Reviewer ’s report  
 
Title: Hepatocellular Carcinoma Occurs Frequently a nd Early After Treatment in HCV 
Genotype 3 Infected Persons Treated with DAA Regimens  
 
Version: 0 Date: 27 Jan 2020  
 
Reviewer: Masaru Enomoto  
 
Reviewer's report:  
 
Tayyab et al prospectively studied 662 HCV -infected persons initiated on a DAA regimen, either 
SOF/RBV+/ -PEG -IFN or SOF/DCV+/ -RBV, in Pakistan. At baseline, 49.4% were cirrhotic, 
91% were genotype 3, and 91.9% attained SVR. I ncident HCC was detected exclusively in 42 
cirrhotic patients (12.8%) within 12 months after treatment completion. The authors concluded 
that in a predominantly genotype 3 cohort, incident HCC occurred frequently after treatment 
completion. In multivariabl e analysis, SVR was associated with a reduced HCC risk (HR 0.35, 
95%CI 0.14 -0.85). In Kaplan -Meier plots, those treated with SOF/RBV/PEG -IFN had a longer 
HCC -free survival.  
 
Major comments  
1. The major limitation of this study is a short observation perio d. The high HCC incidence 
was observed only in cirrhotic patients within 12 months after treatment completion. Therefore, I 
think it reasonable that tiny HCC was already present before the start of therapy, and important 
how HCC was excluded at the start o f therapy. The authors mentioned that 'any new hepatic 
decompensation event, new liver nodule on ultrasound, or an AFP increase of &gt;10 IU/mL 
were followed up by a dynamic CT scan of the liver to rule out HCC' (page 5) after starting 
therapy. Did the aut hors rule out HCC by the same strict strategy at baseline?  
2. PEG -IFN containing regimen was associated with a reduced HCC risk. I speculate that 
patients treated with IFN had less advanced fibrosis. The authors should discuss this properly.  
 
Minor comments  
1. 'The predominant genotype in Pakistan is genotype 3 infection, accounting for 66 -72%' 
(page 4). Why was the proportion of genotype 3 infection much higher in this study?  
2. 'Treatment for HCV was initiated based on preferred regimens list ed in the national 
guidelines' (page 4). Can the authors refer the guidelines in Englich?  
3. 'Presence of liver cirrhosis was determined using … transient elastography' (page 5). The 
author should show the cutoff of elastography to diagnose cirrhosis.  
4. '1.4% were coinfected with hepatitis B virus' (page 6). The author should exclude the 
patients with coinfection with HBV or HIV.  
5. Table 3 shows that an increasing body weight is independently associated with a reduced 
HCC risk. The author should discuss i t. 
6. The author should pay more attention to the use of abbreviations. For example, 
daclatasvir is abbreviated as DCL somewhere and as DCV anywhere else. 'Sustained virologic 
response' or 'hepatocellular carcinoma' appear sometimes even after defining the  abbreviations.  
 
 
 
 
 
 
Are th e methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary co ntrols?  
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 asses s any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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:  
 
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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation t hat 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 recei ved 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 competing interests.  
 
I agree to the open peer  review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the author s' 
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 editor s, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Hepatocellular Carcinoma Occurs Frequently a nd Early After Treatment in HCV 
Genotype 3 Infected Persons Treated with DAA Regimens  
 
Version: 0 Date: 27 Jan 2020  
 
Reviewer: Masaru Enomoto  
 
Reviewer's report:  
 
Tayyab et al prospectively studied 662 HCV -infected persons initiated on a DAA regimen, either 
SOF/RBV+/ -PEG -IFN or SOF/DCV+/ -RBV, in Pakistan. At baseline, 49.4% were cirrhotic, 
91% were genotype 3, and 91.9% attained SVR. I ncident HCC was detected exclusively in 42 
cirrhotic patients (12.8%) within 12 months after treatment completion. The authors concluded 
that in a predominantly genotype 3 cohort, incident HCC occurred frequently after treatment 
completion. In multivariabl e analysis, SVR was associated with a reduced HCC risk (HR 0.35, 
95%CI 0.14 -0.85). In Kaplan -Meier plots, those treated with SOF/RBV/PEG -IFN had a longer 
HCC -free survival.  
 
Major comments  
1. The major limitation of this study is a short observation perio d. The high HCC incidence 
was observed only in cirrhotic patients within 12 months after treatment completion. Therefore, I 
think it reasonable that tiny HCC was already present before the start of therapy, and important 
how HCC was excluded at the start o f therapy. The authors mentioned that 'any new hepatic 
decompensation event, new liver nodule on ultrasound, or an AFP increase of &gt;10 IU/mL 
were followed up by a dynamic CT scan of the liver to rule out HCC' (page 5) after starting 
therapy. Did the aut hors rule out HCC by the same strict strategy at baseline?  
2. PEG -IFN containing regimen was associated with a reduced HCC risk. I speculate that 
patients treated with IFN had less advanced fibrosis. The authors should discuss this properly.  
 
