Reviewer ’s report  
 
Title: Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue -treated  
HBeAg -positive chronic hepatitis B: a retrospective study  
 
Version: 0 Date: 12 Mar 2020  
 
Reviewer: Albert Do  
 
Reviewer's report:  
 
I am appreciative to the editors and authors for the opportunity to review this article, "Impact of 
fatty liver on treatment response in nucleos(t)ide analogue -treated HBeAg -positive chronic 
hepatitis B: a retrospective study," which is an interesting study of patients with biopsy -proven 
hepatic steatosis in patients with chronic HBV treated with antiviral therapy and find hepatic 
steato sis not having an effect on treatment outcomes.. My comments are as follows:  
 
Overall, I appreciate that this reports a null finding to the hypothesis that the presence of hepatic 
steatosis leads to differential e -antigen clearance in patients with HBeAg -positive chronic HBV 
infection. One primary consideration is whether this study is underpowered to detect differences, 
and also some statistical analytic points which I have outlined below.  
 
Major Comments  
* The authors evaluate patients with biopsy proven steatosis however do not perform any 
data extraction or assessment of patients with nonalcoholic steatohepatitis (NASH), which would 
include hepatocyte ballooning degeneration and lobular inflammation. Might there be suggestion 
of NASH, as opposed to hepat ic steatosis, that drives differences observed in patient outcomes? 
Conversely, in this sample of patients with biopsy proven steatosis, were only patients included 
who did not have NASH? The presence of absence of NASH may be a potential confounder in 
the association between hepatic steatosis and treatment outcomes in HBV.  
* There are several statistical questions I feel need to be addressed or revised. First is that 
matching was not discussed in the methods yet was briefly mentioned and then assumed in t he 
results.  
* The multivariable Cox regression model should have included hepatic steatosis 
irrespective of its statistical importance as this appears to be the primary research question. 
Please confirm that this is the case.  
 
Minor Comments  
* I would like more information for proposed mechanisms for how hepatic steatosis 
affect treatment outcomes in chronic HBV infection.  
* While I do not necessarily disagree with the decision to classify as virological non -
responders the patients with missing data or unavailable serum for HBV DNA evaluation, I 
would like to know that there were sensitivity analyses performed which could corroborate this 
decision, and not changing the overall result.  
* Are there data to suggest that smaller magnitudes of antibod y or antigen titers (e.g. 
qHBsAg of HS versus non -HS 3.7 versus 4.0 log) are clinically important? My concern is 
regarding statistical versus clinical importance.  
* There are grammatical errors which warrant close english proofing: "till",  
* I do not unde rstand what "large -scaled" means, but if the authors mean to suggest that 
this study is a study of a large sample of patients, I would argue that this is not the case (196 
patients is not a large study).  
 
 
Are t he 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.  
 
Unable to assess  
 
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  
 
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 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.  
 
I declare that I have no competing interests  
 
I agree to the open peer r eview 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 a s 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: Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue -treated  
HBeAg -positive chronic hepatitis B: a retrospective study  
 
Version: 0 Date: 12 Mar 2020  
 
Reviewer: Albert Do  
 
Reviewer's report:  
 
I am appreciative to the editors and authors for the opportunity to review this article, "Impact of 
fatty liver on treatment response in nucleos(t)ide analogue -treated HBeAg -positive chronic 
hepatitis B: a retrospective study," which is an interesting study of patients with biopsy -proven 
hepatic steatosis in patients with chronic HBV treated with antiviral therapy and find hepatic 
steato sis not having an effect on treatment outcomes.. My comments are as follows:  
 
Overall, I appreciate that this reports a null finding to the hypothesis that the presence of hepatic 
steatosis leads to differential e -antigen clearance in patients with HBeAg -positive chronic HBV 
infection. One primary consideration is whether this study is underpowered to detect differences, 
and also some statistical analytic points which I have outlined below.  
 
Major Comments  
* The authors evaluate patients with biopsy proven steatosis however do not perform any 
data extraction or assessment of patients with nonalcoholic steatohepatitis (NASH), which would 
include hepatocyte ballooning degeneration and lobular inflammation. Might there be suggestion 
of NASH, as opposed to hepat ic steatosis, that drives differences observed in patient outcomes? 
Conversely, in this sample of patients with biopsy proven steatosis, were only patients included 
who did not have NASH? The presence of absence of NASH may be a potential confounder in 
the association between hepatic steatosis and treatment outcomes in HBV.  
* There are several statistical questions I feel need to be addressed or revised. First is that 
matching was not discussed in the methods yet was briefly mentioned and then assumed in t he 
results.  
* The multivariable Cox regression model should have included hepatic steatosis 
irrespective of its statistical importance as this appears to be the primary research question. 
Please confirm that this is the case.  
 
