Korean J Pediatr Gastroenterol Nutr.  2010 Mar;13(1):44-50. 10.5223/kjpgn.2010.13.1.44.

Experience with Entecavir Therapy for Lamivudine-Resistant Chronic Hepatitis B in Korean Children and Adolescents

• Cho SM
• Choe BH
• Chu MA
• Kim JM

• KMID: 1459443
• DOI: http://doi.org/10.5223/kjpgn.2010.13.1.44

Abstract

PURPOSE
To estimate the viral suppressive effect of entecavir monotherapy in Korean children and adolescents with lamivudine-resistant chronic hepatitis B (CHB).
METHODS
One milligram of entecavir was administered once daily to 6 patients (4 boys; mean age, 17.5 years; range, 15.10~24.6 years) with lamivudine-resistant CHB for a mean duration of therapy of 13.4 months (range, 1~21.1 months). The therapeutic results were compared with 11 patients who received adefovir (0.3 mg/kg/day [maximal dose 10 mg]) for at least 12 months (mean, 33.4 months; range, 12.4~58.3 months). The serum HBV DNA level and serologic markers were measured every 2 months.
RESULTS
The interval to a HBV DNA titer decrement (>1 log(10)) was 1.2+/-0.2 and 4.4+/-5.2 months (p=0.185) for the entecavir and adefovir groups, respectively. The interval to a HBV DNA titer decrement (>2 log(10)) was 2.4+/-2.3 and 9.2+/-7.3 months (p=0.025), for the entecavir and adefovir groups, respectively.
CONCLUSION
The therapeutic efficacy of entecavir was favorable in children and adolescents, especially in shortening the interval to a >2 log(10) decrement in the HBV DNA titer. Long-term follow up is needed to determine the therapeutic efficacy of entecavir for lamivudine-resistant CHB in children and adolescents.

Keyword

Entecavir; Adefovir; Lamivudine; Chronic hepatitis B; Resistance

MeSH Terms

Adenine
Adolescent
Child
DNA
Follow-Up Studies
Guanine
Hepatitis B, Chronic
Hepatitis, Chronic
Humans
Lamivudine
Organophosphonates
Adenine
DNA
Guanine
Lamivudine
Organophosphonates

Reference

1. Lok AS. Navigating the maze of hepatitis B treatments. Gastroenterology. 2007. 132:1586–1594.

2. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004. 351:1521–1531.

3. Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001. 33:424–432.

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

5. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003. 124:105–117.

6. Leung N. Recent data on treatment of chronic hepatitis B with nucleos(t)ide analogues. Hepatol Int. 2008. 2:163–178.

7. Kurbegov AC, Sokol RJ. Hepatitis B therapy in children. Expert Rev Gastroenterol Hepatol. 2009. 3:39–49.

8. National Health Insurance Corporation. The Criterias for the Medical Care Benefits. 2010. Available from: http://www.nhic.or.kr.

9. Lee JM, Kim HJ, Park JY, Lee CK, Kim do Y, Kim JK, et al. Rescue monotherapy in lamivudine-resistant hepatitis B e antigen-positive chronic hepatitis B: adefovir versus entecavir. Antivir Ther. 2009. 14:705–712.

10. Hwang SK, Park SM, Choe BH, Kim JM, Kim JO, Kim YM, et al. Therapeutic efficacy of adefovir dipivoxil in korean children and adolescents with chronic hepatitis b who have developed lamivudine resistance. Korean J Pediatr Gastroenterol Nutr. 2008. 11:143–149.

11. Locarnini S, Hatzakis A, Heathcote J, Keeffe EB, Liang TJ, Mutimer D, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther. 2004. 9:679–693.

12. Sokal EM, Kelly D, Wirth S, Mizerski J, Dhawan A, Frederick D. The pharmacokinetics and safety of adefovir dipivoxil in children and adolescents with chronic hepatitis B virus infection. J Clin Pharmacol. 2008. 48:512–517.

13. Jonas MM, Kelly D, Pollack H, Mizerski J, Sorbel J, Frederick D, et al. Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to < 18 years) with chronic hepatitis B. Hepatology. 2008. 47:1863–1871.

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

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

16. Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003. 38:1419–1427.

17. Lee KS, Kim DJ. Guideline Committee of the Korean Association for the Study of the Liver. Management of Chronic Hepatitis B. Korean J Hepatol. 2007. 13:447–488.

18. Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WE 4th. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV. Antivir Ther. 2005. 10:625–633.

19. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998. 339:61–68.

20. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999. 341:1256–1263.

21. Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. 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.

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

23. Park NH, Shin JW, Park JH, Bang SJ, Kim DH, Joo KR. Predictive Factors and Efficacy of Lamivudine Treatment in Chronic Hepatitis B Infection. Korean J Gastroenterol. 2003. 42:303–312.

24. Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol. 2006. 44:283–290.

25. Marcellin P, Asselah T. Resistance to adefovir: a new challenge in the treatment of chronic hepatitis B. J Hepatol. 2005. 43:920–923.

26. Lee YS, Suh DJ, Lim YS, Jung SW, Kim KM, Lee HC, 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.

27. Choe WH, Hong SP, Kim BK, Ko SY, Jung YK, Kim JH, et al. Evolution of hepatitis B virus mutation during entecavir rescue therapy in patients with antiviral resistance to lamivudine and adefovir. Antivir Ther. 2009. 14:985–993.

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

29. Chang TT, Gish RG, de Man RA, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006. 354:1001–1010.

30. Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007. 133:1437–1444.

31. Lange CM, Bojunga J, Hofmann WP, Wunder K, Mihm U, Zeuzem S, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009. 50:2001–2006.

32. Cohen SM, Levy RM, Jovanovich JF, Ahn J. Fatal lactic acidosis associated with the use of combination oral medications to treat reactivation of hepatitis B. J Clin Gastroenterol. 2009. 43:1008–1010.

33. Choe BH, Lee JH, Jang YC, Jang CH, Oh KW, Kwon S, et al. Long-term therapeutic efficacy of lamivudine compared with interferon-alpha in children with chronic hepatitis B: the younger the better. J Pediatr Gastroenterol Nutr. 2007. 44:92–98.