Thymic peptides are hormone-like products secreted by the thymus. The thymus is the organ responsible for the development and regulation of T-cell immunity in both infants and adult, and these substances seem to play a key role in its functioning. They affect the expression of various cytokine receptors on T-cells and induce the secretion of interleukin-2, interferon alfa and interferon gamma when the immune system is challenged.

Researchers are investigating whether these thymic peptides can be used to correct some of the immune abnormalities that occur in HIV infection.

Examples of thymic peptides include thymomodulin, thymostimulin (TP-1), thymopentin (also known as TP-5 or Timunox), thymic humoral factor (THF) and thymosin alpha 1. Thymosin alpha 1 is being developed under the tradename Zadaxin, and has shown some evidence of efficacy in treating chronic hepatitis B infection.

Current use

Thymic peptides are unlicensed, experimental drugs. Two phase II studies of thymopentin found that the asymptomatic people who took the drug were significantly less likely to develop new constitutional symptoms than people given placebo. Other studies have produced suggestions that thymopentin or THF may improve immune responses and CD4 count, but these have been too small to reach clear-cut conclusions. No beneficial effects have been reported from thymostimulin in small controlled studies.

Respiratory congestion has been reported as a side-effect by some people taking thymopentin.

Use in combinations

A trial in which 353 asymptomatic people received either AZT alone or AZT plus thymopentin found that the combination recipients were significantly less likely to experience disease progression than those taking AZT monotherapy. This effect was particularly pronounced among those who were most likely to experience progression (CD4 counts below 400 and at least six months' prior use of AZT).

Getting it

Thymic peptides are not undergoing trials in Britain.

Key research

Thymopentin is a biologically active synthetic pentapeptide that corresponds to the active site of the thymic hormone, thymopoietin. In vitro, thymopentin regulates the function of peripheral T-cells, acting via a cyclic GMP-linked cell surface receptor, and enhances T-cell functions by increasing lymphokine production.

Conant (1992) conducted two phase II double-blind placebo-controlled studies of thymopentin involving 91 HIV-infected people. In both studies patients received thymopentin (50 mg subcutaneously three times weekly) or placebo. In the first study, participants were treated for 24 weeks, compared with 52 weeks in the second study. Participants were stratified at entry by disease status (52 asymptomatic and 39 symptomatic). 26/52 asymptomatic and 20/39 symptomatic people received thymopentin. None of the 26 thymopentin-treated asymptomatic individuals developed new constitutional symptoms compared with 3/24 placebo recipients. Thymopentin did not prevent the development of or reduce the incidence of candidiasis, oral hairy leukoplakia, or herpes zoster in asymptomatic participants. Four symptomatic individuals progressed to AIDS (two on thymopentin and 2 on placebo).

Goldstein enrolled 353 asymptomatic AZT-treated persons with CD4 counts between 200-500 in a placebo-controlled trial of thymopentin (50 mg) or placebo subcutaneously three times a week along with AZT (300-600 mg/day). After a median follow-up of 339 days, 4/173 (2.3%) recipients of thymopentin plus AZT had progressed to ARC, AIDS or death compared with 16/179 (8.9%) people who received AZT alone. In the stratum with the highest rate of progression (CD4 below 400 and at least 6 months prior AZT at baseline) 2 events occurred in the thymopentin plus AZT group versus 13 in the AZT alone group. During follow-up of up to 80 weeks, among participants with more than 6 months prior AZT at baseline, thymopentin delayed disease progression to both AIDS or death, and to ARC, AIDS or death. The low rate of progression among participants with less than 6 months prior AZT at baseline meant that no differences between thymopentin or placebo could be observed.

Thompson stratified 45 HIV-infected individuals into asymptomatic or mildly symptomatic groups and randomly assigned them to receive either thymopentin (50 mg) or placebo 3 times per week for 52 weeks. 4 clinical events occurred in the study, 3 in the placebo group (1 to AIDS and 2 to constitutional symptoms) and 1 in the thymopentin group (1 to AIDS). Too few patients were enrolled to detect significant differences in disease progression. Thymopentin recipients maintained CD4 cells and CD4 percentage at or above entry values, whereas these parameters decreased in the placebo group.

Silvestris treated 29 individuals with lymphadenopathy with thymopentin (59 mg 3 times a week) for 1 year. 13 participants had CD4 count increases to 500 after 4 months and stayed at that level, while CD8 counts fell. Mitogen responses of T- and B-cells improved. There was no clear correlation between these markers and reduction in clinical symptoms.

Thymomodulin is a calf thymus acid lysate. Valesini treated 15 HIV-positive people with thymomodulin syrup (60 mg/day) for 50 days. Clinical benefits including resolution of oral candida and lymphadenopathy were observed. No side-effects were seen.

Thymostimulin (TP-1) is prepared from a partially-purified extract of calf thymus glands. Chachoua treated 15 people with AIDS with TP-1 (1 mg/kg for 15 days then weekly for 12 weeks) or placebo. Adverse events included pain at injection site, fever and chills, skin rash or eosinophilia. No changes in immune function were noted.

Beall conducted a placebo-controlled phase I study of TP-1 (1 mg/kg/day for 14 days followed by twice-weekly injections for 6 months). No effect on clinical or laboratory measures was observed except for a transient decrease in p24 antigen in the treated group.

Barbarini treated 200 asymptomatic people with CD4 counts between 200 and 400 with either AZT alone or AZT plus thymostimulin (70 mg thrice weekly). The combination was reportedly more effective at restoring compromised CD4 counts.

Thymic humoral factor (THF) is a natural peptide hormone isolated from calf thymus. THF is reported to increase the number of T-lymphocytes and augment cell-mediated immunity.

Kouttab enrolled 14 HIV-positive individuals with CD4 count between 100-500 in a phase I study of THF: 5, 10 or 25 mg/kg/day were administered intramuscularly daily on a two-week on/one week off cycle for 12 weeks. All participants were receiving AZT. Overall, an increase in mitogen responses, NK activity and DTH responses were observed.

Handzel treated 15 asymptomatic men with 2 biweekly courses of THF or placebo. After 2 weeks THF-recipients had significant increases in mean CD4, CD3 and total lymphocyte counts compared to the placebo group.

Shohat reported that incubation of lymphocytes from 2 HIV-positive men with THF restored the impaired helper cell activity.

Garaci conducted an uncontrolled pilot study of the combination of AZT (500 mg/day), thymosin alpha 1 (1 mg subcutaneously twice weekly) and interferon alfa (2 million units intramuscularly twice weekly). 7 participants who completed one year of treatment had a significant CD4 count increase, from an average of 309 to 496.

References