Digestive Diseases and Sciences

, Volume 45, Issue 4, pp 690–696 | Cite as

A Randomized, Controlled Study of Thymosin-α1 Therapy in Patients with Anti-HBe, HBV-DNA-Positive Chronic Hepatitis B

  • Claudio Zavaglia
  • Remo Severini
  • Carmine Tinelli
  • Josè S. Franzone
  • Aldo Airoldi
  • Silvana Tempini
  • Giuseppina Bettale
  • Gaetano Ideo

Abstract

No consistently effective therapy is yet available for the treatment of chronic HBsAg, anti-HBe, HBV-DNA-positive hepatitis. A multicenter trial has shown that the response rates are not significantly different when patients with anti-HBe-positive hepatitis are treated with six-month course of thymosin-α1 or of interferon-α. However, since among these patients, interferon's real efficacy is still debated, with sustained biochemical response achieved in only a few of the treated patients, we conducted this controlled study to investigate the safety and efficacy of thymosin-α1 as compared with no treatment. Forty-four chronic hepatitis B virus (HBV) carriers, who were anti-HBe- and HBV-DNA-positive, were randomized, with stratification for the presence of cirrhosis at baseline liver biopsy, to receive either thymosin-α1 at a dose of 900 μg/m2 twice a week for six months or no treatment. At entry, both groups of patients were comparable for sex, age, liver histology, ALT, IgM anti-HBc, and HBV-DNA levels. Forty-two patients were followed-up for 20 months (median; range 12–32 months) after completion of therapy: one dropped out, and one developed hepatocellular carcinoma at six months. Thymosin-α1 treatment had no side effects. Six months after the end of the therapy, HBV-DNA was negative and ALT had normalized in 14% of treated cases and in 4.5% of control group, while IgM anti-HBc was negative (<0.200) in 14% of the treated patients and in 4.5% of the controls. Among the treated patients, the median ALT levels stayed significantly lower compared to the pretreatment values during the treatment period and six months of follow-up. During the first year, there were six flares of hepatitis in the control group and five among the treated patients (P = NS), yielding a per year average of 0.3 and 0.23 flares per patient, respectively. Among the treated patients, median IgM anti-HBc levels were low with respect to baseline values 4–10 months after treatment started. None became HBsAg negative. In conclusion, these results indicate that, in anti-HBe, HBV-DNA-positive chronic hepatitis B, thymosin-α1 therapy alone does not increase the response rate, but may contribute to reduce the immune-mediated liver cell necrosis as indirectly assessed by ALT and IgM anti-HBc levels.

