Multi-institutional study shows immune benefit when interleukin-2 is added to antiretroviral therapy

July 11, 2000

A multicenter U.S. study has found that the addition of the immune stimulator interleukin-2 (IL-2) to antiretroviral therapy (ART) appears to improve immunologic function in patients with an intermediate stage of HIV infection and may augment the anti-HIV activity of potent antiretroviral agents. Patients who took IL-2 in addition to their regular therapy had increases in CD4 cell counts--a type of white blood cell that helps fight HIV--and decreases in the amount of virus detectable in their blood.

The findings are reported in the July 12 special issue of JAMA.

"Our results are consistent with other small, randomized controlled trials of IL-2 that show it can elevate CD4 cell counts safely in HIV-infected patients," said the study's senior author, James O. Kahn, MD, UCSF associate professor of medicine in the Positive Health Program at San Francisco General Hospital Medical Center.

"In addition, the study is the first randomized controlled trial to demonstrate that adding an immune modulator, in this case IL-2, to ART decreases the amount of HIV detectable in the blood," said Kahn.

The investigation, sponsored by Chiron Corporation, was conducted over a one-year period at eight clinical sites in the United States. The study was led by Richard T. Davey, Jr., MD, of the National Institute of Allergy and Infectious Diseases.

A total of 78 adult HIV-infected outpatients completed the study. All were at an "intermediate" stage of infection. Their CD4 cell counts were low enough and the amount of virus in their bloodstream was high enough to indicate that they should receive treatment and might benefit by strategies to increase their CD4 cells. However, they had not yet developed any of the opportunistic illnesses associated with AIDS.

At entry, patients had no or mild symptoms and had moderate illness according to their CD4 cell counts, which ranged from 200-500 cells per microliter. All patients received antiretroviral therapy during the study, the composition of which was left to the discretion of their personal physician. Approximately half of the patients were randomly chosen to supplement their ART with subcutaneous injections of IL-2. The injections were administered over the course of 5 days every 8 weeks for a total of six cycles of therapy. The study design specified one year of trial participation.

"IL-2 appeared to be safe and was generally well tolerated over the long term," said Kahn. Most patients experienced side effects such as fever, fatigue, and muscle aches, but these were generally manageable with pain relievers, fluids, and rest. If side effects were more serious, the IL-2 dosage was reduced.

The study found, at final determination, that patients who were receiving IL-2 in addition to regular therapy had increased their CD4 cell counts an average of 112 percent from the level measured at the beginning of the study, compared with an 18 percent increase for patients who received ART alone. In the IL-2 group, the CD4 cell count increased after the first IL-2 injection series and with each cycle thereafter. The effect also was dependent on the dosage: the more IL-2 the patient was able to tolerate, the better the CD4 cell count improvement, said Kahn.

When researchers measured the amount of virus in the patients' blood, they found it had decreased overall in the IL-2 group, and increased slightly in the control group that received ART alone. In addition, at the end of the study, the virus was measurable only at very low levels (less than 50 RNA copies/ml) in 20 of 30 of the IL-2 patients (67 percent), as compared to 13 out of 36 control patients (36 percent ). In other studies, such low counts appear to be strongly associated with long-term suppression of the virus, according to Kahn.

Ongoing larger investigations will help show whether this viral load reduction occurs consistently with IL-2 therapy, and whether this finding translates to clinical benefit.

Additional studies may also be needed to see whether daily low-dose injections of IL-2, which may be better tolerated, will reproduce the CD4 cell increases associated with the intermittent high-dose therapy used in this study, said Kahn.
Other co-authors of the JAMA paper are Robert L. Murphy, MD, Northwestern University, Chicago; Frank M. Graziano, MD, PhD, University of Wisconsin, Madison; Steven L. Boswell, MD, Fenway Community Health Center, Boston; Andrew T. Pavia, MD, University of Utah, Salt Lake City; Margarita Cancio, MD, St. Joseph's Hospital, Tampa, Fla; Jeffrey P. Nadler, MD, University of South Florida; Doreen G. Chaitt, RN, MPH, National Institute of Health Critical Care Medicine Department; Robin L. Dewar, PhD, Science Applications International Corp, Frederick, Md; David K. Sahner, MD, Anne-Marie Duliege, MD, MS, William B. Capra, PhD, Wai-Ping Leong, MS, and Martin A. Giedlin, PhD, all of Chiron Corporation, Emeryville, Calif.; and H. Clifford Lane, MD, National Institute of Allergy and Infectious Diseases.

University of California - San Francisco

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