Serum hepatitis B surface antigen and hepatitis B e antigen titers: Disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers

Authors

  • Alexander J.V. Thompson,

    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
    2. Department of Pathology, St. Vincent's Hospital, Melbourne, Australia
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  • Tin Nguyen,

    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
    2. Department of Pathology, St. Vincent's Hospital, Melbourne, Australia
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  • David Iser,

    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
    2. Department of Pathology, St. Vincent's Hospital, Melbourne, Australia
    3. Infectious Diseases Unit, Alfred Hospital, Melbourne, Victoria, Australia
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  • Anna Ayres,

    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
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  • Kathy Jackson,

    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
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  • Margaret Littlejohn,

    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
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  • John Slavin,

    1. Department of Pathology, St. Vincent's Hospital, Melbourne, Australia
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  • Scott Bowden,

    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
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  • Edward J. Gane,

    1. New Zealand Liver Unit, Auckland City Hospital, Auckland, New Zealand
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  • William Abbott,

    1. New Zealand Liver Unit, Auckland City Hospital, Auckland, New Zealand
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  • George K.K. Lau,

    1. Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region of China
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  • Sharon R. Lewin,

    1. Infectious Diseases Unit, Alfred Hospital, Melbourne, Victoria, Australia
    2. Monash University, Clayton, Victoria, Australia
    3. Burnet Institute, Melbourne, Australia
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  • Kumar Visvanathan,

    1. Monash University, Clayton, Victoria, Australia
    2. Infectious Diseases Department, Monash Medical Centre, Clayton, Victoria, Australia
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  • Paul V. Desmond,

    1. Department of Pathology, St. Vincent's Hospital, Melbourne, Australia
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  • Stephen A. Locarnini

    Corresponding author
    1. Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
    • Victorian Infectious Diseases Reference Laboratory (VIDRL), 10 Wreckyn St, North Melbourne, Victoria, 3051, Australia
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    • fax: +61 3 9342 2666


  • Supported by a Postgraduate Scholarship from the National Health and Medical Research Council (NHMRC) of Australia (to A.J.V.T).

  • Potential conflict of interest: Abbott Laboratories provided an ARCHITECT machine to VIDRL. Stephen Locarnini has consulted for Abbott Laboratories. Dr. Lau is a consultant for Roche and Novartis. Dr. Locarnini is a consultant for and advises Abbott.

Abstract

Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. Conclusion: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker. (HEPATOLOGY 2010)

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