Reviewer ’s report  
 
Title:  Prior hepatitis B virus infection as a co -factor of chronic hepatitis C patient survival after 
resection of hepatocellular carcinoma  
 
Version: 0 Date: 24 Jun 2019 
 
Reviewer:  Irene Cacciola  
 
Reviewer’s report:  
 
In this retrospective cohort study, Midorikawa and colleagues examine the impact of occult 
hepatitis B virus infection (OBI) on overall survival and recurrence -free survival in 
hepatocellular car cinoma (HCC) related to chronic hepatitis C (HCV) and non -B non -C HCC 
after resection.  The topic is certainly important and falls within the topic of the journal.  
However, in the reviewer opinion, despite these scenarios are very intriguing, some importa nt 
criticism may be raised against this version of the manuscript. Specifically, the decision to 
associate a condition that is defined as " the long -lasting persistence of viral genomes in the liver 
tissue (and in some cases also in the serum) of individua ls negative for the HBV surface antigen 
(HBsAg)" without performing any experimental methods able to demonstrate the presence of 
OBI it is questionable. Perhaps, it would be more appropriate evaluate the possible association 
between the positivity for anti -hepatitis B core antibody and disease progression and, perhaps, 
stating the in the conclusions section possible hypothesis about the potential association linked to 
the presence of occult HBV infection. Therefore, in the reviewer opinion the paper as it n ow 
stands is not ready to be published, but need to address the following Major Comments  in the 
revised paper:  
 
1) Backgroud : page 5 lines 12 -19: The authors write "In clinical practice, serum HBV DNA 
is the only reliable diagnostic marker of OBI, but if highly sensitive HBV DNA testing is 
not available, detection of serum anti -hepatitis B core antibody (HBcAb) may be used as 
a surrogate marker for identifying potential seropositive OBI patients [4, 5]." It should be 
noted that El Sherif et al. (Reference 4) show that: "A significant number of patients with 
anti-HBc had detectable levels of HBV -DNA in the serum" and the "HBV -DNA in the 
serum was detected in 22.5% of anti -HBc-positive chronic HCV patients ". Therefore, in 
this study it is not correct in the reviewer opinion to assume that all anti -HBc-positive 
patients have occult HBV infection.  
 
2) Methods: In the description of the population some data are not indicated. For example 
there is no indication on: 1) how many HCV positive patients have taken IFN therapy; 2) 
when EGDS was performed; 3) when bleeding; 4) how many patients have started beta 
blocker therapy. Ultrasound data are also missing (diameter spleen and portal vein) as 
well as biochemical data (platelet value, bilirubin, creatinine).  
 
3) Result s: page 11 lines 31 -36: the authors write: "On multivariate analysis, independent 
factors for overall survival were OBI (hazard ratio 1.38 [95% CI, 1.02 - 1.87]; p = 0.033), 
multiple tumors (p = 0.007), tumor size (p = 0.002), and liver cirrhosis (p < 0.00 1) (Table 
4)". In the reviewer's opinion it would be more appropriate to include in the multivariate 
analysis the biochemical and instrumental parameters indicated in methods.  
 
4) Conclusions: page 24 lines 12 -17 the authors write "This might be attributed to the 
reactivation of HBV under surgical stress, in addition to HCV infection, and therefore 
careful monitoring of HBV status and appropriate treatment are necessary in such 
patients" In the reviewer opinion the above sentence need to be supported by data  as there 
is no conditions to talk about reactivation,.  
 
According to the above major comments the paper is not recommended for publication in this 
form, but the authors are invited to address the above comments in the revised version of the 
manuscript..  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an ad ditional 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:  
 
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 an y 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 conten t 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' below  
 
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 include d 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:  Prior hepatitis B virus infection as a co -factor of chronic hepatitis C patient survival after 
resection of hepatocellular carcinoma  
 
Version: 0 Date: 24 Jun 2019 
 
Reviewer:  Irene Cacciola  
 
Reviewer’s report:  
 
In this retrospective cohort study, Midorikawa and colleagues examine the impact of occult 
hepatitis B virus infection (OBI) on overall survival and recurrence -free survival in 
hepatocellular car cinoma (HCC) related to chronic hepatitis C (HCV) and non -B non -C HCC 
after resection.  The topic is certainly important and falls within the topic of the journal.  
However, in the reviewer opinion, despite these scenarios are very intriguing, some importa nt 
criticism may be raised against this version of the manuscript. Specifically, the decision to 
associate a condition that is defined as " the long -lasting persistence of viral genomes in the liver 
tissue (and in some cases also in the serum) of individua ls negative for the HBV surface antigen 
(HBsAg)" without performing any experimental methods able to demonstrate the presence of 
OBI it is questionable. Perhaps, it would be more appropriate evaluate the possible association 
between the positivity for anti -hepatitis B core antibody and disease progression and, perhaps, 
stating the in the conclusions section possible hypothesis about the potential association linked to 
the presence of occult HBV infection. Therefore, in the reviewer opinion the paper as it n ow 
stands is not ready to be published, but need to address the following Major Comments  in the 
revised paper:  
 
1) Backgroud : page 5 lines 12 -19: The authors write "In clinical practice, serum HBV DNA 
is the only reliable diagnostic marker of OBI, but if highly sensitive HBV DNA testing is 
not available, detection of serum anti -hepatitis B core antibody (HBcAb) may be used as 
a surrogate marker for identifying potential seropositive OBI patients [4, 5]." It should be 
noted that El Sherif et al. (Reference 4) show that: "A significant number of patients with 
anti-HBc had detectable levels of HBV -DNA in the serum" and the "HBV -DNA in the 
serum was detected in 22.5% of anti -HBc-positive chronic HCV patients ". Therefore, in 
this study it is not correct in the reviewer opinion to assume that all anti -HBc-positive 
patients have occult HBV infection.  
 
