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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 2  |  Page : 141-145

Evaluation of serum hepatitis B surface antigen quantification kinetics in different patterns of chronic hepatitis B infection


Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt

Date of Submission01-Oct-2019
Date of Decision15-Nov-2019
Date of Acceptance16-Dec-2019
Date of Web Publication16-May-2020

Correspondence Address:
Aya A S. Riad
Departments of Tropical Medicine and Gastroenterology, Al-Rajhi Liver University Hospital and Faculty of Medicine, Assiut University, Assiut
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCMRP.JCMRP_152_19

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  Abstract 


Background and aim
Management of chronic hepatitis B (CHB) infection is challenging owing to its wide immunologic phases and pathologic patterns. Quantification of serum HBs-Ag (qHBsAg) has been used as a mirror of intrahepatic viral replication, and therefore, its kinetics in these patterns may reflect diseases severity and hence may help in tailoring the management plan. So, this study was designed to assess the patterns and kinetics of qHBsAg among Egyptian patients presented with different forms of CHB.
Patients and methods
Between December 2016 and December 2017, patients with CHB were enrolled and categorized into three groups. Group I included naive aviremic patients [those with negative hepatitis B virus (HBV)-DNA-PCR without treatment]. Group II included naive low viremic patients (those with HBV-DNA-PCR <2000 IU/ml without treatment). Group III included treatment-experienced aviremic patients (those with negative HBV-DNA-PCR after 6 months of nucleotide analog treatment). All patients were checked for alanine aminotransferase (ALT), qHBsAg, and HBV-DNA-PCR at a regular intervals: at baseline (W0), week 12 (W12), and week 24 (w24).
Results
A total of 90 patients were enrolled, with 30 patients in each group. In group I, qHBsAg and ALT levels exhibited relatively stable detectable positively correlated levels from W0 to W24. In group II, qHBsAg and ALT levels were the same as group I. In group III, qHBsAg, ALT levels, and HBV-DNA exhibited a significant decrease during the follow-up with the use of nucleotide analog therapy.
Conclusion
qHBsAg measurement, which is a cheap and easy test, can replace HBV-DNA and may help in reflection of disease activity and assessment of follow-up.

Keywords: chronic hepatitis B infection, inactive carrier, quantification of serum hepatitis B surface antigen


How to cite this article:
Mekky MA, Mahraan ZG, S. Riad AA, Abu Elfatth AM, Swifee YM. Evaluation of serum hepatitis B surface antigen quantification kinetics in different patterns of chronic hepatitis B infection. J Curr Med Res Pract 2020;5:141-5

How to cite this URL:
Mekky MA, Mahraan ZG, S. Riad AA, Abu Elfatth AM, Swifee YM. Evaluation of serum hepatitis B surface antigen quantification kinetics in different patterns of chronic hepatitis B infection. J Curr Med Res Pract [serial online] 2020 [cited 2020 Jun 5];5:141-5. Available from: http://www.jcmrp.eg.net/text.asp?2020/5/2/141/284397




  Introduction Top


Chronic hepatitis B (CHB) infection is considered one of the major public health problems[1], and its management is faced by a dilemma of when and how to assess disease activity and treatment responses[2]. Hepatitis B surface antigen (HBsAg) is a glycosylated envelope protein of hepatitis B virus (HBV) virion that is synthesized from translated messenger RNAs of transcriptionally active covalently closed circular DNA (cccDNA), which needs liver sampling to be measured[3]. Many trials were designed to assess qHBsAg as a mirror for intrahepatic replication of the virus and to measure cccDNA, and so, can replace liver biopsy[4],[5].

Therefore, we aimed to measure the kinetics of qHBsAg in different forms of CHB infection among Egyptian patients.


  Patients and Methods Top


Patients’ recruitment and characteristics

Between December 2016 and December 2017, a prospective study was designed to include all adult patients with well-proven CHB. Assessment was done in accordance to the guidelines.

