Journal of Clinical Virology 59 (2014) 228–234
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Clinical implications of hepatitis B surface antigen quantitation in the natural history of chronic hepatitis B virus infection Zhaoxia Tan a,c , Maoshi Li a,c,1 , Xuemei Kuang a,c , Yu Tang a,c , Yi Fan a,c , Guohong Deng a,c , Yuming Wang a,c , Dengming He a,b,c,∗ a
Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China Liver Disease Diagnosis and Treatment Center, The 88th Hospital of Chinese PLA, China c The Chongqing Key Laboratory for Research of Infectious Diseases, China b
a r t i c l e
i n f o
Article history: Received 6 September 2013 Received in revised form 20 December 2013 Accepted 19 January 2014 Keywords: HBsAg quantitation HBV DNA Age Natural history
a b s t r a c t Background: HBsAg quantitation may be useful for managing patients with hepatitis B virus (HBV) infection. Objectives: We explored the clinical implications of HBsAg quantitation for patients with HBsAg levels >250 IU/ml (Abbott Diagnostics). Study design: Two hundred and thirty-three HBV-infected patients comprising 29 immune tolerance cases, 49 treatment-naïve HBeAg-positive chronic hepatitis B (CHB) cases, 91 inactive HBV carrier cases, and 64 treatment-naïve HBeAg-negative CHB cases were analyzed. HBsAg was quantified by the Architect HBsAg assay (Abbott Diagnostics) after a 1:500 automated dilution. Results and conclusions: HBsAg (log 10 IU/ml) was established for immune tolerance (4.50 ± 0.43), HBeAg-positive CHB (4.17 ± 0.66), inactive HBV carrier (3.32 ± 0.44), and HBeAg-negative CHB (3.23 ± 0.40); (p = 4.92 × 10−35 ). No significant difference was observed between inactive HBV carrier and HBeAg-negative CHB (p = 0.247). The proportions of HBsAg 250 IU/ml, HBsAg may reflect HBV DNA replication for HBeAg-positive cases. HBsAg is not a suitable marker for evaluating hepatitis activity and distinguishing between cases of HBeAg-negative CHB and inactive HBV carrier state. © 2014 Elsevier B.V. All rights reserved.
1. Background The detection of hepatitis B surface antigen (HBsAg) in serum is crucial to the diagnosis of hepatitis B virus (HBV) infections [1]. HBsAg is produced by the translation of transcriptionally active covalently closed circular (ccc) DNA molecules, and by the translation of viral genes transcribed from integrated HBV DNA sequences in the host genome [2–4]. HBsAg seroclearance reflects the immunological control of HBV infection, and is considered the closest thing to a cure for chronic hepatitis B (CHB). However, the
∗ Corresponding author at: Liver Disease Diagnosis and Treatment Center, The 88th Hospital of Chinese PLA, China. Tel.: +86-538-8839960. E-mail address: [email protected] (D. He). 1 Contributed equally to this work. 1386-6532/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2014.01.013
rates of spontaneous HBsAg seroclearance are extremely low, with annual seroclearance rates 0.72% and 0.07% for European and Asian patients, respectively [2]. Recently, studies on the quantitation of HBsAg during natural history of HBV infection and with antivirus therapy have emerged. Significant differences in serum HBsAg titers were reported across the different phases of chronic HBV infection [3,5]. Several groups have proposed cutoff levels of HBsAg and HBV DNA that, when used together, reliably identify patients with inactive disease [5,6]. However, correlations between HBsAg quantitation and HBV DNA were not in agreement for several studies [3,5,7]. HBsAg serum levels are the resultant of the complex equilibrium between the virus and the host’s immune system as well as transcription products of specific mRNAs rather than of viral replication [8]. HBsAg levels have been found to correlate well with the prognosis of CHB [9–12]. According to the natural history, chronic HBV
Z. Tan et al. / Journal of Clinical Virology 59 (2014) 228–234
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infection was divided into five phases: immune tolerance, immune reactive phase, inactive HBV carrier state, HBeAg-negative CHB, and HBsAg-negative phase [13]. Thus, HBsAg quantitation provides an alternative to, and complementary information, to assist in the characterization of a patient’s infection status. In addition, quantitation of HBsAg offers promise as a prognostic marker during the natural history of chronic HBV infection. The quantitation of HBsAg titters may be a useful tool in managing patients with chronic HBV infections [14]. The quantitation of serum HBsAg levels using the traditional Architect HBsAg assay (Abbott Diagnostics) demonstrated that the majority of patients had HBsAg levels >250 IU/ml. The recently developed Architect HBsAg assay (commercially available since 2013) can quantitate HBsAg levels within the range 175–125,000 IU/ml by an automatic 1:500 dilution.
2. Objectives We aimed to quantitate HBsAg levels in patients with HBsAg levels >250 IU/ml, and to explore the clinical utility in the characterization of infection status during the natural history of chronic HBV infection.
