This hot treatment raises questions but provides one answer:
Scientists shut each other out at their own peril
Even though CD4 count has had its day in the sun as a predictor of HIV disease
progression, the summer's hot new treatment gossip buzzed around a promising therapy
called IL-2 -- whose main effect is to boost CD4 count to sometimes phenomenal heights.
Too good to be true? It may be. But the real news is that a scientific turf battle
may have kept this therapy out of reach for several years longer than necessary.
It sounded like the miracle for which everyone had been praying:
A new treatment was revving up the immune system and increasing CD4
cell production by the hundreds. The CD4 cell counts of men and
women infused with the immune system protein interleukin-2 (or IL-2)
rose more than 50 percent over the course of a single year. One man
watched his counts almost quadruple. The counts of two others had
stayed above 1,000 for almost three years.
The formal research findings announced in March by a team from
the National Institute of Allergy and Infectious Diseases (NIAID)
confirmed the rumors that had been sweeping across the country about
women whose CD4 cells had doubled in three weeks and men whose CD4
counts had reached 3,500, thanks to a drug used originally to treat
metastatic kidney cancer. Patients who found access to the drug --
either through clinical trials or by persuading their physicians to
prescribe it "off-label" -- had become IL-2 crusaders, preaching
conversion from antiretroviral therapy to immune modulation.
Suddenly electronic bulletin boards were alive with discussions of
how to convince wary doctors to prescribe IL-2, how to mix it at
home and how to endure its often-severe side effects. The National
Institutes of Health (NIH) and Chiron, manufacturer of Proleukin
(the brand of IL-2 used in the studies), announced new trials to
test new dosages and new dosing regimens. Dr. Larry Bruni of
Washington, D.C. was one of the first community physicians to jump
on the IL-2 bandwagon. The demand became so great that after Blue
Cross cut him off as a provider, he was still swamped with patients
so desperate to try IL-2 that they were willing to shell out cash --
at $2,400 a course of treatment.
But as IL-2 becomes the nation's latest popular unproved
treatment for people with asymptomatic HIV disease, many physicians
worry that patients with CD4 counts below 100 -- the ones most
likely to be harmed by a drug that promotes the growth of HIV as
well as of CD4 cells -- will begin taking it. Members of Treatment
Action Group (TAG) are furious that some community physicians such
as Bruni have begun to use IL-2's ability to raise CD4 cells as "an
attractive marketing tool for their own practices: 'Come see me and
watch me raise your T-cells,'" says TAG's Gregg Gonsalves. Bruni's
hype, appearing in his advertisements (including in POZ), converted
the experimental therapy into the Wonder Drug. The hype became so
optimistic that Gonsalves wants NIAID director Dr. Anthony Fauci to
issue an official clinical alert to doctors warning that "we do not
know the long-term clinical effects of IL-2 therapy, that IL-2
up-regulates HIV and has its own extreme toxicities." (According to
a September exposé by Bill Gifford in the Washington City Paper,
Bruni has other problems, including a 1994 bankruptcy filing and a
$4.1 million jury verdict against him and two co-defendants last
June in a civil case brought by a former Catholic priest whom Bruni
treated for HIV for years; the priest turned out to be HIV
And savvy treatment activists on both coasts are voicing
skepticism about a treatment regimen that raises more questions than
answers: What do the CD4 cell increases really mean? Are 1,000
IL-2-induced CD4 cells the same as 1,000 naturally induced CD4
cells? Are the new CD4 cells functional? Is IL-2 simply forcing the
body to churn out cells that will turn out to be virus chow? Is it
really safe to infuse patients with the very drug used to grow HIV
in the laboratory?
They aren't getting many answers. Although IL-2 research for AIDS
predates the discovery of HIV, scientists are still stumped by many
of these basic, critical questions. The virology-fixated AIDS
research establishment is woefully bereft both of an understanding
of how HIV damages human immune systems and of tools for developing
such an understanding -- the legacy of a federal AIDS research
program so focused on the "it's the virus, stupid" principle that
scientists, physicians and patients are unprepared to deal with any
therapy with an immunologic basis.
