In the study, patients randomly assigned to receive IL-2 plus
standard antiretroviral therapy had mean CD4+ T cell counts that
increased from 428 cells per cubic millimeter of blood (mm3) at
baseline to 916 cells/mm3 at month 12. Among patients randomly
assigned to receive standard antiretroviral therapy alone, mean CD4+
T cell counts decreased from 406 cells/mm3 to 349 cells/mm3. CD4+
T cells are the main targets of HIV; the progressive loss of these cells
leads to the symptoms of the acquired immunodeficiency syndrome
Joseph A. Kovacs, M.D., H. Clifford Lane, M.D., and their
colleagues report their findings in the Oct. 31 issue of The New
England Journal of Medicine. Dr. Kovacs is a senior investigator in
the Critical Care Medicine Department at the NIH Clinical Center, and
Dr. Lane is the clinical director of the National Institute of Allergy
and Infectious Diseases (NIAID).
"This work highlights the potential role of immune-based
therapies in the treatment of HIV-infected people," says Anthony S.
Fauci, M.D., NIAID director.
Significantly, the amount of HIV in the blood of study patients
receiving IL-2 therapy remained stable over time. Previous studies
had shown that IL-2 treatment can result in transient bursts of virus
production in some patients, but the current data clearly indicate that
these bursts do not lead to sustained increases in viral load.
In addition, the side effects of IL-2 infusions in the current
study were much less severe than those seen in previous studies
using higher doses of intravenous IL-2.
"Our study has clearly demonstrated that IL-2 therapy can
have a substantial positive impact on the major immunologic
abnormality associated with HIV infection, the loss of CD4+ T cells,
without leading to an overall increase in the level of HIV in the
bloodstream or to unmanageable toxicities," says Dr. Kovacs.
Despite flu-like symptoms and other side effects during IL-2
infusions, patients in the study reported feeling as well overall as
patients not receiving IL-2, according to a quality of life analysis
presented at the XIth International Conference on AIDS in Vancouver,
"We are encouraged that the increases in CD4+ T cells
observed in this study did not come at the expense of a patient's
overall quality of life," says Dr. Kovacs. "Additional work by our
group has shown that other dosing regimens, especially subcutaneous
administration of lower IL-2 doses, can further reduce toxicity."
All immunologic studies performed thus far suggest that the
CD4+ cells that proliferate during IL-2 therapy are functional, Dr. Lane
notes. As further evidence of this, "the current study has provided the
first clinical data that IL-2 therapy may be able to prevent new AIDS-
related conditions or death," he says. "Among individuals randomized
to standard antiretroviral therapy, five people developed AIDS-related
symptoms or died, as compared to two in the group randomized to
IL-2 in addition to standard antiretroviral therapy. In each instance,
these events occurred in patients with low CD4+ T cell levels. Phase
III studies are needed to accurately determine the clinical benefits of
IL-2, originally called T cell-growth factor, is produced in the
body by T cells and has potent effects on the maturation and
proliferation of a number of cell types, including T cells, B cells and
natural killer cells. Commercially, IL-2 is produced by recombinant
DNA technology and is licensed in the United Sates for the treatment
of patients with metastatic renal cell cancer. The recombinant IL-2
used in the NIAID study was produced by Chiron Corporation of
The most common side effects during IL-2 administration were
fatigue or malaise, reported by patients during 44 percent of the
five-day treatment cycles, and headache, reported during 7 percent of
treatment cycles. The most common laboratory abnormality, seen
during 8 percent of the treatment cycles, was an elevation in bilirubin
levels, indicating an effect on the liver. The elevations were not
accompanied by clinical symptoms, and levels returned to normal
after the treatment period. The investigators note that toxicities
decreased in frequency during later rounds of treatment as IL-2
dosages were reduced.
In an extension phase of the trial, the investigators found that
increases in CD4+ T cells could be sustained for more than two years
by continuing to administer IL-2 on an individualized schedule. In five
patients, CD4+ T cell counts remained over 1000/mm3 for at least 18
months after discontinuing IL-2.
"To date, no combination of antiretroviral agents has been
shown capable of inducing increases in CD4+ T cell counts of this
magnitude or duration," the authors write.
Because IL-2 targets the immune system rather than HIV
itself, viral mutations should not reduce its effectiveness, the
investigators note. In contrast, resistance to antiretroviral drugs
occurs because of HIV's high rate of mutation.
"The lack of resistance to IL-2 helps explain why some
patients have continued to respond to IL-2 therapy even 50 months
after beginning therapy," says Dr. Kovacs.
While the current study of IL-2 enrolled only patients with
CD4+ T cell counts above 200/mm3, additional Phase II work in
NIAID's AIDS Clinical Trials Group is being planned in patients with
more advanced disease. Ronald T. Mitsuyasu, M.D., director of the
UCLA Center for AIDS Research and Education and associate
professor at the UCLA School of Medicine, is focusing his efforts on
patients with lower CD4+ T cell counts, and will assess IL-2 given with
antiretroviral regimens that include a protease inhibitor.
Next Step: A Phase III Trial of IL-2
Professor David Cooper, M.D., director of the National Centre
in HIV Epidemiology and Clinical Research in Sydney, Australia, has
studied IL-2 and is working closely with the NIH investigators in the
development of a Phase III plan for evaluating IL-2 in HIV-infected
patients with CD4+ T cell counts greater than 400 cells/mm3. He
comments: "Complementing antiretroviral therapy with IL-2 is an
attractive approach to the treatment of HIV-infected people, offering
the opportunity to reduce the amount of virus in the body while
boosting the immune system's capacity. We look forward to a trial
that will clarify the long-term clinical benefits associated with the
IL-2-induced increases in CD4+ T cells."
Professor Maxime Seligmann, M.D., chairman of the Scientific Council
of the ANRS in France, comments, "When given in
conjunction with antiretrovirals, IL-2 has the potential to directly
boost the immune system in a way that may be of clinical benefit. The only
way to definitively establish this is in the context of a well-designed
Phase III trial."
In collaboration with Yves Levy, M.D., Professor Seligmann
currently is conducting a trial comparing intravenous and
subcutaneous modes of IL-2 administration. This study will allow a
detailed analysis of the immunologic changes seen in people
receiving IL-2 therapy and provide insights into how best to administer
Dr. Kovacs' and Dr. Lane's co-authors on the NIH study
include Susan Vogel, B.S., Jeffrey M. Albert, Ph.D., Judith Falloon,
M.D., Richard T. Davey, M.D., Robert Walker, M.D., Michael A. Polis,
M.D., M.P.H., Katherine Spooner, M.D., Julia A. Metcalf, B.A., all of
NIAID; Henry Masur, M.D., of the Clinical Center's Critical Care
Medicine Department; Michael Baseler, Ph.D., and Robin J. Dewar,
Ph.D., of SAIC Inc., Frederick, Md; and Gwendolyn Fyfe, M.D., of
Chiron Corp., 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 HIV disease and other
sexually transmitted diseases, tuberculosis, asthma and allergies.
NIH is an agency of the Public Health Service, U.S. Department of
Health and Human Services.
HIV-infected individuals and their physicians interested in NIH clinical
trials involving interleukin-2 can call 1-800-AIDS-NIH. Information on
other HIV clinical trials is available by calling 1-800-TRIALS-A.
NIAID press releases, fact sheets and other materials are available
on the Internet via the NIAID home page at http://www.niaid.nih.gov.
Barrick B, et al. Quality of life and symptom distress in HIV-infected
persons receiving intravenous interleukin-2 (IL-2). XIth International
Conference on AIDS (abstract #2306), Vancouver, B.C., July 7-12,