AIDS TREATMENT NEWS Issue #179, July 23, 1993
John S. James
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, Muûoz 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.
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