In a small number of HIV-infected patients, infusions of an immune system protein significantly increased levels of the infection-fighting white blood cells normally destroyed during HIV infection, according to researchers at the National Institute of Allergy and Infectious Diseases (NIAID).
As reported in the March 2, 1995 The New England Journal of Medicine, NIAID Clinical Director H. Clifford Lane, M.D., Joseph A. Kovacs, M.D., of the NIH Clinical Center's Critical Care Medicine Department, and their colleagues found that interleukin-2 (IL-2) boosted levels of CD4+ T cells in some patients for more than two years, a far longer time than typically seen with currently available anti-HIV drugs.
This study provides the strongest evidence so far that it may be possible to rebuild and maintain the damaged immune systems of HIV-infected individuals," says Dr. Lane. "Ongoing studies of intermittent infusions of IL-2 will determine whether the increases in CD4+ T cell counts seen in this trial will translate into clinical benefits."
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.
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. The remaining four 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 count. 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.
In several 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. A healthy person usually has 800 to 1,200 CD4+ T cells/mm3.
Although current anti-HIV drugs have transient benefits, especially for individuals in late-stage disease, they do not prevent the immunologic deterioration associated with HIV disease," says Dr. Lane. "It is increasingly evident that preservation and restoration of the immune systems of HIV-infected people are necessary if they are to live for long periods of time. This study shows that IL-2 may help accomplish this. We believe the principles established here for augmentation of the T helper cell limb of the immune system might also benefit patients with other diseases characterized by decreased T cell function."
Side effects were common in the study, including rash, fever, lowering of blood pressure, flu-like symptoms, diarrhea and laboratory abnormalities such as reduced calcium, albumin and magnesium in the blood.
"While receiving infusions of IL-2, patients are extremely uncomfortable, often with symptoms worse than a very bad bout with the flu. Fortunately, none of the side effects we have observed thus far in these studies appear to be life-threatening," says Dr. Lane. "As with any treatment, the potential clinical benefits of IL-2 therapy ultimately will need to be weighed carefully against its potential side effects."
IL-2, originally called T cell-growth factor, is produced in the body by T cells and has potent effects on the proliferation and differentiation of a number of immune cells, including T cells, B cells and natural killer cells. Commercially, IL-2 is produced by recombinant DNA technology and is licensed for the treatment of metastatic renal cell cancer. The recombinant IL-2 used in the NIAID study was produced by Chiron Corporation of Emeryville, Calif.
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, Dr. Lane and collaborators from the U.S. 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, Dr. Lane and his group refined their approach to IL-2 therapy for HIV infection through an ongoing series of laboratory experiments and small clinical trials.
"The development of this treatment regimen, which involves alternately stimulating the immune system with IL-2 and then letting it rest, is the culmination of 13 years of laboratory studies and clinical research," says Anthony S. Fauci, M.D., NIAID director. "This work is a model of NIAID's "bench-to-bedside" philosophy of research: doing laboratory and preclinical studies, learning from preliminary clinical studies, going back to the laboratory bench for further refinement, and then treating patients with the improved regimen. In this instance, the re-circulation of information from the laboratory bench to the patient's bedside, over a period of 13 years, has led to unprecedented results."
Twenty-five patients were enrolled in the NIAID study. Of these, eight HIV-infected men and two HIV-infected women, ranging in age from 29 to 45, had CD4+ T cell counts greater than 200/mm3. These 10 patients received a total of four to 13 courses of IL-2 at the NIH Clinical Center, and were followed for periods of 22 to 40 months. The NIAID researchers found that after one year of therapy, CD4+ T cell counts increased by at least 50 percent in six of these 10 patients. The remaining four patients had no significant increases or showed a slight decline in CD4+ T cell counts.
In seven of the 10 patients, the proportion of cells that carried HLA-DR, a marker of aberrant T cell activation, on their surfaces decreased by at least 25 percent. Increased expression of HLA-DR on immune cells called CD8+ T cells has been associated with more rapid disease progression in HIV-infected individuals.
In nine of the 10 patients, the percentage of cells expressing the high-affinity receptor for IL-2 progressively increased. Cells with the high-affinity receptor on their surfaces appear to be more sensitive to IL-2.
One concern of the investigators was that IL-2 would increase the amount of virus in the body by activating HIV-infected T cells and thereby boosting viral replication. Although the scientists found no consistent changes in the amount of virus in the patients' blood 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, it seems prudent to use the best possible regimen of antiretroviral drugs, perhaps two or more drugs in combination, as an adjunct to IL-2 therapy," says Dr. Kovacs, a senior investigator in the Critical Care Medicine Department of NIH's Clinical Center.
Among the four patients with the most dramatic increases in CD4+ T cell counts, HIV RNA was undetectable throughout therapy. No other consistent increase in HIV RNA was noted in the one other patient tested with the bDNA assay.
During the course of therapy, eight of the 10 patients with baseline CD4+ T cell counts greater than 200/mm3 required reductions in the dose of IL-2, primarily because of fever and severe flu-like symptoms. Two of these patients chose to discontinue IL-2 therapy after four and nine courses, respectively, but continued to be followed during regular visits to the NIAID AIDS Clinic.
In addition to the 10 patients described above, the investigators also enrolled 15 patients with CD4+ T cell counts of 200/mm3 or fewer. In this group of patients, IL-2 therapy was associated with few improvements in immunologic responses, increased HIV replication and substantial toxicity. Of the two patients in this group who showed a sustained increase in their CD4+ T cell counts, both had baseline CD4+ T cell counts above 150 cells/mm3.
"If IL-2 therapy proves to have a beneficial clinical effect in patients with HIV, it most likely will be in those individuals whose immune systems are not severely debilitated," says Dr. Kovacs.
Dr. Lane and his collaborators at Chiron Corporation are working with investigators around the United States and worldwide to build on the current findings.
"We need to find the lowest effective dose of IL-2," says Dr. Lane. "There is substantial toxicity associated with the treatment as it is currently administered."
The 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 is assessing 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.
Co-authors of Drs. Lane and Kovacs include Susan Vogel, Richard T. Davey, M.D., Judith Falloon, M.D., Michael A. Polis, M.D., Robert E. Walker, M.D., and Julia A. Metcalfe, all of the NIAID Laboratory of Immunoregulation; Henry Masur, M.D., of the Critical Care Medicine Department of the Warren Grant Magnuson Clinical Center; and Michael Baseler, Ph.D., Robin J. Dewar, Ph.D., Randy Stevens and Norman P. Salzman, Ph.D., all of Program Resources Inc., Frederick, Md.
NIAID, a component of NIH, supports investigators and scientific studies at universities, medical schools, hospitals and research institutions in the United States and abroad aimed at preventing, diagnosing and treating such illnesses as AIDS, tuberculosis and asthma as well as allergies. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.
HIV-infected individuals and their physicians interested in NIAID 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.