In a one-year study of HIV-infected people, infusions of the immune system protein interleukin-2 (IL-2) have resulted in dramatic and sustained increases in the primary immune system cells depleted during HIV infection, according to investigators at the National Institutes of Health (NIH).
In the study, patients randomly assigned to receive IL-2 plus standard antiretroviral therapy had mean CD4+ T cell counts that increased from 428 cells per cubic millimeter of blood (mm3) at baseline to 916 cells/mm3 at month 12. Among patients randomly assigned to receive standard antiretroviral therapy alone, mean CD4+ T cell counts decreased from 406 cells/mm3 to 349 cells/mm3. CD4+ T cells are the main targets of HIV; the progressive loss of these cells leads to the symptoms of the acquired immunodeficiency syndrome (AIDS).
Joseph A. Kovacs, M.D., H. Clifford Lane, M.D., and their colleagues report their findings in the Oct. 31 issue of The New England Journal of Medicine. Dr. Kovacs is a senior investigator in the Critical Care Medicine Department at the NIH Clinical Center, and Dr. Lane is the clinical director of the National Institute of Allergy and Infectious Diseases (NIAID).
This work highlights the potential role of immune-based therapies in the treatment of HIV-infected people," says Anthony S. Fauci, M.D., NIAID director.
Significantly, the amount of HIV in the blood of study patients receiving IL-2 therapy remained stable over time. Previous studies had shown that IL-2 treatment can result in transient bursts of virus production in some patients, but the current data clearly indicate that these bursts do not lead to sustained increases in viral load.
In addition, the side effects of IL-2 infusions in the current study were much less severe than those seen in previous studies using higher doses of intravenous IL-2.
Our study has clearly demonstrated that IL-2 therapy can have a substantial positive impact on the major immunologic abnormality associated with HIV infection, the loss of CD4+ T cells, without leading to an overall increase in the level of HIV in the bloodstream or to unmanageable toxicities," says Dr. Kovacs.
Despite flu-like symptoms and other side effects during IL-2 infusions, patients in the study reported feeling as well overall as patients not receiving IL-2, according to a quality of life analysis presented at the XIth International Conference on AIDS in Vancouver, B.C.
We are encouraged that the increases in CD4+ T cells observed in this study did not come at the expense of a patient's overall quality of life," says Dr. Kovacs. "Additional work by our group has shown that other dosing regimens, especially subcutaneous administration of lower IL-2 doses, can further reduce toxicity."
All immunologic studies performed thus far suggest that the CD4+ cells that proliferate during IL-2 therapy are functional, Dr. Lane notes. As further evidence of this, "the current study has provided the first clinical data that IL-2 therapy may be able to prevent new AIDS-related conditions or death," he says. "Among individuals randomized to standard antiretroviral therapy, five people developed AIDS-related symptoms or died, as compared to two in the group randomized to IL-2 in addition to standard antiretroviral therapy. In each instance, these events occurred in patients with low CD4+ T cell levels. Phase III studies are needed to accurately determine the clinical benefits of IL-2 therapy."
IL-2, originally called T cell-growth factor, is produced in the body by T cells and has potent effects on the maturation and proliferation of a number of cell types, including T cells, B cells and natural killer cells. Commercially, IL-2 is produced by recombinant DNA technology and is licensed in the United Sates for the treatment of patients with metastatic renal cell cancer. The recombinant IL-2 used in the NIAID study was produced by Chiron Corporation of Emeryville, Calif.
In the study, 60 patients with baseline CD4+ T cell counts above 200/mm3 of blood were randomly assigned to receive IL-2 plus licensed antiretroviral therapy, or antiretroviral therapy alone. IL-2 was administered at a starting dose of 18 million International Units (IU) a day for five days every two months. The dose was reduced as needed; the mean dose used in the latter part of the study was approximately 8 million IU/day.
The most common side effects during IL-2 administration were fatigue or malaise, reported by patients during 44 percent of the five-day treatment cycles, and headache, reported during 7 percent of treatment cycles. The most common laboratory abnormality, seen during 8 percent of the treatment cycles, was an elevation in bilirubin levels, indicating an effect on the liver. The elevations were not accompanied by clinical symptoms, and levels returned to normal after the treatment period. The investigators note that toxicities decreased in frequency during later rounds of treatment as IL-2 dosages were reduced.
