Skip to main content
SpringerLink
Log in

Predictive Factors Associated with the Progression to Hepatic Failure Caused by Lamivudine-Resistant HBV

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The aims of this study were to select the patients with a potential for progression to hepatic failure due to lamivudine-resistant HBV and to standardize the treatment for patients with lamivudine-resistant HBV. Patients (n = 47) with reactivated hepatitis due to lamivudine-resistant HBV were classified into two groups, with and without potential for progression to hepatic failure, according to the criteria using the data of serum bilirubin level and prothrombin activity after the reactivated hepatitis. Multivariate analysis showed that prothrombin activity at the initiation of lamivudine therapy was related to the deterioration of the liver function after the emergence of lamivudine-resistant HBV (P = 0.0025, 95%CI 0.8269–0.9601). We assume that earlier additional or substitutive treatment with other antiviral agent, such as adefovir dipivoxil, should be recommended when the lamivudine-resistant HBV is detected in patients with the history of decompensated liver disease before the administration of lamivudine, even when hepatitis has not been reactivated yet.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lee WH (1997) Hepatitis B infection. N Engl J Med 337:1773–1745

    Article  Google Scholar 

  2. Hoofnagle JH, Peter M, Mullen KD, Jones DB, Rustgi V, Bisceglie AD, Hallahan C, Park Y, Meschivitz C, Jones EA (1988) Randomised controlled trial of recombinant α-interferon in patients with chronic hepatitis B. Gastroenterology 95:1318–1325

    PubMed  CAS  Google Scholar 

  3. Lok ASF, Chung H-T, Liu VWS, Ma OCK (1993) Long-term follow-up of chronic hepatitis B patients treated with interferon alpha. Gastroenterology 105:1833–1838

    PubMed  CAS  Google Scholar 

  4. Lau DT-Y, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, Hoofnagle JH (1997) Long-term follow up of patients with chronic hepatitis B treated with interferon alpha. Gastroenterology 113:1660–1667

    Article  PubMed  CAS  Google Scholar 

  5. Wong DK, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heathcote J (1993) Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 119:312–323

    PubMed  CAS  Google Scholar 

  6. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF (1999) Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 29:971–975

    Article  PubMed  CAS  Google Scholar 

  7. Hoofnagle JH, DiBisceglie AM, Waggoner JG, Park Y (1993) Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 104:1116–1121

    PubMed  CAS  Google Scholar 

  8. Perrilo R, Tamburro C, Regenstein F, Balart L, Bodenheimer H, Silva M, Schiff E, Bodicky C, Miller B, Denham C, Brodeur C, Roach K, Albrecht J (1995) Low dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 109:908–916

    Article  Google Scholar 

  9. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, Bismuth H (1993) Liver transplantation in European patients with hepatitis B surface antigen. N Engl J Med 329:1842–1847

    Article  PubMed  CAS  Google Scholar 

  10. Lai C-L, Chien R-N, Leung NWY, Chang T-T, Guan R, Tai D-R, Ng K-Y, Wu P-C, Dent JC, Barber J, Stephenson SL, Gray DF, Asia Hepatitis lamivudine Study Group (1998) A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 339:61–68

    Article  PubMed  CAS  Google Scholar 

  11. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann H-WL, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA, The U.S. Lamivudine Investigator Group (1999) Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 341:1256–1263

    Article  PubMed  CAS  Google Scholar 

  12. Dienstag JL, Goldin RN, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, Gardner S, Gray DF, Schiff ER (2003) Histological outcome during long-term lamivudine therapy. Gastroenterology 124:105–107

    Article  PubMed  CAS  Google Scholar 

  13. Ling R, Mutimer D, Ahmed M, Boxall EH, Elias E, Dusheiko GM, Harrison TJ (1996) Selection of mutation in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine. Hepatology 24:711–713

    Article  PubMed  CAS  Google Scholar 

  14. Tipples GA, Ma MM, Fisher KP, Bain VG, Kneteaman NW, Tyrrell DL (1996) Mutation in the HBV-RNA dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology 24:714–717

    PubMed  CAS  Google Scholar 

  15. Lok AS, Hussain M, Cursano C, Margotti M, Gramenzi A, Grazi GL, Jovine E, Benardi M, Andreone P (2000) Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy. Hepatology 32:1145–1153

    Article  PubMed  CAS  Google Scholar 

  16. Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, Lim SG, Wu PC, Dent JC, Edmondson S, Condreay LD, Chien RN, On behalf of the Asia Hepatitis Lamivudine Study Group (2001) Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e seroconversion rates: results after 3 years of therapy. Hepatology 33:1527–1532

    Article  PubMed  CAS  Google Scholar 

  17. Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, Brown N, Woessner M, Boehme R, Condreay L (2003) Prevalence and correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 36:687–696