All patients had document presence of hepatitis B surface antigen in serum for more than 6 months and had an age range of 20 and 54 years. Patients were selected from those attending the Viral Hepatitis Outpatients Clinic of Al-Rajhi University Hospital during the study period from December 2016 and December 2017. Any patient with manifestation of liver cell failure or co-infected with other viral hepatitis was excluded.

Enrolled patients were subdivided into three groups (30 patients in each of them).

  1. Group I: naive aviremic patients (those with negative HBV-DNA-PCR without treatment)
  2. Group II: naive low viremic patients (those with HBV-DNA-PCR <2000 IU/ml without treatment)
  3. Group III: treatment-experienced aviremic patients (those with negative HBV-DNA-PCR after 6 months of nucleotide analog treatment for at least 6 months duration).


Study methods

For all patients, CHB workup (HBsAg, anti-HBcAb, HBeAg, and anti-HBeAb) was done by commercially available ELISA kits (Abbott Diagnostics, IL, USA)). Serum alanine aminotransferase (ALT) was tested to evaluate the hepatic necroinflammatory insult. Quantification of serum HBsAg was done by RocheCobas e 411 analyzer with Elecsys HBsAg (all methodology as per Elecsys package inserts for quantitative HBsAg measurement, Quant reagent kits'; Roche Diagnostics, Indianapolis, Indiana, USA). HBV-DNA-PCR was tested by real-time PCR using the QIAampMinElute Virus Spin kit (QIAGEN, Hilden, Germany).

For all patients, qHBsAg, ALT, and HBV-DNA-PCR were serially repeated at baseline (week 0; W0) and then at week 12 (W12) and at week 24 (W24).

Statistical analysis and ethical considerations

-‹Data was collected and analyzed those using SPSS (Statistical Package for the Social Science, version 20, IBM, and Armonk, New York). Continuous data were expressed in the form of mean ± SD or median (range), whereas categorical data were expressed in frequencies (percentage). Pearson correlation test was used to determine the correlation between qHBsAg with HBV-DNA and ALT. P value was considered statistically significant if less than 0.05. This study was approved by our Local Ethical and Research Committee, Faculty of Medicine, Assiut University.


  Results Top


A total of 90 patients were enrolled. Their mean age was 40.45 ± 10.23 years, with an age range of 20–54 years. The patients comprised 82% males.

Group I: naive-aviremic patients

The qHBsAg and ALT levels in those patients were significantly changed (by fluctuation in their levels) at third and sixth month of follow-up in comparison with the baseline level (P < 0.05), whereas HBV-DNA was negative (undetected) during the period of study [Table 1]. Moreover, the level of qHBsAg had positive significant correlation with ALT at baseline and at sixth month of follow-up [Figure 1].
Table 1: Laboratory data for group I patients

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Figure 1: Correlation of quantitative hepatitis B surface antigen with alanine aminotransferase at baseline (a) and at sixth month of follow-up (b) in group I.

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Group II: naive low viremic patients

The levels of qHBsAg, HBV-DNA, and ALT were significantly changed (by fluctuation in their levels) at third and sixth of follow-up in comparison with the baseline level [Table 2]. The qHBsAg level had a negative significant correlation with HBV-DNA level at baseline and at sixth month of follow-up, whereas it had a positive significant correlation with ALT at baseline and at sixth month of follow-up [Figure 2].
Table 2: Laboratory data in group II

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Figure 2: Correlation of quantitative hepatitis B surface antigen with hepatitis B virus-DNA at baseline (a) and at sixth month of follow-up (b) and with alanine aminotransferase at baseline (c) and at sixth month of follow-up (d) in group II.

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Group III: treatment-experienced aviremic patients

It was noticed that quantitative HBsAg level in group III patients was significantly decreased at third and sixth of follow-up in comparison with the baseline level. Moreover, HBV-DNA level in patients was significantly decreased at third and sixth of follow-up in comparison with the baseline level (P = 0.02). The same improvement occurred with ALT [Table 3].
Table 3: Laboratory data in group III

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It was noticed that quantitative HBsAg level had insignificant correlation with HBV-DNA level at baseline and weak positive correlation at sixth month of therapy, but it had a positive significant correlation with ALT at baseline and at sixth month of therapy [Figure 3].
Figure 3: Correlation of quantitative hepatitis B surface antigen with hepatitis B virus-DNA at baseline (a) and at sixth month of follow-up (b) and with alanine aminotransferase at baseline (c) and at sixth month of follow-up (d) in group III.

