Correspondence
Thalidomide for Aphthous Ulcers in HIV Infection
N Engl J Med 1997; 337:1086-1087October 9, 1997
- Article
To the Editor:
Jacobson et al. (May 22 issue)1 report encouraging results in their placebo-controlled trial of thalidomide for aphthous ulceration in patients with human immunodeficiency virus (HIV) infection. However, potential enthusiasm must be muted because of the preliminary nature of the findings and the unanticipated safety issues raised by the results. The data are based on an interim analysis of only 57 patients. Even in this small sample, major adverse events were seen during the four-week treatment phase, including grade 4 neutropenia in two thalidomide recipients. Approximately half the study participants either discontinued the study medication or had a protocol-mandated reduction in the dose during the four-week study period. This raises questions about the tolerability of thalidomide at a dose of 200 mg in this patient population for this indication.
The results of short-term therapy do not address the important issue of whether maintenance therapy will be required in patients whose ulcers respond to thalidomide. Maintenance therapy may also have its own safety problems, such as peripheral neuropathy, a well-recognized complication of long-term exposure to thalidomide.2,3 An additional safety concern is raised by the unexpected finding of increased numbers of copies of HIV RNA from base line to week 4 in patients receiving thalidomide, as compared with those receiving placebo. This finding warrants further investigation, given the recent strides in the development of drugs to lower the viral load in HIV-infected patients.
The results of Jacobson et al. should stimulate further research on the use of thalidomide in HIV-related aphthous ulcers in other body sites and in HIV-infected children with aphthous ulcers. The results also highlight the need to review additional data from the trial before wider use of thalidomide is recommended, especially when one considers the side effects.
3 ReferencesDebra Birnkrant, M.D.
Food and Drug Administration, Rockville, MD 208571
Jacobson JM ,Greenspan JS ,Spritzler J , et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997;336:1487-1493
Full Text | Web of Science | Medline2
Clemmensen OJ ,Olsen PZ ,Andersen KE . Thalidomide neurotoxicity. Arch Dermatol 1984;120:338-341
CrossRef | Web of Science | Medline3
Aronson IK ,Yu R ,West DP ,Van den Broek H ,Antel J . Thalidomide-induced peripheral neuropathy: effect of serum factor on nerve cultures. Arch Dermatol 1984;120:1466-1470
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We do not agree that the findings of our trial of thalidomide for the short-term treatment of oral aphthous ulcers in HIV-infected patients are preliminary. The trial was stopped early because the evidence of the efficacy of thalidomide as compared with placebo (P = 0.0001) was substantially greater than the P value of less than 0.0056 that is required by an O'Brien–Fleming stopping rule when there is one interim and one final analysis with an overall type I error of 5 percent.1 The trial results were definitive rather than preliminary, because even with a small sample the data clearly demonstrated that it would be unethical to continue the placebo treatment in this trial or to conduct any future trial comparing short-term thalidomide treatment with placebo in this patient population. We agree that assessing the need for maintenance therapy is important, and we are doing that in the maintenance-therapy phase of our study. As we stated in our article, the risk of peripheral sensory neuropathy with long-term thalidomide use is of particular concern in this population.
Dr. Birnkrant cites our comment that approximately half the patients who were randomly assigned to receive thalidomide either discontinued the study medication or had the dose reduced before the end of the full four weeks. Nevertheless, of these 14 patients, 8 had complete healing of their ulcers at week 4 and 5 others had partial healing. Thus, almost all these patients tolerated thalidomide at an initial dose of 200 mg per day well enough to get substantial benefit from it.
The only adverse events clearly associated with thalidomide were somnolence and rash, which were reversible. Our study population had particularly advanced HIV disease (median absolute CD4 count, 25 cells per cubic millimeter) and therefore frequently had other clinical problems and received other potentially toxic medications. In such a population adverse drug reactions are common. Many of the patients had neutropenia before the study, including the two thalidomide-treated patients referred to by Dr. Birnkrant in whom grade 4 neutropenia developed. Clinically significant neutropenia also occurred in patients who received placebo, so the relation of the neutropenia to thalidomide therapy was far from certain.
Dr. Birnkrant also comments on our finding that plasma HIV RNA levels unexpectedly increased during the four-week treatment period in the group of patients who received thalidomide. Although the study was done before more effective combination antiretroviral therapies became available, we noted the rise in HIV load with concern and plan follow-up studies to determine its long-term importance. However, there can be little question that thalidomide is dramatically effective in the short-term treatment of aphthous ulceration of the mouth and oropharynx in patients with HIV infection.
1 ReferencesJeffrey M. Jacobson, M.D.
Mount Sinai Medical Center, New York, NY 10029John S. Greenspan, Ph.D.
University of California, San Francisco, San Francisco, CA 94143John Spritzler, Sc.D.
Harvard School of Public Health, Boston, MA 021151
Kim K ,DeMets DL . Design and analysis of group sequential tests based on the type I error spending rate function. Biometrika 1987;74:149-154
CrossRef | Web of Science
- Citing Articles (3)
Citing Articles
1
A. Holmes, M. McMenamin, F. Mulcahy, C. Bergin. (2007) Thalidomide Therapy for the Treatment of Hypertrophic Herpes Simplex Virus--Related Genitalis in HIV-Infected Individuals. Clinical Infectious Diseases 44:11, e96-e99
CrossRef2
A Ross Kerr, Jonathan A Ship. (2003) Management Strategies for HIV-Associated Aphthous Stomatitis. American Journal of Clinical Dermatology 4:10, 669-680
CrossRef3
(1998) Professionalism. New England Journal of Medicine 338:1, 66-66
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