Reviewer’s report
Title:  High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection:
Longitudinal analysis of a German cohort.
Version: 0 Date: 27 Nov 2018
Reviewer: Akihiro Tamori
Reviewer's report:
BMGE-D-18-00611
High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection: Longitudinal
analysis of a German real life cohort
Jan-Hendrik Bockmann, MD; Marcel Grube; Vanessa Hamed; Johann von Felden; Johanna Blöcker;
Malte Wehmeyer; Katja Giersch; Michaela Hall; John M. Murray; Maura Dandri; Stefan Lüth; Ansgar
W. Lohse; Marc Lütgehetmann; Julian Schulze zur Wiesch
Authors enrolled 49 patients positive for HBsAg and anti-HDV into the present retrospective study. In
this cohort, clinical events related to liver diseases occurred in 11/49 patients coinfected with HBV and
HDV . Multivariate analysis showed that progression of liver disease at baseline was associated with
overall clinical events, not with serum HDV RNA positivity. 
Coinfection  with  HBV  and  HBV  is  not  common.  So,  the  present  study had  a  potential  unique
information. However, there were several issues to be revised before conclusions. 
First of all, the patients' backgrounds at baseline were different between HBV+HDV coinfection and
HBV  mono-infection.  Comparing  clinical  events  between  two  groups,  authors  should  match  the
backgrounds; age, gender and cirrhosis etc. Propensity score matching method is usually used. 
Second, it is difficult to understand the efficacy of IFN therapy for coinfected patients. Which was the
aim of IFN therapy, HBV or HDV? There was no information about patients' background treated with
IFN, and outcome of HBV markers except HBsAg. 
Next, in case of HCV, anti-HCV positive but HCV RNA negative patient means past HCV infection;
self-limited infection or treatment cure. Among 49 patients, 15 patients showed negative HDV RNA at
baseline and during follow-up. Why such patients were enrolled to the study? 
Minor; 
Three HIV coinfected patients had better be excluded from the study.
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  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:
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 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 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:  High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection:
Longitudinal analysis of a German cohort.
Version: 0 Date: 27 Nov 2018
Reviewer: Akihiro Tamori
Reviewer's report:
BMGE-D-18-00611
High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection: Longitudinal
analysis of a German real life cohort
Jan-Hendrik Bockmann, MD; Marcel Grube; Vanessa Hamed; Johann von Felden; Johanna Blöcker;
Malte Wehmeyer; Katja Giersch; Michaela Hall; John M. Murray; Maura Dandri; Stefan Lüth; Ansgar
W. Lohse; Marc Lütgehetmann; Julian Schulze zur Wiesch
Authors enrolled 49 patients positive for HBsAg and anti-HDV into the present retrospective study. In
this cohort, clinical events related to liver diseases occurred in 11/49 patients coinfected with HBV and
HDV . Multivariate analysis showed that progression of liver disease at baseline was associated with
overall clinical events, not with serum HDV RNA positivity. 
Coinfection  with  HBV  and  HBV  is  not  common.  So,  the  present  study had  a  potential  unique
information. However, there were several issues to be revised before conclusions. 
First of all, the patients' backgrounds at baseline were different between HBV+HDV coinfection and
HBV  mono-infection.  Comparing  clinical  events  between  two  groups,  authors  should  match  the
backgrounds; age, gender and cirrhosis etc. Propensity score matching method is usually used. 
Second, it is difficult to understand the efficacy of IFN therapy for coinfected patients. Which was the
aim of IFN therapy, HBV or HDV? There was no information about patients' background treated with
IFN, and outcome of HBV markers except HBsAg. 
Next, in case of HCV, anti-HCV positive but HCV RNA negative patient means past HCV infection;
self-limited infection or treatment cure. Among 49 patients, 15 patients showed negative HDV RNA at
baseline and during follow-up. Why such patients were enrolled to the study? 
Minor; 
Three HIV coinfected patients had better be excluded from the study.
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  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:
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 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 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:  High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection:
Longitudinal analysis of a German cohort.
Version: 0 Date: 27 Nov 2018
Reviewer: Akihiro Tamori
Reviewer's report:
BMGE-D-18-00611
High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection: Longitudinal
analysis of a German real life cohort
Jan-Hendrik Bockmann, MD; Marcel Grube; Vanessa Hamed; Johann von Felden; Johanna Blöcker;
Malte Wehmeyer; Katja Giersch; Michaela Hall; John M. Murray; Maura Dandri; Stefan Lüth; Ansgar
W. Lohse; Marc Lütgehetmann; Julian Schulze zur Wiesch
Authors enrolled 49 patients positive for HBsAg and anti-HDV into the present retrospective study. In
this cohort, clinical events related to liver diseases occurred in 11/49 patients coinfected with HBV and
HDV . Multivariate analysis showed that progression of liver disease at baseline was associated with
overall clinical events, not with serum HDV RNA positivity. 
Coinfection  with  HBV  and  HBV  is  not  common.  So,  the  present  study had  a  potential  unique
information. However, there were several issues to be revised before conclusions. 
First of all, the patients' backgrounds at baseline were different between HBV+HDV coinfection and
HBV  mono-infection.  Comparing  clinical  events  between  two  groups,  authors  should  match  the
backgrounds; age, gender and cirrhosis etc. Propensity score matching method is usually used. 
Second, it is difficult to understand the efficacy of IFN therapy for coinfected patients. Which was the
aim of IFN therapy, HBV or HDV? There was no information about patients' background treated with
IFN, and outcome of HBV markers except HBsAg. 
Next, in case of HCV, anti-HCV positive but HCV RNA negative patient means past HCV infection;
self-limited infection or treatment cure. Among 49 patients, 15 patients showed negative HDV RNA at
baseline and during follow-up. Why such patients were enrolled to the study? 
Minor; 
Three HIV coinfected patients had better be excluded from the study.
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  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:
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 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 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