Reviewer ’s report  
Title: Time -varying serum gradient of hepatitis B surface antigen predicts risk of relapses after  
off-NA therapy  
 
Version: 0 Date: 08 Jul 2017  
 
Reviewer: Satoru Joshita  
 
Reviewer's report:  
Comments to the author:  
This is an original article to address whether HBsAg measurement is useful for prediction of 
virological and clinical relapse in the HBV patients who discontinued NAs treatment. The 
author s conducted multicenter prospective study to uncover their questions. Finally, the authors 
concluded that time -varying HBsAg was associated with relapse after NAs cessation. There are 
some critiques as indicated with more detail in the following comments:  
 
Major comments:  
1. HBsAg levels has already known to be associated with relapse after cession of NAs. 
Moreover, if the patients showed undetectable HBV -DNA levels, they will be viologically 
and clinically relapsed after cession of NAs. Indeed, the author s showed that 80% and 43% 
of all patients were virologically or clinically relapsed after secession of NAs within only 2 
years. What is a significant clinical meaning to predict the relapse even though majority of 
patients showed relapse?  
2. Based on this  point, is it better to uncover any factors to predict for no relapse after cession 
of NAs treatment?  
3. How many patients started to be treated with NAs after relapse?  
4. Time -varying HBsAg was associated with the difference between virological and clin ical 
relapse? Or Time -varying HBsAg could predict the difference between virological and 
clinical relapse?  
5. Clinicians have already known that violorogical and clinical relapse happens in most of 
patients who discontinued NAs. It should be concerned tha t how many patients were 
complicated with hepatic decompensation after secession of NAs therapy in this study 
cohort.  
 
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.  
Yes 
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 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.  
I recommend additional statistical review  
Qualit y of written English  
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
Quality of written English  
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
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 m ay 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 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.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understand that my name will be inclu ded 
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: Time -varying serum gradient of hepatitis B surface antigen predicts risk of relapses after  
off-NA therapy  
 
Version: 0 Date: 08 Jul 2017  
 
Reviewer: Satoru Joshita  
 
Reviewer's report:  
Comments to the author:  
This is an original article to address whether HBsAg measurement is useful for prediction of 
virological and clinical relapse in the HBV patients who discontinued NAs treatment. The 
author s conducted multicenter prospective study to uncover their questions. Finally, the authors 
concluded that time -varying HBsAg was associated with relapse after NAs cessation. There are 
some critiques as indicated with more detail in the following comments:  
 
Major comments:  
1. HBsAg levels has already known to be associated with relapse after cession of NAs. 
Moreover, if the patients showed undetectable HBV -DNA levels, they will be viologically 
and clinically relapsed after cession of NAs. Indeed, the author s showed that 80% and 43% 
of all patients were virologically or clinically relapsed after secession of NAs within only 2 
years. What is a significant clinical meaning to predict the relapse even though majority of 
patients showed relapse?  
2. Based on this  point, is it better to uncover any factors to predict for no relapse after cession 
of NAs treatment?  
3. How many patients started to be treated with NAs after relapse?  
4. Time -varying HBsAg was associated with the difference between virological and clin ical 
relapse? Or Time -varying HBsAg could predict the difference between virological and 
clinical relapse?  
5. Clinicians have already known that violorogical and clinical relapse happens in most of 
patients who discontinued NAs. It should be concerned tha t how many patients were 
complicated with hepatic decompensation after secession of NAs therapy in this study 
cohort.  
 
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.  
Yes 
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 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.  
I recommend additional statistical review  
Qualit y of written English  
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
Quality of written English  
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
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 m ay 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 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.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understand that my name will be inclu ded 
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: Time -varying serum gradient of hepatitis B surface antigen predicts risk of relapses after  
off-NA therapy  
 
Version: 0 Date: 08 Jul 2017  
 
Reviewer: Satoru Joshita  
 
Reviewer's report:  
Comments to the author:  
This is an original article to address whether HBsAg measurement is useful for prediction of 
virological and clinical relapse in the HBV patients who discontinued NAs treatment. The 
author s conducted multicenter prospective study to uncover their questions. Finally, the authors 
concluded that time -varying HBsAg was associated with relapse after NAs cessation. There are 
some critiques as indicated with more detail in the following comments:  
 
Major comments:  
1. HBsAg levels has already known to be associated with relapse after cession of NAs. 
Moreover, if the patients showed undetectable HBV -DNA levels, they will be viologically 
and clinically relapsed after cession of NAs. Indeed, the author s showed that 80% and 43% 
of all patients were virologically or clinically relapsed after secession of NAs within only 2 
years. What is a significant clinical meaning to predict the relapse even though majority of 
patients showed relapse?  
2. Based on this  point, is it better to uncover any factors to predict for no relapse after cession 
of NAs treatment?  
3. How many patients started to be treated with NAs after relapse?  
4. Time -varying HBsAg was associated with the difference between virological and clin ical 
relapse? Or Time -varying HBsAg could predict the difference between virological and 
clinical relapse?  
5. Clinicians have already known that violorogical and clinical relapse happens in most of 
patients who discontinued NAs. It should be concerned tha t how many patients were 
complicated with hepatic decompensation after secession of NAs therapy in this study 
cohort.  
 
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.  
Yes 
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 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.  
I recommend additional statistical review  
Qualit y of written English  
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
Quality of written English  
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
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 m ay 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 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.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understand that my name will be inclu ded 
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