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Efficacy of Entecavir and Adefovir Combination Therapy for Patients with Lamivudine- and Entecavir-Resistant Chronic Hepatitis B

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Abstract

Background

The optimal treatment of patients with chronic hepatitis B (CHB) who develop resistance to both lamivudine (LMV) and entecavir (ETV) after sequential monotherapy of LMV and ETV remains little known.

Methods

We evaluated the efficacy of entecavir (ETV) plus adefovir dipivoxil (ADV) combination therapy for patients with resistance to LMV and ETV. We reviewed the medical records of 12 patients, and treated all 12 patients with ETV plus ADV combination therapy for at least 18 months. Quantitative hepatitis B virus (HBV) DNA levels, serologic markers, and hepatic panel values were monitored at baseline and 3-month intervals thereafter for 18 months.

Results

The baseline mean serum HBV DNA level was 7.26 ± 1.11 log10 copies/ml. The mean reductions in serum HBV DNA levels from baseline to 3, 6, 9, 12, 15, and 18 months were −1.98 ± 1.03, −2.87 ± 1.02, −3.32 ± 1.10, −3.92 ± 1.30, −4.36 ± 1.22, and −4.57 ± 1.18 log10 copies/ml, respectively. Complete virological response (HBV DNA of <2 log10 copies/ml) at 6, 12, and 18 months was observed in 1 (8.3%), 4 (33.3%), and 6 (50.0%) patients, respectively. The 2 patients with baseline HBV DNA of <6 log10 copies/ml achieved complete virological response at 18 months, while 4 of 10 patients with baseline HBV DNA of ≥6 log10 copies/ml achieved complete virological response at 18 months. None of the 12 patients experienced virological breakthrough during follow-up.

Conclusions

ETV plus ADV combination therapy effectively reduced serum HBV DNA levels in patients with CHB who developed resistance to both LMV and ETV. Additional long-term studies are needed to assess the effect of long-term treatment with these drugs.

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References

  1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97–107.

    Article  PubMed  CAS  Google Scholar 

  2. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. 1988;61:1942–1956.

    Article  PubMed  CAS  Google Scholar 

  3. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531.

    Article  PubMed  CAS  Google Scholar 

  4. Chang TT, Lai CL, Chien RN, et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol. 2004;19:1276–1282.

    Article  PubMed  CAS  Google Scholar 

  5. Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687–696.

    Article  PubMed  CAS  Google Scholar 

  6. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–539.

    Article  PubMed  CAS  Google Scholar 

  7. Sherman M, Yurdaydin C, Simsek H, et al. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology. 2008;48:99–108.

    Article  PubMed  CAS  Google Scholar 

  8. Ustundag Y, Topalak O. Think twice if you consider entecavir treatment in cases with lamivudine refractoriness. Hepatology. 2010;52:397–398.

    Article  PubMed  Google Scholar 

  9. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–662.

    Article  PubMed  Google Scholar 

  10. Holoman J, Glasa J. EASL clinical practice guidelines. J Hepatol. 2009;51:821–822.

    Article  PubMed  Google Scholar 

  11. Leemans WF, Niesters HG, van der Eijk AA, et al. Selection of an entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: successful rescue therapy with tenofovir. Eur J Gastroenterol Hepatol. 2008;20:773–777.

    Article  PubMed  CAS  Google Scholar 

  12. Kurashige N, Ohkawa K, Hiramatsu N, et al. Two types of drug-resistant hepatitis B viral strains emerging alternately and their susceptibility to combination therapy with entecavir and adefovir. Antivir Ther. 2009;14:873–877.

    Article  PubMed  CAS  Google Scholar 

  13. Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385–1391.

    Article  PubMed  CAS  Google Scholar 

  14. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2:263–283.

    Article  PubMed  Google Scholar 

  15. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.

    Article  PubMed  CAS  Google Scholar 

  16. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–686.

    Article  PubMed  Google Scholar 

  17. Yuen MF, Yuan HJ, Wong DK, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54:1610–1614.

    Article  PubMed  Google Scholar 

  18. Song BC, Suh DJ, Lee HC, et al. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology. 2000;32:803–806.

    Article  PubMed  CAS  Google Scholar 

  19. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315–1341; quiz 1286.

    Google Scholar 

  20. Lok AS, Zoulim F, Locarnini S, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007;46:254–265.

    Article  PubMed  CAS  Google Scholar 

  21. Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130:2039–2049.

    Article  PubMed  CAS  Google Scholar 

  22. Chang TT, Gish RG, Hadziyannis SJ, et al. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology. 2005;129:1198–1209.

    Article  PubMed  CAS  Google Scholar 

  23. Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133:1437–1444.

    Article  PubMed  CAS  Google Scholar 

  24. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–1514.

    Article  PubMed  CAS  Google Scholar 

  25. Villet S, Ollivet A, Pichoud C, et al. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol. 2007;46:531–538.

    Article  PubMed  CAS  Google Scholar 

  26. Baldick CJ, Tenney DJ, Mazzucco CE, et al. Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance. Hepatology. 2008;47:1473–1482.

    Article  PubMed  CAS  Google Scholar 

  27. Lampertico P, Vigano M, Manenti E, et al. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445–1451.

    Article  PubMed  CAS  Google Scholar 

  28. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419–1427.

    PubMed  CAS  Google Scholar 

  29. Fournier C, Zoulim F. Antiviral therapy of chronic hepatitis B: prevention of drug resistance. Clin Liver Dis. 2007;11:869–892.

    Article  PubMed  Google Scholar 

  30. Shim JH, Suh DJ, Kim KM, et al. Efficacy of entecavir in patients with chronic hepatitis B resistant to both lamivudine and adefovir or to lamivudine alone. Hepatology. 2009;50:1064–1071.

    Article  PubMed  CAS  Google Scholar 

  31. Patterson SJ, George J, Strasser SI, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247–254.

    Article  PubMed  CAS  Google Scholar 

  32. Orito E, Mizokami M, Sakugawa H, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C Japan HBV Genotype Research Group. Hepatology. 2001;33:218–223.

    Article  PubMed  CAS  Google Scholar 

  33. Nakayoshi T, Maeshiro T, Nakasone H, et al. Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands: a prospective study. J Med Virol. 2003;70:350–354.

    Article  PubMed  Google Scholar 

  34. Kao JH, Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J Hepatol. 2000;33:998–1002.

    Article  PubMed  CAS  Google Scholar 

  35. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743–1751.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, College of Medicine, Kyung Hee University, 149 Sangil-dong, Gangdong-gu, Seoul, 134-727, Korea

    Jung Won Jeon, Hyun Phil Shin, Joung Il Lee, Kwang Ro Joo, Jae Myung Cha, Jae Jun Park, Jun Uk Lim, Kyuseong Lim & Sunyong Kim

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  1. Jung Won Jeon
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  2. Hyun Phil Shin
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  3. Joung Il Lee
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Correspondence to Joung Il Lee.

Additional information

Jung Won Jeon and Hyun Phil Shin contributed equally to this work.

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Jeon, J.W., Shin, H.P., Lee, J.I. et al. Efficacy of Entecavir and Adefovir Combination Therapy for Patients with Lamivudine- and Entecavir-Resistant Chronic Hepatitis B. Dig Dis Sci 57, 1358–1365 (2012). https://doi.org/10.1007/s10620-011-1988-0

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  • DOI: https://doi.org/10.1007/s10620-011-1988-0

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