Reviewer ’s report  
 
Title: Addition of nucleoside analogues to Peg -IFNα-2a enhan ces virological response in 
chronic  hepatitis B patients without early response to Peg -IFNα-2a: A randomized controlled 
trial 
 
Version: 0 Date: 05 Feb 2017  
 
Reviewer: Mar Riveiro -Barciela  
 
Reviewer's report:  
 
This clinical trial focus on a new treatment strategy with pegIFN plus NAs in patients with CHB 
who presented a poor virological response to 12 -weeks therapy with pegIFN. The therapeutic 
protocol is correct, though sometimes it is doubtful that it is actua lly a prospective controlled 
trial since in some parts of the text the number and percentage of patients with poor response 
change. Another limitation of the protocol is the use of ADV in a brand of treatment, since in 
Europe it is no longer a first -line N As. Other important limitations of the study are the 
definitions of efficacy. According to the current EASL guidelines, early virological response 
during pegIFN therapy, in both HBeAg positive and negative patients, is defined as HBV DNA 
<20.000 IU/mL. Mor eover, off -treatment virological response is defined as HBV DNA < 2000 
IU/mL plus normal ALT levels. Therefore, results should be reviewed in order to be in 
agreement with the EASL´s endpoint definitions.  
 
 
Another issue that needs further revision is the ch aracteristics of patients. According to the 
inclusion criteria, patients with cirrhosis can be recruited. However, there is no data regarding 
the number of patients with liver cirrhosis neither in the text nor in table 1.  
 
 
Overall there are numerous typos a nd grammatical errors throughout the manuscript. A fraction 
of which is listed under "minor points" below. It definitely needs to be carefully edited.  
 
 
 
Minor comments  
 
Abstract  
 
Characteristics of patients, especially HBeAg positivity should be added.  
 
 
Definitions used to guide response to PegIFN (poor virological response) and SVR may be added 
to the abstract in order to improve its understanding.  
 
 
Background.  
 
By the time being, clearance of cccDNA is not a goal of CHB treatment so this sentence may be 
removed.  
 
 
 
Material and methods  
 
Line 4, page 7: there is an extra sentence.  
 
 
Paired liver biopsies were performed in 38 patients, which brand of therapy were these patients?  
 
 
 
Results  
 
Mean HBV DNA differences between PegIFN vs PegIFN plus a NAs may be specified over time 
and add to figure 1.  
 
 
Results should be reanalysis in order to be in line with the EASL guidelines.  
 
 
It is a bit surprising that the combination that achieved the greatest change on HBsAg levels was 
pegIFN plus ADV. Could this fact be linked to low er baseline HBsAg levels? To the greater 
proportion of genotype B patients on this group?  
 
 
If none patient achieve HBsAg loss during or after therapy, this should be pointed out.  
 
 
 
Discussion  
 
In the present study, 138 study patients were treated Peg -IFNα -2a for 12 weeks, and only 95 
patients who had a poor virological response at the end of this period received combination 
therapy of Peg -IFNα -2a with either ETV or ADV for 48 weeks. The number patients initially 
treated with pegIFN was 178 and those with poor r esponse and therefore randomized to the three 
brands of study 138??  
 
 
Achievement of HBeAg seroconversion did not differ from TDF or ETV monotherapy rates. 
According to the authors, what are the benefits of pegIFN combination in comparison with NA 
monothera py? 
Tables  
 
Table 1. "Type" should be removed from genotype. There is no need for explaining the statistical 
analysis since it has been previously exposed in the text.  
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify wh at 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 no t, 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 intere sts 
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 p ublication 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 compet ing 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 a n 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: Addition of nucleoside analogues to Peg -IFNα-2a enhan ces virological response in 
chronic  hepatitis B patients without early response to Peg -IFNα-2a: A randomized controlled 
trial 
 
Version: 0 Date: 05 Feb 2017  
 
Reviewer: Mar Riveiro -Barciela  
 
Reviewer's report:  
 
This clinical trial focus on a new treatment strategy with pegIFN plus NAs in patients with CHB 
who presented a poor virological response to 12 -weeks therapy with pegIFN. The therapeutic 
protocol is correct, though sometimes it is doubtful that it is actua lly a prospective controlled 
trial since in some parts of the text the number and percentage of patients with poor response 
change. Another limitation of the protocol is the use of ADV in a brand of treatment, since in 
Europe it is no longer a first -line N As. Other important limitations of the study are the 
definitions of efficacy. According to the current EASL guidelines, early virological response 
during pegIFN therapy, in both HBeAg positive and negative patients, is defined as HBV DNA 
<20.000 IU/mL. Mor eover, off -treatment virological response is defined as HBV DNA < 2000 
IU/mL plus normal ALT levels. Therefore, results should be reviewed in order to be in 
agreement with the EASL´s endpoint definitions.  
 
 
Another issue that needs further revision is the ch aracteristics of patients. According to the 
inclusion criteria, patients with cirrhosis can be recruited. However, there is no data regarding 
the number of patients with liver cirrhosis neither in the text nor in table 1.  
 
 
Overall there are numerous typos a nd grammatical errors throughout the manuscript. A fraction 
of which is listed under "minor points" below. It definitely needs to be carefully edited.  
 
 
 
Minor comments  
 
Abstract  
 
Characteristics of patients, especially HBeAg positivity should be added.  
 
 
Definitions used to guide response to PegIFN (poor virological response) and SVR may be added 
to the abstract in order to improve its understanding.  
 
 
Background.  
 
By the time being, clearance of cccDNA is not a goal of CHB treatment so this sentence may be 
removed.  
 
 
 
Material and methods  
 
Line 4, page 7: there is an extra sentence.  
 
 
Paired liver biopsies were performed in 38 patients, which brand of therapy were these patients?  
 
 
 
Results  
 
Mean HBV DNA differences between PegIFN vs PegIFN plus a NAs may be specified over time 
and add to figure 1.  
 
 
Results should be reanalysis in order to be in line with the EASL guidelines.  
 
 
It is a bit surprising that the combination that achieved the greatest change on HBsAg levels was 
pegIFN plus ADV. Could this fact be linked to low er baseline HBsAg levels? To the greater 
proportion of genotype B patients on this group?  
 
 
If none patient achieve HBsAg loss during or after therapy, this should be pointed out.  
 
 
 
Discussion  
 
In the present study, 138 study patients were treated Peg -IFNα -2a for 12 weeks, and only 95 
patients who had a poor virological response at the end of this period received combination 
therapy of Peg -IFNα -2a with either ETV or ADV for 48 weeks. The number patients initially 
treated with pegIFN was 178 and those with poor r esponse and therefore randomized to the three 
brands of study 138??  
 
 
Achievement of HBeAg seroconversion did not differ from TDF or ETV monotherapy rates. 
According to the authors, what are the benefits of pegIFN combination in comparison with NA 
monothera py? 
Tables  
 
Table 1. "Type" should be removed from genotype. There is no need for explaining the statistical 
analysis since it has been previously exposed in the text.  
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify wh at 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 no t, 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 intere sts 
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 p ublication 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 compet ing 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 a n 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: Addition of nucleoside analogues to Peg -IFNα-2a enhan ces virological response in 
chronic  hepatitis B patients without early response to Peg -IFNα-2a: A randomized controlled 
trial 
 
Version: 0 Date: 05 Feb 2017  
 
Reviewer: Mar Riveiro -Barciela  
 
Reviewer's report:  
 
This clinical trial focus on a new treatment strategy with pegIFN plus NAs in patients with CHB 
who presented a poor virological response to 12 -weeks therapy with pegIFN. The therapeutic 
protocol is correct, though sometimes it is doubtful that it is actua lly a prospective controlled 
trial since in some parts of the text the number and percentage of patients with poor response 
change. Another limitation of the protocol is the use of ADV in a brand of treatment, since in 
Europe it is no longer a first -line N As. Other important limitations of the study are the 
definitions of efficacy. According to the current EASL guidelines, early virological response 
during pegIFN therapy, in both HBeAg positive and negative patients, is defined as HBV DNA 
<20.000 IU/mL. Mor eover, off -treatment virological response is defined as HBV DNA < 2000 
IU/mL plus normal ALT levels. Therefore, results should be reviewed in order to be in 
agreement with the EASL´s endpoint definitions.  
 
 
Another issue that needs further revision is the ch aracteristics of patients. According to the 
inclusion criteria, patients with cirrhosis can be recruited. However, there is no data regarding 
the number of patients with liver cirrhosis neither in the text nor in table 1.  
 
 
Overall there are numerous typos a nd grammatical errors throughout the manuscript. A fraction 
of which is listed under "minor points" below. It definitely needs to be carefully edited.  
 
 
 
Minor comments  
 
Abstract  
 
Characteristics of patients, especially HBeAg positivity should be added.  
 
 
Definitions used to guide response to PegIFN (poor virological response) and SVR may be added 
to the abstract in order to improve its understanding.  
 
 
Background.  
 
By the time being, clearance of cccDNA is not a goal of CHB treatment so this sentence may be 
removed.  
 
 
 
Material and methods  
 
Line 4, page 7: there is an extra sentence.  
 
 
Paired liver biopsies were performed in 38 patients, which brand of therapy were these patients?  
 
 
 
Results  
 
Mean HBV DNA differences between PegIFN vs PegIFN plus a NAs may be specified over time 
and add to figure 1.  
 
 
Results should be reanalysis in order to be in line with the EASL guidelines.  
 
 
It is a bit surprising that the combination that achieved the greatest change on HBsAg levels was 
pegIFN plus ADV. Could this fact be linked to low er baseline HBsAg levels? To the greater 
proportion of genotype B patients on this group?  
 
 
If none patient achieve HBsAg loss during or after therapy, this should be pointed out.  
 
 
 
Discussion  
 
In the present study, 138 study patients were treated Peg -IFNα -2a for 12 weeks, and only 95 
patients who had a poor virological response at the end of this period received combination 
therapy of Peg -IFNα -2a with either ETV or ADV for 48 weeks. The number patients initially 
treated with pegIFN was 178 and those with poor r esponse and therefore randomized to the three 
brands of study 138??  
 
 
Achievement of HBeAg seroconversion did not differ from TDF or ETV monotherapy rates. 
According to the authors, what are the benefits of pegIFN combination in comparison with NA 
monothera py? 
Tables  
 
Table 1. "Type" should be removed from genotype. There is no need for explaining the statistical 
analysis since it has been previously exposed in the text.  
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify wh at 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 no t, 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 intere sts 
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 p ublication 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 compet ing 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 a n 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