PDF herunterladen
Semin Liver Dis 2013; 33(02): 122-129
DOI: 10.1055/s-0033-1345715
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Chronic Hepatitis B: A Treatment Update

Vincent Wong
1   Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
2   Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
,
Henry Chan
1   Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
2   Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
08. Juni 2013 (online)

    Lizenzen und Reprints

Erratum zu diesem Artikel:

Chronic Hepatitis B: A Treatment UpdateSemin Liver Dis 2013; 33(03): 298-298
DOI: 10.1055/s-0033-1353785

Abstract

In the past two decades, there have been major developments in the treatment of chronic hepatitis B. Peginterferon can be given conveniently with weekly dosing, and its effect on hepatitis B e antigen seroconversion is highly durable. However, it carries numerous side effects and the treatment is successful in only 30 to 40% of patients. On-treatment hepatitis B surface antigen level is an indirect marker of the level and transcriptional activity of covalently closed circular DNA in the liver and may identify nonresponders to peginterferon. New oral nucleos(t)ide analogs such as entecavir and tenofovir can effectively suppress hepatitis B virus with minimal risk of drug resistance. Many patients, however, develop virologic relapse after cessation of oral antiviral therapy despite prolonged viral suppression and would require long-term treatment. During oral antiviral drug treatment, hepatitis B virus DNA monitoring is essential to assess treatment effect and drug adherence and detect drug resistance. In treatment-naïve patients, none of the drug combinations have been shown to be superior to monotherapy. Studies combining peginterferon and potent oral agents (entecavir and tenofovir) are underway. Tenofovir is effective in patients with lamivudine resistance and previous exposure to multiple agents. Its long-term efficacy as monotherapy in this setting warrants more studies.

Keywords

peginterferon - entecavir - tenofovir - cirrhosis - hepatocellular carcinoma
 

  • References

  • 1 Liaw YF, Sung JJ, Chow WC , et al; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351 (15) 1521-1531
    CrossrefPubMedGoogle Scholar
  • 2 Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008; 28 (9) 1067-1077
    CrossrefPubMedGoogle Scholar
  • 3 Wong GL, Yiu KK, Wong VW, Tsoi KK, Chan HL. Meta-analysis: reduction in hepatic events following interferon-alfa therapy of chronic hepatitis B. Aliment Pharmacol Ther 2010; 32 (9) 1059-1068
    CrossrefPubMedGoogle Scholar
  • 4 Wong VW, Wong GL, Chim AM , et al. Surrogate end points and long-term outcome in patients with chronic hepatitis B. Clin Gastroenterol Hepatol 2009; 7 (10) 1113-1120
    CrossrefPubMedGoogle Scholar
  • 5 Wong VW, Wong GL, Yan KK , et al. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010; 51 (6) 1945-1953
    CrossrefPubMedGoogle Scholar
  • 6 Zoutendijk R, Reijnders JG, Zoulim F , et al; for the VIRGIL Surveillance Study Group. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut 2012;
    PubMedGoogle Scholar
  • 7 Moucari R, Korevaar A, Lada O , et al. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol 2009; 50 (6) 1084-1092
    CrossrefPubMedGoogle Scholar
  • 8 Fung J, Lai CL, Tanaka Y , et al. The duration of lamivudine therapy for chronic hepatitis B: cessation vs. continuation of treatment after HBeAg seroconversion. Am J Gastroenterol 2009; 104 (8) 1940-1946 , quiz 1947
    CrossrefPubMedGoogle Scholar
  • 9 Lee HW, Lee HJ, Hwang JS , et al. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B. Hepatology 2010; 51 (2) 415-421
    CrossrefPubMedGoogle Scholar
  • 10 Liang Y, Jiang J, Su M , et al. Predictors of relapse in chronic hepatitis B after discontinuation of anti-viral therapy. Aliment Pharmacol Ther 2011; 34 (3) 344-352
    CrossrefPubMedGoogle Scholar
  • 11 Chen CJ, Yang HI, Su J , et al; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295 (1) 65-73
    CrossrefPubMedGoogle Scholar
  • 12 Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50 (3) 661-662
    CrossrefPubMedGoogle Scholar
  • 13 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
    PubMedGoogle Scholar
  • 14 Liaw YF, Kao JH, Piratvisuth T , et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012; 6 (3) 531-561
    CrossrefPubMedGoogle Scholar
  • 15 Janssen HL, Gerken G, Carreño V , et al. Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology 1999; 30 (1) 238-243
    CrossrefPubMedGoogle Scholar
  • 16 Cooksley WG, Piratvisuth T, Lee SD , et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003; 10 (4) 298-305
    CrossrefPubMedGoogle Scholar
  • 17 Zhao H, Kurbanov F, Wan MB , et al. Genotype B and younger patient age associated with better response to low-dose therapy: a trial with pegylated/nonpegylated interferon-alpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China. Clin Infect Dis 2007; 44 (4) 541-548
    CrossrefPubMedGoogle Scholar
  • 18 Lau GK, Piratvisuth T, Luo KX , et al; Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352 (26) 2682-2695
    CrossrefPubMedGoogle Scholar
  • 19 Marcellin P, Lau GK, Bonino F , et al; Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. 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
    CrossrefPubMedGoogle Scholar
  • 20 Liaw YF, Jia JD, Chan HL , et al. Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C. Hepatology 2011; 54 (5) 1591-1599
    CrossrefPubMedGoogle Scholar
  • 21 Janssen HL, van Zonneveld M, Senturk H , et al; HBV 99-01 Study Group; Rotterdam Foundation for Liver Research. 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
    CrossrefPubMedGoogle Scholar
  • 22 Chan HL, Leung NW, Hui AY , et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005; 142 (4) 240-250
    CrossrefPubMedGoogle Scholar
  • 23 Buster EH, Hansen BE, Lau GK , et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology 2009; 137 (6) 2002-2009
    CrossrefPubMedGoogle Scholar
  • 24 Bonino F, Marcellin P, Lau GK , et al; Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 2007; 56 (5) 699-705
    CrossrefPubMedGoogle Scholar
  • 25 Sonneveld MJ, Wong VW, Woltman AM , et al. Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B. Gastroenterology 2012; 142 (3) 513-520.e1
    CrossrefPubMedGoogle Scholar
  • 26 Fried MW, Piratvisuth T, Lau GK , et al. HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B. Hepatology 2008; 47 (2) 428-434
    CrossrefPubMedGoogle Scholar
  • 27 ter Borg MJ, van Zonneveld M, Zeuzem S , et al; HBV 99-01 Study Group. Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response. Hepatology 2006; 44 (3) 721-727
    CrossrefPubMedGoogle Scholar
  • 28 Chan HL, Wong VW, Wong GL, Chim AM, Chan HY, Sung JJ. Early hepatitis B virus DNA suppression can predict virologic response to peginterferon and lamivudine treatment. Clin Gastroenterol Hepatol 2008; 6 (9) 1022-1026
    CrossrefPubMedGoogle Scholar
  • 29 Chan HL, Thompson A, Martinot-Peignoux M , et al. Hepatitis B surface antigen quantification: why and how to use it in 2011–a core group report. J Hepatol 2011; 55 (5) 1121-1131
    CrossrefPubMedGoogle Scholar
