|IL-2 Immunotherapy Fails to Benefit HIV-Infected
Individuals Already Taking Antiretrovirals
Providing a synthetic form of the immune system protein interleukin-2
(IL-2) to HIV-infected individuals already taking combination antiretroviral
therapy boosts their numbers of CD4+ T cells, the key white blood
cells destroyed by HIV, but fails to reduce their risk of HIV-associated
opportunistic diseases or death compared with combination antiretroviral
These are the findings of two large international clinical trials
presented today at the Conference on Retroviruses and Opportunistic
Infections (CROI) in Montreal.
The Phase III trials, known as the ESPRIT and SILCAAT studies,
were sponsored by the National Institute of Allergy and Infectious
Diseases (NIAID), part of the National Institutes of Health, and
funded respectively by NIAID and Chiron Corp. of Emeryville, Calif.
(since 2006 part of Novartis Pharmaceuticals).
Marcelo H. Losso, M.D., of Hospital José María Ramos Mejía, Buenos
Aires, Argentina, presented the results of ESPRIT, and Yves Levy,
M.D., of Hôpital Henri Mondor, Créteil, France, presented the results
IL-2 is produced naturally in the body and plays an important
role in regulating CD4+ T cell production and survival. As their
CD4+ T cell levels drop, people infected with HIV become more vulnerable
to AIDS-related opportunistic diseases and death. Earlier research
established that giving synthetic IL-2 plus antiretroviral therapy
to people with HIV infection boosts their CD4+ T cell counts more
than does antiretroviral therapy alone, but it was unknown whether
this boost translated into better health. ESPRIT and SILCAAT were
designed to test whether giving IL-2 to HIV-infected individuals
already on antiretroviral therapy would keep them healthier longer
than HIV-infected individuals taking only antiretrovirals.
Together, the ESPRIT and SILCAAT studies involved more than 5,800
HIV-infected volunteers in 25 countries. Participants were assigned
at random to receive either combination antiretroviral therapy
alone or combination antiretrovirals plus injections of Proleukin
(Novartis Pharmaceuticals, Basel, Switzerland), a synthetic form
of IL-2, over several five-day cycles. To evaluate the effects
of IL-2 treatment at different stages of HIV infection, the ESPRIT
study enrolled people with early-stage infection (CD4+ T cell counts
at or above 300 cells per cubic millimeter, or mm3),
while the SILCAAT study enrolled volunteers with later-stage HIV
infection (CD4+ T cell counts between 50 and 299 cells/ mm3).
"In both studies, the volunteers who received IL-2 and antiretrovirals
experienced notable, sustained increases in CD4+ T cell counts,
as anticipated," notes NIAID Director Anthony S. Fauci, M.D. "Unfortunately,
these increases did not translate into reduced risks of HIV-associated
opportunistic diseases or death when compared with the risks in
volunteers who were taking only antiretrovirals. Although further
analyses may help us better understand these findings, the two
studies clearly demonstrated that the use of IL-2 did not improve
health outcomes for HIV-infected people."
It is unclear why increased CD4+ T cell counts did not translate
into better health outcomes. James D. Neaton, Ph.D., of the University
of Minnesota, principal investigator of the global clinical trials
network that conducted ESPRIT, offers two possible explanations. ďIt
could be that the types of CD4+ T cells induced by IL-2 play no
role in protecting the HIV-infected patient, and therefore the
administration of IL-2 has no benefit,Ē says Dr. Neaton. "A second
possibility is that the CD4+ T cells are at least somewhat functional
or that IL-2 has some modest benefit, but that the side effects
of IL-2 may neutralize any possible benefit."
"In the end, the results of these two studies indicate that although
a personís number of CD4+ T cells is a key measure of success in
the treatment of HIV with antiretroviral drugs, we canít rely on
CD4+ T cell counts to predict whether immune-based therapies such
as IL-2 will improve the health of HIV-infected individuals," concludes
Dr. Levy, the principal investigator of SILCAAT.
"The purpose of clinical research is to clearly state and accurately
test hypotheses with an ultimate goal of improving patient care," notes
H. Clifford Lane, M.D., director of clinical research at NIAID
and a member of the executive committee of ESPRIT. "These two clinical
trials successfully reached a definitive answer about the utility
of IL-2 therapy for treating HIV infection. NIAID thanks the thousands
of dedicated volunteers and investigators who made these studies
possible. The results will have significant implications for the
future development of immune-based therapies for HIV and studies
of HIV pathogenesis."
