GMHC Treatment Issues 1992 Jul 20; 6(6): 1
It is now obvious to researchers, doctors, and people with AIDS
that antiretroviral therapies like AZT, ddI and ddC may do
little to repair immunity. Community interests have
consequentially turned toward therapies that may restore
immunity in people with damaged immune systems. "Immune
Reconstitution" have become buzz words in many AIDS circles.
However. reconstitution depends on a substantial understanding
of the immune system, and immunology, the branch of medicine
that studies the immune system, is an infant science. While
some progress has been made recently, little is actually known
about the basic elements which regulate and control the normal
functioning of the human immune system.
The thymus was not a well understood organ until the early
1960's, when pioneering studies showed that infant animals,
whose thymus organs were removed, developed profound immune
deficiencies and died. It was then discovered that these
immuno-deficiencies could be partially corrected when thymic
tissue was reimplanted. As early as 1968, fetal thymic
tissue transplantations in human infants with defective
thymuses resulted in partial correction of immunodeficiencies
and in clinical improvement. Since those experiments, the
thymus has been identified as a key immune system organ. It is
thought to be responsible for the development and regulation of
T cell immunity in both infants and adults. The thymus seems to
exert its regulatory functions through the secretion of various
noncellular, hormonelike products, called thymic peptides.
Several studies have reported that thymic peptides
can develop immature, pre-cursor cells into fully
immune-competent T cells.
Thymic peptides are reported to have many effects on T cells.
Several studies have reported that thymic peptides can assist
development of immature, precursor cells into fully competent T
cells. Thymic peptides seem to regulate the expression of
various cytokine and monokine receptors on T cells and induce
secretion of IL-2, interferon alpha, and interferon gamma
(disease-fighting substances) when the immune system is
challenged. There are reports that the use of thymic
hormones in children with immuno-deficiencies caused by
chemotherapy has resulted in an increase in circulating T
cells, normalization of T cell subsets, and restoration of
delayed hypersensitivity reactions. Nevertheless, the full
extent of the effects of thymic peptides is still not known.
For instance, do they affect cells that are not T cells? Do
they regulate mature T cells? Are they involved with the
neuro-endocrine system? Despite these unanswered questions, it
is clear that thymic peptides are critical to the development
of T cell immunity.
The Thymus and AIDS
From the beginning of the AIDS epidemic, research has been
directed at the effect of HIV on the thymus. However, none of
the reports appears to offer a consistent understanding. Some
researchers report that the thymus in HIV-infected people is
significantly destroyed. In particular, Dr. Grody and
colleagues reported that the parts of the thymus most
responsible for the secretion of thymic peptides -- epithelium
and Hassall's corpuscles--are impaired. Savino and
colleagues reported that the thymus glands of 13 AIDS patients
studied demonstrated consistent thymus abnormalities. This
was not seen in any of the non-HIV-infected controls. The
authors suggest that the thymus is a direct target tissue in
HIV infection. Other research groups offer the exact opposite
analysis. According to Dr. Schuurman and colleagues, there is
no evidence of HIV infection in the thymus or signs of
HIV-specific destruction. It is difficult, therefore, to
have a clear understanding of the role of the thymus in AIDS
from published reports at this time.
Although much interest has focused on thymic peptides as
immune-restoring drugs, studies designed to generate data to
support this claim have yet to be performed. In the best case,
there is a slight hint that thymic peptides might be of some
benefit. In most cases, however, data is either nonexistent or
uninterpretable. It is encouraging, though, that, unlike other
immune products, such as alpha interferon or interleukin-2,
these agents have yet to demonstrate any significant
The various thymic peptide drugs given to HIV-infected people have
produced ambiguous and, in some cases, contradictory results. Since
most reports of thymic peptides in AIDS appear to be in obscure
medical journals, this information remains out of reach to most
physicians treating people with HIV. To understand the bewildering
array of thymic peptides, the following is an overview of the most
widely discussed and used thymic preparations.
Thymomodulin is the natural extract of calf thymus which was
approved in Italy as Leucotrofina. It is used to treat
bacterial and viral infections, food allergies in children, and
immunodeficiencies in the elderly. Unlike most of the synthetic
peptides, thymomodulin is an oral drug. It is made into syrup
from filtered freeze-dried calf thymus extract.
The drug's manufacturer, Ellen Pharmaceuticals, has sponsored
one small, uncontrolled study in people with HIV in Rome in
1987. The study, conducted by Dr. Valesini and colleagues,
enrolled 15 people with HIV. All participants received 60 mg of
the drug twice daily for 50 days. Two patients, those with the
worst clinical condition at entry, died during the study. The
other patients were all reported to have improvements in their
condition and surrogate markers. No side-effects were observed.
Despite these encouraging reports, the study had serious flaws.
It was not randomized, double-blinded, or placebo-controlled.
Additionally, there was no report of other medications used by
trial participants. At the time of writing, the authors
promised results of future, larger studies. No subsequent
reports have been found in any medical literature. However,
there are reports of ongoing community trials of thymomodulin
in San Francisco.
