Reviewer ’s report  
 
Title:  Upcoming pharmacological developments in chronic hepatitis B. Can we glimpse a cure 
on the horizon?  
 
Version: 0 Date: 19 Jul 2017 
 
Reviewer:  Emanuel  Manesis  
 
Reviewer’s report:  
 
The article by Alonso S et al (BMGE -D-17-00246) is an up to date review of the large spectrum 
of anti HBV agents that in the near future are expected to replace classical treatments of chronic 
hepatitis B including the interferon and the nucleos(t)ide anal ogs used so far. The spectrum of 
the newer agents is impressively large and it encompasses investigational agents for all possibly 
susceptible sites of the HBV life circle. The review is rather short but, well -written and, as far as 
I can say, complete. It  keeps the interest of the reader up to the end. My comments to the authors 
follow.  
 
A. General comments:  
 
1. The authors should review the appropriate literature of 2017, including abstracts 
presented at the last ILC Meeting. They are also asked to consider data of the following 
abstracts:  
 
a. Lee GH, Aung MM, Yang C, Hedrick JL, Lim SG, Yang YY, et al. 
Polyeth ylenimines (PEI) polymer functionalized with L -mannose moieties 
inhibits hepatitis B virus (HBV) entry into HepG2 -hNTCP cells with negligible 
cellular toxicity. Hepatology 2017;64:938A  
 
b. Esau C, Limphong P, Tachikawa K, McSwiggen J, Taylor W, Figa PK, et 
al LUNAR™ -HBV, a UNA oligomer combination for the treatment of chronic 
hepatitis B virus infection. Hepatology 2016;64:912A.  
 
c. Huang Q, Zong Y, Mercier A, Kumar R, Mahon C, Zhou Y, et al. 
Blockage of HBV virus replication and inhibition of cccDNA establis hment by 
core protein allosteric modifiers (CpAMs). Hepatology 2017;64:937A.  
 
2. Please correct a few typing errors, including references: 22, 47, 49, 57, 58 and 68.  
 
B. Major Comments:  
 
1. (Page 3, line 8 -9): "Current pharmacological treatment with nucleos(t )ide 
analogues (NA) may suppress...".  
 
2. (Page 4, line 16 -18): "...with 75% of infected population living in China and..."  
 
3. (Page 7, line 24): Please make a comment on the effect of adding -on peg 
interferon in HBeAg -positive and -negative patients, who h ave been on NA treatment for 
several years. A comment, also, should be made on the treatment modality based on 
stopping NAs in HBeAg -negative patients with or without cirrhosis, being on NAs for 
several years.  
 
4. (Page 13, line 26): How long the NAP treatm ent lasted?  
 
5. (Page 13, line 42 -44): Please give a reference.  
 
6. (Page 32, Table 1): Tenofovir alafenamide was approved by FDA on November 
10th, 2016 and by EMA on January 11th, 2017.  
 
C. Minor Comments:  
 
1. (Page 4): Authors should decide if they want to u se NUCs or NAs. Not both. My 
suggestion is to use the NA abbreviation.  
 
2. (Page 5, line 11 -13): "SMAD -mimetic drugs", "TLR -agonists": When writing an 
abbreviation for a first time, please, write explicitly the whole meaning. Add SMAD in the 
Abbreviation Li st. 
 
3. (Page 7, line 38): "virological suppression".  
 
4. (Page 8, line 27): Please, use the abbreviation NTCP.  
 
5. (Page 13, line 55): "...and DNA levels in chimpanzee. Of note, ALT flares..."  
 
6. (Page 14, line 27): Please write PEGIFN in full, or consider adding PEGIFN in 
the Abbreviations List and replacing throughout the text "peginterferon" with this 
abbreviation.  
 
7. (Page 18, line 23 -25): "NUC", "NA": Please, use either abbreviation in the text. 
Not both.  
 
Please include all comments for the authors in t his box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
 
Please overwrite this t ext when adding your comments to the authors.  
 
