"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 drug's potential
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
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 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 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.
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
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Poli G, Kinter A, Justement JS, et al. Tumor necrosis factor alpha
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Sampaio EP, Moreira AL, Sarno EN, Malta AM, Kaplan G. Prolonged
treatment with recombinant interferon induces erythema nodosum
in lepromatous leprosy patients. J Exp Med 1992;175:1729-37.
Sampaio EP, Sarno EN, Galilly R, Cohn ZA, kaplan G. Thalidomide
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Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces
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Wulff CH, Hover H, Asboe-Hansen G, Brodthagen H. Development of
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(NIH). NIAID conducts and supports research to
prevent, diagnose and treat illnesses such as HIV
disease and other sexually transmitted diseases,
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