In a randomized, phase II study at the National Institutes of Health (NIH), self-administered injections of the immune system protein interleukin-2 (IL-2) have dramatically increased levels of CD4+ T cells in patients with early HIV infection. The findings build on previous NIH reports that another regimen of IL-2 -- intravenous infusions of the drug -- can significantly boost numbers of CD4+ T cells in certain patients.
Richard T. Davey, M.D., senior investigator in the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), will present preliminary findings of the ongoing clinical trial at the XIth International Conference on AIDS in Vancouver, British Columbia, on Wednesday, July 10 at 1:30 p.m. Pacific Time.
Our data suggest that therapy with subcutaneous IL-2, in combination with antiretroviral drugs, has the potential to halt the usual progression of HIV disease by maintaining a person's CD4+ T cell count in the normal range for prolonged periods of time," says Dr. Davey. "The CD4+ T cell increases we have seen with injections of IL-2 have been similar to those previously achieved with intravenous IL-2 infusions, but with fewer side effects. In addition to having less toxicity, the current regimen allows patients to self-administer their medication on an outpatient basis."
Further studies are needed to help discern whether the increases in CD4+ T cell counts seen with IL-2 therapy will translate to clinical benefit," he adds.
In the study, 41 of a planned 48 patients with baseline CD4+ T cell counts greater than 500 per cubic millimeter (mm3) of blood have been assigned to one of four subcutaneous IL-2 regimens for at least six months. All the patients are currently taking antiretroviral drugs; none of them had received IL-2 previously. The four subcutaneous IL-2 regimens are:
1) 1.5 million international units (MIU) twice a day for five days every four weeks;
2) 1.5 MIU twice a day for five days every eight weeks;
3) 7.5 MIU twice a day for five days every four weeks;
4) 7.5 MIU twice a day for five days every eight weeks.
All patients are taught to self-administer IL-2 by injection and are seen by study physicians once a month at the NIAID/Clinical Center HIV Research Clinic.
Six months into the study, significant increases in CD4+ T cell counts have been seen in all groups, with the largest rise in group three.
1) The mean CD4+ T cell count of patients in group one has increased from 621/mm3 at baseline to 797 cells/mm3 at six months.
2) The mean CD4+ T cell count of patients in group two has increased from 670/mm3 at baseline to 961 cells/mm3 at six months.
3) The mean CD4+ T cell count of patients in group three has increased from 639/mm3 at baseline to 1488 cells/mm3 at six months.
4) The mean CD4+ T cell count of patients in group four has increased from 635/mm3 at baseline to 1130 cells/mm3 at six months.
The main toxicities associated with subcutaneous IL-2 treatment have been mild to moderate flu-like symptoms such as fatigue, aches and pains, and headache.
"We have seen the same spectrum of toxicities with subcutaneous administration of IL-2 that we've noted with intravenous administration," says Dr. Davey. "However, because the concentration of the drug in the bloodstream quickly peaks following injection and then declines, the severity of the side effects tend to be less than with intravenous IL-2."
"Characteristically, the side effects with subcutaneous dosing peak four to six hours after the injection. Over the next few hours, as drug levels start to come down, side effects begin to decrease as well."
In the four treatment groups, viral burden at baseline as measured by the bDNA assay ranged from 13,000 to 23,000 HIV RNA copies per milliliter of blood; these levels have not increased significantly in any group over the six-month study period.
NIAID Clinical Director H. Clifford Lane, M.D., says, "We anticipate that these positive findings will set the stage for a phase III trial to determine the clinical efficacy of subcutaneous IL-2 in combination with antiretrovirals for the treatment of HIV-infected people. We are currently working with Chiron Corporation, and with scientific colleagues in the United States and abroad to plan such a trial."
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 a kind of kidney cancer. The recombinant IL-2 used in the NIAID study was produced by Chiron Corporation.
Dr. Davey's co-authors include Dr. Lane, Doreen Chaitt, Joseph Kovacs, M.D., Robert E. Walker, M.D., Michael Polis, M.D., M.P.H., Judy Falloon, M.D., Henry Masur, M.D., Julia A. Metcalf, and Stephen C. Piscitelli, PharmD, all of NIH; and Gwendolyn Fyfe, M.D., of Chiron Corporation, Emeryville, Calif.
NIAID and the Clinical Center are components of the National Institutes of Health. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
Davey RT, et al. Subcutaneous IL-2 therapy is capable of inducing marked, sustained increases in CD4 counts un early HIV-infected patients. XIth International Conference on AIDS (Abstract #2305), Vancouver, July 7-12, 1996.
Kovacs JA, et al. Increases in CD4 lymphocytes with intermittent courses on interleukin-2 in patients with human immunodeficiency virus infection. N Engl J Med 1995;332(9):567-75.
Kovacs JA, et al. Randomized trial of intermittent interleukin-2 therapy in HIV-infected patients with CD4 counts >200 cells/mm3. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract LB-8), San Francisco, Sept. 17-20, 1995.
NIAID press releases, fact sheets and other materials are available on the internet via the NIAID home page. The address is http://www.niaid.nih.gov.