Reviewer ’s report  
 
Title: Low v itamin D levels are associated with high viral loads in patients with chronic hepatitis 
B: A systematic review and meta -analysis  
 
Version: 1 Date: 10 Oct 2018  
 
Reviewer: Masanori Atsukawa  
 
Reviewer's report:  
 
In the manuscript entitled 'Low vitamin D levels are associated with high viral loads in patients 
with chronic hepatitis B: A systematic review and meta -analysis', the authors carried out meta -
analysis to assess vitamin D levels in patients with chronic hepatitis B compared with healthy 
people and showed an inverse correlation between serum vitamin D levels and HBV  viral loads. 
Although this study seems well designed and the results are relevant to clinical practice, there are 
several points should be properly addressed.  
 
MAJOR comments  
1. In this study, serum vitamin D levels in patients with chronic hepatitis B we re 
significantly lower than those in healthy controls. Previous study reported that gender and 
season of sampling were important factors contributing to serum vitamin D levels. 
Authors should mention proportion of gender and sampling season among patients with 
chronic hepatitis B and healthy control.   
 
2. Authors showed that the vitamin D levels were also lower in patients with chronic 
hepatitis B compared with healthy controls, irrespective of latitude and this difference 
was more obvious in low latitude areas. The reason or speculations should be discussed 
in more detail.  
 
3. The serum vitamin D level significantly differed according to HBV genotypes in previous 
studies. The distribution of HBV genotype in patients with chronic hepatitis B should be 
included in this analysis.  
 
4. Concerning correlation between HBV viral loads and vitamin D levels, number of articles 
included in this study was too small as meta -analysis.  
 
5. Among patients with chronic hepatitis B, HBV DNA levels in patients with HBeAg -
positive were higher than those with negative patients in general, and according to 
previous reports, the serum vitamin D level in HBeAg -positive patients was lower than 
that in HBeAg -negative patients. Therefore, authors should include HBeAg -positive or 
negative in the analysis items for correlation between HBV viral loads and vitamin D 
levels.  
 
MINOR comments  
1. Author needs to show a new table to describe characteristics (gender, season of sampling, 
HBV genotype, HBeAg -positive or negative, HBVDNA and so on) of patients in each 
article.  
Are the metho ds 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 am able to assess the 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 futu re? 
 
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 tha t I have no competing interests . 
 
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 a ccepted 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://creativecomm ons.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: Low v itamin D levels are associated with high viral loads in patients with chronic hepatitis 
B: A systematic review and meta -analysis  
 
Version: 1 Date: 10 Oct 2018  
 
Reviewer: Masanori Atsukawa  
 
Reviewer's report:  
 
In the manuscript entitled 'Low vitamin D levels are associated with high viral loads in patients 
with chronic hepatitis B: A systematic review and meta -analysis', the authors carried out meta -
analysis to assess vitamin D levels in patients with chronic hepatitis B compared with healthy 
people and showed an inverse correlation between serum vitamin D levels and HBV  viral loads. 
Although this study seems well designed and the results are relevant to clinical practice, there are 
several points should be properly addressed.  
 
MAJOR comments  
1. In this study, serum vitamin D levels in patients with chronic hepatitis B we re 
significantly lower than those in healthy controls. Previous study reported that gender and 
season of sampling were important factors contributing to serum vitamin D levels. 
Authors should mention proportion of gender and sampling season among patients with 
chronic hepatitis B and healthy control.   
 
2. Authors showed that the vitamin D levels were also lower in patients with chronic 
hepatitis B compared with healthy controls, irrespective of latitude and this difference 
was more obvious in low latitude areas. The reason or speculations should be discussed 
in more detail.  
 
3. The serum vitamin D level significantly differed according to HBV genotypes in previous 
studies. The distribution of HBV genotype in patients with chronic hepatitis B should be 
included in this analysis.  
 
4. Concerning correlation between HBV viral loads and vitamin D levels, number of articles 
included in this study was too small as meta -analysis.  
 
5. Among patients with chronic hepatitis B, HBV DNA levels in patients with HBeAg -
positive were higher than those with negative patients in general, and according to 
previous reports, the serum vitamin D level in HBeAg -positive patients was lower than 
that in HBeAg -negative patients. Therefore, authors should include HBeAg -positive or 
negative in the analysis items for correlation between HBV viral loads and vitamin D 
levels.  
 
MINOR comments  
1. Author needs to show a new table to describe characteristics (gender, season of sampling, 
HBV genotype, HBeAg -positive or negative, HBVDNA and so on) of patients in each 
article.  
Are the metho ds 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 am able to assess the 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 futu re? 
 
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 tha t I have no competing interests . 
 
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 a ccepted 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://creativecomm ons.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: Low v itamin D levels are associated with high viral loads in patients with chronic hepatitis 
B: A systematic review and meta -analysis  
 
Version: 1 Date: 10 Oct 2018  
 
Reviewer: Masanori Atsukawa  
 
Reviewer's report:  
 
In the manuscript entitled 'Low vitamin D levels are associated with high viral loads in patients 
with chronic hepatitis B: A systematic review and meta -analysis', the authors carried out meta -
analysis to assess vitamin D levels in patients with chronic hepatitis B compared with healthy 
people and showed an inverse correlation between serum vitamin D levels and HBV  viral loads. 
Although this study seems well designed and the results are relevant to clinical practice, there are 
several points should be properly addressed.  
 
MAJOR comments  
1. In this study, serum vitamin D levels in patients with chronic hepatitis B we re 
significantly lower than those in healthy controls. Previous study reported that gender and 
season of sampling were important factors contributing to serum vitamin D levels. 
Authors should mention proportion of gender and sampling season among patients with 
chronic hepatitis B and healthy control.   
 
2. Authors showed that the vitamin D levels were also lower in patients with chronic 
hepatitis B compared with healthy controls, irrespective of latitude and this difference 
was more obvious in low latitude areas. The reason or speculations should be discussed 
in more detail.  
 
3. The serum vitamin D level significantly differed according to HBV genotypes in previous 
studies. The distribution of HBV genotype in patients with chronic hepatitis B should be 
included in this analysis.  
 
4. Concerning correlation between HBV viral loads and vitamin D levels, number of articles 
included in this study was too small as meta -analysis.  
 
5. Among patients with chronic hepatitis B, HBV DNA levels in patients with HBeAg -
positive were higher than those with negative patients in general, and according to 
previous reports, the serum vitamin D level in HBeAg -positive patients was lower than 
that in HBeAg -negative patients. Therefore, authors should include HBeAg -positive or 
negative in the analysis items for correlation between HBV viral loads and vitamin D 
levels.  
 
MINOR comments  
1. Author needs to show a new table to describe characteristics (gender, season of sampling, 
HBV genotype, HBeAg -positive or negative, HBVDNA and so on) of patients in each 
article.  
Are the metho ds 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 am able to assess the 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 futu re? 
 
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 tha t I have no competing interests . 
 
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 a ccepted 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://creativecomm ons.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