That's hardly surprising given the stranglehold virologists
established over most of AIDS research in the early 1980s. Dr. Nancy
Klimas of the University of Miami began to understand that reality
at her first meeting of Veterans Administration AIDS researchers in
1986. A young immunologist, she was anxious to apply her newly
developed skills to the new disease, but her enlistment in the war
against AIDS was hardly greeted with hurrahs. Instead, a senior
researcher dismissed her fliply: "Immunologists have no role to play
in AIDS." Klimas was stunned. Sure, a virus was involved, but the
disease was destroying CD4 cells and deregulating immune systems.
How could immunology be irrelevant?
It never has been, but that has not stopped the official AIDS
research establishment from putting virtually all of its eggs into
the virology basket and ignoring treatments designed to bolster the
immune system rather than murder the virus. As Klimas begged for
funds to devise ways to rebuild decimated immune systems, she
watched while her Miami colleague, Dr. Margaret Fischl, pulled in
millions of dollars in major grants from the federal government and
pharmaceutical companies to test drugs that might kill, or at least
slow, the virus. Her experience became the plaint of immunologists
across the country.
After all, immune manipulation wasn't as sexy as a magic
Frustrated by the overconcentration on the search for such
weaponry -- which, even if the elusive magic bullet were found,
would still leave physicians clueless as to how to rebuild
permanently damaged immune systems -- West Coast activists, lead by
Martin Delaney and Jesse Dobson of Project Inform, organized their
own immune reconstitution think tanks. These have evolved into
regular seminars on whether immune systems can recover from HIV
infection -- and to foster cooperation among scientists interested
in figuring out how to do so. While federally funded scientists
poured millions of dollars into testing and retesting AZT and its
cousin drugs -- ddI, ddC and d4T -- Project Inform pushed research
into the basic science of immunology, immune-boosting drugs and the
transplantation of healthy immune cells.
Then came the International AIDS Conference in Berlin and the
watershed year of 1993. The simple -- some might say simplistic --
model of HIV as Pac-man coursing through the bloodstream, gobbling
up CD4 cells left and right until the body was left depleted of all
defense, was collapsing. Senior researchers were beginning to talk
seriously that HIV's most dangerous trick may be deregulating the
immune system rather than murdering CD4 cells directly. But still
there was no consensus as to whether the virus forces uninfected
cells to merge with infected ones, whether HIV proteins cause
infected cells to commit mass suicide, whether HIV simply turns CD4
cells off or whether HIV fools killer CD8 cells into destroying
What little consensus there was surrounded the success of the
multibillion dollar charge to locate the magic bullet against HIV:
It was widely acknowledged to be a dismal failure. Dr. David Ho of
New York City's Aaron Diamond Lab admitted to the press that
researchers had hit a "biological wall." Early in the epidemic
"scientists went for the home run: A cure, a treatment or a
vaccine," he said. "But now we realize we haven't even made it to
first base." Even virologist Dr. Robert Gallo, former chief of the
Laboratory of Tumor Cell Biology at the National Cancer Institute
and a longtime advocate of hitting HIV with a Mack truck of drugs,
told delegates to forget antiretrovirals and get on with more
In other words, maybe it's time to look beyond virology.
