Abstract
Since active replication of hepatitis B virus is strongly associated with the development of cirrhosis, hepatocellular carcinoma, and liver-related mortality, antiviral therapy is aimed at maximal viral suppression. However, as no antiviral therapy is perfect due to the emergence of resistant strains and suboptimal efficacy in some patients, modifying the treatment strategies for certain patients in advance is important through prediction of treatment responses. Recently, along with serial monitoring of hepatitis B virus DNA level, quantitative analysis of the serologic markers HBsAg (qHBsAg) and HBeAg (qHBeAg) has been used to predict responses to antiviral therapy. The clinical usefulness of both pretreatment qHBsAg and decline in qHBsAg during treatment was assessed in patients treated with pegylated interferon, suggesting that they might be used as another criterion to identify good and poor responders. Similarly, in patients treated with oral nucleos(t)ide analogues (NAs), the clinical significance of qHBsAg has been reported in some studies. However, as the decline in qHBsAg is much slower during NA therapy and the data on the use of qHBsAg to predict response to NA treatment are very preliminary, its wide application remains to be determined. Another serologic marker (qHBeAg) measured at baseline and during treatment might be applied for identifying good or poor responders to antiviral therapy. Unfortunately, measurement of qHBeAg has not been widely used because it is expensive, nonstandardized, and unavailable in patients with HBeAg-negative chronic hepatitis B (CHB). In conclusion, serologic markers may be potential predictors of response to antiviral therapy in CHB, allowing delivery of the most appropriate treatments to the most suitable patients. Further investigations into the universal clinical usefulness of such markers are needed.
Journal Section:
Paper
References
1.
Lok AS: Chronic hepatitis B: N Engl J Med 2002;346:1682–1683.
2.
Ahn SH, Han KH, Park JY, Lee CK, Kang SW, Chon CY, Kim YS, Park K, Kim DK, Moon YM: Association between hepatitis B virus infection and HLA-DR type in Korea. Hepatology 2000;31:1371–1373.
[PubMed]
3.
Lee JM, Ahn SH: Quantification of HBsAg: basic virology for clinical practice. World J Gastroenterol 2011;17:283–289.
[PubMed]
4.
Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH: Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65–73.
[PubMed]
5.
Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ: Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678–686.
[PubMed]
6.
Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane EJ, Jacobson IM, Lim SG, Naoumov N, Marcellin P, Piratvisuth T, Zoulim F: Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol 2007;5:890–897.
[PubMed]
7.
Wong GL, Chan HL: Predictors of treatment response in chronic hepatitis B. Drugs 2009;69:2167–2177.
[PubMed]
8.
Tuttleman JS, Pourcel C, Summers J: Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 1986;47:451–460.
[PubMed]
9.
Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, Trepo C, Marcellin P, Goodman Z, Delaney WE 4th, Xiong S, Brosgart CL, Chen SS, Gibbs CS, Zoulim F: Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004;126:1750–1758.
[PubMed]
10.
Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T, Schirmacher P, Metzler F, Zankel M, Fischer C, Currie G, Brosgart C, Petersen J: Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology 2006;44:675–684.
[PubMed]
11.
Chan HL, Wong VW, Tse AM, Tse CH, Chim AM, Chan HY, Wong GL, Sung JJ: Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response. Clin Gastroenterol Hepatol 2007;5:1462–1468.
[PubMed]
12.
Janssen HL, Kerhof-Los CJ, Heijtink RA, Schalm SW: Measurement of HBsAg to monitor hepatitis B viral replication in patients on alpha-interferon therapy. Antiviral Res 1994;23:251–257.
[PubMed]
13.
Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL: Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 2010;52:1251–1257.
[PubMed]
14.
Chan HL, Wong VW, Chim AM, Chan HY, Wong GL, Sung JJ: Serum HBsAg quantification to predict response to peginterferon therapy of e antigen positive chronic hepatitis B. Aliment Pharmacol Ther 2010;32:1323–1331.
[PubMed]
15.
Brunetto MR, Moriconi F, Bonino F, Lau GK, Farci P, Yurdaydin C, Piratvisuth T, Luo K, Wang Y, Hadziyannis S, Wolf E, McCloud P, Batrla R, Marcellin P: Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009;49:1141–1150.
[PubMed]
16.
Moucari R, Mackiewicz V, Lada O, Ripault MP, Castelnau C, Martinot-Peignoux M, Dauvergne A, Asselah T, Boyer N, Bedossa P, Valla D, Vidaud M, Nicolas-Chanoine MH, Marcellin P: Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology 2009;49:1151–1157.
[PubMed]
17.
Rijckborst V, Hansen BE, Cakaloglu Y, Ferenci P, Tabak F, Akdogan M, Simon K, Akarca US, Flisiak R, Verhey E, Van Vuuren AJ, Boucher CA, ter Borg MJ, Janssen HL: Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatology 2010;52:454–461.
[PubMed]
18.
Marcellin P, Brunetto M, Bonino F, Hadziyannis E, Kapprell H, McCloud P, Batrla R: 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;48:718A.
19.
Piratvisuth T, Marcellin P: Further analysis is required to identify an early stopping rule for peginterferon therapy that is valid for all hepatitis B e antigen-positive patients. Hepatology 2011;53:1054–1055; author reply 1055.
[PubMed]
20.
Ma H, Yang RF, Wei L: Quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa-2b in HBeAg-positive patients. J Gastroenterol Hepatol 2010;25:1498–1506.
[PubMed]
21.
Lu L, Ye D, Wang Y, Kwok A, Wong A, Yueng Y, Zhang H, Chen Y, Bowden S, Batrla-Utermann R, Locarnini S, Lau G: Correlation between HBV cccDNA and HBsAg levels and their reduction by peginterferon alfa-2a based therapy in patients with chronic hepatitis B. Hepatology 2008;48:746A.
22.
Liaw YF: Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology 2011;53:2121–2129.
[PubMed]
23.
Manesis EK, Hadziyannis ES, Angelopoulou OP, Hadziyannis SJ: Prediction of treatment-related HBsAg loss in HBeAg-negative chronic hepatitis B: a clue from serum HBsAg levels. Antivir Ther 2007;12:73–82.
[PubMed]
24.
Chen J, Wang Z, Guo Y, Peng J, Sun J, Ahmed CS, Zhou Y, Hou J: Serum HBsAg changes in HBeAg-positive chronic hepatitis B patients with continuous viral load reductions during treatment with adefovir or peg-interferon-alpha-2a. Antiviral Res 2009;81:88–91.
[PubMed]
25.
Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N, Naoumov NV, Di Bisceglie AM, Zeuzem S, Moon YM, Goodman Z, Chao G, Constance BF, Brown NA: Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007;357:2576–2588.
[PubMed]
26.
Jung YK, Kim JH, Lee YS, Lee HJ, Yoon E, Jung ES, Hong SK, Joo MK, Yeon JE, Park JJ, Kim JS, Bak YT, Byun KS: Change in serum hepatitis B surface antigen level and its clinical significance in treatment-naive, hepatitis B e antigen-positive patients receiving entecavir. J Clin Gastroenterol 2010;44:653–657.
[PubMed]
27.
Lee JM, Ahn SH, Kim HS, Park H, Chang HY, Kim do Y, Hwang SG, Rim KS, Chon CY, Han KH, Park JY: Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology 2011;53:1486–1493.
[PubMed]
28.
Reijnders JG, Rijckborst V, Sonneveld MJ, Scherbeijn SM, Boucher CA, Hansen BE, Janssen HL: Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir. J Hepatol 2011;54:449–454.
[PubMed]
29.
Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou E, Anderson J, Sorbel J, Rousseau F: Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011;140:132–143.
[PubMed]
30.
Gish RG, Chang TT, Lai CL, de Man R, Gadano A, Poordad F, Yang J, Brett-Smith H, Tamez R: Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B. J Viral Hepat 2010;17:16–22.
[PubMed]
31.
Wursthorn K, Jung M, Riva A, Goodman ZD, Lopez P, Bao W, Manns MP, Wedemeyer H, Naoumov NV: Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology 2010;52:1611–1620.
[PubMed]
32.
Cai W, Xie Q, An B, Wang H, Zhou X, Zhao G, Guo Q, Gu R, Bao S: On-treatment serum HBsAg level is predictive of sustained off-treatment virologic response to telbivudine in HBeAg-positive chronic hepatitis B patients. J Clin Virol 2010;48:22–26.
[PubMed]
33.
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;6:1022–1026.
[PubMed]
34.
Heijtink RA, Janssen HL, Hop WC, Osterhaus AD, Schalm SW: Interferon-alpha therapy in chronic hepatitis B: Early monitoring of hepatitis B e antigen may help to decide whether to stop or to prolong therapy. J Viral Hepat 2000;7:382–386.
[PubMed]
35.
Heijtink RA, Kruining J, Honkoop P, Kuhns MC, Hop WC, Osterhaus AD, Schalm SW: Serum HBeAg quantitation during antiviral therapy for chronic hepatitis B. J Med Virol 1997;53:282–287.
[PubMed]
36.
Fried MW, Piratvisuth T, Lau GK, Marcellin P, Chow WC, Cooksley G, Luo KX, Paik SW, Liaw YF, Button P, Popescu M: HBsAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B. Hepatology 2008;47:428–434.
[PubMed]
37.
Park NH, Shin JW, Park JH, Bang SJ, Kim DH, Joo KR: Monitoring of HBeAg levels may help to predict the outcomes of lamivudine therapy for HBeAg-positive chronic hepatitis B. J Viral Hepat 2005;12:216–221.
[PubMed]
38.
Zhang X, Lin SM, Ye F, Chen TY, Liu M, Chen YR, Zheng SQ, Zhao YR, Zhang SL: An early decrease in serum HBeAg titre is a strong predictor of virological response to entecavir in HBeAg-positive patients. J Viral Hepat 2011;18:e184–e190.
[PubMed]
39.
Brunetto M, Bonino F, Marcellin P, Button P, Batrla R: Kinetics of HBsAg decline in patients with HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a according to genotype and its association with sustained HBsAg clearance 4 years post-treatment. Hepatology 2008;48:740A.
© 2011 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2011
You do not currently have access to this content.
