Thalidomide and HIV: Background

Starting in early July, extensive news reports appeared
about possible use of thalidomide in treating certain AIDS
patients, including accounts of rapid regaining of normal weight
in some cases of wasting syndrome. There is also a new interest
in using this drug in treating tuberculosis. Because the reports
were positive and from credible sources, and because of the
prevailing pessimism about other treatment options, this news
received mtion, and many people called AIDS TREATMENT NEWS and
other treatment organizations for more information.

At this time our information is incomplete, since we were
not able to reach some key people by press time. We need details
on the human experience which is behind much of the current
interest -- such as what kinds of patients might be likely to
benefit from this treatment. (The news reports were set off by
the publication of a major article in the July Proceedings of the
National Academy of Sciences, USA.(1) This article is readily
available, but it only reports laboratory results -- not tests in
which thalidomide was given to people.)

Thalidomide is related to a large and potentially important
area of immune suppression as a potential HIV therapy -- a
therapy which might be used in both early and late disease,
although probably in different forms, and probably only in
carefully selected patients, so that the treatment does not do
more harm than good. In early infection, one possibility is to
prevent immune activation in order to slow down viral activity.
In late-stage AIDS, some patients have symptoms very much like
those of certain kinds of graft-versus-host disease, a serious
complication of organ transplantation -- and it is possible that
some might benefit by being treated for that condition. We hope
to cover such possibilities in future articles.

Thalidomide is not new in AIDS treatment. Before the
current news, 32 published reports were cited in the AIDSLINE
database produced by the U. S. National Library of Medicine; most
of them concern human use in one or a few cases. These reports
appeared between February 1989 and February 1993. Taken as a
whole, they suggest (1) that the drug is highly effective in
relieving or curing one condition, aphthous ulcers which are not
due to infectious causes, but (2) that because of side effects,
especially neuropathy, many physicians try other treatments first
and use thalidomide only when necessary.

We are still investigating whether the new results have
changed this picture by using thalidomide in different ways, or
with different patients.

Thalidomide History

Thalidomide was the horror drug of the early 1960s, because
it caused thousands of birth defects when taken by pregnant
women; this had not shown up in the animal species on which the
drug had been tested before it was released. Most of these cases
occurred in Europe, because the FDA had not approved the drug for
U. S. use.

Before the problem was known, doctors had seen thalidomide
as a safe substitute for barbiturates, since animal tests had
found the drug nontoxic enough that a lethal dose could not be
determined. But later it was also discovered that long-term use
could cause nerve damage.

It was also learned that thalidomide is highly effective for
treating certain complications of leprosy; as a result, the drug
started to come back into limited medical use. It has also been
tried for a number of conditions, many of them autoimmune,
including lupus, rheumatoid arthritis, and graft-versus-host
disease.

The best single source for background information on
thalidomide and HIV is "Thalidomide in Human Immunodeficiency
Virus (HIV) Patients: A Review of Safety Considerations," a 19-
page review article published in 1992.(2) This article points out
how much is unknown about the drug. No one knows how it works,
either to produce its therapeutic effects or its harmful ones.
There may be up to 50 metabolites (different chemicals produced
from thalidomide in the body); no one knows which ones are
responsible for the different effects. The paper also reviews a
number of studies on immune effects of the drug, and of adverse
reactions in HIV patients, such as neuropathy and skin rash. It
includes over 300 references on thalidomide.

Although focusing mainly on safety, the review briefly
summarizes a number of reports on the use of thalidomide for
treating aphthous ulcers which were not caused by infectious
organisms such as candida, herpes, and CMV. Infectious causes
need to be ruled out first, since thalidomide does not suppress
these organisms.

A published letter, too recent for inclusion in the review,
reported a case of an esophageal ulcer in AIDS, which could
easily have been misdiagnosed as lymphoma even after initial
histologic examination, but which healed completely with
thalidomide treatment.(3) The authors suggested that there could
be other cases wrongly diagnosed as lymphoma which could be
easily treated if diagnosed correctly.

More recently, a group in Madrid reported that two patients
with Mycobacterium avium complex (MAC) responded to thalidomide,
after they had failed standard treatments. Laboratory tests,
however, found no activity of thalidomide against MAC directly,
suggesting that the drug worked by affecting the immune
response.(4)

References

1. Makonkawkeyoon S, Limson-Pobre RNR, Moreira AL, Schauf V, and
Kaplan G. Thalidomide inhibits the replication of human
immunodeficiency virus type 1. PROCEEDINGS OF THE NATIONAL
ACADEMY OF SCIENCES, USA. July 1993; volume 90, pages 5974-5978.

2. Gunzler V. Thalidomide in human immunodeficiency virus (HIV)
patients: A review of safety considerations. DRUG SAFETY. 1992;
volume 7, number 2, pages 116-134.

3. Ryan J, Colman J, Pedersen J, and Benson E. Thalidomide to
treat esophageal ulcer in AIDS. THE NEW ENGLAND JOURNAL OF
MEDICINE. July 16, 1992; volume 327, number 3, pages 208-209.

4. Vicente T, Ortega A, Muoz P, Diaz MD, and Bouza E. In vitro
activity of thalidomide against Mycobacterium avium complex.
ARCHIVES OF INTERNAL MEDICINE. February 22, 1993; volume 153,
page 534.