For the team led by NIAID director Dr. Anthony Fauci, himself an
immunologist, that meant looking for ways to guide the body's immune
system to contain HIV rather than for ways to kill the virus. His
approach was to manipulate the body's cytokines -- a network of
proteins that serve as chemical messengers of the immune system. In
HIV disease the balance of cytokines is thrown awry. Some cytokines,
like tumor necrosis factor-alpha (TNF-alpha) and interleukin-6
(IL-6) are overproduced -- which apparently stimulates and
perpetuates replication of HIV. Others, like IL-2, are underproduced
-- which seemingly contributes to the depletion of both CD4 and CD8
Re-regulation of cytokines became Fauci's strategy for containing
Fauci's cytokine of choice was IL-2, which stimulates production
of both CD4 cells and CD8 suppressor cells, which many believe to be
the body's most potent weapon for containing HIV. In HIV infection,
CD4 cells seem to lose their capacity to produce IL-2, and even to
respond to the cytokine's signals. Without sufficient IL-2, CD8
cells aren't activated to fight HIV. CD4 production diminishes.
Programmed cell death begins.
IL-2 therapy was hardly a new approach. Dr. Clifford Lane of
NIAID's Laboratory of Immunoregulation had started experimenting
with it even before the discovery of HIV. Lane had no idea what was
causing the immune destruction that was AIDS, but he set his sights
on replacing the cells being destroyed in order to stop the disease.
In the test tube, at least, IL-2, which was originally called T-Cell
Growth Factor, did just that.
There were, however, two major problems. At the initial doses
both Lane and oncologists testing the cytokine against cancer were
using, IL-2 proved incredibly toxic. Patients suffered from high
fevers, lung congestion and swelling, capillary leakage and skin
problems. They experienced liver, kidney and gall bladder disorders,
low neutrophils and platelets, hypotension and glucose intolerance.
When produced naturally, IL-2 is secreted in tiny concentrations at
specific locations by specific cells. Human bodies simply aren't
designed to cope with the large quantities of the cytokine dumped
into the bloodstream by infusions.
Even more frightening, once HIV had been isolated, was the
discovery that IL-2 is a powerful activator of the virus. In fact,
it was the addition of IL-2 to HIV-infected cells that allowed bench
scientists to grow HIV in their laboratories.
Nonetheless, Lane persisted -- with discouraging results. When he
infused patients continuously with the cytokine, its positive impact
disappeared within weeks. Finally, he and his colleague Joseph
Kovacs tried a cyclical regimen keyed to the cycles during which
cells develop and mature. They admitted study volunteers to the
hospital, hooked them up to infusion pumps and gave them 6 to 18
million international units of IL-2 a day for five days, then
allowed the patients -- and their immune systems -- to rest for
eight weeks. Six of the 10 volunteers in the trial who began
treatment with more than 200 CD4 cells saw their counts increase
more than 50 percent. Three had 300-to-400 percent increases. Lane
had managed to keep the CD4 cells of three patients above 1,000 for
almost three years with five-day booster infusions whenever their
counts fell below 1,000.
These were the success stories everyone started talking about
this spring. And NIAID, which had been losing its hegemony over AIDS
research for two years, promoted it to the hilt. "Although current
anti-HIV drugs have transient benefits, especially for individuals
in late-stage disease, they do not prevent the immunologic
deterioration associated with HIV disease," said Lane. "It is
increasingly evident that preservation and restoration of the immune
systems of HIV-infected people are necessary if they are to live for
long periods of time. This study shows that IL-2 may help accomplish
Fauci practically gushed. "This work is a model of NIAID's 'bench
to bedside' philosophy of research. In this instance, the
recirculation of information from the laboratory bench to the
patient's bedside, over a period of 13 years, has led to
No one wanted to focus on the less-successful patients. Four of
the 10 early volunteers did not respond or simply maintained their
counts. No one knows why. One of the nonresponders came down with
PCP several months after quitting IL-2 therapy; his count was stable
at 400 cells. Lane insisted that PCP was not unheard of in HIV
positive people with such high CD4 cells, but many scientists and
patients worried that IL-2 had maintained the patient's count with
non-functional CD4 cells.