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  Discussion Top


The longitudinal follow-up of ALT and HBV-DNA levels and/or assessment of liver histology in CHB patients is considered the main important factor in determining the phases of CHB infection and the guide for best treatment choice. However, this method is not applicable to the limited-resource countries because of the high cost involved and the need for frequent testing[6]. Recent studies have incorporated the use of qHBsAg to classify the patients and to predict antiviral therapy response and also have created a new role for serum qHBsAg in clinical practice[7]. Moreover, qHBsAg (qHBsAg) was introduced as a mirror that may reflect the integrated cccDNA inside the hepatocytes nucleus[8],[9].

So, in this study, we aimed to evaluate the kinetics of qHBsAg among Egyptian patients with different forms of CHB. A well-defined grouping was designed to cover all possible patients with different spectrum of CHB, either treatment naïve or experienced. In patients with spontaneous negative viremia, qHBsAg and ALT levels were significantly changed (by fluctuation in their levels) at W12 or W24 of follow-up in comparison with the baseline level, with persistently negative HBV-DNA (undetected) all over the study period. To the best of our knowledge, we did not find any published article that tested qHBsAg among this unique group. So our result may be the first to tackle this issue. Interestingly, in spite of negative viremia, we found a fluctuation in the level of qHBsAg, which may denote the persistence of viral particle integrated inside the hepatocyte, and this may indicate the need for long-term follow-up of this group for the fear of viral flare. This finding meets with the conclusion of the study of Tanaka et al. [10] on a similar group of patients with CHB (HBsAg positive and HBV-DNA negative), as they concluded that undetectable level of DNA might not accurately reflect the true proportion of subviral particles vs virions.

In the second group, low viremic naive patients, we found the same fluctuation between qHBsAg and ALT during the follow-up in comparison with the baseline level. Moreover, qHBsAg level had a negative significant correlation with HBV-DNA level at baseline and at sixth month of follow-up, but it had a positive significant correlation with ALT level at baseline and at sixth month of follow-up. In the same context, Gunal et al. [11] reported that the values of qHBsAg levels were significantly higher in patient with positive HBV-DNA than those with undetectable HBV-DNA level, and also they found a weak significant correlation between qHBsAg and ALT level. Balkan et al.[12], who evaluate correlation between serum qHBsAg, ALT, and HBV-DNA levels, in the inactive carrier and CHB, reported different finding. Their study revealed no correlation was noted between serum qHBsAg, ALT, and HBV-DNA levels, for inactive HBV carriers and HBeAg-negative patients with CHB. However, a moderate positive correlation was determined between serum qHBsAg levels and HBV-DNA in the HBeAg-positive patients with CHB.

In patients who received oral NAs, levels of qHBsAg and HBV- DNA were significantly decreased during the follow-up. Moreover, qHBsAg level showed insignificant correlation with HBV-DNA level at baseline and a weak positive correlation at sixth month of therapy, which may reflect the potency of the treatment on the viral replication and cccDNA. This notion was also reported by Fung et al. [2] where the profound HBV-DNA suppression was not associated by significant change in qHBsAg of most patients. A possible explanation for this can be explained by the fact that in spite of the potency of oral nucleotide analog, they did not affect the cccDNA integration[1],[2]. In agreement with our study, Gish et al. [13] reported that no correlation was observed between on-treatment changes in qHBsAg and changes at HBV-DNA. This observation was consistent with other studies assessing the relationship between HBV-DNA levels, qHBsAg levels, and serological responses in HBeAg-positive patient treated with oral NAs.

In our study, the lack of correlation between the on–treatment kinetics of qHBsAg and serum HBV-DNA can be possibly explained by the same fact of the lack of potency of NAs on cccDNA and its sole action on the inhibition of HBV-DNA replication[13],[14].


