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| |  NIH Study Shows IL-2 Boosts Immune Cell Levels in HIV Patients EMERYVILLE, Calif. -- March 24, 1997-- A study by the National Institutes of Health (NIH) demonstrates that subcutaneous administration recombinant interleukin (IL-2) in outpatients infected with HIV can produce substantial and sustained increases in CD4 cells levels. The study, published in the April issue of the Journal of Infectious Diseases, was reported by Richard Davey, M.D., Clifford Lane, M.D. and their colleagues. These results corroborate the findings from another NIH study with IL-2 in HIV, reported in the October 31, 1996 New England Journal of Medicine, in which the NIH researchers showed that in some patients, continuous infusion of IL-2 therapy resulted in marked increases in functional CD4 immune cells. In addition to demonstrating immunologic benefits, the follow-on study's results also indicate that subcutaneous administration of IL-2 provided on an outpatient basis is associated with noticeably less toxicity compared to continuous infusion regimens, allowing for improved patient management. "With these data, we have made significant progress in finding a tolerable outpatient dosing regimen that will achieve considerable, long-term increases in patients' CD4 immune cell levels that have not been realized with antiretroviral therapy alone," said Peter T. Curtin, M.D., Associate Director of Clinical Development for Chiron Technologies, who developed the drug. "While subcutaneous dosing of IL-2 was associated with similar side effects reported with the continuous infusion regimen, the intensity and duration of these effects was markedly reduced in the outpatient regimen, usually peaking four hours after administration and abating over a four to eight hour period." In the study, 18 HIV-infected patients with baseline CD4 cell counts greater than 200 cells/mm3 received a maximum tolerated dose of 15 MIU of IL-2 therapy daily via subcutaneous injection in combination with standard antiviral therapy. Eight patients (44%) showed a greater than 200 cells/mm3 rise in CD4 cell levels from baseline after 12 months. Six patients (33%) experienced an increase of 0-200 cells/mm3 and four patients (22%) experienced a gradual decline in CD4 cell counts. Importantly, in extended follow-up of eight patients continuing outpatient IL-2 therapy for a period approaching three years, five people have maintained CD4 cells counts in the range of 800-2000 cells/mm3, and three patients have sustained CD4 cells counts in the range of 400-600 cells/mm3. The researchers found that the likelihood and magnitude of increases in CD4 cell levels correlated directly with patients' baseline cells counts, where patients with higher CD4 cell counts at baseline had greater positive response to immunotherapy. Overall, there was no significant increase in HIV RNA plasma (viral load) or p24 antigen levels from baseline in this patient group. This subcutaneous regimen may represent a significant therapeutic advance as it provides the immuno-stimulatory benefits of IL-2 in the treatment of HIV while reducing the toxicity associated with continuous intravenous administration, the company noted said in a statement. Chiron Therapeutics intends to collaborate with the NIH to support a Phase III clinical trial using this subcutaneous outpatient regime in a larger patient group. Adverse effects associated with subcutaneous administration of IL-2 were similar in nature, although considerably lower in severity and duration, to those associated with continuous infusion of IL-2. These mild to moderate constitutional effects included fever, fatigue and associated symptoms which were not treatment-limiting. As the regimen progressed, patients were able to anticipate the onset of side effects following administration, and pre-treat and lessen these effects with oral medications, such as analgesics, antipyretics and antiemetics. Chiron supplied the recombinant IL-2 used in the study, which it markets under the trade name Proleukin (aldesleukin) for injection for the treatment of metastatic renal cell cancer. "This new study demonstrates that subcutaneous IL-2, used in combination with protease inhibitors and other antiretroviral drugs, has the potential to enhance the therapeutic effects conferred by antiretroviral treatments alone," comments Dr. Davey. "The CD4+ T cell increases we've seen with injections of IL-2 are similar to those previously achieved with intravenous IL-2 infusions. The subcutaneous regimen represents an improvement, however, because the side effects are less severe and less prolonged, and the treatment can be administered by the patient at home." Phase III studies are needed to determine if these substantial rises in CD4+ T cell counts, a marker of immunologic