Minor Comments  
* I would like more information for proposed mechanisms for how hepatic steatosis 
affect treatment outcomes in chronic HBV infection.  
* While I do not necessarily disagree with the decision to classify as virological non -
responders the patients with missing data or unavailable serum for HBV DNA evaluation, I 
would like to know that there were sensitivity analyses performed which could corroborate this 
decision, and not changing the overall result.  
* Are there data to suggest that smaller magnitudes of antibod y or antigen titers (e.g. 
qHBsAg of HS versus non -HS 3.7 versus 4.0 log) are clinically important? My concern is 
regarding statistical versus clinical importance.  
* There are grammatical errors which warrant close english proofing: "till",  
* I do not unde rstand what "large -scaled" means, but if the authors mean to suggest that 
this study is a study of a large sample of patients, I would argue that this is not the case (196 
patients is not a large study).  
 
 
Are t he 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.  
 
Unable to assess  
 
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  
 
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 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.  
 
I declare that I have no competing interests  
 
I agree to the open peer r eview 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 a s 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: Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue -treated  
HBeAg -positive chronic hepatitis B: a retrospective study  
 
Version: 0 Date: 12 Mar 2020  
 
Reviewer: Albert Do  
 
Reviewer's report:  
 
I am appreciative to the editors and authors for the opportunity to review this article, "Impact of 
fatty liver on treatment response in nucleos(t)ide analogue -treated HBeAg -positive chronic 
hepatitis B: a retrospective study," which is an interesting study of patients with biopsy -proven 
hepatic steatosis in patients with chronic HBV treated with antiviral therapy and find hepatic 
steato sis not having an effect on treatment outcomes.. My comments are as follows:  
 
Overall, I appreciate that this reports a null finding to the hypothesis that the presence of hepatic 
steatosis leads to differential e -antigen clearance in patients with HBeAg -positive chronic HBV 
infection. One primary consideration is whether this study is underpowered to detect differences, 
and also some statistical analytic points which I have outlined below.  
 
Major Comments  
* The authors evaluate patients with biopsy proven steatosis however do not perform any 
data extraction or assessment of patients with nonalcoholic steatohepatitis (NASH), which would 
include hepatocyte ballooning degeneration and lobular inflammation. Might there be suggestion 
of NASH, as opposed to hepat ic steatosis, that drives differences observed in patient outcomes? 
Conversely, in this sample of patients with biopsy proven steatosis, were only patients included 
who did not have NASH? The presence of absence of NASH may be a potential confounder in 
the association between hepatic steatosis and treatment outcomes in HBV.  
* There are several statistical questions I feel need to be addressed or revised. First is that 
matching was not discussed in the methods yet was briefly mentioned and then assumed in t he 
results.  
* The multivariable Cox regression model should have included hepatic steatosis 
irrespective of its statistical importance as this appears to be the primary research question. 
Please confirm that this is the case.  
 
Minor Comments  
* I would like more information for proposed mechanisms for how hepatic steatosis 
affect treatment outcomes in chronic HBV infection.  
* While I do not necessarily disagree with the decision to classify as virological non -
responders the patients with missing data or unavailable serum for HBV DNA evaluation, I 
would like to know that there were sensitivity analyses performed which could corroborate this 
decision, and not changing the overall result.  
* Are there data to suggest that smaller magnitudes of antibod y or antigen titers (e.g. 
qHBsAg of HS versus non -HS 3.7 versus 4.0 log) are clinically important? My concern is 
regarding statistical versus clinical importance.  
* There are grammatical errors which warrant close english proofing: "till",  
* I do not unde rstand what "large -scaled" means, but if the authors mean to suggest that 
this study is a study of a large sample of patients, I would argue that this is not the case (196 
patients is not a large study).  
 
 
Are t he 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.  
 
Unable to assess  
 
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  
 
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 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.  
 
I declare that I have no competing interests  
 
I agree to the open peer r eview 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 a s confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant