Treatment Issues; Vol. 9, No. 5 - May 1995
Brett Lowell

History

Thalidomide was developed and marketed in Europe in the late 1950s as a safer alternative to barbiturate sedatives. By 1960, it was observed that long-term, high-dose thalidomide administration was associated with peripheral neuropathy. In 1961, when it was demonstrated that it had severe teratogenic effects in pregnant women taking it for morning sickness, the drug was withdrawn from the European market.1 The first evidence that thalidomide has beneficial non- sedative effects came when trials showed that it was about 90 percent effective as a treatment for erythema nodosum leprosum (ENL), a skin complication of lepromatous leprosy. Leprosy is caused by a mycobacterial infection. Lepromatous leprosy develops if the T-cell response is compromised by the course of the disease, and ENL can develop as a complication of the immune response. Since thalidomide has no antimicrobial effects, it was determined that the drug must have a direct effect on the immune system.1

The immunosuppressive effects of thalidomide led to its use in other immune modulated diseases, including graft-versus- host disease (GVHD), systemic lupus erythematosus (SLE), rheumatoid arthritis, and Behìet's disease (which causes severe ulceration of the mouth and genitalia).1 Some people with AIDS develop Behìet's disease or have very similar aphthous ulcers not caused by infectious agents. One aspect of immune activation that these conditions have in common is high production of TNF.

TNF, Wasting, and HIV

TNF levels are also elevated in AIDS (see box on TNF). Overproduction of TNF may play a role in the development of wasting syndrome and has been shown to activate latent HIV in cells. A group of researchers led by Gilla Kaplan, M.D., at Rockefeller University in New York has demonstrated that thalidomide selectively inhibits TNF production by monocytes from people with HIV.2 Thalidomide had previously been shown to reduce circulating TNF levels in lepromatous leprosy patients with ENL, and this reduction had been correlated with the clinical benefits seen with thalidomide in ENL.3

The researchers at Rockefeller University have further shown that thalidomide in lab experiments can inhibit the TNF- induced activation of HIV-1 in a number of cell lines, including CD4 cells.4 They also showed that thalidomide inhibited HIV activation in peripheral blood mononuclear cells taken from HIV-positive patients with low CD4 counts.5 Thalidomide might be beneficial to HIV patients in two ways: It may suppress the production of TNF by monocytes, reducing the elevated levels believed to be a major factor in wasting syndrome and AIDS mortality. Second, since TNF is a particularly potent activator of latent HIV, reducing TNF levels may reduce the viral burden.

Clinical Data

The first report on the use of thalidomide in AIDS-related wasting was presented by Couderc et al. at a conference last year in Milan. Dr. Couderc treated three patients exhibiting AIDS-related wasting with thalidomide (100 mg a day). All three gained around ten pounds within three weeks. There was no effect on CD4 cell counts or other measurements of immune function, including reduced TNF (see box on TNF for a caution about TNF lab tests).6

At the 1994 Tenth International Conference on AIDS in Yokohama, two encouraging trials were presented. The first was a Mexico City study led by Gustavo Reyes-Teran, M.D. Adult volunteers, who had AIDS but no active opportunistic infections and who had lost ten percent or more of body weight within the last six months, were assigned either oral thalidomide (100 mg four times a day) or placebo in a randomized, double-blind fashion. Of the 23 people enrolled, eighteen (nine on thalidomide and nine on placebo) had completed the regimen. Weight stabilization or gain occurred in eight of the nine thalidomide patients, and two of the nine placebo patients. This was statistically significant. Two side effects, mild sleepiness and erythema (rash), were seen only in the thalidomide group. There were no changes in CD4 counts or HIV levels in either group.7

The other report was from a study conducted in Thailand by a team headed by Dr. Kaplan from Rockefeller University. In this double-blind, randomized trial, male AIDS patients with weight loss were given 300 mg thalidomide or placebo nightly for 21 days. Sixteen thalidomide patients (48 percent with tuberculosis) showed increased appetite, and gained an average of 4.5 percent of their usual body weight, compared to only 0.9 percent weight gain in sixteen controls (45 percent with tuberculosis). Six thalidomide patients developed drug rashes. CD4 counts did not change, and HIV viral burden results are not yet available.8

Another, just published placebo-controlled study by the group from Rockefeller found significant weight gains in people with tuberculosis (about half of whom were also HIV-positive) treated with two weeks of thalidomide at 300 mg a day (all patients were also given standard TB therapy). When thalidomide treatment was stopped, participants either stopped gaining weight or lost weight.

After the initial study, investigators treated a subgroup of patients with sequential cycles of thalidomide or placebo. Three patients were treated with another fourteen day cycle of thalidomide after seven days of washout, three others were given placebo, and two patients initially on placebo were treated with thalidomide. The rate of weight gain was significantly higher on thalidomide, whether or not they had been treated with thalidomide in previous cycles. Caloric intake was the same among people on placebo and thalidomide, so the weight gain from thalidomide was not due to any difference in diet or appetite.9

Aphthous Ulcers

A case study and review of the English literature, at the Tenth International Conference identified at least 26 cases of aphthous ulcers treated with thalidomide.10 Earlier, a placebo-controlled study of thalidomide for recurrent aphthous ulcers in 73 people with AIDS reported complete resolution in about 45 percent of patients treated with thalidomide, but all treated patients had dramatic reductions in the number of ulcers.11

The FDA currently provides thalidomide free to people with HIV who have aphthous ulcers of unknown cause, (when ulcers are caused by infection with, for example, candida, herpes, or CMV, thalidomide seems not to be effective). This program does not provide access to thalidomide for people with wasting syndrome or other AIDS-related indications. For more information about the FDA program, physicians should call Brenda Atkins or Matthew Tarosky at 301/443-9553.

