POZ IRELAND
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POZ IRELAND
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INTERLEUKINS INTERLEUKIN-12DESCRIPTION: IL-12 is a cytokine. It is naturally produced by macrophages and B-lymphocytes. A recombinant version is under investigation. MECHANISM OF ACTION: IL-12 stimulates the TH1 subset of CD4+ cells, which may help prevent disease progression. In one model, IL-12 induced TH1 development in naive CD4+ cells undergoing primary activation (Schearer; Hsieh). SIDE EFFECTS: Due to a high number of hospitalisations and deaths possibly resulting from IL-12 administration in a non-AIDS kidney cancer study, additional safety studies for cancer and HIV are being developed. TRIAL RESULTS: Two phase I clinical trials of IL-12 in HIV+ people with CD4+ counts between 100 and 300 cells/mm3 and 300 and 500 cells/mm3 have been completed. Single doses of 3, 10, 100, 300, 1000, 3000, and 4000 ng/kg were found to be safe in both clinical trials. However, one study reported no marked effects on viral load levels or CD4+ counts in patients receiving single-dose treatment. IL-12 at doses of 100, 300 and 500 ng/kg have been studied in small numbers of patients as treatment for Kaposi's sarcoma. Sustained, partial responses were noted at the higher doses. CD4+ cell counts and viral load were stable during treatment. Side effects included reversible neutropenia, hepatotoxicity, and self-limiting constitutional symptoms. Approved for non-HIV-related indications. Phase III trials for HIV. INTERLEUKIN-2DESCRIPTION: Interleukin-2 (IL-2) is a natural substance that stimulates the production and maturation of CD4 cells. A recombinantly produced form is being studied in clinical trials. DOSE: Various doses and dosing regimens are under evaluation. There are reports that low-dose subcutaneous IL-2 produces immune stimulation as effectively as high-doses but with less toxicity. MECHANISM OF ACTION: IL-2 is a lymphokine central to the immune response; it promotes the proliferation and expansion of activated T lymphocytes, potentiates B cell growth and activates monocytes and natural killer cells. Activation of NK cells and expansion of naive T-cells has been observed in HIV-infected patients. SIDE EFFECTS: IL-2 has significant short-term toxicity, Severe flu-like symptoms are dose-dependent. In a high-dose study, capillary leak, hepatic and renal dysfunction, thrombocytopenia, and neutropenia were reported. Other toxicity includes anaemia, chills, fevers, muscle pains, fatigue, headache, nausea, loose stools and elevated liver function tests. TRIAL RESULTS: Chronic Infection Comparing IL-2 in doses of 4.5 or 7.5 MIU BID for 5-day courses every 8 weeks versus no IL-2 in people who were stable on background HAART. Those receiving IL-2 had sustained increases in CD4+ counts of over 276 cells/mm3. IL-2/HAART vs. HAART. A greater percentage of viral load decrease in IL-2 group. Those on IL-2 had a greater increase in CD4+ cell count, which persisted after discontinuation of IL-2. The French government has approved IL-2 treatment for those whose CD4 counts do not spontaneously increase after successful HIV suppression with HAART. IL-2/nucleoside analogues vs. nucleoside analogues. In those receiving IL-2, the average CD4+ cell count increased from 428 cells/mm3 to 916 cells/mm3 at month 12. Increases in viral load levels did not differ significantly between the two groups. IL-2/plus two nucleoside analogues vs. nucleoside analogues. CD4+ increases after 12 months of treatment were: 698, 625, 726 cells/mm3 for the IL-2 groups and 103 cells/mm3 for the control group. There were fewer side effects on subcutaneous, low-dose IL-2.
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