    Article  PubMed  CAS  Google Scholar 

  18. Ono-Nita SK, Kato N, Shiratori Y, Masaki T, Lan KH, Carrilho FJ, Omata M (1999) YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: a study by in vitro full-length viral DNA transfection. Hepatology 29:939–945

    Article  PubMed  CAS  Google Scholar 

  19. Bruno R, Sacchi P, Filice C, Filice G (2001) Acute liver failure during lamivudine treatment in a hepatitis B cirrhotic patient. Am J Gastroenterol 95:265

    Article  Google Scholar 

  20. Wang JH, Lu SN, Lee CM, Lee JF, Chou YP (2002) Fatal hepatic failure after the emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis. Scand J Gastroenterol 27:366–369

    Article  Google Scholar 

  21. Kuwahara R, Kumashiro R, Inoue H, Tanabe R, Tanaka E, Hino T, Ide T, Koga Y, Sata M (2004) Adefovir dipivoxil as a treatment for hepatic failure caused by lamivudine-resistant HBV strains. Dig Dis Sci 49:300–303

    Article  PubMed  Google Scholar 

  22. Liaw YF, Chien RN, Yhe CT, Tsai SL, Chu CM (1999) Acute exacerbation and hepatitis B clearance after emergence of YMDD mutation during lamivudine therapy. Hepatology 30:567–572

    Article  PubMed  CAS  Google Scholar 

  23. Kobayashi S, Shimada K, Suzuki H, Tanikawa K, Sata M (2000) Development of a new method for detecting a mutation in the gene coding hepatitis B virus reverse transcriptase active site (YMDD motif). Hepatol Res 17:31–42

    Article  Google Scholar 

  24. Villeneuve J, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M, Heathcote EJ (2000) Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 31:207–210

    Article  PubMed  CAS  Google Scholar 

  25. Yao FY, Bass NM (2000) Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol 33:301–307

    Article  PubMed  CAS  Google Scholar 

  26. Yao FY, Terrault NA, Freise C, Maslow L, Bass NM (2001) Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and activity replicating hepatitis B infection awaiting liver transplantation: a comparative study using matched, untreated cohort. Hepatology 34:411–416

    Article  PubMed  CAS  Google Scholar 

  27. Kapoor D, Guptan RC, Wakil SM, Kazim SM, Kaul R, Agarwal SR, Raisuddin S, Hasnain SE, Sarin SK (2000) Beneficial effect of lamivudine in hepatitis B virus related decompensated cirrhosis. J Hepatol 33:308–312

    Article  PubMed  CAS  Google Scholar 

  28. Fontana RJ, Keefe EB, Carey W, Fried M, Reddy R, Kowdley KV, Soldevila-Pico C, McClure LA, Lok ASF, for the National Institutes of Health Hepatitis B Virus Orthotopic Liver Transplantation Study Group (2002) Effect of lamivudine treatment on survival of 309 North American patients awaiting liver transplantation for chronic hepatitis B. Liver Transpl 8:433–439

    Article  PubMed  Google Scholar 

  29. Manolakopoulos S, Karatapanis S, Elefsiniotis J, Mathou N, Vlachogiannakos J, Iliadou E, Kougioumtzan A, Economou M, Triantos C, Tzourmakliotis D, Avgerinos A (2004) Clinical course of lamivudine monotherapy in patients with decompensated cirrhosis due to HBeAg negative chronic HBV infection. Am J Gastroenterol 99:57–63

    Article  PubMed  CAS  Google Scholar 

  30. Pelliro RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, Martin P, Dienstag J, Adams P, Dickson R, Anschuetz G, Bell S, Condreay L, Brown N, The Lamivudine North American Transplant Group (2001) A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 33:424–432

    Article  Google Scholar 

  31. Oberti F, Valsesia E, Pilette C, Rousselet MC, Bedossa P, Aube C, Gallois Y, Rifflet MY, Penneau-Fontbonne D, Cales P (1997) Noninvasive diagnosis of hepatic fibrosis and cirrhosis. Gastroenterology 113:1609–1616

    Article  PubMed  CAS  Google Scholar 

  32. Williams AL, Hoofnagle JH (1988) Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 95:734–739

    PubMed  CAS  Google Scholar 

  33. Giannini E, Botta F, Fasoli A, Ceppa P, Risso D, Lantieri PB, Celle G, Testa R (1999) Progressive liver functional impairment is associated with an increase in AST/ALT ratio. Dig Dis Sci 44:1249–1253

    Article  PubMed  CAS  Google Scholar 

  34. Ballmer PE, Reichen J, McNurlan MA, Sterchi AB, Anderson SE, Garlick PJ (1996) Albumin but not fibrinogen synthesis correlates with galactose elimination capacity in patients with cirrhosis of the liver. Hepatology 24:53–59

    Article  PubMed  CAS  Google Scholar 

  35. Barle H, Nyberg B, Essen P, Anderson K, McNurlan MA, Wernerman J, Garlick PJ (1997) The synthesis rates of total liver protein and plasma albumin determined simultaneously in vivo in humans. Hepatology 25:154–158