Ongoing Clinical Trials

Three clinical trials of thalidomide in people with AIDS are currently underway in the US. The studies are evaluating the use of thalidomide as a treatment for aphthous ulcers, primary HIV infection or wasting syndrome.

ACTG 251 is a phase II/III randomized, multicenter, placebo- controlled trial in people with HIV who have had mouth ulcers for more than two weeks. Patients randomized to drug will be given 200 mg of thalidomide a day for four weeks, followed by a maintenance dose of 100 mg three times a week. Those who do not respond will be given thalidomide open label. The trial is also evaluating thalidomide's effect on p24 (HIV core protein) levels, HIV load as measured by quantitative PCR (polymerase chain reaction) and serum TNF.

Another NIH-sponsored trial, ACTG 267, is a phase I placebo- controlled, dose-escalation study in people with CD4 cell counts between 200 and 500. Doses of 50, 150 and 300 mg per day will be tested, with twelve patients per dose. Patients must be on a stable regimen of AZT or be taking no antiviral for 30 days before the start of the trial. After determining the maximum tolerated dose, the study will add eighteen additional patients and monitor the drug's effect on TNF, viral load, CD4 cell counts and other immunologic markers. For more information about enrolling in either of the ACTG studies, call the National AIDS Clearinghouse at 800/TRIALS- A.

A large multicenter trial sponsored by Celgene (the exclusive licensee of a thalidomide use-patent filed by Rockefeller University) is also underway at six centers around the country. This study intends to examine an endpoint missing from previous studies -- the impact of thalidomide on body mass composition. The study will compare two doses of thalidomide, 100 and 200 mg a day, to placebo. After eight weeks, participants will be offered up to four weeks of open label thalidomide, 200 mg a day. To enroll in the study, patients must have lost at least 10 percent of their pre- illness body weight and have no active opportunistic infections. People with peripheral neuropathy, chronic diarrhea, or ongoing treatment with immune modulators or anabolic steroids are excluded. Anyone interested in enrolling in this study should call Peggy Hempstead at 212/327-7794 for information.

According to Patrick Haslett, M.D., a researcher at Rockefeller University, which is the New York trial site, this study is "having an incredibly hard time recruiting patients." He attributes this to a number of factors: the requirement that trial participants be on stable antiretroviral therapy, the competition for volunteers from other research studies, and the hopelessness felt by profoundly sick patients. Also, Celgene excludes from this study non-sterilized or premenopausal women, which Dr. Haslett considers "unfortunate" and unnecessary. Sally Cooper, executive director of the PWA Health Group in New York, an AIDS buyers' club for unapproved therapies, thinks that a study which has difficulty recruiting participants must have design flaws that discourage potential volunteers. For example, this study protocol offers only four weeks of open-label thalidomide to trial participants initially randomized to placebo, rather than a longer compassionate use program. (But patients at the Rockefeller University site who do well on thalidomide may be able to continue the drug through Dr. Kaplan's own compassionate use protocol.)

Like Dr. Haslett, Ms. Cooper is critical of the exclusion criterion for women of childbearing potential and feels that the dangers of thalidomide have been blown out of proportion. To help address the needs of both men and women with AIDS- related wasting, the PWA Health Group and Healing Alternatives in California has set up a Thalidomide Compassionate Use Program -- supplies and the Food and Drug Administration permitting (see box on the FDA's attitude).

Future Directions

Thalidomide may be studied for a number of other AIDS-related indications. As with other mycobacterial diseases such as TB, thalidomide may reduce the symptoms of MAC. Thalidomide also inhibits the development of new blood vessels that can feed tumors and cancerous lesions, so it may have activity against Kaposi's sarcoma and lymphomas.

Finally, Celgene is developing new analogs of thalidomide that may be more potent and less toxic. Since these analogs are patentable, they could well be more expensive should they ever reach market.

References

1 Gfnzler V. Drug Safety. Mar-Apr 1992; 7(2):116-34.

2 Moreira AL et al. Journal of Experimental Medicine. June 1993; 177(6):1675-1680.

3 Sampaio EP et al. Journal of Experimental Medicine. Mar 1991; 173(3):699-703.

4 Schauf V et al. Thirty-Second Interscience Conference on Antimicrobial Agents and Chemotherapy. Oct 1992; (abstract 593):209.

5 Makonkawkwoon S et al. Proceedings of the National Academy of Science USA. July 1993; 90(13):5974-78.

6 Couderc LJ et al. Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Apr 1994; (Abstract P321).

7 Reyes-Teran G et al. Tenth International Conference on AIDS. Aug 1994; 2(abstract 536B):65.

8 Klausner JD et al. Tenth International Conference on AIDS. Aug 1994; 1(abstract PB0312):221.

9 Tramontana JM et al. Journal of Molecular Medicine. May 1995; 1(4):1-14.

10 Ball SC et al. Tenth International Conference on AIDS. Aug 1994; 2(abstract PB0327):22.

11 Revuz J et al. Archives of Dermotology. Jul 1990; 126(7):923-927.

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