Reviewer ’s report  
 
Title:  Add-on neurological benefits of antiviral therapy in HCV patients with Chronic Kidney 
Disease —A Nationwide Cohort Study  
 
Version: 0 Date: 16 Apr 2017 
 
Reviewer:  Michel  Jadoul  
 
Reviewer’s report:  
 
Lin e t al. have performed an observational study of the association of having had an interferon -
based treatment (IBT) vs no IBT, in a large cohort of Taiwanese subjects with HCV and CKD. 
They have studied the impact of IBT on mortality and various cardiovascula r outcomes.  
 
 
Their results may be summarized as follows  
 
1)Both all cause mortality and hemorrhagic stroke were significantly less frequent by 
multivariable analysis in the IBT (completely treated ) than no IBT group  
 
2)New -onset dialysis was also significa ntly  less frequent in the completely treated cohort  
 
3)The authors conclude that "antiviral therapy reduced the risks of all cause mortality , 
hemorrhagic stroke and new -onset dialysis in HCV -infected patients with CKD  
 
 
General comments  
 
1. The last word ha s not been said on the potential benefits of antiHCV treatment, and the 
present study thus of potential interest in the current DAA era.  
 
2. As in any observational study, the key question is the risk of residual confounding, or 
hidden factors that may acco unt for the observed difference(s) but were not measured. Thus, the 
wording of the paper should be adapted to reflect the observational design: avoid "impact "or 
reduce etc… Associations are described, not impacts  
 
3. In that respect, the authors should ad dress the question of treatment bias , as this was not 
an RCT. In particular, can they comment on the impact of year of treatment with IBT? Was this 
adjusted for in this study? Similarly, does the study database account for socio -economic status, 
or educat ion level , and/or rural versus urban setting. Intuitively, each of these factors might be 
associated with a modification of interest for good health -care, even though health care is 
accessible in Taiwan. Please, clarify and comment.  
 
4. Do the authors have  any information regarding the type and number of antihypertensive 
drugs during the study course? This would be interesting as kidney disease induced HT might 
trigger stroke  
 
5. The authors eventually subdivided the treated cohort into completely (> 16 week s) versus 
incompletely treated subgroups. They should provide a comparison of these subgroups for the 
readers interest. Indeed, this comparison is relevant for the selection bias.  
 
6. On page 11, the authors mention that there were differences in ESRD prev alence between 
groups prior to propensity matching, and similarly that the prevalence of liver cirrhosis without 
hepatic decompensation was higher in the treated group. It should be mentioned (and discussed) 
that ERSD (dialysis) patients usually have much lower ALT levels than the general population, 
and thus a detection bias may impact here on the rate of diagnosis of cirrhosis .  
 
7. In the conclusion the authors claim "patients with HCV, with comorbid CKD, and on 
dialysis had no long -term benefits from DAA  therapy". How is this claim possible. The DAA era 
just started in dialysis. The present study dealt with IBT! Please adapt  
 
8. Do the authors have information on sustained viral response rates in the IBT group? Did 
the SVR subgroup from the completely trea ted but without SVR group?  
 
 
Specific comments  
 
1. Some key references on DAA therapy in dialysis /CKD patients would be most welcome. 
Such as : Jadoul and Horsmans Lancet 2015. Roth et al Lancet 2015. Jadoul and Martin Blood 
Purif 2017., etc…  
 
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 nec essary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
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 am able to assess the statistics  
 
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 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 have been a speaker for Abbvie and MSD (both market DAAs)  
 
I agree to th e 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:  Add-on neurological benefits of antiviral therapy in HCV patients with Chronic Kidney 
Disease —A Nationwide Cohort Study  
 
Version: 0 Date: 16 Apr 2017 
 
Reviewer:  Michel  Jadoul  
 
Reviewer’s report:  
 
Lin e t al. have performed an observational study of the association of having had an interferon -
based treatment (IBT) vs no IBT, in a large cohort of Taiwanese subjects with HCV and CKD. 
They have studied the impact of IBT on mortality and various cardiovascula r outcomes.  
 
 
Their results may be summarized as follows  
 
1)Both all cause mortality and hemorrhagic stroke were significantly less frequent by 
multivariable analysis in the IBT (completely treated ) than no IBT group  
 
2)New -onset dialysis was also significa ntly  less frequent in the completely treated cohort  
 
3)The authors conclude that "antiviral therapy reduced the risks of all cause mortality , 
hemorrhagic stroke and new -onset dialysis in HCV -infected patients with CKD  
 
 
General comments  
 
1. The last word ha s not been said on the potential benefits of antiHCV treatment, and the 
present study thus of potential interest in the current DAA era.  
 
2. As in any observational study, the key question is the risk of residual confounding, or 
hidden factors that may acco unt for the observed difference(s) but were not measured. Thus, the 
wording of the paper should be adapted to reflect the observational design: avoid "impact "or 
reduce etc… Associations are described, not impacts  
 
3. In that respect, the authors should ad dress the question of treatment bias , as this was not 
an RCT. In particular, can they comment on the impact of year of treatment with IBT? Was this 
adjusted for in this study? Similarly, does the study database account for socio -economic status, 
or educat ion level , and/or rural versus urban setting. Intuitively, each of these factors might be 
associated with a modification of interest for good health -care, even though health care is 
accessible in Taiwan. Please, clarify and comment.  
 
