Reviewer ’s report  
 
Title: Distinct patterns of serum hepatitis B core -related antigen during the natural history of 
chronic hepatitis B  
 
Version: 0 Date: 27 Jun 2017  
 
Reviewer: Emanuel Manesis  
 
Reviewer's report:  
 
The article by Zhan -Qing  Zhang, et al (BMGE -D-17-00202), addresses the inter -relationships of 
serum HBcrAg, HBsAg and HBV DNA with liver HBsAg and HBcAg. The work involves 444 
treatment -naïve Chinese patients with chronic hepatitis B, selected to represent all the four 
immunologi cal phases in the natural history of HBV infection. The investigation is not original, 
as there have been already a few recent publications on the same subject (J Virol Methods 
2016;235:92, Clin Microbiol Infect 2015;21:606, Clin Microbiol Infect 2014;20:1 173). It also, 
relies on immunohistochemistry rather and not on direct intrahepatic measurements of HBV 
replication parameters. However, the study includes one of the largest liver biopsy cohorts 
reported so far. In addition, the reported findings are welc omed, since they strengthen the value 
of HBcrAg, as an important novel marker in the evaluation of HBV -infected patients. The 
investigation is well -conducted and the article is written in good English, well documented and 
discussed. A few comments follow:  
 
A. Major Comments:  
1. (Line 103): Please give a reference.  
2. (Lines 165 & 177): Please, describe more explicitly the correlation in HBeAg -negative low -
replicators (LR) and hepatitis (ENH) cases of:  
i. HBcrAg with serum HBV DNA.  
ii. HBcrAg with serum and liver HBsAg.  
iii. HBcrAg with liver HBcAg.  
iv. HBsAg with serum HBV DNA  
 
B. Minor Comments:  
1. Please correct a few typing errors.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary  controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to as sess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess t he statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary 
from an  organisation that may in any way gain or lose financially from the 
publication of this  manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of 
the manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
My answer is "No" in all the above questions.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Distinct patterns of serum hepatitis B core -related antigen during the natural history of 
chronic hepatitis B  
 
Version: 0 Date: 27 Jun 2017  
 
Reviewer: Emanuel Manesis  
 
Reviewer's report:  
 
The article by Zhan -Qing  Zhang, et al (BMGE -D-17-00202), addresses the inter -relationships of 
serum HBcrAg, HBsAg and HBV DNA with liver HBsAg and HBcAg. The work involves 444 
treatment -naïve Chinese patients with chronic hepatitis B, selected to represent all the four 
immunologi cal phases in the natural history of HBV infection. The investigation is not original, 
as there have been already a few recent publications on the same subject (J Virol Methods 
2016;235:92, Clin Microbiol Infect 2015;21:606, Clin Microbiol Infect 2014;20:1 173). It also, 
relies on immunohistochemistry rather and not on direct intrahepatic measurements of HBV 
replication parameters. However, the study includes one of the largest liver biopsy cohorts 
reported so far. In addition, the reported findings are welc omed, since they strengthen the value 
of HBcrAg, as an important novel marker in the evaluation of HBV -infected patients. The 
investigation is well -conducted and the article is written in good English, well documented and 
discussed. A few comments follow:  
 
A. Major Comments:  
1. (Line 103): Please give a reference.  
2. (Lines 165 & 177): Please, describe more explicitly the correlation in HBeAg -negative low -
replicators (LR) and hepatitis (ENH) cases of:  
i. HBcrAg with serum HBV DNA.  
ii. HBcrAg with serum and liver HBsAg.  
iii. HBcrAg with liver HBcAg.  
iv. HBsAg with serum HBV DNA  
 
B. Minor Comments:  
1. Please correct a few typing errors.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary  controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to as sess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess t he statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary 
from an  organisation that may in any way gain or lose financially from the 
publication of this  manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of 
the manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
My answer is "No" in all the above questions.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Distinct patterns of serum hepatitis B core -related antigen during the natural history of 
chronic hepatitis B  
 
Version: 0 Date: 27 Jun 2017  
 
Reviewer: Emanuel Manesis  
 
Reviewer's report:  
 
The article by Zhan -Qing  Zhang, et al (BMGE -D-17-00202), addresses the inter -relationships of 
serum HBcrAg, HBsAg and HBV DNA with liver HBsAg and HBcAg. The work involves 444 
treatment -naïve Chinese patients with chronic hepatitis B, selected to represent all the four 
immunologi cal phases in the natural history of HBV infection. The investigation is not original, 
as there have been already a few recent publications on the same subject (J Virol Methods 
2016;235:92, Clin Microbiol Infect 2015;21:606, Clin Microbiol Infect 2014;20:1 173). It also, 
relies on immunohistochemistry rather and not on direct intrahepatic measurements of HBV 
replication parameters. However, the study includes one of the largest liver biopsy cohorts 
reported so far. In addition, the reported findings are welc omed, since they strengthen the value 
of HBcrAg, as an important novel marker in the evaluation of HBV -infected patients. The 
investigation is well -conducted and the article is written in good English, well documented and 
discussed. A few comments follow:  
 
A. Major Comments:  
1. (Line 103): Please give a reference.  
2. (Lines 165 & 177): Please, describe more explicitly the correlation in HBeAg -negative low -
replicators (LR) and hepatitis (ENH) cases of:  
i. HBcrAg with serum HBV DNA.  
ii. HBcrAg with serum and liver HBsAg.  
iii. HBcrAg with liver HBcAg.  
iv. HBsAg with serum HBV DNA  
 
B. Minor Comments:  
1. Please correct a few typing errors.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary  controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to as sess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess t he statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary 
from an  organisation that may in any way gain or lose financially from the 
publication of this  manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of 
the manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
My answer is "No" in all the above questions.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant