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 regulations.

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 immune deficiency.

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.

Current Trials 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 ulcers.

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 TNF production.

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.

Other Access 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 their physician.

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.