Interleukin-2 (IL-2), an immune system protein, has been shown to increase the number of CD+ T cells in many people with HIV infection. Studies conducted before the era of potent antiretroviral therapy, however, suggested IL-2 was less effective in patients with very low levels of these cells, which HIV destroys. Now the AIDS Clinical Trials Group (ACTG) reports that IL-2 can increase the CD4+ T-cell levels in these patients if other drugs have already reduced the level of HIV in the blood. The study, known as ACTG 328, is the largest randomized study of IL-2 completed in advanced HIV patients to date. The results will be presented Wednesday, October 25, by lead investigator Ronald Mitsuyasu, M.D., of the University of California at Los Angeles, at the 5th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland.
"Because patients with very low CD4+ T-cell levels are those at greatest risk of quickly developing opportunistic illness, they might show the most immediate benefit from IL-2's T-cell-boosting properties," says Lawrence Fox, M.D., Ph.D., medical officer in the National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS, which funds the ACTG. "For these patients this is very good news."
IL-2 is a protein best known for its ability to stimulate T cells to multiply. Before multi-drug AIDS cocktails became the standard of care, however, studies of IL-2 showed little promise in people with extremely low CD4+ T-cell counts. They rarely benefited from IL-2 and often had severe toxic reactions to the treatment.
Highly active antiretroviral therapy, or HAART, is now the most effective tool for treating people infected with HIV. HAART uses a combination of drugs to directly attack the virus and reduce its levels in the blood. Recently, NIAID reported the results of CPCRA 059, the largest study to date on the effects of IL-2 in conjunction with HAART for treating HIV infections. The results of that trial supported the safety and efficacy of IL-2, but the trial did not include people with CD4+ T-cell counts below 350 cells per cubic millimeter (mm3). In the ACTG study, Dr. Mitsuyasu, director of UCLA's Clinical AIDS Research and Education Center, led a team to determine how people with low levels of CD4+ T cells (50-350 cells/mm3) would respond to IL-2 therapy if administered after HAART.
Two-hundred-four individuals were treated with HAART for 12 weeks. Those patients whose viral load dropped dramatically continued to receive HAART with or without a laboratory-synthesized (recombinant) form of IL-2. Recombinant IL-2 was administered either intravenously or under the skin, and individuals received the drug for five-day periods every eight weeks for up to 84 weeks. Dr. Mitsuyasu will report on data to 60 weeks.
The patients receiving recombinant IL-2 had significant increases in CD4+ T-cell counts when compared with those receiving HAART alone. While HAART produced a median increase of 97 cells/mm3, the addition of intravenous or subcutaneous IL-2 resulted in median increases of 309 and 240 cells/mm3, respectively. In addition, individuals who received IL-2 did not suffer from the severe toxic reactions that plagued many with low CD4+ T-cell levels in earlier, pre-HAART era studies. Finally, IL-2 did not appear to trigger an increase in viral load when it stimulated the T cells.
This study demonstrates that HAART followed by IL-2 regimens can significantly increase levels of CD4+ T cells in patients severely depleted of such cells, and can usually do so with minimal adverse effects. These results offer promise to the sickest of HIV patients by providing a way to partially reconstitute the immune system by increasing the CD4+ T-cell pool.
This study also helps lay the groundwork for two ongoing major Phase III trials assessing the clinical outcomes of IL-2 treatment for HIV. NIAID's ESPRIT trial will enroll 4,000 patients and involves 227 sites in 20 countries. The SILCAAT trial , conducted by Chiron Corporation, will enroll 1,400 patients at 100 sites in eight countries. The two trials focus on patients with different starting CD4+ T-cell levels. For more information on the ESPRIT trial contact (800) 422-1222. Information on SILCAAT is available at www.silcaat.com.
NIAID is a component of the National Institutes of Health(NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.