thymosin-α1 therapy chronic hepatitis B 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    Hadziyannis SJ, Lieberman HM, Karvountzis GG, Shafritz DA: Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg vs. antiHBe positive carriers of hepatitis B virus. Hepatology 3:656–662, 1983Google Scholar
  2. 2.
    Fattovich G, Rugge M, Brollo L, Pontisso P, Noventa F, Guido M, Alberti A, Realdi G: Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 6:167–172, 1986Google Scholar
  3. 3.
    Bonino F, Rosina F, Rizzetto M, Rizzi R, Chiaberge E, Tardanico R, Callea F, Verme G: Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology 90:1268–1273, 1986Google Scholar
  4. 4.
    Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, Mc-Garvey MJ, Makris A, Thomas HC: Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 2:588–591, 1989Google Scholar
  5. 5.
    Brunetto MR, Stemler M, Schödel F, Will H, Ottobrelli A, Rizzetto M, Verme G, Bonino F: Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis. Ital J Gastroenterol 21:151–154, 1989Google Scholar
  6. 6.
    Mels GC, Bellati G, Leandro G, Brunetto MR, Vicari O, Borzio M, Piantino P, Fornaciari G, Scudeller G, Angeli G, Bonino F, Ideo G: Fluctuations in viremia, aminotransferases and IgM antibody to hepatitis B core antigen in chronic hepatitis B patients with disease exacerbations. Liver 14:175–181, 1994Google Scholar
  7. 7.
    Brunetto MR, Oliveri F, Rocca G, Criscuolo D, Chiaberge E, Capalbo M, David E, Verme G, Bonino F: Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen. Hepatology 10:198–202, 1989Google Scholar
  8. 8.
    Hadziyannis S, Bramou T, Makris A, Moussoulis G, Zignego L, Papaioannou C: Interferon alfa-2b treatment of HBeAgnegative/ serum HBV-DNA-positive chronic active hepatitis type B. J Hepatol 11:S133–S136, 1990Google Scholar
  9. 9.
    Pastore G, Santantonio T, Milella M, Monno L, Mariano N, Moschetta R, Pollice L: Anti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6–month course of lymphoblastoid interferon. J Hepatol 14:221–225, 1992Google Scholar
  10. 10.
    Fattovich G, Farci P, Rugge M, Brollo L, Mandas A, Pontisso P, Giustina G, Lai ME, Belussi F, Busatto G, Balestrieri A, Ruol A, Alberti A: A randomized controlled trial of lymphoblastoid interferon-α in patients with chronic hepatitis B lacking HBeAg. Hepatology 15:584–589, 1992Google Scholar
  11. 11.
    Sztein MB, Goldstein AL: Thymic hormones-a clinical update. Springer Semin Immunopathol 9:1–18, 1986Google Scholar
  12. 12.
    Goldstein AL: Clinical applications of thymosin alpha-1. Cancer Invest 12:545–547, 1994Google Scholar
  13. 13.
    Ernst E: Thymus therapy for cancer? A criteria-based, systematic review. Eur J Cancer 33:531–535, 1997Google Scholar
  14. 14.
    Mutchnick MG, Appelman HD, Chung HT, Aragona E, Gupta TP, Cummings GD, Waggoner JG, Hoofnagle JH, Shafritz DA: Thymosin treatment of chronic hepatitis B: A placebocontrolled pilot trial. Hepatology 14:409–415, 1991Google Scholar
  15. 15.
    Zavaglia C, Bottelli R, Smedile A, Iamoni G, Mondazzi L, Airoldi A, Lanzani F, Ideo G: A pilot study of thymosin-α1 therapy for chronic hepatitis D. J Clin Gastroenterol 23:162–163, 1996Google Scholar
  16. 16.
    Andreone P, Cursaro C, Gramenzi A, Zavaglia C, Rezakovic I, Altomare E, Severini R, Franzone JS, Albano O, Ideo G, Bernardi M, Gasbarrini G: A randomized controlled trial of thymosin-α1 versus interferon alfa treatment in patients with hepatitis B e antigen antibody-and hepatitis B virus DNA-positive chronic hepatitis B. Hepatology 24:774–777, 1996Google Scholar
  17. 17.
    Chisari FV, Ferrari C: Viral Hepatitis. In Viral Pathogenesis. N Nathanson (ed) Lippincott-Raven Publishers, Philadelphia 1997, pp 745–778Google Scholar
  18. 18.
    Casagrande JT, Pike MC: An improved approximate formula for calculating sample sizes for comparing two binomial distributions. Biometrics 34:483–486, 1978Google Scholar
  19. 19.
    Rezakovic I, Zavaglia C, Bottelli R, Ideo G: Sustained response to thymosin alpha 1 therapy in chronic HBsAg, HBeAb, HBVDNA positive hepatitis. Ital J Gastroenterol 25(suppl. 1):150–151, 1993 (abstract)Google Scholar
  20. 20.