Background Information on ESPRIT and SILCAAT
The ESPRIT study — which stands for "Evaluation of
Subcutaneous Proleukin in a Randomized International Trial" — began
in March 2000 and ended as scheduled in November 2008. It was coordinated
by the international centers of the NIAID-sponsored International
Network for Strategic Initiatives in Global HIV Trials (INSIGHT).
These centers are the Medical Research Council Clinical Trials
Unit in London; the Copenhagen HIV Program in Denmark; the National
Centre in HIV Epidemiology and Clinical Research at the University
of New South Wales in Sydney, Australia; and the Community Programs
for Clinical Research on AIDS (CPCRA) unit in Washington, D.C.
The studyís statistical and data management center was based at
the University of Minnesota in Minneapolis.
The study investigators followed 4,111 HIV-infected men and women
ages 18 and older in 25 countries at 252 clinical trial sites. Half
of the volunteers were injected with 7.5 million international units
(MIUs) of Proleukin twice a day for five consecutive days every eight
weeks for at least six months. After six months, volunteers could
receive additional IL-2 cycles at the discretion of their physicians
to maintain CD4+ T cell counts at twice their baseline levels or
greater than 1,000 cells/mm3 for as long as possible.
All volunteers were assessed every four months for an average of
seven years to monitor CD4+ T cell counts, viral load (the amount
of HIV in the blood) and signs of illness. In analyzing the ESPRIT
results, researchers found that although volunteers who received
IL-2 maintained a higher CD4+ T cell count (an average of 160 cells/mm3 higher)
than those in the antiretroviral-only study group, there was no difference
in the rate of HIV-associated opportunistic diseases or death between
the two groups.
The SILCAAT study — short for "Subcutaneous, Recombinant,
Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts
under Active Antiretroviral Therapy" — began in April
1999, ended in November 2008, and was conducted by the same international
coordinating center structure that conducted ESPRIT. While SILCAAT
was funded primarily by Chiron Corp., sponsorship of SILCAAT shifted
from the Chiron Corp. to NIAIDís Division of Clinical Research
in 2003. The study investigators followed 1,695 HIV-infected adults
in 11 countries at 114 clinical trial sites. Volunteers assigned
to the IL-2 group received 4.5 MIUs of Proleukin twice a day for
five consecutive days every eight weeks for one year. After that
point, participants could receive additional IL-2 cycles to maintain
their CD4+ T cell counts at 125 to 175 cells/mm3 above
baseline. All volunteers were assessed every four months for approximately
As in the ESPRIT study, the SILCAAT volunteers who received IL-2
experienced a higher CD4+ T cell count (an average of 59 cells/3 higher)
than those who received only antiretrovirals, but there was no
difference in health outcomes between the two groups.
Additionally, IL-2 recipients in both studies experienced a greater
number of serious clinical events already known to be associated
with IL-2, including disorders of the heart and blood vessels,
injection site reactions and such psychiatric disorders as depression
and suicidal behavior.
Participants in the ESPRIT and SILCAAT clinical trials were promptly
informed of the findings. Additionally, NIAID has discontinued
the use of IL-2 in a separate, 20-country clinical trial known
as STALWART (which stands for "Study of Aldesleukin with and
Without Antiretroviral Therapy"). The study was comparing
the effects of providing no treatment with the effects of intermittent
cycles of IL-2 alone or IL-2 plus antiretrovirals in participants
with early-stage HIV infection who do not yet meet the criteria
to begin antiretroviral treatment. STALWART began in November 2005,
and routine follow-up of the participants will continue until the
end of February as originally planned.
Proleukin is approved by the U.S. Food and Drug Administration
to treat adults with metastatic melanoma or metastatic kidney cell
carcinoma. As a cancer treatment in the United States, it is administered
to hospitalized patients for a shorter duration and at a higher
dosage than those used in the ESPRIT and SILCAAT clinical trials.
For more information about the ESPRIT and SILCAAT clinical trials,
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States, and worldwide — to study the causes of infectious and immune-mediated
diseases, and to develop better means of preventing, diagnosing
and treating these illnesses. News 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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