May 21, 1997
Thalidomide effectively heals severe mouth and throat ulcers in people with HIV infection, according to a study supported by the National Institute of Allergy and Infectious Diseases (NIAID) and reported in the May 22, 1997, issue of The New England Journal of Medicine.
"For the many patients with HIV infection who suffer from these ulcers, eating can be excruciatingly painful, which exacerbates wasting and debilitation," says Division of AIDS Director Jack Y. 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 drugs potential toxicity."
The ulcers of 55 percent of the patients receiving four weeks of thalidomide healed completely, compared to healing in only 7 percent 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 clinical trial 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 for HIV-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 they were 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 at both Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, New York.
A second reason for caution, according to the study results, is that 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 associated with 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 in initial screenings, in baseline physical examinations, and then weekly throughout the study. Because of thalidomides 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 serum thalidomide levels, and evaluation of liver and kidney function.
The National Center for Research Resources supported this study in part through the General Clinical Research Center Units. Andrulis Pharmaceutical Corporation of Beltsville, Md., provided thalidomide 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 of Medicine, 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 Medical Center, New York; University of Hawaii, Manoa; University of Southern 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.