J Korean Med Assoc.  2014 Jan;57(1):60-67. 10.5124/jkma.2014.57.1.60.

Oral antiviral agents for treatment of chronic hepatitis B

• Ko SY
• Choe WH

• KMID: 2194835
• DOI: http://doi.org/10.5124/jkma.2014.57.1.60

Abstract

The goal of antiviral therapy for chronic hepatitis B virus (HBV) infection is to eliminate or suppress HBV with the aim of preventing the devastating complications of cirrhosis, hepatic failure, and hepatocellular carcinoma. Oral antiviral agents suppress but do not eradicate HBV, therefore long-term treatment is necessary to achieve the sustained suppression of viral replication. To optimize the treatment response, treatment should be initiated at an appropriate time with the best available drugs. The indications for treatment are generally based on HBeAg status, serum HBV-DNA level, serum alanine aminotransferase, and the severity of the liver disease. Patients with clinical evidence of active viral replication either with liver inflammation or potentially evolving to cirrhosis should be treated. Nowadays, lamivudine, adefovir, clevudine, telbivudine, entecavir, and tenofovir have been approved for chronic hepatitis B (CHB). Among these, tenofovir and entecavir are potent HBV inhibitors with a high genetic barrier to resistant mutants, so they are recommended by the current treatment guidelines as preferred first-line monotherapies. Failure of antiviral therapy for CHB results in a partial virological response and virological breakthrough, which are related to antiviral-resistant mutants. If genotypic resistance is confirmed, rescue therapy should be initiated, and the regimen should include a potent drug without cross-resistance to prior antiviral agents to minimize the risk of emergence of multiple drug-resistant mutants. This article reviews the current developments in oral antiviral agents, recommendations in CHB treatment guidelines, the medical insurance policy of Korea's National Health Insurance, and the optimal strategies for using these drugs in clinical practice.

Keyword

Hepatitis B virus; Antiviral agents

MeSH Terms

Alanine Transaminase
Antiviral Agents*
Carcinoma, Hepatocellular
Fibrosis
Hepatitis B e Antigens
Hepatitis B virus
Hepatitis B, Chronic*
Hepatitis, Chronic*
Humans
Inflammation
Insurance
Lamivudine
Liver
Liver Cirrhosis
Liver Diseases
National Health Programs
Tenofovir
Viruses
Alanine Transaminase
Antiviral Agents
Hepatitis B e Antigens
Lamivudine

Reference

1. Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia. J Hepatol. 2009; 51:403–410.

2. Korean Association for the Study of the Liver. KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol. 2012; 18:109–162.

3. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF. Asia Hepatitis Lamivudine Study Group. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med. 1998; 339:61–68.

4. Yuen MF, Fung J, Wong DK, Lai CL. Prevention and management of drug resistance for antihepatitis B treatment. Lancet Infect Dis. 2009; 9:256–264.

5. Scaglione SJ, Lok AS. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology. 2012; 142:1360–1368.e1.

6. General principles of oral anti-viral agents for chronic hepatitis B. Health Insurance Review and Assessment Service.org [Internet]. updated 2013 June 1. Available from: http://www.hira.or.kr/.

7. Liaw YF. Impact of therapy on the long-term outcome of chronic hepatitis B. Clin Liver Dis. 2013; 17:413–423.

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

9. European Association For The Study Of The Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012; 57:167–185.

10. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL, Heathcote EJ, Little NR, Griffiths DA, Gardner SD, Castiglia M. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003; 125:1714–1722.

11. Fung J, Lai CL, Seto WK, Yuen MF. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. J Antimicrob Chemother. 2011; 66:2715–2725.

12. Lampertico P, Viganò M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology. 2005; 42:1414–1419.

13. Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, Frederick D, Rousseau F. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008; 48:750–758.

14. Ko SY, Kwon SY, Choe WH, Kim BK, Kim KH, Lee CH. Clinical and virological responses to clevudine therapy in chronic hepatitis B patients: results at 1 year of an open-labelled prospective study. Antivir Ther. 2009; 14:585–590.

15. Choung BS, Kim IH, Jeon BJ, Lee S, Kim SH, Kim SW, Lee SO, Lee ST, Kim DG. Long-term treatment efficacy and safety of clevudine therapy in naïve patients with chronic hepatitis B. Gut Liver. 2012; 6:486–492.

16. Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, Heathcote EJ, Manns M, Bzowej N, Niu J, Han SH, Hwang SG, Cakaloglu Y, Tong MJ, Papatheodoridis G, Chen Y, Brown NA, Albanis E, Galil K, Naoumov NV. GLOBE Study Group. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009; 136:486–495.

17. Zou XJ, Jiang XQ, Tian DY. Clinical features and risk factors of creatine kinase elevations and myopathy associated with telbivudine. J Viral Hepat. 2011; 18:892–896.

18. Pan CQ, Lee HM. Antiviral therapy for chronic hepatitis B in pregnancy. Semin Liver Dis. 2013; 33:138–146.

19. Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HS, Carrilho FJ, Poordad F, Halota W, Horsmans Y, Tsai N, Zhang H, Tenney DJ, Tamez R, Iloeje U. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010; 51:422–430.

20. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013; 381:468–475.

21. Park MS, Kim BK, Kim KS, Kim JK, Kim SU, Park JY, Kim DY, Baartarkhuu O, Han KH, Chon CY, Ahn SH. Antiviral efficacies of currently available rescue therapies for multidrug-resistant chronic hepatitis B. Clin Mol Hepatol. 2013; 19:29–35.

22. Choe WH, Hong SP, Kim BK, Ko SY, Jung YK, Kim JH, Yeon JE, Byun KS, Kim KH, Ji SI, Kim SO, Lee CH, Kwon SY. 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.

23. Yim HJ, Hwang SG. Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade. Clin Mol Hepatol. 2013; 19:195–209.

24. Ko SY, Choe WH, Kwon SY, Kim JH, Seo JW, Kim KH, Lee CH. Long-term impact of entecavir monotherapy in chronic hepatitis B patients with a partial virologic response to entecavir therapy. Scand J Gastroenterol. 2012; 47:1362–1367.