Reviewer ’s report  
 
Title: A case report of psychiatric symptoms following direct -acting antiviral and ribavirin 
combination therapy for chronic hepatitis C in a patient with innate anxiety  
 
Version: 1 Date: 22 Feb 2019  
 
Reviewer: Yvonne Gilleece  
 
Reviewer's report:  
 
Whilst new information on patient related outcomes when treating Hepatitis C with DAAs are 
welcome I do not feel the standard of this submission is adequate and it does not provide new 
insights to the  field.  
 
My comments are as follows:  
Page 4, line 49: The discontinuation of the therapies made improve the symptoms  and she 
continued to liver supporting therapies for HCV hepatitis.  
This sentence is unclear and does not use standard medical treatment l anguage.  
 
Page 6, line 4: Continuous hepatitis C virus (HCV) infection is not a term used in the context of 
hepatitis C.   
It should read Chronic hepatitis C virus infection.  
 
Page 6, lines 7 -11: In addition, 10% -15% of these cases progress to liver ci rrhosis and 
hepatocellular carcinoma, leading to a fatal outcome [2].  
One reference for this is insufficient.  
 
Page 6, line 20: Single -dose IFN therapy resulted in sustained virological response (SVR) in only 
5% in resistant cases such as genotype 1 with  high viral ribonucleic acid levels;  
This is poorly written and could be interpreted as a stat dose of interfero n rather than what I am 
presuming is IFN monotherapy daily for a specified duration of treatment.  
 
Page 6, line 37: Conversely, in some cases, IFN induces various adverse events including 
anemia; neutropenia; thrombocytopenia; and  influenza -like, gastroin testinal, and psychiatric 
symptoms that may require discontinuation of..  
This is not correct. Ribavirin usually causes the cytopenias stated.  
 
Page 7, line 55: However, the promise of the DAA for IFN -intolerant patients has been recently 
cracked with the  reports of an existing low incidence of psychiatric adverse effects.  
Poor use of English resulting in confusing sentence.  
 
Page 10, line 11: Therefore, several HCV cases with psychiatric symptoms have not been cleared 
because of the tolerance of IFN.  
The meaning of this sentence is unclear.  
 
Page 10, line 29: ribavirin combination therapy for genotype 2 HCV patients also  reported a 
highly SVR rate and fewer adverse events [18].  
What is ribavirin combination therapy? This is unclear.  
 
Page 10, line 36: "was evidenced" should read "was reported".  
Page 10, line 36: The authors suggested that anxiety for the antiviral treatment might be 
worsened the depressive scores regardless of the regimen, which is consistent with the clinical 
cours e observed in our case.  
Suggest "might be worsened" should read "might worsen".  
 
Page 15, line 42:   typo "choronic"  
The literature search has missed multiple papers relevant to the topic reporting many patients 
with similar issues. This does not giv e confidence in the discussion section.  
Some examples are included here.  
Volpato S, et al. Neuropsychiatric performance and treatment of hepatitis C with direct -acting 
antivirals: a prospective study. 2017 BMC Gastroenterol.  
Sockalingam S, et al. Psychia tric treatment considerations with direct acting antivirals in 
hepatitis C  BMC Gastroenterol. 2013; 13: 86.  
McNutt, M, et al. Neurobehavioral Effects of Interferon -α in Patients with Hepatitis -C: Symptom 
Dimensions and Responsiveness to Paroxetine. Neurop sychopharmacology. 2012 May; 37(6): 
1444 -1454.  
All symptoms are attributed to DAAs and nothing to Ribavirin which is often co -administered 
with DAAs including in the other papers not referenced by the authors. I think this is an 
oversight by the author s and again reduces confidence in the discussion.  
Are the methods appropriate and well described?  
If not, pl ease 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.  
 
