Combination therapy of chronic hepatitis B

Czech version

Authors: V. Hejda
Authors‘ workplace: Gastroenterologické a hepatologické oddělení, 1. interní klinika LF UK a FN Plzeň
Published in: Gastroent Hepatol 2016; 70(1): 65-73
Category: Hepatology: Review article
doi: https://doi.org/10.14735/amgh201665

Overview

Chronic hepatitis B infection is still a major global medical problem because of the risk it poses for progression to liver cirrhosis and its associated complications (portal hypertension, liver failure, and hepatocellular carcinoma). However, a very effective therapy based on nucleos(t)ide analogues is now available. This therapy, which is associated with a very low risk of development of resistant mutations, is very effective for the suppression of hepatitis B virus DNA. However, it has a minimal effect on the intracellular reservoir of hepatitis B virus (covalently closed circular DNA) and has a no effect on HBsAg synthesis; thus, it does not provide a definitive cure. Medication must be taken long-term (eventually lifelong), because stopping treatment leads to the reemergence of viremia. Therapy with pegylated interferon is another treatment option. Interferon, with its antiviral and imunomodulatory properties, can lead to clearance of infected hepatocytes and therefore a decrease in the level of covalently closed circular DNA in the liver. This therapy is taken only for a limited duration (48 weeks) and, although it has more side effects than nucleos(t)ide analogue therapy, it is associated with a higher chance of eliminating HBsAg. This paper will review the feasibility of using combinatory therapy with nucleos(t)ide analogues and pegylated interferon to shorten of length of therapy and increase the chance of obtaining a definitive cure for HBV infection, i.e., HBsAg clearance.

Key words:
HBV – HBsAg – nucleos(t)ide analogue – PEG-IFN

The author declares he has no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

Submitted:
30. 10. 2015

Accepted:
1. 12. 2016

Sources

1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004; 11(2): 97– 107.

2. Wasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitis – United States, 2006. MMWR Surveill Summ 2008; 57(2): 1– 24.

3. Státní zdravotní ústav. Vybrané infekční nemoci v ČR v letech 2005– 2014 – absolutně. [online]. Dostupné z: www.szu.cz/ publikace/ data/ vybrane-infekcni-nemoci-v-cr-v-letech-2003-2012-absolutne.

4. Cadranel JF, Lahmek P, Causse X et al. Epidemiology of chronic hepatitis B infection in France: risk factors for significant fibrosis – results of a nationwide survey. Aliment Pharmacol Ther 2007; 26(4): 565– 576.

5. Hatzakis A, Wait S, Bruix J et al. The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference. J Viral Hepat 2011; 18 (Suppl 1): 1– 16. doi: 10.1111/ j.1365-2893.2011.01499.x.

6. 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(1): 65– 73.

7. Iloeje UH, Yang HI, Su J et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130(3): 678– 686.

8. Lee MH, Yang HI, Liu J et al. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology 2013; 58(2): 546– 554. doi: 10.1002/ hep.26385.

9. Tseng TC, Liu CJ, Yang HC et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 2013; 57(2): 441– 450.

10. Fattovich G, Giustina G, Sanchez-Tapias J et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol 1998; 93(6): 896– 900.

11. Chan HL, Wong VW, Chim AM et al. Serum HBsAg quantification to predict response to peginterferon therapy of e antigen positive chronic hepatitis B. Aliment Pharmacol Ther 2010; 32(11– 12): 1323– 1331. doi: 10.1111/ j.1365-2036.2010.04474.x.

12. Nguyen T, Thompson AJ, Bowden S et al. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol 2010; 52(4): 508– 513. doi: 10.1016/ j.jhep.2010.01.007.

13. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000; 64(1): 51– 68.

14. Thompson AJ, Nguyen T, Iser D et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010; 51(6): 1933– 1944. doi: 10.1002/ hep.23571.

15. Martinot-Peignoux M, Lapalus M, Asselah T et al. HBsAg quantification: useful for monitoring natural history and treatment outcome. Liver Int 2014; 34 (Suppl 1): 97– 107. doi: 10.1111/ liv.12403.

16. Moucari R, Mackiewicz V, Lada O et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology 2009; 49(4): 1151– 1157. doi: 10.1002/ hep.22744.

