Limited Course of Thalidomide Effective in Treating AIDS-Related Mouth Ulcers

"For the many patients with HIV infection who suffer fromthese ulcers, eating can be excruciatingly painful, which exacerbates wasting and debilitation," says Division of AIDS Director Jack Killen, M.D. "Thalidomide is the first treatment shown in a scientific study to heal these ulcers, but the course should be carefully monitored and limited in its duration because of the drug's potential toxicity."

The ulcers of 55 percent of the patients receiving four weeksof thalidomide healed completely, compared to healing in only 7percent of the patients receiving placebo. Almost all (90 percent) of those receiving thalidomide had at least partial healing.

The AIDS Clinical Trials Group (ACTG), a network of clinicaltrial sites supported by NIAID, conducted this study, called ACTG 251. Baseline and weekly health evaluations of study volunteers included a quality-of-life questionnaire to assess pain and discomfort during eating. Results from these questionnaires showed that the thalidomide group improved much more than the placebo group in regaining comfort while eating.

"Thalidomide appears to have great potential as a therapy forHIV-infected patients who have severe oral aphthous ulcers," says Lawrence Fox, M.D., Ph.D., one of two NIAID authors, "but only when administered by a physician who is vigilant for the possible serious side effects, including irreversible, painful peripheral nerve damage, rash and birth defects.

Patients experienced only minimal adverse effects while theywere taking thalidomide. Seven patients reported drowsiness and seven had rashes. The authors caution, however, that those patients who received thalidomide showed a small, but statistically significant increase in HIV ribonucleic acid (RNA) blood levels from the baseline through the fourth week of the study as compared to patients receiving placebo. "There is not sufficient information, however, to judge whether this increase is of any clinical significance," says study director Jeffrey M. Jacobson, M.D., of the Departments of Medicine atboth Bronx Veterans' Affairs Medical Center and Mount Sinai School of Medicine, New York.

A second reason for caution, according to the study results, isthat patients taking thalidomide had elevated plasma levels of tumor necrosis factor (TNF)-alpha, a substance released from phagocytes and from some T cells during the immune response and known to provoke HIV replication and expression from infected cells. This was unanticipated because earlier studies had reported that thalidomide inhibited production of TNF-alpha . These patients also showed increased soluble TNF-alpha receptor levels, a phenomenon shown to be associatedwith clinical progression of HIV disease.

Scientists at 19 sites conducted the double-blind, randomized,placebo-controlled study. Of 57 volunteers, 29 received thalidomide. The remaining patients received placebo, but were offered open-label thalidomide at the endpoint of the study. All patients in the study were HIV-positive and had oral or throat ulcers for at least two weeks before the start of the study.

At each of the study sites, physicians evaluated patients ininitial screenings, in baseline physical examinations, and then weekly throughout the study. Because of thalidomide's well-known ability to cause severe birth defects, every precaution was taken to prevent pregnancy, and pregnancy tests were given weekly to women of childbearing age. Each baseline and weekly evaluation included an assessment of nerve function, (peripheral sensory nerve disorders are a known complication of longer-term thalidomide treatment), laboratory analyses of blood cells, serum chemistries and serumthalidomide levels, and evaluation of liver and kidney function. The National Center for Research Resources supported thisstudy in part through the General Clinical Research Center Units. Andrulis Pharmaceutical Corporation of Beltsville, Md., providedthalidomide and placebo for the study.

In addition to Drs. Jacobson and Fox, authors are John S.Greenspan, B.Sc., B.D.S., Ph.D., and Laurie A. MacPhail, D.M.D., Ph.D., both of the Department of Stomatology, University of California, San Francisco; John Spritzler, Sc.D., and Miriam Chernoff, Ph.D., both from the Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Mass.; Nzeera Ketter, M.D., Division of AIDS, NIAID, Bethesda, Md.; John L. Fahey, M.D., Department of Medicine, University of California, Los Angeles; J. Brooks Jackson, M.D., Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md.; Albert W. Wu, M.D., M.P.H., Department ofMedicine, Johns Hopkins University School of Medicine, Baltimore, Md.; Guillermo J. Vasquez, M.D., Department of Medicine, University of Puerto Rico Medical School, San Juan; and David A. Wohl, M.D., Department of Medicine, University of North Carolina, Chapel Hill.

Other participating study sites are Mount Sinai MedicalCenter, New York; University of Hawaii, Manoa; University ofSouthern California, Los Angeles; Northwestern University, Chicago; University of Washington, Seattle; Stanford University, Palo Alto, Calif.; Harvard Medical School, Boston, Mass.; New York University, New York; Indiana University, Indianapolis; Meharry Medical College, Nashville, Tenn.; University of Pennsylvania, Philadelphia; Case Western Reserve University, Cleveland, Ohio; University of Colorado Health Sciences Center, Denver; University of Rochester, New York; and Albert Einstein College of Medicine, New York.

NIAID, a component of the National Institutes of Health (NIH),conducts and supports research aimed at preventing, diagnosing and treating illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services. ### References:Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey J, Jackson JB, Fox L, Chernoff M, Wu AW, MacPhail LA, Vasquez GJ, Wohl DA. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. New Engl J Med 1997;336:1487-93.

Makonkawkeyoon S, Limson-Pobre RNR, Moreira AL, Schauf V, Kaplan G. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1993;90:5974-8.

Peterson PK, Hu S, Sheng WS, et al. Thalidomide inhibits tumor necrosis factor-alpha production by lipopolysaccharide- and lipoarabinomannan-stimulated human microglial cells. J Infect Dis 1995;172:1137-40.

Poli G, Kinter A, Justement JS, et al. Tumor necrosis factor alpha functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci USA 1990;87:782-5.

Sampaio EP, Moreira AL, Sarno EN, Malta AM, Kaplan G. Prolonged treatment with recombinant interferon induces erythema nodosum leprosum in lepromatous leprosy patients. J Exp Med 1992;175:1729-37.

Sampaio EP, Sarno EN, Galilly R, Cohn ZA, kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991;173:699-703.

Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995;1:384-97.

Wulff CH, Hover H, Asboe-Hansen G, Brodthagen H. Development of polyneuropathy during thalidomide therapy. Br J Dermatol 1985;112:475-80.

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