No 
 
Are the conclusions drawn adequately supported by the da ta 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.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript : 
 
Not suitable for publication unless extensively edited  
 
  
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, writ e 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare tha t 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 Acc ess 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: A case report of psychiatric symptoms following direct -acting antiviral and ribavirin 
combination therapy for chronic hepatitis C in a patient with innate anxiety  
 
Version: 1 Date: 22 Feb 2019  
 
Reviewer: Yvonne Gilleece  
 
Reviewer's report:  
 
Whilst new information on patient related outcomes when treating Hepatitis C with DAAs are 
welcome I do not feel the standard of this submission is adequate and it does not provide new 
insights to the  field.  
 
My comments are as follows:  
Page 4, line 49: The discontinuation of the therapies made improve the symptoms  and she 
continued to liver supporting therapies for HCV hepatitis.  
This sentence is unclear and does not use standard medical treatment l anguage.  
 
Page 6, line 4: Continuous hepatitis C virus (HCV) infection is not a term used in the context of 
hepatitis C.   
It should read Chronic hepatitis C virus infection.  
 
Page 6, lines 7 -11: In addition, 10% -15% of these cases progress to liver ci rrhosis and 
hepatocellular carcinoma, leading to a fatal outcome [2].  
One reference for this is insufficient.  
 
Page 6, line 20: Single -dose IFN therapy resulted in sustained virological response (SVR) in only 
5% in resistant cases such as genotype 1 with  high viral ribonucleic acid levels;  
This is poorly written and could be interpreted as a stat dose of interfero n rather than what I am 
presuming is IFN monotherapy daily for a specified duration of treatment.  
 
Page 6, line 37: Conversely, in some cases, IFN induces various adverse events including 
anemia; neutropenia; thrombocytopenia; and  influenza -like, gastroin testinal, and psychiatric 
symptoms that may require discontinuation of..  
This is not correct. Ribavirin usually causes the cytopenias stated.  
 
Page 7, line 55: However, the promise of the DAA for IFN -intolerant patients has been recently 
cracked with the  reports of an existing low incidence of psychiatric adverse effects.  
Poor use of English resulting in confusing sentence.  
 
Page 10, line 11: Therefore, several HCV cases with psychiatric symptoms have not been cleared 
because of the tolerance of IFN.  
The meaning of this sentence is unclear.  
 
Page 10, line 29: ribavirin combination therapy for genotype 2 HCV patients also  reported a 
highly SVR rate and fewer adverse events [18].  
What is ribavirin combination therapy? This is unclear.  
 
Page 10, line 36: "was evidenced" should read "was reported".  
Page 10, line 36: The authors suggested that anxiety for the antiviral treatment might be 
worsened the depressive scores regardless of the regimen, which is consistent with the clinical 
cours e observed in our case.  
Suggest "might be worsened" should read "might worsen".  
 
Page 15, line 42:   typo "choronic"  
The literature search has missed multiple papers relevant to the topic reporting many patients 
with similar issues. This does not giv e confidence in the discussion section.  
Some examples are included here.  
Volpato S, et al. Neuropsychiatric performance and treatment of hepatitis C with direct -acting 
antivirals: a prospective study. 2017 BMC Gastroenterol.  
Sockalingam S, et al. Psychia tric treatment considerations with direct acting antivirals in 
hepatitis C  BMC Gastroenterol. 2013; 13: 86.  
McNutt, M, et al. Neurobehavioral Effects of Interferon -α in Patients with Hepatitis -C: Symptom 
Dimensions and Responsiveness to Paroxetine. Neurop sychopharmacology. 2012 May; 37(6): 
1444 -1454.  
All symptoms are attributed to DAAs and nothing to Ribavirin which is often co -administered 
with DAAs including in the other papers not referenced by the authors. I think this is an 
oversight by the author s and again reduces confidence in the discussion.  
Are the methods appropriate and well described?  
If not, pl ease 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.  
 
