ZDV, and 3TC which they take for the next 2 years. The key procedure done one week after starting combination therapy is immunization with KLH and tetanus to assess responses to neoantigens and recall antigens. These immunizations are repeated every 6 months thereafter. At the end of the first 6 weeks (42 days) of combination antiretroviral therapy, the patients are randomized either to receive a thymic transplant or to be in the control group. On day 42, patients all have a lymph node biopsy to assess viral burden in the tissue. Half of the patients receive a thymic transplant. The patients' thymus transplants are biopsied 2 and 6 months later. All patients receive a lymph node biopsy at 6 months. The primary hypothesis being tested is that CD4 T cell counts will increase more in thymic transplant patients than in control patients who are on combination antiretroviral therapy. A secondary hypothesis is that T cell function will improve more in thymic transplant patients than in control patients. An additional secondary hypothesis is that thymic transplants will not be rejected. Preliminary data from the trial shows that approximately < of the patients do not develop responses to neoantigens after 1 year of combination antiretroviral therapy. Also, patients who begin therapy with 200 - 500 CD4 cells/cumm have enough immune function to reject thymus grafts.

在HIV血清阳性的成人中，高活性抗逆转录病毒联合治疗