17. Rehermann B, Ferrari C, Pasquinelli C et al. The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 1996; 2(10): 1104– 1108.

18. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012; 57(1): 167– 185. doi: 10.1016/ j.jhep.2012.02.010.

19. Zoutendijk R, Hansen BE, van Vuuren AJet al. Serum HBsAg decline during long-term potent nucleos(t)ide analogue therapy for chronic hepatitis B and prediction of HBsAg loss. J Infect Dis 2011; 204(3): 415– 418. doi: 10.1093/ infdis/ jir282.

20. Husa P, Šperl J, Urbánek P et al. Diag-nosis and therapy of chronic hepatitis B: Czech national guidelines. Klin Mikrobiol Infekc Lek 2014; 20(4): 121– 132.

21. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005; 352(26): 2673– 2681.

22. Chevaliez S, Hézode C, Bahrami S et al. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/ nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol 2013; 58(4): 676– 683. doi: 10.1016/ j.jhep.2012.11.039.

23. Petersen J, Ratziu V, Buti M et al. Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: an international multicenter cohort study. J Hepatol 2012; 56(3): 520– 526. doi: 10.1016/ j.jhep.2011.09.018.

24. Marcellin P, Lau GK, Bonino F et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351(12): 1206– 1217.

25. Lau GK, Piratvisuth T, Luo KX et al. Peg-interferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352(26): 2682– 2695.

26. Janssen HL, van Zonneveld M, Senturk H et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005; 365(9454): 123– 129.

27. Wursthorn K, Lutgehetmann M, Dandri M et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology 2006; 44(3): 675– 684.

28. Lutgehetmann M, Volzt T, Quaas A et al. Sequential combination therapy leads to biochemical and histological improvement despite low ongoing intrahepatic hepatitis B virus replication. Antivir Ther 2008; 13(1): 57– 66.

29. Takkenberg RB, Jansen L, de Niet A et al. Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treatedwith pegylated interferon-alpha2a and adefovir. Antivir Ther 2013; 18(7): 895– 904.

30. Brouwer WP, Xie Q, Sonneveld MJ et al. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study). Hepatology 2015; 61(5): 1512– 1522. doi: 10.1002/ hep.27586.

31. Xie Q, Zhou H, Bai X et al. A randomized, open-label clinical study of combined pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B „e“ antigen-positive chronic hepatitis B. Clin Infect Dis 2014; 59(12): 1714– 1723. doi: 10.1093/ cid/ ciu702.

32. Li GJ, Yu YQ, Chen SL et al. Sequential combination therapy with pegylated interferon leads to loss of hepatitis B surface antigen and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients receiving long-term entecavir treatment. Antimicrob Agents Chemother 2015; 59(7): 4121– 4128. doi: 10.1128/ AAC.00249-15.

33. Bourlière M, Rabiega P, Ganne-Carrie N et al. HBsAg clearance afer addition of 48 weeks of PEGIFN in HBeAg negative CHB patients on nucleos(t)ide therapy with undetectable HBV DNA for at least one year: a multicenter randomized controlled phase III trial ANRS-HB06 PEGAN study: preliminary findings. Hepatology 2014; 60 (Suppl): 1094A (abstr. 1863).

34. Marcellin P, Ahn SH, Ma X et al. Combination of tenofovir disoproxil fumarate and peginterferon alfa-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology 2016; 150(1): 134– 144. doi: 10.1053/ j.gastro.2015.09.043.

35. Lok AS, Trinh H, Carosi G et al. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naive patients with chronic hepatitis B. Gastroenterology 2012; 143(3): 619– 628. doi: 10.1053/ j.gastro.2012.05.037.

36. Manns MP, Akarca US, Chang TT et al. Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901. Expert Opin Drug Saf 2012; 11(3): 361– 368. doi: 10.1517/ 14740338.2012.653340.

37. Pipili C, Cholongitas E, Papatheodoridis G. Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. Aliment Pharmacol Ther 2014; 39(1): 35– 46. doi: 10.1111/ apt.12538.

38. Liang TJ, Block TM, McMahon BJ et al. Present and future therapies of hepatitis B: from discovery to cure. Hepatology 2015; 62(6): 1893– 1908. doi: 10.1002/ hep.28025.