No 
 
Are the conclusions drawn adequately supported by the da ta 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.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript : 
 
Not suitable for publication unless extensively edited  
 
  
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, writ e 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare tha t 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 Acc ess 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: A case report of psychiatric symptoms following direct -acting antiviral and ribavirin 
combination therapy for chronic hepatitis C in a patient with innate anxiety  
 
Version: 1 Date: 22 Feb 2019  
 
Reviewer: Yvonne Gilleece  
 
Reviewer's report:  
 
Whilst new information on patient related outcomes when treating Hepatitis C with DAAs are 
welcome I do not feel the standard of this submission is adequate and it does not provide new 
insights to the  field.  
 
My comments are as follows:  
Page 4, line 49: The discontinuation of the therapies made improve the symptoms  and she 
continued to liver supporting therapies for HCV hepatitis.  
This sentence is unclear and does not use standard medical treatment l anguage.  
 
Page 6, line 4: Continuous hepatitis C virus (HCV) infection is not a term used in the context of 
hepatitis C.   
It should read Chronic hepatitis C virus infection.  
 
Page 6, lines 7 -11: In addition, 10% -15% of these cases progress to liver ci rrhosis and 
hepatocellular carcinoma, leading to a fatal outcome [2].  
One reference for this is insufficient.  
 
Page 6, line 20: Single -dose IFN therapy resulted in sustained virological response (SVR) in only 
5% in resistant cases such as genotype 1 with  high viral ribonucleic acid levels;  
This is poorly written and could be interpreted as a stat dose of interfero n rather than what I am 
presuming is IFN monotherapy daily for a specified duration of treatment.  
 
Page 6, line 37: Conversely, in some cases, IFN induces various adverse events including 
anemia; neutropenia; thrombocytopenia; and  influenza -like, gastroin testinal, and psychiatric 
symptoms that may require discontinuation of..  
This is not correct. Ribavirin usually causes the cytopenias stated.  
 
Page 7, line 55: However, the promise of the DAA for IFN -intolerant patients has been recently 
cracked with the  reports of an existing low incidence of psychiatric adverse effects.  
Poor use of English resulting in confusing sentence.  
 
Page 10, line 11: Therefore, several HCV cases with psychiatric symptoms have not been cleared 
because of the tolerance of IFN.  
The meaning of this sentence is unclear.  
 
Page 10, line 29: ribavirin combination therapy for genotype 2 HCV patients also  reported a 
highly SVR rate and fewer adverse events [18].  
What is ribavirin combination therapy? This is unclear.  
 
Page 10, line 36: "was evidenced" should read "was reported".  
Page 10, line 36: The authors suggested that anxiety for the antiviral treatment might be 
worsened the depressive scores regardless of the regimen, which is consistent with the clinical 
cours e observed in our case.  
Suggest "might be worsened" should read "might worsen".  
 
Page 15, line 42:   typo "choronic"  
The literature search has missed multiple papers relevant to the topic reporting many patients 
with similar issues. This does not giv e confidence in the discussion section.  
Some examples are included here.  
Volpato S, et al. Neuropsychiatric performance and treatment of hepatitis C with direct -acting 
antivirals: a prospective study. 2017 BMC Gastroenterol.  
Sockalingam S, et al. Psychia tric treatment considerations with direct acting antivirals in 
hepatitis C  BMC Gastroenterol. 2013; 13: 86.  
McNutt, M, et al. Neurobehavioral Effects of Interferon -α in Patients with Hepatitis -C: Symptom 
Dimensions and Responsiveness to Paroxetine. Neurop sychopharmacology. 2012 May; 37(6): 
1444 -1454.  
All symptoms are attributed to DAAs and nothing to Ribavirin which is often co -administered 
with DAAs including in the other papers not referenced by the authors. I think this is an 
oversight by the author s and again reduces confidence in the discussion.  
Are the methods appropriate and well described?  
If not, pl ease 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.  
 
No 
 
Are the conclusions drawn adequately supported by the da ta 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.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript : 
 
Not suitable for publication unless extensively edited  
 
  
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, writ e 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare tha t 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 Acc ess 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