improvement, translate into clinical benefits, he adds. The trial, which began in 1993, enrolled 18 HIV-infected people with CD4+ T cell counts greater than 200/mm3 of blood (average 350). None had previously received IL-2. During the study, the patients continued taking approved antiretrovirals of their choice, including protease inhibitors. The primary objectives of the study were to determine the highest tolerated dose and potential limiting side effects of IL-2 when self-injected daily for five days every two months. The investigators sought to identify an IL-2 regimen that conferred the same immunologic benefit, as gauged by increased CD4+ T cells, as seen with continuous intravenous IL-2 infusion but that was easier to administer and better tolerated. To determine how much drug patients could tolerate, the investigators started the first group of patients on low-dose (3 MIU) subcutaneous IL-2, and gradually increased the dosage in subsequent groups of patients until serious toxicities arose. Using predefined guidelines, the investigators determined 15 MIU/day to be the maximum tolerated dose for this IL-2 regimen. At this and lower dosages, the main side effects reported were mild to moderate flu-like symptoms such as fatigue, aches and pains, and headache. Typically side effects peak around four hours after IL-2 is injected, Dr. Davey explains, at the same time that blood concentrations of IL-2 crest. Over the next few hours, as drug levels taper off, the side effects diminish. Patients received a minimum of three cycles (six months) of therapy. One year after the start of therapy, eight patients had sustained a substantial rise (at least 200) in their CD4+ T cell counts, and six others had experienced a change between zero and 200. CD4+ T cell counts in the remaining four patients had gradually declined from their baseline levels. "Both the likelihood of a positive CD4 cell count change during therapy and the magnitude of the absolute rise from baseline appeared to correlate directly with patients' baseline CD4 cell counts," the authors write. Overall, viral load as measured by the bDNA assay did not increase significantly in any group during the study period. In extended follow-up, eight patients have remained on subcutaneous IL-2 therapy for more than three years. Five have sustained CD4+ T cell levels of 800 to 2,000 cells/mm3 by self-injecting 12 to 15 MIU/day IL-2 (either once daily or a split dose) every two to four months. The other three have maintained CD4+ T cell counts of 400 to 600 on lower doses of IL-2, with cycles about every two months. In late 1994, the NIH team began an extension of the present study comparing low-dose to high-dose subcutaneous IL-2 in 48 patients with baseline CD4+ T cell counts greater than 500. The patients, divided into four study groups, self-inject low-dose (1.5 MIU) or high-dose (7.5 MIU) IL-2 twice daily for five days every four or eight weeks. As Dr. Davey reported at the international AIDS conference in Vancouver last summer, a preliminary examination of the data indicates significant increases in CD4+ T cell counts in all groups. In the two groups of patients taking high-dose treatments, more than half achieved at least a doubling of their baseline CD4+ T cell counts within the first six months of therapy. Final analysis of this follow-up study should be completed in the next few months. Based on these positive findings, NIAID, in collaboration with its domestic AIDS clinical trials program, the National Centre for HIV Epidemiology and Clinical Research in Sydney, Australia, and other international partners is working on a plan for a Phase III efficacy trail of subcutaneous IL-2 in patients with early HIV disease. This study will be an international effort designed to determine the clinical efficacy of this novel form of intervention as a complement to standard antiretroviral therapy. IL-2 originally called T-cell growth factor, is produced in the body by T cells and has potent effects on the proliferation and maturation of several types of immune system cells, including T cells, B cells and natural killer cells. Commercially, IL-2 is produced by recombinant DNA technology and is approved for treating one type of kidney cancer. The recombinant IL-2 used in the NIAID study was produced by Chiron Corporation of Emeryville, Calif. Dr. Davey's co-authors include Dr. H. Clifford Lane, M.D., Doreen Chaitt, Stephen Piscitelli, Pharm.D., Mary Wells, Joseph A. Kovacs, M.D., Robert E. Walker, M.D., Judith Falloon, M.D., Michael Polis, M.D., M.P.H., Julia A. Metcalf, and Henry Masur, M.D., all of NIH; and Gwendolyn Fyfe, M.D., of Chiron Corporation. NIAID and the Clinical Center are components of the National Institutes of Health. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
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