AIDS TREATMENT NEWS #218, March 3, 1995
Results of the leading study of interleukin-2 (IL-2), an
experimental immune-based treatment for HIV, were published in
the NEW ENGLAND JOURNAL OF MEDICINE on March 3. While this
research, conducted by H. Clifford Lane, M.D., and 12 other
researchers at the U.S. National Institute of Allergy and
Infectious Diseases, is an important contribution to developing
a new kind of treatment for AIDS, and for other diseases as
well, IL-2 is not a treatment that many patients will want to
IL-2 is a substance normally produced in the body which
stimulates the growth and development of T-cells and other
immune cells. It is also a prescription drug, approved for use
in treating metastatic renal cancer. IL-2 treatment can cause
serious toxicities, however, because the body's own IL- 2 is
produced in small amounts and used locally; but when the same
substance is injected, it raises the level throughout the
bloodstream, which is not how the body's own IL-2 acts.
At this time IL-2 has serious drawbacks as an AIDS treatment:
* It did not work in persons with low CD4 (T-helper) counts; in
those with a CD4 count under 200, it seldom showed any
benefit, and it also caused more serious side effects than in
those with higher counts.
* Even in those with CD4 counts over 200, it did not
substantially raise CD4 counts in four out of ten of the
patients, for unknown reasons.
* While IL-2 was being administered (usually for five days
every two months), it often caused severe side effects,
described as worse than a bad case of the flu. Some patients
had to spend part of each five-day treatment in bed.
* When IL-2 did work, it greatly raised the CD4 count, and with
repeated treatments, the count remained high. But it is not
known how well the CD4 cells are working; and there is no
proof yet that the treatment provides overall clinical
benefit to patients.
* IL-2 also stimulates the growth of HIV. About half the people
treated have a large but temporary jump in viral load right
after each injection -- even though everyone receiving IL-2
was also taking an anti-HIV treatment, such as AZT or ddI, to
* The results so far are based on uncontrolled studies of only
a small number of patients.
* IL-2 is expensive.
The main reason why it is unlikely that IL-2 will be widely
used at this time is that, at least with the antivirals now
available, it does not work for those with advanced AIDS. And
those who are doing well enough to use the drug may not want an
experimental treatment with considerable drawbacks and no
proven clinical benefit yet.
But there are also reasons why this research is important:
* When IL-2 does raise CD4 counts, they often went up by
several hundred or more, bringing them into the normal range,
and keeping them there for a year or longer.
* In the future, when better antivirals (such as protease
inhibitors) are available, it is possible that IL-2 may work
for patients with more advanced disease. This is because the
drug may be failing in more advanced patients because it is
stimulating the growth of HIV. So far this is only a theory;
it is now being tested in a trial which combines IL-2 with
the Merck protease inhibitor.
* It may be possible to use IL-2 in lower doses, or with
different dosing schedules, to reduce side effects.
* The IL-2 studies are producing new knowledge about the immune
system in HIV disease, knowledge which could lead to a new
class of immune-based treatments.
* If IL-2 is indeed improving immune response, that could be
useful in many different diseases. For example, a NIAID trial
of IL-2 for treating drug-resistant tuberculosis or other
refractory mycobacterial infection (in persons without HIV)
is now open and recruiting volunteers.
The March 2 Report
The information published March 2, which represents the state
of IL-2 research as of about a year and a half ago, has
basically been known to the AIDS community for some time. A few
HIV physicians are already treating patients with IL-2, based
on this work.
The article reports on three groups of patients:
(1) The first group -- 23 patients in a dose-escalating trial,
all with CD4 counts greater than 200 -- received a single
course of treatment, a continuous intravenous infusion
lasting either five or 21 days. The doses ranged from 1.8
million IU (international units) to 24 million IU per day.
The maximum tolerated dose was found to be 18 million IU
per day, when the drug was given for five days.
(2) The second group, of ten patients with CD4 count over 200,
received a five-day course of intravenous treatment
(initial dose 18 million IU per day) every eight weeks.
Eight of the ten required dose reductions (to 12 million IU
or 6 million IU per day) due to side effects, and two of
these eight chose to discontinue the treatment, although
they remained in the study for followup.
At the time data was collected for publication, five of the
ten had received IL-2 treatment for two years. The average
CD4 count (for all ten of these ten patients) went from
about 400 to almost one thousand during the first year of
treatment; the maximum CD4 increase was over 2200. But four
of the ten did not respond -- their count stayed about the
same, or even continued to decline.
CD8 counts generally remained stable. An analysis of the
cells using 2-color flow cytometry showed that the
proportion of CD8 cells positive for HLA-DR was reduced --
which is considered a potentially good sign.
Four of the ten patients showed a consistent increase in
viral load (HIV RNA) after each infusion; but then the
viral load quickly returned to baseline. There was no
corresponding increase in p24 antigen. Another four of the
ten had a viral load which remained below the 10,000-copy
cut-off value of the test which was used (the Chiron
branched DNA); if they had an increase in viral load, it
was too small to be detected by the test.
Two of the ten patients developed pneumocystis; both had
failed to respond to IL-2, and both had a very high viral
load, 555,000 and 435,000 copies per ml. Their last CD4
counts before being diagnosed with pneumocystis were 400
and 31, respectively. There were no other opportunistic
infections in these ten patients.
(3) The third group was 15 patients with CD4 counts under 200.
Their side effects were more severe, and all 12 who
received two or more courses of treatment required dose
reduction. One patient, who took trichosanthin (compound Q)
several days after an IL-2 treatment without telling the
researchers, died two days later "from hypotension and
Two of the six patients who started with CD4 of 100-200 had
increases of at least 50 percent. But none of the six who
started with under 100 had CD4 increases, and two of these
patients developed opportunistic infections and died, about
two and seven months after their last IL-2 treatment.
Immunological tests showed that even in those with CD4
count under 100, their cells may have responded to the
drug, suggesting that it may have been the virus which was
preventing the CD4 count from increasing.
Additional IL-2 Studies
Three other studies at NIH of IL-2 in patients with HIV are now
recruiting volunteers. One will test IL-2 in combination with
strategies to reduce the activity of tumor necrosis factor
(TNF), in the hope that this could improve the results of IL-2
treatment by reducing the side effects and/or viral increase
which IL-2 can cause. Another is for people with T- helper
count over 500, and will test two doses, given subcutaneously
instead of intravenously, and every four weeks instead of every
eight weeks. The third study is examining different durations
of infusion, and different intervals of IL-2 infusion.
Other IL-2 trials include randomized studies in the U.S. and
Australia, and also a trial which combines IL-2 with the Merck
For information about volunteering for IL-2 clinical trials,
call the AIDS Clinical Trials Information Service,
800/TRIALS-A. You can also find out about AIDS-related trials
conducted by the National Institute of Allergy and Infectious
Diseases by calling 800/AIDS-NIH.