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 necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
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, p lease specify what aspects require further 
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
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, e ither 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 relatin g 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 unde r 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:  Upcoming pharmacological developments in chronic hepatitis B. Can we glimpse a cure 
on the horizon?  
 
Version: 0 Date: 19 Jul 2017 
 
Reviewer:  Emanuel  Manesis  
 
Reviewer’s report:  
 
The article by Alonso S et al (BMGE -D-17-00246) is an up to date review of the large spectrum 
of anti HBV agents that in the near future are expected to replace classical treatments of chronic 
hepatitis B including the interferon and the nucleos(t)ide anal ogs used so far. The spectrum of 
the newer agents is impressively large and it encompasses investigational agents for all possibly 
susceptible sites of the HBV life circle. The review is rather short but, well -written and, as far as 
I can say, complete. It  keeps the interest of the reader up to the end. My comments to the authors 
follow.  
 
A. General comments:  
 
1. The authors should review the appropriate literature of 2017, including abstracts 
presented at the last ILC Meeting. They are also asked to consider data of the following 
abstracts:  
 
a. Lee GH, Aung MM, Yang C, Hedrick JL, Lim SG, Yang YY, et al. 
Polyeth ylenimines (PEI) polymer functionalized with L -mannose moieties 
inhibits hepatitis B virus (HBV) entry into HepG2 -hNTCP cells with negligible 
cellular toxicity. Hepatology 2017;64:938A  
 
b. Esau C, Limphong P, Tachikawa K, McSwiggen J, Taylor W, Figa PK, et 
al LUNAR™ -HBV, a UNA oligomer combination for the treatment of chronic 
hepatitis B virus infection. Hepatology 2016;64:912A.  
 
c. Huang Q, Zong Y, Mercier A, Kumar R, Mahon C, Zhou Y, et al. 
Blockage of HBV virus replication and inhibition of cccDNA establis hment by 
core protein allosteric modifiers (CpAMs). Hepatology 2017;64:937A.  
 
2. Please correct a few typing errors, including references: 22, 47, 49, 57, 58 and 68.  
 
B. Major Comments:  
 
1. (Page 3, line 8 -9): "Current pharmacological treatment with nucleos(t )ide 
analogues (NA) may suppress...".  
 
2. (Page 4, line 16 -18): "...with 75% of infected population living in China and..."  
 
3. (Page 7, line 24): Please make a comment on the effect of adding -on peg 
interferon in HBeAg -positive and -negative patients, who h ave been on NA treatment for 
several years. A comment, also, should be made on the treatment modality based on 
stopping NAs in HBeAg -negative patients with or without cirrhosis, being on NAs for 
several years.  
 
4. (Page 13, line 26): How long the NAP treatm ent lasted?  
 
5. (Page 13, line 42 -44): Please give a reference.  
 
6. (Page 32, Table 1): Tenofovir alafenamide was approved by FDA on November 
10th, 2016 and by EMA on January 11th, 2017.  
 
C. Minor Comments:  
 
1. (Page 4): Authors should decide if they want to u se NUCs or NAs. Not both. My 
suggestion is to use the NA abbreviation.  
 
2. (Page 5, line 11 -13): "SMAD -mimetic drugs", "TLR -agonists": When writing an 
abbreviation for a first time, please, write explicitly the whole meaning. Add SMAD in the 
Abbreviation Li st. 
 
3. (Page 7, line 38): "virological suppression".  
 
4. (Page 8, line 27): Please, use the abbreviation NTCP.  
 
5. (Page 13, line 55): "...and DNA levels in chimpanzee. Of note, ALT flares..."  
 
6. (Page 14, line 27): Please write PEGIFN in full, or consider adding PEGIFN in 
the Abbreviations List and replacing throughout the text "peginterferon" with this 
abbreviation.  
 
7. (Page 18, line 23 -25): "NUC", "NA": Please, use either abbreviation in the text. 
Not both.  
 
Please include all comments for the authors in t his box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
 
Please overwrite this t ext when adding your comments to the authors.  
 