Minor comments  
1. 'The predominant genotype in Pakistan is genotype 3 infection, accounting for 66 -72%' 
(page 4). Why was the proportion of genotype 3 infection much higher in this study?  
2. 'Treatment for HCV was initiated based on preferred regimens list ed in the national 
guidelines' (page 4). Can the authors refer the guidelines in Englich?  
3. 'Presence of liver cirrhosis was determined using … transient elastography' (page 5). The 
author should show the cutoff of elastography to diagnose cirrhosis.  
4. '1.4% were coinfected with hepatitis B virus' (page 6). The author should exclude the 
patients with coinfection with HBV or HIV.  
5. Table 3 shows that an increasing body weight is independently associated with a reduced 
HCC risk. The author should discuss i t. 
6. The author should pay more attention to the use of abbreviations. For example, 
daclatasvir is abbreviated as DCL somewhere and as DCV anywhere else. 'Sustained virologic 
response' or 'hepatocellular carcinoma' appear sometimes even after defining the  abbreviations.  
 
 
 
 
 
 
Are th e methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary co ntrols?  
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 asses s any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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:  
 
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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation t hat 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 recei ved 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 competing interests.  
 
I agree to the open peer  review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the author s' 
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 editor s, 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: Hepatocellular Carcinoma Occurs Frequently a nd Early After Treatment in HCV 
Genotype 3 Infected Persons Treated with DAA Regimens  
 
Version: 0 Date: 27 Jan 2020  
 
Reviewer: Masaru Enomoto  
 
Reviewer's report:  
 
Tayyab et al prospectively studied 662 HCV -infected persons initiated on a DAA regimen, either 
SOF/RBV+/ -PEG -IFN or SOF/DCV+/ -RBV, in Pakistan. At baseline, 49.4% were cirrhotic, 
91% were genotype 3, and 91.9% attained SVR. I ncident HCC was detected exclusively in 42 
cirrhotic patients (12.8%) within 12 months after treatment completion. The authors concluded 
that in a predominantly genotype 3 cohort, incident HCC occurred frequently after treatment 
completion. In multivariabl e analysis, SVR was associated with a reduced HCC risk (HR 0.35, 
95%CI 0.14 -0.85). In Kaplan -Meier plots, those treated with SOF/RBV/PEG -IFN had a longer 
HCC -free survival.  
 
Major comments  
1. The major limitation of this study is a short observation perio d. The high HCC incidence 
was observed only in cirrhotic patients within 12 months after treatment completion. Therefore, I 
think it reasonable that tiny HCC was already present before the start of therapy, and important 
how HCC was excluded at the start o f therapy. The authors mentioned that 'any new hepatic 
decompensation event, new liver nodule on ultrasound, or an AFP increase of &gt;10 IU/mL 
were followed up by a dynamic CT scan of the liver to rule out HCC' (page 5) after starting 
therapy. Did the aut hors rule out HCC by the same strict strategy at baseline?  
2. PEG -IFN containing regimen was associated with a reduced HCC risk. I speculate that 
patients treated with IFN had less advanced fibrosis. The authors should discuss this properly.  
 
Minor comments  
1. 'The predominant genotype in Pakistan is genotype 3 infection, accounting for 66 -72%' 
(page 4). Why was the proportion of genotype 3 infection much higher in this study?  
2. 'Treatment for HCV was initiated based on preferred regimens list ed in the national 
guidelines' (page 4). Can the authors refer the guidelines in Englich?  
3. 'Presence of liver cirrhosis was determined using … transient elastography' (page 5). The 
author should show the cutoff of elastography to diagnose cirrhosis.  
4. '1.4% were coinfected with hepatitis B virus' (page 6). The author should exclude the 
patients with coinfection with HBV or HIV.  
5. Table 3 shows that an increasing body weight is independently associated with a reduced 
HCC risk. The author should discuss i t. 
6. The author should pay more attention to the use of abbreviations. For example, 
daclatasvir is abbreviated as DCL somewhere and as DCV anywhere else. 'Sustained virologic 
response' or 'hepatocellular carcinoma' appear sometimes even after defining the  abbreviations.  
 
 
 
 
 
 
Are th e methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary co ntrols?  
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 asses s any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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:  
 
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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation t hat 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 recei ved 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 competing interests.  
 
I agree to the open peer  review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the author s' 
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 editor s, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant