Vol. 47, No. 6, 2004
Issue release date: 2004
Intervirology 2004;47:335–341
Original Paper
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Benefit of Lamivudine Therapy and Factors Associated with Clinical Outcome in Spontaneous Severe Acute Exacerbation of Chronic Hepatitis B Virus Infection

Tsubota A.a,b · Arase Y.b · Suzuki Y.b · Suzuki F.b · Hosaka T.b · Akuta N.b · Someya T.b · Kobayashi M.b · Saitoh S.b · Ikeda K.b · Kumada H.b
aInstitute of Clinical Medicine and Research (ICMR), Jikei University School of Medicine, Chiba; bDepartment of Gastroenterology, Toranomon Hospital, Tokyo, Japan
email Corresponding Author

 goto top of outline Key Words

  • Lamivudine
  • Severe acute exacerbation
  • Chronic hepatitis B virus infection
  • Chronic hepatitis B
  • Severe acute exacerbation
  • Hepatic failure

 goto top of outline Abstract

Objective: During the course of chronic hepatitis B virus (HBV) infection, severe acute exacerbations of the infection often occur spontaneously and follow a fulminating progression to fatal hepatic failure. The aim of this study was to clarify potential factors, including benefit of lamivudine therapy, which could influence clinical course of the serious disease in an area of intermediate HBV endemicity. Methods and Results: Using a database of 3,163 chronically HBV-infected patients, 418 (13.2%) developed acute exacerbation of hepatitis B. Of the 418 patients, 52 (12.4%) spontaneously developed severe acute exacerbation and were included in this study. Of the 52 patients, 23 were treated with lamivudine. In multivariate analyses, fulminating progression to hepatic failure (odds ratio, 15.45; 95% confidence interval, 3.71–64.41; p = 0.0002) was a significantly independent predictor of patient survival. Three variables were independently associated with fulminating development of hepatic failure: presence of cirrhosis (29.06, 1.74–85.56, 0.019, respectively), higher baseline bilirubin level (14.89, 1.31–52.91, 0.029, respectively), and genotype B (22.14, 1.59–29.68, 0.021, respectively). Treatment lacking lamivudine was a significant factor that contributed to shorter survival time, development of hepatic failure, and progression to cirrhosis in univariate analyses (p = 0.014, 0.012 and 0.0030, respectively). Conclusion: In an area of intermediate HBV endemicity, certain proportion of chronic hepatitis B patients could spontaneously develop the serious disease. Factors influencing clinical course of the disease should be identified to improve prognosis and establish more rational and effective therapeutic strategies. Lamivudine therapy could potentially benefit the serious disease, although larger series of patients and longer follow-up periods are needed.

Copyright © 2004 S. Karger AG, Basel

 goto top of outline References
  1. Maddrey WC: Hepatitis B: An important public health issue. J Med Virol 2000;61:362–366.
  2. Chen CJ, Wang LY, Yu MW: Epidemiology of hepatitis B virus infection in the Asia-Pacific region. J Gastroenterol Hepatol 2000;15 (suppl):E3–E6.

