By testing gradually higher daily dosages of IL-2 in different groups of patients, the investigators also established that intermittent cycles of subcutaneous IL-2 therapy can be self-administered safely at a maximum tolerated dose of 15 million international units (MIU) per day.
The latest findings by Richard T. Davey, M.D., senior investigator in the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), and his colleagues build on earlier reports by this NIH team that infusing IL-2 intravenously can significantly raise levels of CD4+ T cells in certain HIV-infected patients.
"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 2000 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 trial 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
Davey RT, et al. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infec Dis 1997;175(4):781-89.
Kovacs JA, et al. Sustained increases in CD4 counts in HIV-infected patients treated with interleukin-2 during a randomized, controlled trial. N Engl J Med 1996;335:1350-56.
Davey RT, et al. Subcutaneous IL-2 therapy is capable of inducing marked, sustained increases in CD4 counts in early HIV-infected patients. Xith International Conference on AIDS (Abstract #2305), Vancouver, July 7-12, 1996.
Kovacs JA, et al. Increases in CD4 lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. N Engl J Med 1995;332(9):567-75.
NIAID press releases, fact sheets and other materials are available on the Internet via the NIAID home page at http://www.niaid.nih.gov.
The above story is based on materials provided by National Institute of Allergy and Infectious Diseases. Note: Materials may be edited for content and length.
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