In an extension phase of the trial, the investigators found that increases in CD4+ T cells could be sustained for more than two years by continuing to administer IL-2 on an individualized schedule. In five patients, CD4+ T cell counts remained over 1000/mm3 for at least 18 months after discontinuing IL-2.
"To date, no combination of antiretroviral agents has been shown capable of inducing increases in CD4+ T cell counts of this magnitude or duration," the authors write.
Because IL-2 targets the immune system rather than HIV itself, viral mutations should not reduce its effectiveness, the investigators note. In contrast, resistance to antiretroviral drugs occurs because of HIV's high rate of mutation.
"The lack of resistance to IL-2 helps explain why some patients have continued to respond to IL-2 therapy even 50 months after beginning therapy," says Dr. Kovacs.
While the current study of IL-2 enrolled only patients with CD4+ T cell counts above 200/mm3, additional Phase II work in NIAID's AIDS Clinical Trials Group is being planned in patients with more advanced disease. Ronald T. Mitsuyasu, M.D., director of the UCLA Center for AIDS Research and Education and associate professor at the UCLA School of Medicine, is focusing his efforts on patients with lower CD4+ T cell counts, and will assess IL-2 given with antiretroviral regimens that include a protease inhibitor.
NEXT STEP: A PHASE III TRIAL OF IL-2
The NIH investigators currently are working with scientific colleagues in the United States and abroad to develop a Phase III strategy to determine whether the increases in CD4+ T cells achieved with IL-2 therapy will translate to fewer AIDS-related complications and improved survival for HIV-infected people.
Professor David Cooper, M.D., director of the National Centre in HIV Epidemiology and Clinical Research in Sydney, Australia, has studied IL-2 and is working closely with the NIH investigators in the development of a Phase III plan for evaluating IL-2 in HIV-infected patients with CD4+ T cell counts greater than 400 cells/mm3. He comments: "Complementing antiretroviral therapy with IL-2 is an attractive approach to the treatment of HIV-infected people, offering the opportunity to reduce the amount of virus in the body while boosting the immune system's capacity. We look forward to a trial that will clarify the long-term clinical benefits associated with the IL-2-induced increases in CD4+ T cells."
Professor Maxime Seligmann, M.D., chairman of the Scientific Council of the ANRS in France, comments, "When given in conjunction with antiretrovirals, IL-2 has the potential to directly boost the immune system in a way that may be of clinical benefit. The only way to definitively establish this is in the context of a well-designed Phase III trial."
In collaboration with Yves Levy, M.D., Professor Seligmann currently is conducting a trial comparing intravenous and subcutaneous modes of IL-2 administration. This study will allow a detailed analysis of the immunologic changes seen in people receiving IL-2 therapy and provide insights into how best to administer IL-2.
Dr. Kovacs' and Dr. Lane's co-authors on the NIH study include Susan Vogel, B.S., Jeffrey M. Albert, Ph.D., Judith Falloon, M.D., Richard T. Davey, M.D., Robert Walker, M.D., Michael A. Polis, M.D., M.P.H., Katherine Spooner, M.D., Julia A. Metcalf, B.A., all of NIAID; Henry Masur, M.D., of the Clinical Center's Critical Care Medicine Department; Michael Baseler, Ph.D., and Robin J. Dewar, Ph.D., of SAIC Inc., Frederick, Md; and Gwendolyn Fyfe, M.D., of Chiron Corp., Emeryville, Calif.
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 HIV disease and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the Public Health Service, U.S. Department of Health and Human Services.
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.
Barrick B, et al. Quality of life and symptom distress in HIV-infected persons receiving intravenous interleukin-2 (IL-2). XIth International Conference on AIDS (abstract #2306), Vancouver, B.C., July 7-12, 1996.
HIV-infected individuals and their physicians interested in NIH clinical trials involving interleukin-2 can call 1-800-AIDS-NIH. Information on other HIV clinical trials is available by calling 1-800-TRIALS-A.
NIAID press releases, fact sheets and other materials are available on the Internet via the NIAID home page at http://www.niaid.nih.gov.