The role of HBsAg levels in the current management of chronic HBV infection

Christoph Höner Zu Siederdissen, Markus Cornberg, Christoph Höner Zu Siederdissen, Markus Cornberg

Abstract

Chronic hepatitis B virus (HBV) infection can result in liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). However, the natural course of the disease is highly dynamic and not every patient requires therapy. The challenges for optimal management are who to treat, which therapeutic regimen to use, and when to begin or stop treatment. Constant monitoring is mandatory to predict the natural course and guide treatment decisions. Surrogate markers for baseline and on treatment decisions are needed. Besides HBV DNA, hepatitis B surface antigen levels also proved to be useful to help judge the natural course and guide treatment. High levels of HBsAg are suggestive of low fibrosis and immune tolerance in hepatitis B e antigen (HBeAg) positive patients; whereas low levels of HBsAg indicate a lower risk for HCC and inactive carrier state in HBeAg negative patients. Data also support the possible use of HBsAg levels as an on-treatment response marker. So far, the best evidence exists for treatment with interferon (IFN)-α where lack of HBsAg decline after 12 weeks is associated with non-response. Thus, stopping rules after 12 weeks therapy could be established for HBeAg positive as well as for HBeAg negative patients. However, the positive predictive value for achieving sustained response is still vague. The value of HBsAg monitoring is less clear during treatment with nucleos(t)ide analogues (NA) but it can be a useful marker for new concepts such as stopping NA or add-on IFN strategies. Currently, several studies are underway to validate HBsAg in these settings.

Keywords: Chronic hepatitis B; hepatitis B surface antigen; interferon α; nucleos(t)ide analogues.

Conflict of interest statement

Conflict of interest related to HBsAg: Christoph Höner zu Siederdissen has no conflict of interest. Markus Cornberg has received lectures and consultant fees as well as grant support from Roche Pharma and Roche Diagnostics

References

    1. Goldstein ST, Zhou F, Hadler SC, et al. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol. 2005;34:1329–1339.
    1. Perz JF, Armstrong GL, Farrington LA, Hutin YJF, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:529–538.
    1. Liang TJ GM. Current and future therapies for Hepatitis C virus infection. N Engl J Med. 2013;368:1907–1917.
    1. EASL clinical practice guidelines: Management of chronic hepatitis B, virus infection. J Hepatol. 2012;57:167–185.
    1. Papatheodoridis GV, Hadziyannis SJ. Diagnosis and management of pre-core mutant chronic hepatitis B. J Viral Hepat. 2001;8:311–321.
    1. Deguchi M, Yamashita N, Kagita M, et al. Quantitation of hepatitis B surface antigen by an automated chemiluminescent microparticle immunoassay. J Virol Methods. 2004;115:217–222.
    1. Zacher BJ, Moriconi F, Bowden S, et al. Multicenter evaluation of the Elecsys hepatitis B surface antigen quantitative assay. Clin Vaccine Immunol. 2011;18:1943–1950.
    1. Wursthorn K, Jaroszewicz J, Zacher BJ, et al. Correlation between the Elecsys HBsAg II assay and the Architect assay for the quantification of hepatitis B surface antigen (HBsAg) in the serum. J Clin Virol. 2011;50:292–296.
    1. Sonneveld MJ, Rijckborst V, Boucher CAB, et al. A comparison of two assays for quantification of Hepatitis B surface Antigen in patients with chronic hepatitis B. J Clin Virol. 2011;51:175–178.
    1. Chan HL-Y, 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;55:1121–1131.
    1. Jaroszewicz J, Calle Serrano B, Wursthorn K, et al. Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective. J Hepatol. 2010;52:514–522.
    1. Nguyen T, Thompson AJV, Bowden S, et al. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol. 2010;52:508–513.
    1. Chan HL-Y, Wong VW-S, Wong GL-H, et al. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology. 2010;52:1232–1241.
    1. Seto W-K, Wong DK-H, Fung J, et al. High hepatitis B surface antigen levels predict insignificant fibrosis in hepatitis B e antigen positive chronic hepatitis B. PLoS One. 2012;7:e43087.
    1. Martinot-Peignoux M, Carvalho-Filho R, Lapalus M, et al. Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naïve, e antigen-positive patients. J Hepatol. 2013;58:1089–1095.
    1. Martinot-Peignoux M, Boyer N, Colombat M, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol. 2002;36:543–546.
    1. Liaw Y-F, Chu C-M. Hepatitis B virus infection. Lancet. 2009;373:582–592.
    1. Chen C-J, Yang H-I, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.
    1. Martinot-Peignoux M, Lada O, Cardoso AC, et al. Quantitative HBsAg: a new specific marker for the diagnosis of HBsAg inactive carriage. Hepatology. 2010;52:992A.
    1. Yakut M, Bektas M, Seven G, et al. Characterization of the inactive HBsAg carrier state with 3 year follow-up. J Hepatol. 2011;54:S159. Abstract 398.
    1. Brunetto MR, Oliveri F, Colombatto P, et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology. 2010;139:483–490.
    1. Chen C-J, Yang H-I, Iloeje UH. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology. 2009;49:S72–S84.
    1. 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;93:896–900.
    1. Liu J, Lee M-H, Batrla-Utermann R, et al. A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection. J Hepatol. 2012;58:853–860.
    1. Sugiyama M, Tanaka Y, Kato T, et al. Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens. Hepatology. 2006;44:915–924.
    1. Perrillo RP. Therapy of hepatitis B - viral suppression or eradication? Hepatology. 2006;43:S182–S193.
    1. Van Zonneveld M, Honkoop P, Hansen BE, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology. 2004;39:804–810.
    1. Lau GKK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682–2695.
    1. Van Nunen AB, Hansen BE, Suh DJ, et al. Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase. Gut. 2003;52:420–424.
    1. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422–1427.
    1. Liaw Y-F, Jia J-D, Chan HLY, 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;54:1591–1599.
    1. Marcellin P, Bonino F, Lau GKK, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a. (e1-e4).Gastroenterology. 2009;136:2169–2179.
    1. Sonneveld MJ, Rijckborst V, Zeuzem S, et al. Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2012;56:67–75.
    1. 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 treated with peginterferon alfa-2a and adefovir. Antivir Ther. 2013;18:895–904.
    1. Sonneveld MJ, Rijckborst V, Cakaloglu Y, et al. Durable hepatitis B surface antigen decline in hepatitis B e antigen-positive chronic hepatitis B patients treated with pegylated interferon-α2b: relation to response and HBV genotype. Antivir Ther. 2011;17:9–17.
    1. Chan HL-Y, Wong VW-S, Chim AM-L, et al. Serum HBsAg quantification to predict response to peginterferon therapy of e antigen positive chronic hepatitis B. Aliment Pharmacol Ther. 2010;32:1323–1331.
    1. Lau G, Marcellin PBM. On treatment monitoring of HBsAg levels to predict response to peginterferon alfa-2a in patients with HBeAg-positive chronic hepatitis B. J Hepatol. 2009;50:333.
    1. Sonneveld MJ, Rijckborst V, Boucher CAB, Hansen BE, Janssen HLA. Prediction of sustained response to peginterferon alfa2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology. 2010;52:1251–1257.
    1. Sonneveld MJ, Hansen BE, Piratvisuth T, et al. Response-guided peginterferon therapy in HBeAg-positive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology. 2013;58:872–880.
    1. 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;49:1151–1157.
