(Background for presentation by Dr. H. Clifford Lane, NIAID, at "JAMA" Media Briefing on July 8 in Durban, South Africa)
TO: Editors, Reporters and Producers
FROM: Laurie K. Doepel Office of Communications and Public Liaison, NIAID
SUBJECT: Update on Clinical Trials of Interleukin-2 (IL-2) as Immune-Based Therapy for HIV (Background for presentation by Dr. H. Clifford Lane, NIAID,at "JAMA" Media Briefing on July 8 in Durban, South Africa)
The article in the July 12 issue of the "Journal of the American Medical Association" ("JAMA") by Dr. Richard T. Davey, Jr., of the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues heralds a series of anticipated papers and presentations over the coming months. All will report new data on the potential role of interleukin-2 (IL-2) in treating people with HIV infection. An immune-based therapy, IL-2 is a laboratory-engineered product modeled after a substance the body makes that promotes T-cell growth.
These reports include long-term follow-up data on the earliest study groups of HIV-infected people treated with IL-2; preliminary data on IL-2's effects in the absence of antiretroviral drugs; and results from the largest randomized, controlled trials to date in people with either early- or late-stage HIV infection. Thus far, the available data from these studies support the hypothesis that the increases in CD4+ T cells (HIV's primary target) induced by IL-2 may be clinically beneficial. This emerging information highlights the importance of quickly completing enrollment in two ongoing Phase 3 studies designed to evaluate the clinical significance of this immune-based therapy for patients with HIV infection.
The "JAMA" article describes results from the first randomized, controlled trial of IL-2 conducted in the era of highly active antiretroviral therapy, or HAART. Eight participating centers evaluated data from 78 trial volunteers assigned at random to simply continue on their current antiretroviral drug regimen or to add IL-2 to their regimen. After one year of treatment, CD4+ T-cell counts in those who received IL-2 rose by an average of 112 percent compared with 18 percent in the group receiving antiretroviral drugs alone. In addition, using sensitive tests to detect HIV RNA, the investigators found the IL-2 group had a slightly greater decrease in average viral load as compared with the control group.
In August, a paper in the "Journal of Infectious Diseases" by Dr. Sean Emery and colleagues will reveal long-term follow-up data on 157 patients enrolled in the first three randomized, controlled trials of IL-2. This comparison of immediate versus deferred IL-2 will report finding sustained increases in CD4+ T-cell counts as well as small but statistically significant decreases in levels of HIV RNA in the people who received IL-2. Overall, 16 AIDS-defining events occurred in the volunteers in the control groups compared with nine AIDS-defining events in the volunteers who received IL-2. Although the numbers are not large enough to draw conclusions, they suggest a possible trend in favor of IL-2 treatment.
Thus far, all reported trials of IL-2 have involved patients also receiving antiretroviral therapy. At the International AIDS Conference in Durban, a late-breaker abstract by Dr. Mike Youle and colleagues describes the results of a randomized controlled trial of IL-2 given without concomitant antiretroviral drugs. This study, carried out in the United Kingdom, will likely be followed up with additional work exploring this approach in a group of patients with early-stage HIV infection.
Two NIAID-supported clinical networks, the Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG), will soon complete randomized, controlled trials of IL-2. Results of these two trials are expected to be made public before the end of the year. The CPCRA explored this strategy in 511 patients with early-stage HIV infection (CD4+ T-cell counts >350/cubic millimeter[mm3]), while the ACTG trial enrolled 204 patients with more advanced disease (CD4+ T-cell counts of 50-300/mm3).
Clinical trials have already established that intermittent, high-dose IL-2 can substantially increase CD4+ T-cell counts in the majority of patients with early-stage HIV infection. Any form of immune system activation, however, may also boost levels of HIV, and some patients on IL-2 experience transient increases in HIV RNA levels. It is hoped that the data emerging from the CPCRA and ACTG studies, like the one appearing in "JAMA", will provide additional information on the overall effect of IL-2 on HIV viral load.
Having thus defined the effects of IL-2 on CD4+ T-cell counts and HIV RNA levels, the only remaining step will be to determine the overall clinical impact of these changes on patients with either early or advanced HIV infection. IL-2 therapy is associated with well-described, generally manageable, dose-related side effects, including flu-like symptoms, fluid retention, and upset stomach or diarrhea. It cannot be assumed, however, that the changes in surrogate markers of HIV disease that correlate with short-term improvements in clinical outcome for antiretroviral therapy will lead to improved long-term clinical outcome in patients receiving an immune-based therapy. In fact, the recent recognition of the constellation of side effects associated with antiretroviral therapy suggests that long-term clinical outcome studies of antiretroviral therapy need to be pursued as well.
Only carefully designed, large-scale studies mapping the comparative number of AIDS-defining illnesses and deaths between people taking antiviral therapy plus IL-2 or antiviral therapy alone can determine the true long-term effectiveness of IL-2 as a treatment strategy. Two Phase 3 studies currently under way are designed to directly address this question. The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) will enroll 4,000 patients with HIV infection and CD4+ T-cell counts greater than 300 over the next two years and follow them for an additional four years. This study, a cooperative effort between the University of Minnesota and NIAID, involves 227 sites in 20 countries. A Study of Interleukin-2 (IL-2) in People with Low CD4+ T-Cell Counts on Active Anti-HIV Therapy (SILCAAT) will enroll 1,400 patients with CD4+ T-cell counts of 50-300 and will have a similar duration of follow-up. This study will involve more than 100 sites in eight countries. SILCAAT is sponsored by Chiron Corporation. Patients and their physicians can obtain information about the ESPRIT study by calling 1-800-AIDS-NIH, while information about SILCAAT can be obtained at http://www.silcaat.com.
IL-2, originally called T-cell growth factor, is produced by T cells and has potent effects on the maturation and proliferation of several immune system cells, including T cells, B cells and natural killer cells. A complementary therapy to antiretroviral drugs, which attack HIV directly, IL-2 boosts the immune system. Current studies of IL-2 build on 18 years of NIAID research into the role of IL-2 in the immune system and its possible use as an HIV therapy. It has been studied in patients with HIV infection since 1983.
Commercially, IL-2 is produced by recombinant DNA technology and is currently licensed in the United States for treating metastatic melanoma and kidney cell carcinoma. A patent, licensed to Chiron, has been issued to NIAID/NIH on the use of IL-2 to raise CD4+ T-cell counts.
Remarkable strides have been made in developing antiretroviral therapies for HIV. Likewise, IL-2 is perhaps the best-studied and best-characterized immune-based therapy for HIV to date. In people with HIV, it exerts a dose-dependent positive effect on CD4+ T-cell counts. Within five to seven years, the collaborative international trials known as ESPRIT and SILCAAT should provide answers to the most important question: do these immunologic and virologic changes translate to clinical benefits for people infected with HIV?
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.