  Conclusion Top


In conclusion, the incorporation of qHBsAg assays was found to be a quite useful test when used together with ALT and HBV-DNA levels in distinguishing inactive carrier from patients with CHB. Moreover, it can replace the repetition of expensive tests, especially in those who need long-term follow-up. More intense research studies are needed to elucidate the potential role of qHBsAg assay in tailoring treatment responses and strategies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Frontiers Immunol 2013; 4:57.  Back to cited text no. 1
    
2.
Fung J, Lai C-L, Young J, Wong DK-H, Yuen J, Seto W-K, et al. Quantitative hepatitis B surface antigen levels in patients with chronic hepatitis B after 2 years of entecavir treatment. Am J Gastroenterol 2011; 106:1766.  Back to cited text no. 2
    
3.
Tseng T-C, Kao J-H. Clinical utility of quantitative HBsAg in natural history and nucleos (t) ide analogue treatment of chronic hepatitis B: new trick of old dog. J Gastroenterol 2013; 48:13–21.  Back to cited text no. 3
    
4.
Sonneveld MJ, Hansen BE, Piratvisuth T, Jia JD, Zeuzem S, Gane E, et al. Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology 2013; 58:872–880.  Back to cited text no. 4
    
5.
Reijnders JG, Rijckborst V, Sonneveld MJ, Scherbeijn SM, Boucher CA, Hansen BE, et al. Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir. J Hepatol 2011; 54:449–454.  Back to cited text no. 5
    
6.
Ungtrakul T, Sriprayoon T, Kusuman P, Chunnuan P, Soonklang K, Sornsamdang G, et al. Role of quantitative hepatitis B surface antigen in predicting inactive carriers and HBsAg seroclearance in HBeAg-negative chronic hepatitis B patients. Medicine 2017;96:13(e6554).  Back to cited text no. 6
    
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Karra VK, Chowdhury SJ, Ruttala R, Polipalli SK, Kar P. Clinical significance of quantitative HBsAg titres and its correlation with HBV DNA levels in the natural history of hepatitis B virus infection. J Clin Exp Hepatol 2016; 6:209–215.  Back to cited text no. 7
    
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Cornberg M, Wong VW-S, Locarnini S, Brunetto M, Janssen HL, Chan HL-Y. The role of quantitative hepatitis B surface antigen revisited. J Hepatol 2017; 66:398–411.  Back to cited text no. 8
    
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Viganò M, Lampertico P. Clinical implications of HBsAg quantification in patients with chronic hepatitis B. Saudi J Gastroenterol 2012; 18:81.  Back to cited text no. 9
    
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Tanaka E, Matsumoto A, Suzuki F, Kobayashi M, Mizokami M, Tanaka Y, et al. Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance. Liver Int 2006; 26:90–96.  Back to cited text no. 10
    
11.
Günal Ö, Barut Ş, Etikan İ, Duygu F, Tuncel U, Sünbül M. Relation between serum quantitative HBsAg, ALT and HBV DNA levels in HBeAg negative chronic HBV infection. Turk J Gastroenterol 2014; 25:142–146.  Back to cited text no. 11
    
12.
Balkan A, Namıduru M, Balkan Y, Mete AÖ, Karaoǧlan İ, Boşnak VK. Are serum quantitative hepatitis b surface antigen levels, liver histopathology and viral loads related in chronic hepatitis b-infected patients? Saudi J Gastroenterol 2016; 22:208.  Back to cited text no. 12
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13.
Gish RG, Chang TT, Lai CL, de Man RA, Gadano A, Llamoso C, et al. Quantitative hepatitis B surface antigen analysis in hepatitis B e antigen-positive nucleoside-naive patients treated with entecavir. Antivir Ther 2013; 18:691–698.  Back to cited text no. 13
    
14.
Chen C-H, Lee C-M, Lu S-N, Wang J-H, Tung H-D, Hung C-H, et al. Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants. J Hepatol 2004; 41:454–461.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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