More troubling was that the treatment caused an initial burst of
virus production -- up to a sixfold increase. That was hardly
surprising since HIV's favorite targets for infection and
replication are the same activated CD4 cells promoted by IL-2. With
strong antiretroviral therapy such as AZT, ddI or ddC, volunteers
with higher CD4s to start with managed to fight off the viral
increase. But the picture was alarmingly different for those who
began with CD4 counts below 200. Only two of six patients who began
treatment with CD4 counts between 100 and 200 had significant CD4
increases. None of the six patients with counts below 100 enjoyed
any benefit. In fact, most of the study participants with low CD4
counts couldn't fight off the increase in virus; the effect of IL-2
was a lasting rise in the HIV levels in their blood.
Physicians looked at Lane's and Kovacs' results and wondered if
it was worth using the new regimen at all. It was clearly too
dangerous to give the drug to the patients most in need of a new
weapon. And they wondered if it was smart to subject healthy
patients with 400 and 600 CD4 cells to a treatment that promised to
give them rashes, fevers, low blood pressure, diarrhea, flu-like
symptoms and a wide range of laboratory abnormalities including
reduced calcium, albumin and magnesium without any evidence that the
increases in CD4 count correlated in any way to greater health or
Dr. William Paul, head of federal AIDS research, put it bluntly:
"While extremely provocative, it remains to be shown that this will
translate into resistance to opportunistic infections or
prolongation of life."
Such skepticism infuriated patients shopping for new treatments.
Few denied the severity of the toxicities of the infusions used by
Lane, but many believed the increase in CD4 cells were worth the
misery -- or insisted that newer regimens, especially ones allowing
patients to inject themselves with IL-2 at home, made the risks
minimal. They didn't want to hear a lot of scientific double-talk
that might take the edge off their hope.
Byron Graham of Washington, D.C. had tried AZT and given up when
it made him sick. He'd been on ddI for three years but put most of
his faith in a healthy lifestyle. No white bread or sugar has passed
though his system for five years. He keeps his stress low and
teaches yoga. Still, last fall his CD4s fell below 200 and he began
to look into IL-2. "The day after the study results were released
the naysayers were out in full force," Graham said. He read their
arguments on a computer bulletin board and suddenly felt himself get
sicker. He injected himself with IL-2 subcutaneously for four and a
half days and simply stopped reading the chat group on which they
posted their concerns.
But ignoring the skeptics won't change the reality that IL-2 is a
therapy thriving without any proof of effectiveness -- and with
clear proof of significant, and potentially dangerous, side effects.
Increases in the cytokine TNF-alpha, believed to be responsible for
most of IL-2's toxicity, can further deregulate the immune system
and can damage the thymus gland. The jump in viral load, controlled
by antiretrovirals in patients with higher CD4 counts, can become
permanent should resistance to those drugs develop.
And increasing IL-2 levels might, in fact, be counteracting an
intelligent immune response to HIV infection. Some scientists
believe that the best way to combat HIV is not to increase but to
eliminate activated CD4 cells, which are believed to be the main
site of HIV production. The underexpression of IL-2 in the bodies of
HIV-infected individuals, according to this theory, might then be
the immune system's way of depriving the virus of the chow it uses
Even if IL-2 therapy is safe, its effectiveness remains open to
question because more does not necessarily equal better, even in CD4
cells. Lane himself acknowledges that "the question is whether these
new T-cells are good at fighting infection." Arthur Gottlieb,
chairman of the department of microbiology and immunology at Tulane
University School of Medicine, explained the dilemma: "Excessive
emphasis [is] paid to CD4 cell numbers as opposed to CD4 cell
function. The latter is the really critical issue determining a
patient's course. Of course, CD4 cells decline in number over the
course of HIV disease, but every CD4 cell is not equal to every
other CD4 cell."
Theoretically, Dr. Nancy Klimas explains, IL-2 induces the body
to produce entirely new sets of naïve CD4 cells -- CD4 cells that
haven't yet learned where they should go or how to do their jobs. No
one is sure how long it takes for naïve cells to learn or whether
IL-2-induced CD4 cells can learn as well as naturally produced ones.