Thymostimulin, also known as TP-1, is another natural extract
from a calf thymus. No evidence indicates how it differs from
thymomodulin. This drug is made by Serono Pharmaceuticals in
Italy and is available only as an injectable drug. An initial
study, reported by Dr. Lazzarin and colleagues in Milan,
enrolled nine HIV-infected IV drug users with persistent
generalized lymphadenopathy (PGL--an AIDS-related condition
consisting of swollen lymph glands). Participants were
given 1 mg / kg of thymostimulin each day and all were reported
to have increases in T cells. Like the thymomodulin study, this
study was flawed. It had a very high rate of patient dropouts
who were not included in the final analysis. Additionally,
several subgroup analyses were performed which were not
accounted for in the original study design.
A follow-up, double-blinded, randomized, placebo-controlled
study using the same dose in 50 individuals with ARC failed to
duplicate the results. The followup study, reported by Dr.
Beall and colleagues at the University of California at Los
Angeles, showed no difference in progression of disease, mean
T4 and T8 numbers, or body weight in patients treated with
thymostimulin or placebo.
The most recent study from Italy, released as an abstract at
the VII International Conference, compared a combination of
thymostimulin (70 mg three times a week) and AZT (500 mg daily)
versus AZT alone. Participants included 30 individuals
(men) with asymptomatic HIV infection and T4 counts of over
400. The study suggests that the combination arm did much
better than AZT alone. The authors, Dr. Barbarini and
colleagues, claimed that the combination had significantly
greater increases in T4 cells, improved "nutritional status,"
and slowed disease progression. The authors did not provide any
specific information, such as actual T cell number, or baseline
characteristics of the patients. This data, therefore, remains
difficult to interpret.
Thymopentin is a small, synthesized thymic peptide drug, also
known as TP-5 or Timunox. In the U.S. it is being developed as
an AIDS therapy by the Immunobiology Research Institute.
Thymopentin has been studied more extensively than most other
thymic peptide drugs. However, the results of these studies
remain ambiguous due to their small size and flawed design.
Nevertheless, several community physicians, including Dr.
Howard Grossman in New York and Dr. Marcus Conant of San
Francisco, are evaluating thymopentin through clinical trials
in their own practices. Dr. Grossman reports that 52
HIV-infected participants have completed a randomized, blinded
study of 300-500 mg of AZT daily plus 50 mg of thymopentin, 3
times per week versus AZT plus placebo.13 As of this date, the
results have not been released. The initial report of
thymopentin in AIDS came from Dr. Barcellini and colleagues in
a small study of IV drug users with PGL in Milan. The study
noted improved surrogate markers in some patients who had taken
50 mg thymopentin three times a week. However, no clinical
improvement was noted. Notably, many patients dropped out, and
analysis of the study results is difficult.
It is encouraging, that, unlike other immune
products, such as alpha interferon or interleukin-2,
thymic peptide drugs have yet to demonstrate any
Follow-up studies by Dr. Silvestris and colleagues and Dr.
Costigliola and colleagues have offered some confirmation of
the original report. Silvestris conducted a year-long study
following 21 patients.15 The study claimed a significant rise
in T cells and slight clinical improvement in those patients
who received 50 mg of thymopentin three times a week, compared
to untreated control participants. Dr. Costigliola conducted a
trial of 12 patients treated with the same dose of thymopentin.
Compared to the 14 untreated control participants, those taking
the drug showed greater "immunologic stability" and some
clinical improvement. Reported side effects of thymopentin have
been limited to local pain and swelling at the site of the
Thymosin Alpha 1
Thymosin is a small synthetic peptide first characterized in
the 1970's. It has just been licensed in Italy for the
treatment of primary immunodeficiencies and as a booster for
influenza vaccine in renal dialysis patients. The drug is being
developed by Alpha One Biomedicals and is being tested in
ongoing clinical trials for activity against chronic hepatitis
B and C, HIV infection, and certain forms of cancer. It is by
far the most thoroughly studied of all the thymic peptide
drugs. However, the published results from ongoing trials
The initial report of thymosin in AIDS was made by Dr. Schulof
and colleagues in Washington, D.C. In this phase I/II study
of 42 HIV-infected men, no immunological effects, as measured
by T cell increases, natural killer cell activity, HIV antibody
levels, or clinical improvements were noted in patients taking
600 ug of thymosin, injected under the skin every day (4.2 mg
per week). These results have led some believers in thymosin to
speculate that, since the drug is an immunomodulator, it needs
to be combined with an antiretroviral agent. Subsequent studies
of thymosin have been performed by Dr. Garaci and colleagues at
the University of Rome. Garaci's study reported that the
combination of thymosin (1 mg twice weekly, subcutaneously),
AZT (500 mg/day), and alpha interferon (2 million units, twice
weekly, injected under the skin), resulted in increased T4
counts for a longer duration than either AZT alone or AZT with
alpha interferon. During the first six months of this study,
both the thymosin / AZT / interferon group and the
AZT/interferon group had similar increases in T4 counts, which
were both superior to the AZT-alone arm. However, after six
months T4 counts in the AZT / interferon group peaked while
those in the three-drug regimen continued to increase through
the one-year period. This study is still underway with
anecdotal reports of continued benefits seen in the
thymosin/AZT/ interferon group. No adverse effects or major
toxicities have been observed in any patients. However, this
study should be viewed with caution in light of the fact that
there were only 25 people in the entire three-arm study and
that reported results represent only one year of follow-up.
