Reviewer ’s report  
 
Title:  Upcoming pharmacological developments in chronic hepatitis B. Can we glimpse a cure 
on the horizon?  
 
Version: 0 Date: 18 Jul 2017 
 
Reviewer:  Ju- Tao Guo 
 
Reviewer’s report:  
 
This is a timely and concise review on the current development of therapeutics for treatment of 
chronic hepatitis B, particularly emphasizing on preclinical and clinical evaluation of antiviral 
efficacy. The article presents a clear landscape of current status of anti -HBV therapy and 
emerging therapeutics in the horiz on. It will be of great interesting for both clinicians and basic 
scientists. I have only some minor points to improve the manuscript.  
 
1. Page 2, Line 6, in the sentence "HBV covalently closed circular DNA (cccDNA) plays a 
critical role in HBV persistence and replication." , should be "… plays an essential role 
...". 
 
2. Pgae 3, Line 52, "…ccc -DNA that is used to produce viral proteins;" should be "… 
cccDNA that is used to transcribe viral RNAs;"  
 
3. In many occasions, cccDNA has been written as ccc -DNA.  
 
4. Page 3, Line 60, "reactivation" is not a proper word in this context, it should be 
"rebounding of viral replication".  
 
5. HBV life cycle is very nicely described, but not complete. It will be better to include a 
concise description on the pgRNA encapsidation  and reverser transcription, which are the 
main targets of drugs under development or in clinical use.  
 
6. For capsid assembly modulators, this paper should be cited.  
 
Zongxing Qiu, et al. Discovery and Pre -Clinical Characterization of Third -Generation 4 -H 
Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors. J. 
Med. Chem., 2017, 60 (8), pp 3352 -3371  
 
7. I am not sure "Its intranuclear location makes ccc -DNA a difficult target for immune 
response".  
 
8. In consistency with the emphasis of the article, I suggest that Table 1 should only list the 
compounds in clinical trials. For preclinical compounds, only that with animal efficacy 
should b e considered.  
 
9. Active research is under way for discovery and development of RNase H inhibitors and 
STING agonists for treatment of chronic hepatitis B. Those studies should also be 
discussed.  
 
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: 18 Jul 2017 
 
Reviewer:  Ju- Tao Guo 
 
Reviewer’s report:  
 
This is a timely and concise review on the current development of therapeutics for treatment of 
chronic hepatitis B, particularly emphasizing on preclinical and clinical evaluation of antiviral 
efficacy. The article presents a clear landscape of current status of anti -HBV therapy and 
emerging therapeutics in the horiz on. It will be of great interesting for both clinicians and basic 
scientists. I have only some minor points to improve the manuscript.  
 
1. Page 2, Line 6, in the sentence "HBV covalently closed circular DNA (cccDNA) plays a 
critical role in HBV persistence and replication." , should be "… plays an essential role 
...". 
 
2. Pgae 3, Line 52, "…ccc -DNA that is used to produce viral proteins;" should be "… 
cccDNA that is used to transcribe viral RNAs;"  
 
3. In many occasions, cccDNA has been written as ccc -DNA.  
 
4. Page 3, Line 60, "reactivation" is not a proper word in this context, it should be 
"rebounding of viral replication".  
 
5. HBV life cycle is very nicely described, but not complete. It will be better to include a 
concise description on the pgRNA encapsidation  and reverser transcription, which are the 
main targets of drugs under development or in clinical use.  
 
6. For capsid assembly modulators, this paper should be cited.  
 
Zongxing Qiu, et al. Discovery and Pre -Clinical Characterization of Third -Generation 4 -H 
Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors. J. 
Med. Chem., 2017, 60 (8), pp 3352 -3371  
 
7. I am not sure "Its intranuclear location makes ccc -DNA a difficult target for immune 
response".  
 
8. In consistency with the emphasis of the article, I suggest that Table 1 should only list the 
compounds in clinical trials. For preclinical compounds, only that with animal efficacy 
should b e considered.  
 
9. Active research is under way for discovery and development of RNase H inhibitors and 
STING agonists for treatment of chronic hepatitis B. Those studies should also be 
discussed.  
 
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: 18 Jul 2017 
 
Reviewer:  Ju- Tao Guo 
 
Reviewer’s report:  
 
This is a timely and concise review on the current development of therapeutics for treatment of 
chronic hepatitis B, particularly emphasizing on preclinical and clinical evaluation of antiviral 
efficacy. The article presents a clear landscape of current status of anti -HBV therapy and 
emerging therapeutics in the horiz on. It will be of great interesting for both clinicians and basic 
scientists. I have only some minor points to improve the manuscript.  
 
1. Page 2, Line 6, in the sentence "HBV covalently closed circular DNA (cccDNA) plays a 
critical role in HBV persistence and replication." , should be "… plays an essential role 
...". 
 
2. Pgae 3, Line 52, "…ccc -DNA that is used to produce viral proteins;" should be "… 
cccDNA that is used to transcribe viral RNAs;"  
 
3. In many occasions, cccDNA has been written as ccc -DNA.  
 
4. Page 3, Line 60, "reactivation" is not a proper word in this context, it should be 
"rebounding of viral replication".  
 
5. HBV life cycle is very nicely described, but not complete. It will be better to include a 
concise description on the pgRNA encapsidation  and reverser transcription, which are the 
main targets of drugs under development or in clinical use.  
 
6. For capsid assembly modulators, this paper should be cited.  
 
Zongxing Qiu, et al. Discovery and Pre -Clinical Characterization of Third -Generation 4 -H 
Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors. J. 
Med. Chem., 2017, 60 (8), pp 3352 -3371  
 
7. I am not sure "Its intranuclear location makes ccc -DNA a difficult target for immune 
response".  
 
8. In consistency with the emphasis of the article, I suggest that Table 1 should only list the 
compounds in clinical trials. For preclinical compounds, only that with animal efficacy 
should b e considered.  
 
9. Active research is under way for discovery and development of RNase H inhibitors and 
STING agonists for treatment of chronic hepatitis B. Those studies should also be 
discussed.  
 
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