    PubMed  CAS  Google Scholar 

  36. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL, for the Adefovir Dipivoxil 438 Study Group (2003) Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 348:800–807

    Article  PubMed  CAS  Google Scholar 

  37. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL, for the Adefovir Dipivoxil 437 Study Group (2003) Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 348:808–816

    Article  PubMed  CAS  Google Scholar 

  38. Ono-Nita SK, Kato N, Shiratori Y, Lan KH, Yoshida H, Carrilho FJ, Omata M (1999) Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors. J Clin Invest 103:1635–1640

    Article  PubMed  CAS  Google Scholar 

  39. Westland C, Delaney IV W, Yang H, Chen SS, Marcellin P, Hadziyannis S, Gish R, Fry J, Brosgart C, Bibbs C, Miller M, Xiong S (2003) Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology 125:107–116

    Article  PubMed  CAS  Google Scholar 

  40. Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, Moorat A, Gardner S, Woessner M, Bourne E, Brosgart CL, Schiff E (2004) Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 126:81–90

    Article  PubMed  CAS  Google Scholar 

  41. Augus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, Brosgart C, Colledge D, Edwards R, Ayres A, Bartholomeusz A, Locarnini S (2003) Resistance to adefovir dipivoxil therapy associated with the selection of novel mutation in the HBV polymerase. Gastroenterology 125:292–297

    Article  Google Scholar 

  42. Peters MG, Hann HW, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray DF, Sullivan M, Kleber K, Ebrahimi R, Xiong S, Brosgart CL, for the GS–00–461 study group (2004) Adefovir dipivoxil alone or combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 126:91–101

    Article  PubMed  CAS  Google Scholar 

  43. Lai CL, Rosmawati M, Lao J, Vlierberghe HV, Anderson FH, Thomas N, Dehertogh D (2002) Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology 123:1831–1838

    Article  PubMed  CAS  Google Scholar 

  44. Rosmawati M, Schiff E, Parana R, Sievert W, Zhu J, Cross A, Dehertogh D, Apelian D, for the BEHoLD Study Group (2004) ntecavir is superior to lamivudine at reducing HBV DNA in patients with chronic hepatitis B regardless of baseline alanine aminotransferase levels. Hepatology 40(suppl):656A

    Google Scholar 

  45. Shermann M, Yurdaydin C, Sollano J, Silva M, Goodman Z, Chen L, Cross A, Dehertogh D, Hindes R, for the BEHoLD Study Group (2004) Entecavir is superior to continued lamivudine for the treatment of lamivudine-refractory, HBeAg(+) chronic hepatitis B: results of phase III study ETV–026. Hepatology 40(suppl):664A

    Google Scholar 

  46. van Bommel F, Wunsche T, Mauss S, Reinke P, Bergk A, Schurmann D, Wiedenmann B, Berg T (2004) Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 40:1421–1425

    Article  PubMed  Google Scholar 

  47. Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, Plym M, Pokornowski K, Yu CF, Angus P, Ayres A, Bartholomeusz A, Sievert W, Thompson G, Warner N, Locarnini S, Colonno RJ (2004) Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant lamivudine. Antimicrob Agents Chemother 48:3498–3507

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are deeply grateful to Ms. Ogo and Ms. Handa for their handling of the blood samples. The authors also thank Dr. Yasuhiko Kubo, Dr. Hirohiko Abe, Dr. Hiroshi Yoshida, Dr. Kunihide Ishii, Dr. Kunitaka Fukuizumi, Dr. Yasuyo Morita, Dr. Ichiro Miyajima, Dr. Shiro Murashima, Dr. Miki Shirachi, Dr. Akira Shirachi, Dr. Sanki Yamasaki, Dr. Hidetoshi Takedatsu, Dr. Manabu Satani, Dr. Madoka Yanaga, Dr. Yusuke Ishida and Dr. Kotaro Kuwaki for their generous assistance in collecting clinical data.

Author information

Authors and Affiliations

  1. Kurume University School of Medicine, Kurume, 830-0011, Japan

    Reiichiro Kuwahara, Ryukichi Kumashiro, Tatsuya Ide, Yuriko Koga, Teruko Hino, Akiko Hisamochi, Kazuo Tanaka, Kei Ogata, Hiroyuki Koga, Yukari Takao & Michio Sata

Authors
  1. Reiichiro Kuwahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryukichi Kumashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuya Ide
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuriko Koga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teruko Hino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akiko Hisamochi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuo Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kei Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroyuki Koga
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yukari Takao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michio Sata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reiichiro Kuwahara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuwahara, R., Kumashiro, R., Ide, T. et al. Predictive Factors Associated with the Progression to Hepatic Failure Caused by Lamivudine-Resistant HBV. Dig Dis Sci 53, 2999–3006 (2008). https://doi.org/10.1007/s10620-008-0384-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-008-0384-x

Keywords

Search

Navigation