What they cannot learn is immune tricks the body has already
forgotten, and in HIV disease, the body gradually develops holes in
its immunologic repertoire. Even people with relatively high CD4
counts have such gaps, and IL-2 cannot increase the types of CD4
cells that are no longer there. If the body has already "forgotten"
how to fight PCP or CMV, IL-2 isn't going to reteach it.
So physicians know that an IL-2-induced CD4 cell increase from
200 to 1,200 doesn't necessarily put a person out of the range of
opportunistic infections. Both Lane and Dr. Gwen Fyfe of Chiron
worry that once IL-2 treatment has begun, CD4 count and its rate of
decline will become meaningless measures by which to make decisions
about the initiation of prophylaxis.
Many HIV positive people are willing to take the chance that IL-2
might not be so miraculous and are avoiding the toxicities by using
a lower dose given by subcutaneous -- under the skin -- injection.
But low-dose IL-2 (defined as between 36,000 units twice weekly and
3.6 million units per square meter of body surface daily) is, in
essence, a different drug than the high-dose cytokine described by
Lane and Kovacs. It binds to a different set of immune cells and is
used to produce decidedly different results. While high-dose IL-2 is
meant to increase CD4 cell counts, low-dose IL-2 targets natural
killer cells in order to improve their functioning -- something the
high-dose version seems unable to accomplish. Dr. Larry Bruni began
playing with low-dose subcutaneous IL-2 almost five years ago and
was not impressed with the results. He now uses it only for
maintenance therapy. Other physicians, however -- particularly Dr.
Hedy Teppler of Philadelphia -- believe that the relatively nontoxic
therapy is a promising adjunct to antiretrovirals.
Teppler's patient Jonathan Lax probably has more experience with
low-dose subcutaneous IL-2 than anyone in the nation: He has used as
little as one-half and as much as four million units, on and off,
since March 1993. The rise in his CD4 count has never been as
dramatic as those in Lane's patients -- the first round they rose
from 350 to 540 -- and the increase hasn't lasted more than eight
months. Two years after he began therapy, his counts are down to
220, but Lax remains a believer.
"I'm convinced IL-2 works best right after you switch
antiretrovirals. For those running out of efficacy on
antiretrovirals, it is only marginally effective. IL-2 is a bit of a
pact with the devil: You get an increase in CD4 cells, but you also
get an increase in viral production. Sometimes you wonder, is this
doing me good or doing me harm."
Lax has been waiting for scientists to answer that and dozens of
other immunologic questions for years. When Fauci hyped IL-2 and
immune therapies in Berlin in 1993, Lax sat in the audience and
wondered, "Where's he been? Why didn't he push AIDS research this
way from the beginning?"
Lax provides his own answer. "Infectious-disease doctors and
virologists grabbed this disease with their 'kill the germ' model.
Only after Berlin did the immunomodulatory approach come to the
fore, the idea of supporting the host. And even then, they've never
sought out people like Hedy Teppler who've been using this approach
They still aren't. The Department of Immunology and Microbiology
at the University of Miami recently invited a prominent outside
virologist to speak at an AIDS workshop during a planning retreat.
After speaking about therapies to expand CD8 cells, he argued that
immunomodulation had no role to play in HIV disease treatment.
How could that be, Nancy Klimas and others argued? Expanding CD8
cells is immunomodulation, after all. No, the virologist insisted,
it's antiviral therapy.
"The politics have become a question of semantics," Klimas says,
still astonished at the virologic expropriation of an immunologic
For people with AIDS, that question of semantics can be a matter
of life and death. Despite the change in climate after Berlin -- and
the efforts of activists on both coasts -- the federal AIDS research
establishment remains dominated by virologists who now seem to be
teaching themselves immunology rather than turning the reins of
power -- and the federal research dollars -- over to their
No one can calculate how many will die before they master