    Kuhns MC, McNamara AL, Cabal CM, Decker RH, Thiers V, Bréchot C, Tiollais P: A new assay for the quantitative detection of hepatitis B viral DNA in human serum. In Viral Hepatitis and Liver Disease. AJ Zuckerman (ed). Alan R. Liss, New York, 1988, pp 258–262Google Scholar
  21. 21.
    Scheuer PJ: Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 13:372–374, 1991Google Scholar
  22. 22.
    Zavaglia C, Mondazzi L, Maggi G, Iamoni G, Gelosa F, Bellati G, Colloredo G, Bottelli R, Ideo G: Are alanine-aminotransferase, hepatitis B virus DNA or IgM antibody to hepatitis B core antigen serum levels predictors of histological grading in chronic hepatitis B? Liver 17:83–87, 1997Google Scholar
  23. 23.
    Marinos G, Smith HM, Naoumov NV, Williams R: Quantitative assessment of serum IgM anti-HBc in the natural course and during interferon treatment of chronic hepatitis B virus infection. Hepatology 19:303–311, 1994Google Scholar
  24. 24.
    Brunetto MR, Cerenzia MT, Oliveri F, Piantino P, Randone A, Calvo P-L, Manzini P, Rocca G, Galli C, Bonino F: Monitoring the natural course and response to therapy of chronic hepatitis B with an automated semi-quantitative assay for IgM anti-HBc. J Hepatol 19:431–436, 1993Google Scholar
  25. 25.
    Matthews JNS, Altman GB, Campbell MJ, Royston P: Analysis of serial measurements in medical research. Br Med J 300:230–235, 1990Google Scholar
  26. 26.
    Liaw Y-F, Tai D-I, Chu C-M, Chen T-J: The development of cirrhosis in patients with chronic type B hepatitis: A prospective study. Hepatology 8:493–496, 1988Google Scholar
  27. 27.
    Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, Realdi G, Ruol A: Natural history and prognostic factors for chronic hepatitis type B. Gut 32:294–298, 1991Google Scholar
  28. 28.
    Lampertico P, Del Ninno E, Manzin A, Donato MF, Rumi MG, Lunghi G, Morabito A, Clementi M, Colombo M: A randomized, controlled trial of a 24–month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology 26:1621–1625, 1997Google Scholar
  29. 29.
    Sherman KE, Jones CC, Goldstein AL, Naylor PH: Low thymosin alpha-1 concentrations in patients chronically infected with the hepatitis B virus. Viral Immunol 4:195–199, 1991Google Scholar
  30. 30.
    Chien RN, Liaw Y-F, Chen T-C, Yeh C-T, Sheen I-S: Efficacy of thymosin-α1 in patients with chronic hepatitis B: A randomized, controlled trial. Hepatology 27:1383–1387, 1998Google Scholar
  31. 31.
    Wang BE, Yu CZ, Thien GS, Tao QM, Liu DG, Min ZL, Wu SM, Yao JL, Lu WL, Peng WW, China Thymosin-a1 Study Group: Treatment of chronic hepatitis B with thymosin-α1: experiences in China. Hepatology 26:626A, 1997Google Scholar
  32. 32.
    Fang BF, Sun Y, Wang H, Zhang L, Tao QM: A pilot study of thymosin-α1 for the treatment of chronic hepatitis B. Hepatology 26:504A, 1997Google Scholar
  33. 33.
    Colloredo G, Bellati G, Sonzogni A, Zavaglia C, Fracassetti O, Leandro G, Ghislandi R, Minola E, Ideo G: Semiquantitative assessment of IgM antibody to hepatitis B core antigen and prediction of the severity of chronic hepatitis B. J Viral Hepatitis 6:423–434, 1999Google Scholar
  34. 34.
    Moshier JA, Mutchnick MG, Dosescu J, Holtz TK, Akkary S, Mahakala K, Merline JR, Naylor PH: Thymosin-α1, but not interferon-α, specifically inhibits anchorage-independent growth of hepatitis B viral transfected HepG2 cells. J Hepatol 25:814–820, 1996Google Scholar
  35. 35.
    Rasi G, Mutchnick MG, Di Virgilio D, Sinibaldi-Vallebona P, Pierimarchi P, Colella F, Favalli C, Garaci E: Combination low-dose lymphoblastoid interferon and thymosin-α1 therapy in the treatment of chronic hepatitis B. J Viral Hepatitis 3:191–196, 1996Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Claudio Zavaglia
    • 1
    • 2
    • 3
  • Remo Severini
    • 1
    • 2
    • 3
  • Carmine Tinelli
    • 1
    • 2
    • 3
  • Josè S. Franzone
    • 1
    • 2
    • 3
  • Aldo Airoldi
    • 1
    • 2
    • 3
  • Silvana Tempini
    • 1
    • 2
    • 3
  • Giuseppina Bettale
    • 1
    • 2
    • 3
  • Gaetano Ideo
    • 1
    • 2
    • 3
  1. 1.Divisione di Medicina Generale e Servizio di EpatologiaOspedale NiguardaMilanItaly
  2. 2.Direzione MedicaSclavo, SienaItaly
  3. 3.Direzione Scientifica, IRCSS, Policlinico S. MatteoPaviaItaly

Personalised recommendations