    1. Rijckborst V, Hansen BE, Cakaloglu Y, et al. 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.
    1. 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;56:1006–1011.
    1. Marcellin P, Gane E, Buti M, et al. 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.
    1. Chang T-T, Liaw Y-F, Wu S-S, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886–893.
    1. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol. 2010;53:348–356.
    1. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98–107.
    1. Reijnders JGP, Perquin MJ, Zhang N, Hansen BE, Janssen HLA. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology. 2010;139:491–498.
    1. Reijnders JGP, Rijckborst V, Sonneveld MJ, et al. Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir. J Hepatol. 2011;54:449–454.
    1. Manesis EK, Papatheodoridis GV, Tiniakos DG, et al. Hepatitis B surface antigen: relation to hepatitis B replication parameters in HBeAg-negative chronic hepatitis B. J Hepatol. 2011;55:61–68.
    1. Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky J-M. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration unlikely. J Hepatol. 2012;58:683–676.
    1. Zoutendijk R, Hansen BE, van Vuuren AJ, Boucher CAB, Janssen HLA. 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;204:415–418.
    1. Jaroszewicz J, Ho H, Markova A, et al. Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide analogues. Antivir Ther. 2011;16:915–924.
    1. Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T Cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;143:963–973.
    1. Wursthorn K, Jung M, Riva A, et al. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology. 2010;52:1611–1120.
    1. Cai W, Xie Q, An B, et al. 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.
    1. Chan HL-Y, Wong GL-H, Chim AM-L, et al. Prediction of off-treatment response to lamivudine by serum hepatitis B surface antigen quantification in hepatitis B e antigen-negative patients. Antivir Ther. 2011;16:1249–1257.
    1. Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAgnegative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology. 2012;143:629–636.e1.
    1. Marcellin P, Lau GKK, 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;351:1206–1217.
    1. Janssen HLA, 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;365:123–129.
    1. 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;44:675–684.
    1. Kittner JM, Sprinzl MF, Grambihler A, et al. Adding pegylated interferon to a current nucleos(t)ide therapy leads to HBsAg seroconversion in a subgroup of patients with chronic hepatitis B. J Clin Virol. 2012;54:93–95.
    1. Ning Q, Han M, Sun Y, et al. New treatment strategy: switching from long-term entecavir to peginterferon alfa-2a (40 kD) induces anti-HBe seroconversion /HBsAg loss in patients with HBeAg-positive chronic hepatitis B. Hepatology. 2012;56:300A. Abstract 216.
    1. Raimondo G, Brunetto MR, Pontisso P, et al. Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus hepatitis C virus-coinfected patients. Hepatology. 2006;43:100–107.
    1. Potthoff A, Wedemeyer H, Boecher WO, et al. The HEP-NET B/C co-infection trial: a prospective multicenter study to investigate the efficacy of pegylated interferon-alpha 2b and ribavirin in patients with HBV/HCV co-infection. J Hepatol. 2008;49:688–694.
    1. Potthoff A, Berg T, Wedemeyer H. Late hepatitis B virus relapse in patients co-infected with hepatitis B virus and hepatitis C virus after antiviral treatment with pegylated interferon-a2b and ribavirin. Scand J Gastroenterol. 2009;44:1487–1490.
    1. Wiegand SB, Jaroszewicz J, Potthoff A, et al. Dominance of HCV in HBV/HCV co-infected patients is associated with lower quantitative HBsAg and higher serum IP-10 levels. Z Gastroenterol. 2013:51–59.
    1. Jaroszewicz J, Reiberger T, Meyer-Olson D, et al. Hepatitis B surface antigen concentrations in patients with HIV/HBV coinfection. PLoS One. 2012;7:e43143.
    1. Arendt E, Jaroszewicz J, Rockstroh J, et al. Improved immune status corresponds with long-term decline of quantitative serum hepatitis B surface antigen in HBV/HIV co-infected patients. Viral Immunol. 2012;25:442–447.
    1. Maylin S, Boyd A, Lavocat F, et al. Kinetics of hepatitis B surface and envelope antigen and prediction of treatment response to tenofovir in antiretroviral-experienced HIV-hepatitis B virus-infected patients. AIDS. 2012;26:939–949.
    1. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7:31–40.
    1. Heidrich B, Deterding K, Tillmann HL, et al. Virological and clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat. 2009;16:883–894.
    1. Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364:322–331.
    1. Heidrich B, Manns MP, Wedemeyer H, et al. Long-term follow-up after PEG-IFN2a-based therapy of chronic hepatitis delta. J Hepatol. 2013;58:S20. Abstract 46.
    1. Erhardt A, Gerlich W, Starke C, et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int. 2006;26:805–810.
    1. Manesis EK, Schina M, Le Gal F, et al. Quantitative analysis of hepatitis D virus RNA and hepatitis B surface antigen serum levels in chronic delta hepatitis improves treatment monitoring. Antivir Ther. 2007;12:381–388.
    1. Ouzan D, Pénaranda G, Joly HHP. Optimized HBsAg titer monitoring improves interferon therapy in patients with chronic hepatitis delta. J Hepatol. 2013;58:1258–1259.
    1. Lau DT, Kleiner DE, Park Y, Di Bisceglie AM, Hoofnagle JH. Resolution of chronic delta hepatitis after 12 years of interferon alfa therapy. Gastroenterology. 1999;117:1229–1233.

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