Questions and Answers about the NIAID Interleukin-2 Study
1. WHAT IS INTERLEUKIN-2?
Interleukin-2 (IL-2) is an immune system protein produced in the body by T cells. IL-2 has potent effects on the proliferation, differentiation and activity of a number of immune system cells, including T cells, B cells and natural killer cells. Commercially, IL-2 is produced by recombinant DNA technology and is FDA-approved for the treatment of metastatic renal cell cancer. The recombinant IL-2 (aldesleukin) used in the study was provided by Chiron Corporation of Emeryville, California.
2. WHAT IS THE RATIONALE FOR STUDYING IL-2 AS A TREATMENT FOR HIV-INFECTED INDIVIDUALS?
Current therapy of HIV infection relies on the use of drugs that can provide a transient clinical benefit, but do not prevent the immunologic deterioration seen in HIV infection. Studies have shown that in the test tube, addition of IL-2 can improve some of the immunologic functions that are abnormal in HIV-infected patients. In addition, IL-2 is a growth factor for T cells, causing them to increase in number.
3. HOW LONG HAS IL-2 BEEN STUDIED AS A POSSIBLE THERAPY FOR HIV INFECTION?
The current study builds on more than a decade of NIAID research into the role of IL-2 in the immune system and its possible use as an HIV therapy. In 1982, before the identification of HIV as the cause of AIDS, NIAID researchers and collaborators from the US Food and Drug Administration demonstrated that IL-2 could enhance the activity of immune system cells taken from AIDS patients. In 1983, the first AIDS patients were infused with IL-2, during the same period when cancer patients were first treated with the substance. Over the next 12 years, the NIAID researchers refined their approach to IL-2 therapy for HIV infection through an ongoing series of laboratory experiments and small clinical trials.
4. WHERE WAS THE STUDY CONDUCTED?
The study was conducted at the Warren Grant Magnuson Clinical Center of the National Institutes of Health in Bethesda, MD, under the direction of H Clifford Lane, MD, and Joseph A Kovacs, MD.
5. WHO PARTICIPATED IN THE CURRENT STUDY?
A total of 25 patients participated in the study. Ten individuals started the study with CD4+ T cell counts greater than 200 per cubic millimeter (mm3) of blood. Another 15 individuals had baseline CD4+ T cells counts of less that 200/mm3.
6. WHAT ARE CD4+ T CELLS?
CD4+ T cells, also known as "T-helper" cells, play a crucial role in the immune response, signalling other cells in the immune system to perform their special functions. They have been called the "conductors" of the immune "orchestra." A healthy person usually has 800 to 1,200 CD4+ T cells/mm3. During the course of HIV disease, CD4+ T cells are disabled and killed, and their numbers progressively decline. When an HIV-infected person's CD4+ T cell count falls below 200/mm3, he or she becomes particularly vulnerable to the opportunistic infections and cancers that typify AIDS, the late stage of HIV disease. Physician often use measurements of a patients CD4+ T cells as an indication of the individual's level of immune deficiency.
7. WHAT TREATMENT DID PATIENTS IN THE STUDY RECEIVE?
In the NIAID study, patients received IL-2 intravenously for five consecutive days every two months. All participants took at least one approved antiretroviral drug such as zidovudine (AZT) or didanosine (ddI) during the study. CD4+ T cell measurements were made one and two months after each course of IL-2.
8. WHAT WERE THE MAIN FINDINGS OF THE STUDY?
In six of 10 patients who started the study with CD4+ T cell counts higher than 200 per cubic millimeter (mm3) of blood, CD4+ T cell counts rose by more than 50 percent after 12 months. In several of these patients, the rise in CD4+ T cells was dramatic -- for example, one individual's CD4+ T cell count rose from 554 to 1,998 cells/mm3 after 12 months on IL-2. Follow-up of several of these patients has shown that CD4+ T cell increases have persisted for more than two years. The remaining four patients had stable CD4+ T cell counts or showed a slight decline. Of the 15 patients who started the study with CD4+ T cell counts below 200/mm3, only two showed a 50 percent increase in their CD4+ T cell counts. In the remaining 13, no significant increases in CD4+ T cell counts were observed, and side effects were considerably more severe than in the patients with baseline CD4+ T cell counts above 200/mm3.
9. WHAT WERE THE SIDE EFFECTS OF IL-2 IN THE STUDY?
Side effects were common in the study, including rash, mouth ulcers, fever, fatigue, nausea, lowering of blood pressure, flu-like symptoms, diarrhea and laboratory abnormalities such as reduced calcium, albumin and magnesium in the blood. A number of patients have said the side effects of IL-2 are worse than the "worst ever" bout with the flu. None of the side effects observed in the study were life-threatening, and most severe side effects generally subsided within a few days after terminating the IL-2 infusion. Side effects were more common and more severe in patients who started the study with CD4+ T cell counts lower than 200/mm3 than in individuals with higher baseline CD4+ T cell counts.
10. WHAT DID MEASUREMENTS OF HIV IN THE PATIENTS SHOW?
In the 10 patients with baseline CD4+ T cell counts above 200/mm3, no consistent changes in the amount of virus in the patients' blood were seen using measurements of an HIV protein called p24. A more sensitive test called the branched-DNA (bDNA) assay revealed a transient increase in HIV RNA in the blood of four of the 10 patients with baseline CD4+ T cell counts greater than 200/mm3 following each infusion of IL-2. Although no obvious detrimental effects were associated with the transient bursts of viral replication seen in these four patients following IL-2 infusion, the study investigators suggest that it may prove to be important to use the best possible regimen of antiretroviral drugs, particularly during IL-2 infusions. Among the four patients with the most dramatic increases in CD4+ T cell counts, HIV RNA was undetectable by the bDNA assay throughout therapy. No other consistent increase in HIV RNA was noted in the one other patient tested with the bDNA assay. Among patients with baseline CD4+ T cell counts below 200/mm3, sustained increases in p24 or HIV RNA were noted in 10 of 12 patients evaluated.
11. WHAT DO THESE FINDINGS SUGGEST FOR THE CARE OF HIV-INFECTED INDIVIDUALS?
The clinical significance of the changes in CD4+ T cells seen in this study is currently unknown. Before recommendations concerning the use of IL-2 in HIV-infected people can be made, it must be shown, in randomized clinical trials, that the drug slows disease progression in addition to increasing CD4+ T cell counts.
12. WHERE WERE THE RESULTS OF THE STUDY PUBLISHED?
A complete report of the study can be found in The New England Journal of Medicine, Volume 332, pp. 567-575, March 2, 1995.
13. WHAT OTHER TRIALS OF IL-2 ARE ENROLLING PATIENTS AT NIAID?
NIAID investigators are currently recruiting patients for a new series of studies at NIAID. In the first of these, the timing of IL-2 infusions are linked to changes in a patient's CD4+ T cell count. Another study is examining the safety and potential effectiveness of subcutaneous, rather than intravenous, IL-2 therapy. A third trial will assess whether blockade of tumor necrosis factor (TNF), production of which is increased by IL-2, will diminish the side effects and/or burst in viral replication associated with IL-2 infusions.
14. WHERE CAN I GET ENROLLMENT INFORMATION ABOUT CLINICAL TRIALS OF IL-2?
HIV-infected individuals and their physicians interested in clinical trials at NIAID involving interleukin-2 can call 1-800-AIDS-NIH. Information on other HIV clinical trials is available by calling 1-800-TRIALS-A.