Dr. Alan Goldstein, who first developed thymosin, disclosed to
Treatment Issues that a multicenter trial is being planned for
the U.S. using the same combination regimen that was used by
Promising results using thymosin as a treatment for chronic
hepatitis have also been reported. This may provide significant
hope for the large number of HIV-infected individuals with
chronic hepatitis. In a pilot study of 12 people with chronic
hepatitis B infection, Dr. Mutchnik and colleagues compared
seven patients treated with thymosin with five individuals who
were given placebo.ls After one year, the authors reported
significantly improved liver function tests in all of the
treatment group but not in the placebo groups. Loss of
hepatitis B DNA was observed in six of the seven patients in
the treatment group compared to one in five patients of the
placebo. No significant side effects were observed. Dr.
Mutchnick reports that a multicenter chronic hepatitis B trial
has begun and that a trial for HIV-infected individuals with
chronic hepatitis C is also being planned.
Thymic Humoral Factor (THF)
THF is a synthetic thymic peptide being examined as an anti-HIV
treatment by researchers in France, Israel, and the U.S.
Although this compound has generated considerable interest
among some people with HIV, there is no clinical data at this
time to support its efficacy. However, in preclinical studies
in rats with CMV-related immunosuppression, THF restored immune
competence through modulation of T cells. In studies in
humans, Dr. Handzel and colleagues in Israel evaluated THF in
"asymptomatic" homosexual men. Strangely enough,
participants in the study were not HIV-infected; therefore,
this data has limited usefulness in evaluating THF's role as an
AIDS treatment. Nevertheless, Israeli researchers also report
that when individuals with severe herpes virus infections were
treated with THF intramuscularly, the viral infections
"regressed rapidly and T-cell populations increased
remarkably. Treatment consisted of 2 ng/kg of THF, six days
per week for four weeks. While no other clinical data has been
published on the use of THF for HIV, clinical trials are
presently under way at Brown University, the University of
Arizona, and in France. The U.S. sites are using daily
intramuscular doses of THF (from 5ng/kg to 50 ng/kg) for two
weeks on, one week off, in combination with AZT. Participants
in this open-label, dose-ranging study are HIV-infected and
have T4 counts between 100-500. The French studies, conducted
by Dr. Jean-Claude Chermann, have been the subject of rumors
and hope within the community. It is believed that Dr. Chermann
is using significantly higher doses of THF than that being used
in the U.S. However, Dr. Chermann has not published any
efficacy data at this point. Therefore, we must wait until the
ongoing studies begin to yield data before this agent can be
considered a truly promising therapy.
Responding to the recent surge of interest in thymic peptide
drugs, several groups have made various thymic products
available through underground channels. Many of the AIDS
buyers' clubs are ethical and responsible community
organizations helping thousands of people obtain lifesaving
medication. However, there are always some blatant profiteers.
We advise readers to watch out for exaggerated claims of
efficacy and high prices for any underground drugs. When buying
an underground drug, remember that you have a right to know who
is selling the medication, how it has been priced, and who is
ultimately accountable for any problems with the drug.
Presently, there is little clear scientific data to support
claims that thymic peptides are effective treatments for HIV
infection. Of course, they may ultimately prove to be valuable
therapies, particularly since preclinical models and certain
clinical reports suggest some promise. At this point, the
thymic peptides have demonstrated no evidence of any systemic
toxicities. With the widespread interest in these compounds and
the lack of truly promising immunorestorative agents in
development, it is disappointing, to say the least, that
neither the National Institute of Allergies and Infectious
Diseases (NIAID) nor the National Cancer Institute has
initiated clinical trials designed to provide reliable
information about these therapies. Moreover, few of the ongoing
trials of the various thymic peptides appear to be designed to
provide convincing evidence of efficacy in the treatment of HIV
infection. Without well-designed clinical trials for these
therapies, we will probably be dealing with ambiguous data and
anecdotal reports for the foreseeable future.
1. Levy RH et al. Evidence for function of thymic tissue
in diffusion chambers implanted in neonatally thymectomized
mice. Preliminary report. J Natl Cancer Inst. 31:199-217,1963.
2. Cleveland WW et al. Fetal thymic transplantation in a
case of DiGeorge Syndrome. The Lancet 2:1211-4,1963
3. Fried man H et al. Thymic Hormones. In Goldstein.
Thymic Hormones and Lymphokines. Plenum Press, New York, 1984.
4. Garaci E. Enhanced immune response and antitumour
immunity with combinations of biological response modifiers.
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GH et al. Immunomodulating peptides. Experientia
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12. VII Int'l Conf on AIDS, Abstract #WB2130, Florence,
13. Personal communication, H. Grossman
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17. Personal communication, A. Goldstein, June, 1992.
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21. Trainin N et al. Thymic function. Lancet 338:1533,1991
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