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  3. Takahashi Y, Shimizu M, The study group of fulminant hepatitis: Aetiology and prognosis of fulminant viral hepatitis in Japan: A multicentre study. J Gastroenterol Hepatol 1991;6:159–164.
  4. Doong SL, Tsai CH, Schinazi RF, Liotta DC, Cheng YC: Inhibition of the replication of hepatitis B virus in vitro by 2′, 3′-dideoxy-3′-thiacytidine and related analogues. Proc Natl Acad Sci USA 1991;88:8495–8499.
  5. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M: A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995;333:1657–1661.
  6. Nevens F, Main J, Honkoop P, Tyrrell DL, Barber J, Sullivan MT, Fevery J, De Man RA, Thomas HC: Lamivudine therapy for chronic hepatitis B: A six-month randomized dose-ranging study. Gastroenterology 1997;113:1258–1263.
  7. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF: A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998;339:61–68.
  8. Tsubota A, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Chayama K, Murashima N, Ikeda K, Kobayashi M, Kumada H: Lamivudine therapy for spontaneously occurring severe acute exacerbation in chronic hepatitis B virus infection: A preliminary study. Am J Gastroenterol 2001;96:557–562.
  9. Chan HL, Tsang SW, Hui Y, Leung NW, Chan FK, Sung JJ: The role of lamivudine and predictors of mortality in severe flare-up of chronic hepatitis B with jaundice. J Viral Hepat 2002;9:424–428.
  10. Tsang SW, Chan HL, Leung NW, Chau TN, Lai ST, Chan FK, Sung JJ: Lamivudine treatment for fulminant hepatic failure due to acute exacerbation on chronic hepatitis B infection. Aliment Pharmacol Ther 2001;15:1737–1744.
  11. Chien RN, Lin CH, Liaw YF: The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B. J Hepatol 2003;38:322–327.
  12. Lok AS, Heathcote EJ, Hoofnagle JH: Management of Hepatitis B: 2000 – Summary of a Workshop. Gastroenterology 2001;120:1828–1853.
  13. Lok ASF, McMahon BJ: Chronic hepatitis B. Hepatology 2001;34:1225–1241.
  14. Trey C, Davidson LS: The management of fulminant hepatic failure; in Popper H, Schaffner F (eds): Progress in Liver Disease. New York, Grune & Stratton, 1970, vol 3, pp 282–298.
  15. Tsubota A, Chayama K, Ikeda K, Yasuji A, Koida I, Saitoh S, Hashimoto M, Iwasaki S, Kobayashi M, Hiromitsu K: Factors predictive of response to interferon-α therapy in hepatitis C virus infection. Hepatology 1994;19:1088–1094.
  16. Usuda S, Okamoto H, Iwanari H, Baba K, Tsuda F, Miyakawa Y, Mayumi M: Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product. J Virol Methods 1999;80:97–112.
  17. Chayama K, Suzuki Y, Kobayashi M, Kobayashi M, Tsubota A, Hashimoto M, Miyano Y, Koike H, Kobayashi M, Koida I, Arase Y, Saitoh S, Murashima N, Ikeda K, Kumada H, et al: Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild type after cessation of therapy. Hepatology 1998;27:1711–1716.
  18. Yuen MF, Lai CL: Natural history of chronic hepatitis B virus infection. J Gastroenterol Hepatol 2000;15(suppl):E20–E24.
  19. Kidd-Ljunggren K, Miyakawa Y, Kidd AH: Genetic variability in hepatitis B viruses. J Gen Virol 2002;83:1267–1280.
  20. Kao JH, Chen PJ, Lai MY, Chen DS: Acute exacerbations of chronic hepatitis B are rarely associated with superinfection of hepatitis B virus. Hepatology 2001;34:817–823.
  21. Kobayashi M, Arase Y, Ikeda K, Tsubota A, Suzuki Y, Saitoh S, Kobayashi M, Suzuki F, Akuta N, Someya T, Matsuda M, Sato J, Kumada H: Clinical characteristics of patients infected with hepatitis B virus genotypes A, B, and C. J Gastroenterol 2002;37:35–39.
  22. Chan HL, Tsang SW, Wong ML, Tse CH, Leung NW, Chan FK, Sung JJ: Genotype B hepatitis B virus is associated with severe icteric flare-up of chronic hepatitis B virus infection in Hong Kong. Am J Gastroenterol 2002;97:2629–2633.
  23. Sugauchi F, Orito E, Ichida T, Kato H, Sakugawa H, Kakumu S, Ishida T, Chutaputti A, Lai CL, Ueda R, Miyakawa Y, Mizokami M: Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene. J Virol 2002;76:5985–5992.
  24. Suzuki Y, Kumada H, Ikeda K, Chayama K, Arase Y, Saitoh S, Tsubota A, Kobayashi M, Koike M, Ogawa N, Tanikawa K: Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection. J Hepatol 1999;30:743–748.
  25. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA: Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256–1263.
  26. Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, Lim SG, Wu PC, Dent JC, Edmundson S, Condreay LD, Chien RN, on behalf of the Asia Hepatitis Lamivudine Study Group: Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: Results after 3 years of therapy. Hepatology 2001;33:1527–1532.
  27. Chien RN, Liaw YF, Atkins M: Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Hepatology 1999;30:770–774.
  28. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Chien RN, Dent J, Roman L, Edmundson S, Lai CL: Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000;119:172–180.
  29. Chang TT, Lai CL, Liaw YF: Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV (CHB) patients treated with lamivudine for years (abstract). Antivir Ther 2000;5(suppl 1):44A.
  30. Liaw YF, Tsai SL, Chien RN, Yeh CT, Chu CM: Prednisolone priming enhances Th1 response and efficacy of subsequent lamivudine therapy in patients with chronic hepatitis B. Hepatology 2000;32:604–609.
  31. Moraleda G, Saputelli J, Aldrich CE, Averett D, Condreay L, Mason WS: Lack of effect of antiviral therapy in non-dividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus. J Virol 1997;71:9392–9399.
  32. Lau DT, Khokhar MF, Doo E, Ghany MG, Herion D, Park Y, Kleiner DE, Schmid P, Condreay LD, Gauthier J, Kuhns MC, Liang TJ, Hoofnagle JH, et al: Long-term therapy of chronic hepatitis B with lamivudine. Hepatology 2000;32:828–834.

 goto top of outline Author Contacts

Akihito Tsubota, MD
Institute of Clinical Medicine and Research (ICMR)
Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa
Chiba 277-8567 (Japan)
Tel. +81 47 164 1111, Fax +81 47 166 8638, E-Mail atsubo@jikei.ac.jp

 goto top of outline Article Information

Received: October 20, 2003
Accepted: November 24, 2003
Number of Print Pages : 7
Number of Figures : 3, Number of Tables : 1, Number of References : 32

 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 47, No. 6, Year 2004 (Cover Date: 2004)

Journal Editor: U.G. Liebert, Leipzig
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/int

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