  • 30 Piratvisuth T, Marcellin P, Popescu M, Kapprell HP, Rothe V, Lu ZM. Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. Hepatol Int 2011; . [Epub ahead of print]
    PubMedGoogle Scholar
  • 31 Rijckborst V, Hansen BE, Ferenci P , et al. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a. J Hepatol 2012; 56 (5) 1006-1011
    CrossrefPubMedGoogle Scholar
  • 32 Marcellin P, Brunetto MR, Bonino F , et al. In patients with HBeAg-negative chronic hepatitis B HBsAg serum levels early during treatment with peginterferon alfa-2a predict HBsAg clearance 4 years post-treatment. Hepatology 2008; ; 48 (4, Suppl): 718A-719A
    PubMedGoogle Scholar
  • 33 Hui AY, Chan HL, Cheung AY, Cooksley G, Sung JJ. Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon. Aliment Pharmacol Ther 2005; 22 (6) 519-528
    CrossrefPubMedGoogle Scholar
  • 34 Piccolo P, Lenci I, Demelia L , et al. A randomized controlled trial of pegylated interferon-alpha2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B. Antivir Ther 2009; 14 (8) 1165-1174
    PubMedGoogle Scholar
  • 35 Sheng JF, Bai XF, Wu SH , et al. A novel combination regimen of peginterferon alfa-2a and entecavir results in sustained post-treatment HBsAg clearance in HBeAg-positive chronic hepatitis B (CHB). Hepatology 2011; 54 (Suppl. 01) 1017A
    PubMedGoogle Scholar
  • 36 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
    PubMedGoogle Scholar
  • 37 Gish RG, Lau DT, Schmid P, Perrillo R. A pilot study of extended duration peginterferon alfa-2a for patients with hepatitis B e antigen-negative chronic hepatitis B. Am J Gastroenterol 2007; 102 (12) 2718-2723
    CrossrefPubMedGoogle Scholar
  • 38 Lampertico P, Viganò M, Di Costanzo GG , et al; PegBeLiver Study Group. Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B. Gut 2013; 62 (2) 290-298
    CrossrefPubMedGoogle Scholar
  • 39 Tenney DJ, Rose RE, Baldick CJ , et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology 2009; 49 (5) 1503-1514
    CrossrefPubMedGoogle Scholar
  • 40 Wong GL, Wong VW, Chan HY , et al. Undetectable HBV DNA at month 12 of entecavir treatment predicts maintained viral suppression and HBeAg-seroconversion in chronic hepatitis B patients at 3 years. Aliment Pharmacol Ther 2012; 35 (11) 1326-1335
    CrossrefPubMedGoogle Scholar
  • 41 Yuen MF, Seto WK, Fung J, Wong DK, Yuen JC, Lai CL. Three years of continuous entecavir therapy in treatment-naïve chronic hepatitis B patients: VIRAL suppression, viral resistance, and clinical safety. Am J Gastroenterol 2011; 106 (7) 1264-1271
    CrossrefPubMedGoogle Scholar
  • 42 Heathcote EJ, Marcellin P, Buti M , et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011; 140 (1) 132-143
    CrossrefPubMedGoogle Scholar
  • 43 Amini-Bavil-Olyaee S, Herbers U, Sheldon J, Luedde T, Trautwein C, Tacke F. The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen-positive and hepatitis B e antigen-negative hepatitis B virus strains. Hepatology 2009; 49 (4) 1158-1165
    CrossrefPubMedGoogle Scholar
  • 44 van Bömmel F, Zöllner B, Sarrazin C , et al. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 2006; 44 (2) 318-325
    CrossrefPubMedGoogle Scholar
  • 45 Tan J, Degertekin B, Wong SN, Husain M, Oberhelman K, Lok AS. Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations. J Hepatol 2008; 48 (3) 391-398
    CrossrefPubMedGoogle Scholar
  • 46 Berg T, Marcellin P, Zoulim F , et al. Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection. Gastroenterology 2010; 139 (4) 1207-1217
    CrossrefPubMedGoogle Scholar
  • 47 van Bömmel F, de Man RA, Wedemeyer H , et al. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology 2010; 51 (1) 73-80
    CrossrefPubMedGoogle Scholar
  • 48 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 (2) 247-254
    CrossrefPubMedGoogle Scholar
  • 49 Izzedine H, Hulot JS, Launay-Vacher V , et al; Adefovir Dipivoxil International 437 Study Group; Adefovir Dipivoxil International 438 Study Group. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies. Kidney Int 2004; 66 (3) 1153-1158
    CrossrefPubMedGoogle Scholar
  • 50 Stellbrink HJ, Orkin C, Arribas JR , et al; ASSERT Study Group. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010; 51 (8) 963-972
    CrossrefPubMedGoogle Scholar
  • 51 Liaw YF, Gane E, Leung N , et al; GLOBE Study Group. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009; 136 (2) 486-495
    CrossrefPubMedGoogle Scholar
  • 52 Sung JJ, Lai JY, Zeuzem S , et al. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol 2008; 48 (5) 728-735
    CrossrefPubMedGoogle Scholar
  • 53 Lai CL, Leung N, Teo EK , et al; Telbivudine Phase II Investigator Group. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005; 129 (2) 528-536
    CrossrefPubMedGoogle Scholar
  • 54 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
    CrossrefPubMedGoogle Scholar
  • 55 Lok AS, Trinh H, Carosi G , et al. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naïve patients with chronic hepatitis B. Gastroenterology 2012; 143 (3) 619-628 , e1
    CrossrefPubMedGoogle Scholar
  • 56 Chan HL, Wong GL, Chim AM, Chan HY, Chu SH, Wong VW. Prediction of off-treatment response to lamivudine by serum hepatitis B surface antigen quantification in hepatitis B e antigen-negative patients. Antivir Ther 2011; 16 (8) 1249-1257
    CrossrefPubMedGoogle Scholar