Reviewer ’s report  
 
Title: Distinct patterns of serum hepatitis B core -related antigen during the natural history of 
chronic hepatitis B  
 
Version: 0 Date: 28 Jun 2017  
 
Reviewer: Spilios Manolakopoulos  
 
Reviewer's report:  
 
Dear Authors,  
 
Your study "Distinct patterns of serum hepatitis B core -related antigen during the natural history 
of chronic hepatitis B" represents an interesting topic in recent literature of hepatitis B.  
I would suggest the following comments:  
 According to the last European Gu idelines (EASL 2017) the phases of HBV infection have 
been changed. You should mention this in the background and to explain that probably it 
doesn't have any major effect in your classification and results.  
 Patients were classified into phases according  to the HBV DNA and ALT levels. You also 
have to take under consideration histological features by your biopsies (or non invasive 
biomarkers) for a more accurate differentiation.  
 The appropriate references for the assays should be added in the paragraph "laboratory 
assays"  
 P-values have to be added on the graphs of figure 1 (I think that the only significant p -value 
is between the LR and the other groups regarding the HBcrAg and HBV DNA). It is not clear 
at least by the figure that HBsAg levels have a s ignificant difference (p=0.006) between IT 
and IC group.  
 I would suggest to add the results of the correlation between HBV DNA and HBsAg levels of 
the ENH group at the figure 2 and to explain why you did not show the results of the 
correlation in the LR  group.  
 The lines 183 -185 [it was found that there was a barely significant positive correlation 
between HBsAg score and HBsAg titre in IT (p=0.10 and IC (p=0.04)]: The statistical term 
correlation is not correct and obviously there is no high significan ce. Could you explain why 
you did not present results of the analysis of the circulating antigens and their intrahepatic 
status in the ENH group?  
 Line 236 -237: We cannot conclude anything about HBcrAg and effectiveness of antiviral 
therapy by this study as you mentioned in this sentence.  
 At the end, the assumption that "HBcrAg levels can be decomposed into two major 
constituents i.e. HBeAg and HBV DNA" cannot be regarded as a conclusion.  
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 nece ssary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess 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.  
 
Not relevant to this manuscript  
 
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 received 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 r elation 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.  
 
I declare that I have no competing interests  
 
I agree to the open peer revie w 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: 28 Jun 2017  
 
Reviewer: Spilios Manolakopoulos  
 
Reviewer's report:  
 
Dear Authors,  
 
Your study "Distinct patterns of serum hepatitis B core -related antigen during the natural history 
of chronic hepatitis B" represents an interesting topic in recent literature of hepatitis B.  
I would suggest the following comments:  
 According to the last European Gu idelines (EASL 2017) the phases of HBV infection have 
been changed. You should mention this in the background and to explain that probably it 
doesn't have any major effect in your classification and results.  
 Patients were classified into phases according  to the HBV DNA and ALT levels. You also 
have to take under consideration histological features by your biopsies (or non invasive 
biomarkers) for a more accurate differentiation.  
 The appropriate references for the assays should be added in the paragraph "laboratory 
assays"  
 P-values have to be added on the graphs of figure 1 (I think that the only significant p -value 
is between the LR and the other groups regarding the HBcrAg and HBV DNA). It is not clear 
at least by the figure that HBsAg levels have a s ignificant difference (p=0.006) between IT 
and IC group.  
 I would suggest to add the results of the correlation between HBV DNA and HBsAg levels of 
the ENH group at the figure 2 and to explain why you did not show the results of the 
correlation in the LR  group.  
 The lines 183 -185 [it was found that there was a barely significant positive correlation 
between HBsAg score and HBsAg titre in IT (p=0.10 and IC (p=0.04)]: The statistical term 
correlation is not correct and obviously there is no high significan ce. Could you explain why 
you did not present results of the analysis of the circulating antigens and their intrahepatic 
status in the ENH group?  
 Line 236 -237: We cannot conclude anything about HBcrAg and effectiveness of antiviral 
therapy by this study as you mentioned in this sentence.  
 At the end, the assumption that "HBcrAg levels can be decomposed into two major 
constituents i.e. HBeAg and HBV DNA" cannot be regarded as a conclusion.  
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 nece ssary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess 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.  
 
Not relevant to this manuscript  
 
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 received 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 r elation 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.  
 
I declare that I have no competing interests  
 
I agree to the open peer revie w 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: 28 Jun 2017  
 
Reviewer: Spilios Manolakopoulos  
 
Reviewer's report:  
 
Dear Authors,  
 
Your study "Distinct patterns of serum hepatitis B core -related antigen during the natural history 
of chronic hepatitis B" represents an interesting topic in recent literature of hepatitis B.  
I would suggest the following comments:  
 According to the last European Gu idelines (EASL 2017) the phases of HBV infection have 
been changed. You should mention this in the background and to explain that probably it 
doesn't have any major effect in your classification and results.  
 Patients were classified into phases according  to the HBV DNA and ALT levels. You also 
have to take under consideration histological features by your biopsies (or non invasive 
biomarkers) for a more accurate differentiation.  
 The appropriate references for the assays should be added in the paragraph "laboratory 
assays"  
 P-values have to be added on the graphs of figure 1 (I think that the only significant p -value 
is between the LR and the other groups regarding the HBcrAg and HBV DNA). It is not clear 
at least by the figure that HBsAg levels have a s ignificant difference (p=0.006) between IT 
and IC group.  
 I would suggest to add the results of the correlation between HBV DNA and HBsAg levels of 
the ENH group at the figure 2 and to explain why you did not show the results of the 
correlation in the LR  group.  
 The lines 183 -185 [it was found that there was a barely significant positive correlation 
between HBsAg score and HBsAg titre in IT (p=0.10 and IC (p=0.04)]: The statistical term 
correlation is not correct and obviously there is no high significan ce. Could you explain why 
you did not present results of the analysis of the circulating antigens and their intrahepatic 
status in the ENH group?  
 Line 236 -237: We cannot conclude anything about HBcrAg and effectiveness of antiviral 
therapy by this study as you mentioned in this sentence.  
 At the end, the assumption that "HBcrAg levels can be decomposed into two major 
constituents i.e. HBeAg and HBV DNA" cannot be regarded as a conclusion.  
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 nece ssary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess 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.  
 
Not relevant to this manuscript  
 
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 received 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 r elation 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.  
 
I declare that I have no competing interests  
 
I agree to the open peer revie w 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