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 necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
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, p lease specify what aspects require further 
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
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, e ither 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 relatin g 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 unde r 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:  Upcoming pharmacological developments in chronic hepatitis B. Can we glimpse a cure 
on the horizon?  
 
Version: 0 Date: 19 Jul 2017 
 
Reviewer:  Emanuel  Manesis  
 
Reviewer’s report:  
 
The article by Alonso S et al (BMGE -D-17-00246) is an up to date review of the large spectrum 
of anti HBV agents that in the near future are expected to replace classical treatments of chronic 
hepatitis B including the interferon and the nucleos(t)ide anal ogs used so far. The spectrum of 
the newer agents is impressively large and it encompasses investigational agents for all possibly 
susceptible sites of the HBV life circle. The review is rather short but, well -written and, as far as 
I can say, complete. It  keeps the interest of the reader up to the end. My comments to the authors 
follow.  
 
A. General comments:  
 
1. The authors should review the appropriate literature of 2017, including abstracts 
presented at the last ILC Meeting. They are also asked to consider data of the following 
abstracts:  
 
a. Lee GH, Aung MM, Yang C, Hedrick JL, Lim SG, Yang YY, et al. 
Polyeth ylenimines (PEI) polymer functionalized with L -mannose moieties 
inhibits hepatitis B virus (HBV) entry into HepG2 -hNTCP cells with negligible 
cellular toxicity. Hepatology 2017;64:938A  
 
b. Esau C, Limphong P, Tachikawa K, McSwiggen J, Taylor W, Figa PK, et 
al LUNAR™ -HBV, a UNA oligomer combination for the treatment of chronic 
hepatitis B virus infection. Hepatology 2016;64:912A.  
 
c. Huang Q, Zong Y, Mercier A, Kumar R, Mahon C, Zhou Y, et al. 
Blockage of HBV virus replication and inhibition of cccDNA establis hment by 
core protein allosteric modifiers (CpAMs). Hepatology 2017;64:937A.  
 
2. Please correct a few typing errors, including references: 22, 47, 49, 57, 58 and 68.  
 
B. Major Comments:  
 
1. (Page 3, line 8 -9): "Current pharmacological treatment with nucleos(t )ide 
analogues (NA) may suppress...".  
 
2. (Page 4, line 16 -18): "...with 75% of infected population living in China and..."  
 
3. (Page 7, line 24): Please make a comment on the effect of adding -on peg 
interferon in HBeAg -positive and -negative patients, who h ave been on NA treatment for 
several years. A comment, also, should be made on the treatment modality based on 
stopping NAs in HBeAg -negative patients with or without cirrhosis, being on NAs for 
several years.  
 
4. (Page 13, line 26): How long the NAP treatm ent lasted?  
 
5. (Page 13, line 42 -44): Please give a reference.  
 
6. (Page 32, Table 1): Tenofovir alafenamide was approved by FDA on November 
10th, 2016 and by EMA on January 11th, 2017.  
 
C. Minor Comments:  
 
1. (Page 4): Authors should decide if they want to u se NUCs or NAs. Not both. My 
suggestion is to use the NA abbreviation.  
 
2. (Page 5, line 11 -13): "SMAD -mimetic drugs", "TLR -agonists": When writing an 
abbreviation for a first time, please, write explicitly the whole meaning. Add SMAD in the 
Abbreviation Li st. 
 
3. (Page 7, line 38): "virological suppression".  
 
4. (Page 8, line 27): Please, use the abbreviation NTCP.  
 
5. (Page 13, line 55): "...and DNA levels in chimpanzee. Of note, ALT flares..."  
 
6. (Page 14, line 27): Please write PEGIFN in full, or consider adding PEGIFN in 
the Abbreviations List and replacing throughout the text "peginterferon" with this 
abbreviation.  
 
7. (Page 18, line 23 -25): "NUC", "NA": Please, use either abbreviation in the text. 
Not both.  
 
Please include all comments for the authors in t his box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
 
Please overwrite this t ext when adding your comments to the authors.  
 
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 necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
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, p lease specify what aspects require further 
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
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, e ither 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 relatin g 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 unde r 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