3. Study design 3.1. Patients and groups The study included 233 patients (163 male, 70 female, mean age 37 ± 12 years) with chronic HBV infection and serum HBsAg levels >250 IU/ml. Patients were classified according to four phases of the natural history of chronic HBV infection: immune tolerance state, treatment-naïve HBeAg-positive CHB, inactive HBV carrier state, or treatment-naïve HBeAg-negative CHB. The diagnostic criteria followed the guidelines of the European Association for The Study of The Liver (EASL) [13]. The commonly accepted criteria for inactive HBV carrier state was adopted for the current study; that is, a minimum follow-up of 1 year, and the measurement of persistently normal alanine aminotransferase (ALT) levels (approx. 40 IU/ml) and serum HBV DNA levels
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Clinical implications of hepatitis B surface antigen quantitation in the natural history of chronic hepatitis B virus infection Zhaoxia Tan a,c , Maoshi Li a,c,1 , Xuemei Kuang a,c , Yu Tang a,c , Yi Fan a,c , Guohong Deng a,c , Yuming Wang a,c , Dengming He a,b,c,∗ a
Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, China Liver Disease Diagnosis and Treatment Center, The 88th Hospital of Chinese PLA, China c The Chongqing Key Laboratory for Research of Infectious Diseases, China b
a r t i c l e
i n f o
Article history: Received 6 September 2013 Received in revised form 20 December 2013 Accepted 19 January 2014 Keywords: HBsAg quantitation HBV DNA Age Natural history
a b s t r a c t Background: HBsAg quantitation may be useful for managing patients with hepatitis B virus (HBV) infection. Objectives: We explored the clinical implications of HBsAg quantitation for patients with HBsAg levels >250 IU/ml (Abbott Diagnostics). Study design: Two hundred and thirty-three HBV-infected patients comprising 29 immune tolerance cases, 49 treatment-naïve HBeAg-positive chronic hepatitis B (CHB) cases, 91 inactive HBV carrier cases, and 64 treatment-naïve HBeAg-negative CHB cases were analyzed. HBsAg was quantified by the Architect HBsAg assay (Abbott Diagnostics) after a 1:500 automated dilution. Results and conclusions: HBsAg (log 10 IU/ml) was established for immune tolerance (4.50 ± 0.43), HBeAg-positive CHB (4.17 ± 0.66), inactive HBV carrier (3.32 ± 0.44), and HBeAg-negative CHB (3.23 ± 0.40); (p = 4.92 × 10−35 ). No significant difference was observed between inactive HBV carrier and HBeAg-negative CHB (p = 0.247). The proportions of HBsAg 250 IU/ml, HBsAg may reflect HBV DNA replication for HBeAg-positive cases. HBsAg is not a suitable marker for evaluating hepatitis activity and distinguishing between cases of HBeAg-negative CHB and inactive HBV carrier state. © 2014 Elsevier B.V. All rights reserved.
1. Background The detection of hepatitis B surface antigen (HBsAg) in serum is crucial to the diagnosis of hepatitis B virus (HBV) infections [1]. HBsAg is produced by the translation of transcriptionally active covalently closed circular (ccc) DNA molecules, and by the translation of viral genes transcribed from integrated HBV DNA sequences in the host genome [2–4]. HBsAg seroclearance reflects the immunological control of HBV infection, and is considered the closest thing to a cure for chronic hepatitis B (CHB). However, the
∗ Corresponding author at: Liver Disease Diagnosis and Treatment Center, The 88th Hospital of Chinese PLA, China. Tel.: +86-538-8839960. E-mail address: [email protected] (D. He). 1 Contributed equally to this work. 1386-6532/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2014.01.013
rates of spontaneous HBsAg seroclearance are extremely low, with annual seroclearance rates 0.72% and 0.07% for European and Asian patients, respectively [2]. Recently, studies on the quantitation of HBsAg during natural history of HBV infection and with antivirus therapy have emerged. Significant differences in serum HBsAg titers were reported across the different phases of chronic HBV infection [3,5]. Several groups have proposed cutoff levels of HBsAg and HBV DNA that, when used together, reliably identify patients with inactive disease [5,6]. However, correlations between HBsAg quantitation and HBV DNA were not in agreement for several studies [3,5,7]. HBsAg serum levels are the resultant of the complex equilibrium between the virus and the host’s immune system as well as transcription products of specific mRNAs rather than of viral replication [8]. HBsAg levels have been found to correlate well with the prognosis of CHB [9–12]. According to the natural history, chronic HBV
Z. Tan et al. / Journal of Clinical Virology 59 (2014) 228–234
229
infection was divided into five phases: immune tolerance, immune reactive phase, inactive HBV carrier state, HBeAg-negative CHB, and HBsAg-negative phase [13]. Thus, HBsAg quantitation provides an alternative to, and complementary information, to assist in the characterization of a patient’s infection status. In addition, quantitation of HBsAg offers promise as a prognostic marker during the natural history of chronic HBV infection. The quantitation of HBsAg titters may be a useful tool in managing patients with chronic HBV infections [14]. The quantitation of serum HBsAg levels using the traditional Architect HBsAg assay (Abbott Diagnostics) demonstrated that the majority of patients had HBsAg levels >250 IU/ml. The recently developed Architect HBsAg assay (commercially available since 2013) can quantitate HBsAg levels within the range 175–125,000 IU/ml by an automatic 1:500 dilution.
2. Objectives We aimed to quantitate HBsAg levels in patients with HBsAg levels >250 IU/ml, and to explore the clinical utility in the characterization of infection status during the natural history of chronic HBV infection.
3. Study design 3.1. Patients and groups The study included 233 patients (163 male, 70 female, mean age 37 ± 12 years) with chronic HBV infection and serum HBsAg levels >250 IU/ml. Patients were classified according to four phases of the natural history of chronic HBV infection: immune tolerance state, treatment-naïve HBeAg-positive CHB, inactive HBV carrier state, or treatment-naïve HBeAg-negative CHB. The diagnostic criteria followed the guidelines of the European Association for The Study of The Liver (EASL) [13]. The commonly accepted criteria for inactive HBV carrier state was adopted for the current study; that is, a minimum follow-up of 1 year, and the measurement of persistently normal alanine aminotransferase (ALT) levels (approx. 40 IU/ml) and serum HBV DNA levels
