The first randomized, controlled trial of interleukin-2 (IL-2) therapy conducted in the era of highly active antiretroviral therapy, or HAART, has found that combining the immune-based therapy with potent antiretrovirals markedly boosts CD4+ T-cell counts without increasing the amount of HIV in the blood.
Results of the multicenter study are reported in the July 12 HIV/AIDS theme issue of the Journal of the American Medical Association (JAMA) by Richard T. Davey, Jr., M.D., of the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH), and his colleagues.*
A series of prior studies has established that periodic, high-dose IL-2 therapy can substantially increase CD4+ T-cell counts in patients with early HIV infection. But generally, these studies took place before HAART first became available in 1996, so it remained unclear how the response to IL-2 might differ when given in combination with potent combination antiretroviral therapy.
"These studies formed the backbone for our work," explains Dr. Davey. "We wanted to explore if we could elevate CD4+ T-cell numbers in IL-2 recipients to a greater extent than is possible using antiretroviral drugs alone."
The current trial, conducted from April 1996 to April 1998 at eight clinical centers nationwide, evaluated 78 HIV-infected patients already receiving combination antiretroviral drug therapy prescribed by their own physicians. At entry, the volunteers had no or mild symptoms and had moderate illness according to their CD4+ T-cell counts, which ranged from 200 to 500 cells per microliter (µL).
The volunteers were randomly assigned to one of two groups: 37 added IL-2 to their current anti-HIV drug regimen and 41 continued on antiretroviral therapy alone. Those in the IL-2 group received twice-daily, five-day courses of IL-2 (at a starting dose of 7.5 million international units) injected under the skin every eight weeks for a total of six cycles during the year of active treatment. All volunteers were followed for an additional one-year period.
After one year of treatment, CD4+ T-cell counts in the group receiving both IL-2 and antiretrovirals had risen an average of 112 percent from entry levels compared with an 18 percent rise in the group receiving antiretroviral drugs alone. Additionally, the IL-2 group had a slightly lower average viral load than did the control group, and the proportion of study volunteers who achieved virus levels below 50 copies per millilter, a level that indicates potent viral suppression, was greater in the IL-2 group than in the control group.
Although this is the first study to suggest a positive effect of IL-2 on viral load, these differences were not large, says Dr. Davey, and suggest that the effects of IL-2 in the setting of HAART may be partly overshadowed by the potent antiviral properties of the HAART medications themselves. Additional information from two larger Phase 2 studies, information expected to be made public before the end of the year, will help clarify the effects of IL-2 on viral load.
"I'm also very heartened," adds Dr. Davey, "that two large-scale, collaborative Phase 3 trials are currently enrolling patients in many countries and should answer the most probing question regarding IL-2: does it improve clinical outcomes over time?" Results from these trials, called ESPRIT and SILCAAT, are not expected before another five years.
"Overall, IL-2 is probably the best characterized and most developed immune-based therapy," comments Dr. Davey. The JAMA study builds on 18 years of NIAID research into the role of IL-2 in the immune system and its possible use in HIV therapy. NIAID began trials of IL-2 in HIV-infected patients in 1983. Originally called T-cell growth factor, IL-2 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.
Recombinant IL-2 used in the trial is a lab-manufactured product currently approved in the United States for treating metastic melanoma and kidney cell carcinoma. A patent, licensed to Chiron Corporation of Emeryville, CA, has been issued to NIAID/NIH on the use of IL-2 to raise CD4+ T-cell counts. Chiron funded the JAMA study.
"The ultimate role of IL-2, if it is found to benefit patients already on antiretroviral therapy," explains Dr. Davey, "would be to offer yet another means of maintaining quality of life and decreasing the incidence of AIDS-defining events. That is the goal. That is the hope. At the present time," he adds, "it remains unproven. But there's considerable optimism for further development of this drug."
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illness such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
REFERENCE: RT Davey et al. Immunologic and virologic effects of subcutaneous IL-2 treatment in combination with antiretroviral therapy: a randomized controlled trial. Journal of the American Medical Association 284:183-89 (2000).
*NOTE: An update on this and all trials testing IL-2 in HIV infection is scheduled to be presented by co-author H. Clifford Lane, M.D., NIAID clinical director, at a special AMA media briefing in Durban, South Africa prior to this year's International AIDS Conference. The briefing will take place at Durban's Holiday Inn Elangeni on Saturday, July 8, at 4:00 a.m. Eastern Time.
TV OUTLETS: New NIAID AIDS B-roll is available on request by contacting NIAID's Office of Communications and Public Liaison at 301-402-1663.
For more information about the two Phase 3 IL-2 trials currently enrolling patients, call 800-AIDS-NIH (for the ESPRIT study) or visit http://www.silcaat.com (for the SILCAAT study).
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
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