Using IL-2 with Triple Combination

gangbang at ix.netcom.com gangbang at ix.netcom.com
Mon Nov 4 09:23:05 EST 1996


"John P. Laehy" <laehy at wt.net> wrote:

>I have been on triple combination since mid April 1996. The combination is
>Crixivan, d4t, and 3tc. My viral load dropped from 55,000 to below
>detection, and my T-cells increase from 160 to 280. My doctor is
>recommending that I start subcutaneous shots of interleukin-2 for five days
>every eight weeks. I have review AIDS information off the net, but there is
>not much on triple combination with IL-2. Does anybody have any information
>about this treatment?

The following is the latest press release on the IL-2 studies...

NIH NEWS
_________________________________________________
National Institutes of Health
National Institute of Allergy and Infectious Diseases

EMBARGOED FOR RELEASE                        Greg Folkers
Wednesday, Oct. 30, 1996                               (301) 402-1663
5:00 p.m. Eastern Time
folkers at nih.gov

IL-2 THERAPY DOUBLES CD4+ T CELL COUNTS IN 
HIV-INFECTED PEOPLE

    In a one-year study of HIV-infected people, infusions of the
immune system protein interleukin-2 (IL-2) have resulted in dramatic
and sustained increases in the primary immune system cells depleted
during HIV infection, according to investigators at the National
Institutes of Health (NIH).

    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
(AIDS).  

    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,
B.C.

    "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 therapy."

    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
Emeryville, Calif.

STUDY DETAILS
    In the study, 60 patients with baseline CD4+ T cell counts
above 200/mm3 of blood were randomly assigned to receive IL-2 plus
licensed antiretroviral therapy, or antiretroviral therapy alone.
IL-2
was administered at a starting dose of 18 million International Units
(IU) a day for five days every two months.  The dose was reduced as
needed; the mean dose used in the latter part of the study was
approximately 8 million IU/day.

    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
    The NIH investigators currently are working with scientific
colleagues in the United States and abroad to develop a Phase III
strategy to determine whether the increases in CD4+ T cells achieved
with IL-2 therapy will translate to fewer AIDS-related complications
and improved survival for HIV-infected people.

    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
IL-2.

    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.
                                        ###
References:
Kovacs JA, et al.  Sustained increases in CD4 counts in HIV-infected
patients treated with interleukin-2 during a randomized, controlled
trial.  N Engl J Med  1996;335:1350-56.

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,
1996.

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.
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