The purpose of this ACTG protocol is to evaluate the effect of intermittent recombinant human interleukin-2 (rhIL-2) by intravenous or subcutaneous administraton in subjects with HIV infection on highly-active antiretroviral therapy (HAART) compared to HAART alone. The primary hypotheses include 1) that there will be a difference between different routes of intermittently administered rhIL-2 (IV vs subcutaneous admininistration) with a highly active antiretroviral regimen compared to highly active antiretroviral therapy alone with respect to the proportion of subjects achieving 50% increase in CD4 counts above pre-randomization baseline values after one year of rhIL-2 and the rate of change in CD4 counts; 2) that there will be a difference between the safety, tolerance, and effect on quality of life of these regimens, and 3) that there will be measureable changes in immune cell phenotypes and function and on HIV viral load and rate of antiviral drug resistance development when HAART is used in the setting of rhIL-2 compared to HAART alone. The ACTG 872 substudy has as a secondary hypothesis that there will be specific and different immunologic effects when comparing the two regimens of rhIL-2 plus HAART vs. HAART alone. The ACTG 874 substudy has as a secondary aim the assessment of the cellular source of HIV production in lymph node tissue before and after treatment with HAART, and the changes induced in lymph node tissue with the addition of exogenous rhIL-2, in a subset of subjects (n=12). HIV disease is characterized by a progressive decline in CD4 T-lymphocytes and increasing viral burden that are only marginally improved with the use of nucleoside analogues. These improvements in CD4 counts, however, do correlate with clinical benefit and, in some circumstances, with a survival advantage. Even in the most promising studies where peripheral HIV viral RNA levels are decreased by two or more logs or where improved clinical outcomes were observed, however, the effect on CD4 cell counts remained modest, and CD4 counts were not restored to normal levels. An attractive proposition for the development of effective treatment for HIV which may also stimulate reconstitution of the deficient and dysfunctional immune system caused by HIV is the use of potent antiretroviral drugs in conjunction with cytokines or other immune stimulatory factors such as interleukin-2 (rhIL-2).
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