4. Do the authors have  any information regarding the type and number of antihypertensive 
drugs during the study course? This would be interesting as kidney disease induced HT might 
trigger stroke  
 
5. The authors eventually subdivided the treated cohort into completely (> 16 week s) versus 
incompletely treated subgroups. They should provide a comparison of these subgroups for the 
readers interest. Indeed, this comparison is relevant for the selection bias.  
 
6. On page 11, the authors mention that there were differences in ESRD prev alence between 
groups prior to propensity matching, and similarly that the prevalence of liver cirrhosis without 
hepatic decompensation was higher in the treated group. It should be mentioned (and discussed) 
that ERSD (dialysis) patients usually have much lower ALT levels than the general population, 
and thus a detection bias may impact here on the rate of diagnosis of cirrhosis .  
 
7. In the conclusion the authors claim "patients with HCV, with comorbid CKD, and on 
dialysis had no long -term benefits from DAA  therapy". How is this claim possible. The DAA era 
just started in dialysis. The present study dealt with IBT! Please adapt  
 
8. Do the authors have information on sustained viral response rates in the IBT group? Did 
the SVR subgroup from the completely trea ted but without SVR group?  
 
 
Specific comments  
 
1. Some key references on DAA therapy in dialysis /CKD patients would be most welcome. 
Such as : Jadoul and Horsmans Lancet 2015. Roth et al Lancet 2015. Jadoul and Martin Blood 
Purif 2017., etc…  
 
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 nec essary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
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 am able to assess the statistics  
 
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 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 have been a speaker for Abbvie and MSD (both market DAAs)  
 
I agree to th e 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:  Add-on neurological benefits of antiviral therapy in HCV patients with Chronic Kidney 
Disease —A Nationwide Cohort Study  
 
Version: 0 Date: 16 Apr 2017 
 
Reviewer:  Michel  Jadoul  
 
Reviewer’s report:  
 
Lin e t al. have performed an observational study of the association of having had an interferon -
based treatment (IBT) vs no IBT, in a large cohort of Taiwanese subjects with HCV and CKD. 
They have studied the impact of IBT on mortality and various cardiovascula r outcomes.  
 
 
Their results may be summarized as follows  
 
1)Both all cause mortality and hemorrhagic stroke were significantly less frequent by 
multivariable analysis in the IBT (completely treated ) than no IBT group  
 
2)New -onset dialysis was also significa ntly  less frequent in the completely treated cohort  
 
3)The authors conclude that "antiviral therapy reduced the risks of all cause mortality , 
hemorrhagic stroke and new -onset dialysis in HCV -infected patients with CKD  
 
 
General comments  
 
1. The last word ha s not been said on the potential benefits of antiHCV treatment, and the 
present study thus of potential interest in the current DAA era.  
 
2. As in any observational study, the key question is the risk of residual confounding, or 
hidden factors that may acco unt for the observed difference(s) but were not measured. Thus, the 
wording of the paper should be adapted to reflect the observational design: avoid "impact "or 
reduce etc… Associations are described, not impacts  
 
3. In that respect, the authors should ad dress the question of treatment bias , as this was not 
an RCT. In particular, can they comment on the impact of year of treatment with IBT? Was this 
adjusted for in this study? Similarly, does the study database account for socio -economic status, 
or educat ion level , and/or rural versus urban setting. Intuitively, each of these factors might be 
associated with a modification of interest for good health -care, even though health care is 
accessible in Taiwan. Please, clarify and comment.  
 
4. Do the authors have  any information regarding the type and number of antihypertensive 
drugs during the study course? This would be interesting as kidney disease induced HT might 
trigger stroke  
 
5. The authors eventually subdivided the treated cohort into completely (> 16 week s) versus 
incompletely treated subgroups. They should provide a comparison of these subgroups for the 
readers interest. Indeed, this comparison is relevant for the selection bias.  
 
6. On page 11, the authors mention that there were differences in ESRD prev alence between 
groups prior to propensity matching, and similarly that the prevalence of liver cirrhosis without 
hepatic decompensation was higher in the treated group. It should be mentioned (and discussed) 
that ERSD (dialysis) patients usually have much lower ALT levels than the general population, 
and thus a detection bias may impact here on the rate of diagnosis of cirrhosis .  
 
7. In the conclusion the authors claim "patients with HCV, with comorbid CKD, and on 
dialysis had no long -term benefits from DAA  therapy". How is this claim possible. The DAA era 
just started in dialysis. The present study dealt with IBT! Please adapt  
 
8. Do the authors have information on sustained viral response rates in the IBT group? Did 
the SVR subgroup from the completely trea ted but without SVR group?  
 
 
Specific comments  
 
1. Some key references on DAA therapy in dialysis /CKD patients would be most welcome. 
Such as : Jadoul and Horsmans Lancet 2015. Roth et al Lancet 2015. Jadoul and Martin Blood 
Purif 2017., etc…  
 
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 nec essary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
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 am able to assess the statistics  
 
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 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 have been a speaker for Abbvie and MSD (both market DAAs)  
 
I agree to th e 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