AIDS TREATMENT NEWS Issue #221, April 21, 1995
The drug thalidomide has lately become the object of wide-
ranging research for its proposed value in treating a number
of AIDS-related conditions, including aphthous ulcers,
wasting, and tuberculosis, as well as for treating HIV
infection itself. If its promise holds true, thalidomide will
become pharmaceutical medicine's most famous come-back story.
The word thalidomide provokes alarm in those who remember it
as the notorious cause of birth defects in thousands of
European babies born in the 1950s and 60s. It had been widely
prescribed as a sedative under the trade name Contergan until
its teratogenic effects became apparent. It was never
marketed in the U.S., and in fact has been used, often
irrelevantly, as a defense of stringent U.S. drug
Most people think that after the thalidomide disaster the
drug was shelved forever, but actually it has been studied
extensively in auto-immune disease research, and it happens
to be very useful for managing a consequence of the
medications used to treat Hansen's disease (leprosy). It is
now routinely and safely administered to people with Hansen's
around the world.
The rationale behind the use of this drug in HIV disease is
somewhat involved. Rather paradoxically, it appears to work
by pacifying part of the immune response, a property which
would not at first seem to benefit a disease described as an
However, HIV causes not simply a deficiency, but an
"autoaggressive" reaction. In the protracted war against the
virus, the immune system begins OVERproducing certain
chemical messengers called cytokines which immune cells use
to communicate. Cytokines are potent and their pathways are
extremely complex, and, depending on the situation, some can
serve more than one function. All considered, it is not
surprising that the chaos fostered by too many messengers and
messages could cause more harm than good. Excessive levels of
one cytokine in particular, tumor necrosis factor, or TNF,
have been associated with the development of aphthous ulcers,
dementia, fevers, fatigue and wasting.
Not only does HIV stimulate TNF production, but TNF in turn
can enhance HIV replication.
A number of agents are reported to inhibit the production of
TNF, including pentoxifylline, sulfasalazine, cyclosporine,
N-acetyl cysteine, ketotifen, corticosteroids and
thalidomide. Currently, the most prominent TNF inhibitor
under study is thalidomide, perhaps because it is relatively
strong and selective in this regard. Some of the other drugs
have effects which are not completely understood or desired.
(Some are also in use in HIV treatment for other rationales.)
The capacity of thalidomide to inhibit TNF was demonstrated
by researchers at The Rockefeller University with funding by
Celgene Corporation. Consequently, development rights to this
use of thalidomide are owned by Celgene, which calls the drug
Synovir. Sol Barer, Ph.D., president of the company, spoke to
us at length about the drug's status.
Interest in thalidomide has blossomed in the past year, given
its multiple possibilities and the expanding research into
TNF. The drug is under study in a number of HIV-related
clinical trials in Europe and North America, and in some
countries it is also available on a compassionate-use basis.
In the U.S., a few HIV buyers' clubs are planning to carry
thalidomide, a choice which may turn confrontational with the
Food and Drug Administration.
Celgene is currently developing several new TNF inhibitors
which are chemically analogous to thalidomide but which might
be safer or more effective.
Thalidomide also inhibits angiogenesis, the development of
new blood vessels. This property which unfortunately
inhibited the normal growth of fetal limbs has garnered it
research interest in diseases characterized by uncontrolled
angiogenesis, such as cancer and Kaposi's sarcoma. Dr. Barer
noted that TNF stimulates the growth of new blood vessels, so
that the inhibition of TNF may still be the operative
mechanism in angiogenesis research.
Many people with HIV are bothered by recurring, painful oral
ulcers that are frustratingly difficult to treat. The ulcers
are apparently not caused by an opportunistic agent, like
herpes, and so they are generically described as aphthous,
meaning simply that they occur on a mucous membrane. A biopsy
can determine if an ulcer is not indeed herpes, which would
make a difference in the choice of treatment. The common
treatment for aphthous ulcers has been to suppress, broadly,
the immune response, which includes TNF production. This is
easily accomplished with corticosteroids like prednisone. A
topical oral elixir of prednisone may work well enough for
some people. But many others need a stronger, systemic
formulation, and since long-term use of these steroids has
serious side effects, it is not a tenable permanent solution.
A better solution, theoretically, would be to inhibit TNF
production more specifically, such as with thalidomide, and
leave other immune responses alone. There are at least 38
sites around the country testing thalidomide for HIV-related
Wasting is an even more serious problem for many people. It
has been well documented as a cause of death even in the
absence of opportunistic illnesses. The origins of wasting
are complex and variable, and include loss of appetite, poor
intestinal absorption, low testosterone production and high
Wasting now has quite a few possible treatments, including
endocrine modifiers like human growth hormone, testosterone,
nandrolone or oxandrolone, and appetite/nutritional enhancers
like megestrol acetate, marijuana or dronabinol, and total
parenteral nutrition (TPN). None of these, however, work by
decreasing TNF levels. Based on some promising earlier
research, there are now six trial sites around the country
testing thalidomide in people with wasting syndrome.
Thalidomide has developed a somewhat contradictory
relationship to the diagnosis and treatment of tuberculosis
and MAC. It is being studied as a adjunctive treatment to the
standard therapies because it relieves some of the symptoms
associated with TB. But for the same reason it may mask an
undiagnosed TB or MAC infection and thus delay timely
treatment. Consequently, physicians who have patients using
thalidomide, whether through a trial or not, should monitor
them for mycobacterial infections and consider prophylaxis
for those at risk.
Finally, thalidomide may be useful for treating primary HIV
infection, and is in trials for that purpose at five sites.
It is unclear, however, if the drug has any activity on HIV
beyond inhibiting TNF. Dr. Barer feels that it might make a
very good complement to a combination antiretroviral regimen.
He also is optimistic that second or third generation TNF
inhibitors will surpass thalidomide's efficacy and diminish
some of the toxicity.
Persons interested in any of these studies should call
800/TRIALS-A for more specific contact information.
One of the possible side effects of thalidomide, and a
potentially irreversible one, is peripheral neuropathy.
Individuals with a history of neuropathy may be disqualified
from thalidomide trials.
Importantly, persons who for reasons other than neuropathy do
not meet the entry criteria of the oral ulcer trials may
qualify for a little-known compassionate-use program, managed
somewhat guardedly by the FDA. For information about that
program, physicians only should call Brenda Atkins or Matthew
Tarosky at 301-443-9553. In some instances the drug has been
released for vaginal or anal ulcers as well.
Several investigators told us that the thalidomide trials
have been slow to recruit, in spite of the apparent community
interest in this treatment. One problem was articulated by
Kathleen Mulligan, Ph.D., who is a co-investigator for the
wasting trials at San Francisco General Hospital. Dr.
Mulligan has encountered disbelief from many people,
including physicians, that the drug thalidomide would ever be
offered to anyone for anything. She hopes that as accurate
information becomes more available, thalidomide's
catastrophic history, and its real promise, will be
understood in a broader context.
Another reason for the slow recruitment may be a very old
problem: both the wasting and ulcer protocols involve a
placebo arm, a contingency which many people in ill health
find very unattractive. As has been the case before, the HIV
treatment community will soon pave its own road, as the drug
becomes available through the Thalidomide Underground
Compassionate Use Program, offered by the PWA Health Group in
New York and the Healing Alternatives Foundation in San
Francisco, the largest HIV buyers' clubs in the country.
The clubs had planned to carry it earlier, but were
approached by the FDA last November and encouraged not to do
so, because of the seriousness of thalidomide's potential
side effects, and presumably the attendant emotional and
political charge that surrounds the drug as well.
Both Sally Cooper, Director of the PWA Health Group, and
Matthew Sharp, Director of Healing Alternatives, had strong
rebuttals to the FDA concern. They say that the clinical
trials of thalidomide cannot enroll everyone who needs the
drug, and that many people do not wish to and should not have
to endure the risk of a placebo in this situation. (And the
small compassionate use program is only for ulcers, not for
persons with wasting syndrome.) They also point out that a
number of seriously teratogenic drugs are already approved
for marketing by the FDA, including megace, and including an
acne drug used by teenagers.
[Comment: ANYONE TAKING THALIDOMIDE MUST UNDERSTAND THE
GRAVITY OF ITS DANGER TO DEVELOPING FETUSES AND ABSOLUTELY
AVOID STARTING A PREGNANCY. Given that, why would thalidomide
be withheld from responsible people, including women, who
desperately need it and who do not qualify for or choose to
participate in clinical trials? People facing serious health
concerns deserve to make their own informed treatment
decisions. Also, the trials have not been uniformly open to
women. Celgene has agreed to change that, with the
stipulation that pre-menopausal women agree to pregnancy
testing and reliable contraception.]
In this context, the buyers' clubs are proceeding with what
they consider the only ethical course. They will test the
product they carry to ensure its quality, and will offer
thorough counseling about the use and cautions of the drug.
Moreover, they will require a prescription for its release,
and a consent form that must be signed by the patient and
The PWA Health Group can be reached at 212-255-0520, and
Healing Alternatives at 415-626-4053.
The wasting trials are still new, so data is not available.
But for aphthous ulcers, a number of researchers and people
who have themselves used the drug have told us that it has
been very effective. Since the thalidomide causes drowsiness,
it is best taken before sleep.
Unfortunately, some people have experienced a serious
allergic reaction to the drug, especially in the higher dose
range (300 to 400 mg daily). The reaction may appear several
days after starting the drug, and involves a rash, high
fevers and extreme flu-like discomfort; it sometimes warrants
permanent discontinuation of the drug. However, the problem
may be avoided or controlled by starting at 100 mg a day and
increasing the dose if needed (but not to exceed a daily dose
of 400 mg).
Dr. Gilla Kaplan, a key thalidomide researcher at Rockefeller
University, told us that HIV-infected people who are also
being treated for tuberculosis seem curiously to be spared
the allergy to thalidomide. And clinicians at the Hansen's
Disease Center in Louisiana say that the reaction has not
been a problem for patients there. In fact, thalidomide is
used in Hansen's precisely to CONTROL an inflammatory
process, erythema nodosum leprosum (ENL), which can be a
sequela--not a true drug reaction--during the treatment of
the disease. (Hansen's disease, like MAC and tuberculosis, is
caused by a mycobacterium, and not coincidentally, ENL is
thought to result from high TNF levels.)
At any rate, the saga of thalidomide's reincarnation will
continue as more clinical research is completed, as patients
and physicians gain more experience with empirical use, and
particularly as the HIV community pushes for reasonable
access to valuable treatments.