2) Methods: In the description of the population some data are not indicated. For example 
there is no indication on: 1) how many HCV positive patients have taken IFN therapy; 2) 
when EGDS was performed; 3) when bleeding; 4) how many patients have started beta 
blocker therapy. Ultrasound data are also missing (diameter spleen and portal vein) as 
well as biochemical data (platelet value, bilirubin, creatinine).  
 
3) Result s: page 11 lines 31 -36: the authors write: "On multivariate analysis, independent 
factors for overall survival were OBI (hazard ratio 1.38 [95% CI, 1.02 - 1.87]; p = 0.033), 
multiple tumors (p = 0.007), tumor size (p = 0.002), and liver cirrhosis (p < 0.00 1) (Table 
4)". In the reviewer's opinion it would be more appropriate to include in the multivariate 
analysis the biochemical and instrumental parameters indicated in methods.  
 
4) Conclusions: page 24 lines 12 -17 the authors write "This might be attributed to the 
reactivation of HBV under surgical stress, in addition to HCV infection, and therefore 
careful monitoring of HBV status and appropriate treatment are necessary in such 
patients" In the reviewer opinion the above sentence need to be supported by data  as there 
is no conditions to talk about reactivation,.  
 
According to the above major comments the paper is not recommended for publication in this 
form, but the authors are invited to address the above comments in the revised version of the 
manuscript..  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an ad ditional 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:  
 
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 an y 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 conten t 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' below  
 
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 include d 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:  Prior hepatitis B virus infection as a co -factor of chronic hepatitis C patient survival after 
resection of hepatocellular carcinoma  
 
Version: 0 Date: 24 Jun 2019 
 
Reviewer:  Irene Cacciola  
 
Reviewer’s report:  
 
In this retrospective cohort study, Midorikawa and colleagues examine the impact of occult 
hepatitis B virus infection (OBI) on overall survival and recurrence -free survival in 
hepatocellular car cinoma (HCC) related to chronic hepatitis C (HCV) and non -B non -C HCC 
after resection.  The topic is certainly important and falls within the topic of the journal.  
However, in the reviewer opinion, despite these scenarios are very intriguing, some importa nt 
criticism may be raised against this version of the manuscript. Specifically, the decision to 
associate a condition that is defined as " the long -lasting persistence of viral genomes in the liver 
tissue (and in some cases also in the serum) of individua ls negative for the HBV surface antigen 
(HBsAg)" without performing any experimental methods able to demonstrate the presence of 
OBI it is questionable. Perhaps, it would be more appropriate evaluate the possible association 
between the positivity for anti -hepatitis B core antibody and disease progression and, perhaps, 
stating the in the conclusions section possible hypothesis about the potential association linked to 
the presence of occult HBV infection. Therefore, in the reviewer opinion the paper as it n ow 
stands is not ready to be published, but need to address the following Major Comments  in the 
revised paper:  
 
1) Backgroud : page 5 lines 12 -19: The authors write "In clinical practice, serum HBV DNA 
is the only reliable diagnostic marker of OBI, but if highly sensitive HBV DNA testing is 
not available, detection of serum anti -hepatitis B core antibody (HBcAb) may be used as 
a surrogate marker for identifying potential seropositive OBI patients [4, 5]." It should be 
noted that El Sherif et al. (Reference 4) show that: "A significant number of patients with 
anti-HBc had detectable levels of HBV -DNA in the serum" and the "HBV -DNA in the 
serum was detected in 22.5% of anti -HBc-positive chronic HCV patients ". Therefore, in 
this study it is not correct in the reviewer opinion to assume that all anti -HBc-positive 
patients have occult HBV infection.  
 
2) Methods: In the description of the population some data are not indicated. For example 
there is no indication on: 1) how many HCV positive patients have taken IFN therapy; 2) 
when EGDS was performed; 3) when bleeding; 4) how many patients have started beta 
blocker therapy. Ultrasound data are also missing (diameter spleen and portal vein) as 
well as biochemical data (platelet value, bilirubin, creatinine).  
 
3) Result s: page 11 lines 31 -36: the authors write: "On multivariate analysis, independent 
factors for overall survival were OBI (hazard ratio 1.38 [95% CI, 1.02 - 1.87]; p = 0.033), 
multiple tumors (p = 0.007), tumor size (p = 0.002), and liver cirrhosis (p < 0.00 1) (Table 
4)". In the reviewer's opinion it would be more appropriate to include in the multivariate 
analysis the biochemical and instrumental parameters indicated in methods.  
 
4) Conclusions: page 24 lines 12 -17 the authors write "This might be attributed to the 
reactivation of HBV under surgical stress, in addition to HCV infection, and therefore 
careful monitoring of HBV status and appropriate treatment are necessary in such 
patients" In the reviewer opinion the above sentence need to be supported by data  as there 
is no conditions to talk about reactivation,.  
 
According to the above major comments the paper is not recommended for publication in this 
form, but the authors are invited to address the above comments in the revised version of the 
manuscript..  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an ad ditional 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:  
 
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 an y 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 conten t 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' below  
 
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 include d as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant