TREATMENT ISSUES, Volume 6, Number 6 - July, 1992; The Gay Men's Health Crisis Newsletter of Experimental AIDS Therapies
Derek Link

The Thymus

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.[1] As early as 1968, fetal thymic tissue transplantations in human infants with defective thymuses resulted in partial correction of immunodeficiencies and in clinical improvement.[2] 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.[3]

-------------------------------------------------- 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.[4] 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.[5] 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.[6] Savino and colleagues reported that the thymus glands of 13 AIDS patients studied demonstrated consistent thymus abnormalities.[7] 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.[8] It is difficult, therefore, to have a clear understanding of the role of the thymus in AIDS from published reports at this time.

Thymus Peptides

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 toxicities.

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

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.[9] 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

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).[10] 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.[11]

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.[12] 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

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.[14] 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 significant toxicities. ---------------------------------------------------

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 subcutaneous injections.

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 remain indeterminate.

The initial report of thymosin in AIDS was made by Dr. Schulof and colleagues in Washington, D.C.[16] 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 Dr. Garaci.[17]

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.[19] In studies in humans, Dr. Handzel and colleagues in Israel evaluated THF in "asymptomatic" homosexual men.[20] 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.[21] 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.

"Thymo-Ripoffs"

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.

Conclusion

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.

References:

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. Bulletin of NY Academy of Science. 65:111-119, 1989 and Werner GH et al. Immunomodulating peptides. Experientia 42:521-531,1986.

5. Trainin N. Prospects of AIDS therapy by thymic humoral factor, a thymic hormone. Nat Immun Cell Growth Regul 9:155-159,1990

6. Grody Wet al. Thymus involution in AIDS. Amer J Clin Pathol 84:85-95,1985.

7. Savino W et al. Thymic epithelium in AIDS, an immunohistologic study. Am J Pathol. 122:302-307,1986.

8. Schuurman, Hl. The thymus in AIDS. Amer J Pathol 134:1329-1338,1989.

9. Valesini G. A calf thymus acid lysate improves clinical symptoms and T-cell defects in early stages of HIV infection: second report. European J Cancer and Clin Oncol 23:521-531,1987.

10. Lazarrin A et al. Increase of OK-T4 positive cells during treatment with thymostimulin in parenteral drug addicts with PGL. J Clin Lab Immunol 20:57-61,1986.

11. Beall G. A double-blinded, placebo-controlled trial of thymostimulin in symptomatic HIV-infected patients. AIDS 4:679-681,1990.

12. VII Int'l Conf on AIDS, Abstract #WB2130, Florence, June, 1991.

13. Personal communication, H. Grossman

14. Barcellini Wet al. Effect of subcutaneous thymopentin treatment in drug addicts with PGL. Clin Exper Immunol 67:537-543, 1987.

15. Silvestris F et al. Immunologic effects of long-term thymopentin treatment in patients with HIV-induced lymphadenopathy syndrome. J Lab and Clin Med 113:139-144.1 989.

16. Schulof RS. Phase I/II trial of thymosin fraction 5 and thymosin alpha-one in HTLV-III seropositive subjects. J Biol Response Mod 5:429-443, 1986.443, 1986.

17. Personal communication, A. Goldstein, June, 1992.

18. Mutchnick M et al. Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial. Hepatology 14:409-415,1991.

19. Katorza R et al. Restoration of immunological responses by THF, a thymic hormone, in rats inflected with murine CMV. Clin Exp. Immunol. 70:268-275, 1897.

20. Handzel ZT et al. Immuno-reconstitution of T-cell impairments in asymptomatic male homosexuals by thymic humoral factor. Intern J Immunophramacol 9:165-173, 1987.

21. Trainin N et al. Thymic function. Lancet 338:1533,1991

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