Reviewer ’s report  
 
Title: Micro -costing analysis of guideline -based treatment by direct -acting agents: the real -life 
case of hepatitis C management in Brazil  
 
Version: 0 Date: 19 May 2017  
 
Reviewer: Jona Stahmeyer  
 
Reviewer's report:  
 
The article "Treatment by direct -acting agents might be cost -saving: the real -life case of hepatitis 
C management at a public national reference healthcare institute in Brazil" describes an 
interesting topic. Especially in middle and lower income countries treatment of hepatitis C is 
aggravated by high costs of antiviral treatment, especially interferon -free regimens. The authors 
present the case of Brazil in their study. Although this is a highly relevant topic there are some 
structural and context -related aspects which have to be taken into account.  
 
General considerations:  
 The authors focus on two aspects of HCV -treatment: (1.) use of transient elastography (TE) 
and (2.) newly introduced antiviral treatment and associated total treatment costs of Brazilian 
guideline -based treatment  
 These aspects should be clearly separated. Even if TE has facilitated determination of  liver 
cirrhosis, these techniques are of minor importance given recent developments in antiviral 
treatment. It should be highlighted that these non -invasive methods could provide an accurate 
determination of liver fibrosis/cirrhosis at lower risk for the patients compared to biopsy.  
 The article should mainly focus on the calculation of guideline -based treatment costs 
including the different regimens which are analyzed. In the introduction, it should be 
mentioned that high discounts are given by pharmaceu tical companies in Brazil.  
 
Introduction:  
 It is doubtful if TE techniques can reduce the burden. The disease burden could be primarily 
decreased by effective antiviral treatments, but TE facilitates determination of liver cirrhosis 
and could be used large -scale.  
 Aspects of TE and antiviral treatments should be clearly separated.  
 The authors state that few studies have estimated the costs of TE and alternative methods. 
One reason for this is that these costs are negligible compared to antiviral tr eatment. Further 
there are standardized fees in most healthcare systems. For example, costs in Great Britain 
are about 50 GBP and in Germany costs range between 50€ -100€.  
 The authors state that the aim of the analysis is to give information if TE and DAA treatment 
is cost -saving. The authors must state a comparator as savings can usually occur in 
comparison with an alternative treatment strategy. If TE is cheaper than bio psy, it might be 
cost-saving for determination of liver -cirrhosis (nevertheless sensitivity and specific could be 
taken into account). Further treatment with new DAAs could be cost -saving compared to 
non-treatment or alternative treatment options. Usually Markov -model are used to calculate 
cost-effectiveness.  
 
Methods:  
 Please explain the activity -based costing method in more detail. In this equivalent to the 
micro or macro -costing approach? (Drummond et al. 2005. Methods for The Economic 
Evaluation of Health Care Programmes)  
 
Results:  
 The authors should focus on guideline -based treatment costs  
 Were costs for liver biopsy also calculated with the ABC approach? It is stated that biopsy is 
cheaper than TE, which is surprising as invasive methods are u sually more expensive (e.g. 
US, GB and Germany). A direct cost comparison is only reasonable if the same costing 
method is applied.  
 Treatment costs for different regimens should not be stated in costs per pill, but in weekly 
costs and total costs per tre atment course as this is the most relevant aspect comparing 
different treatments  
 The paragraph on the literature review regarding real -world efficacy should be extended to 
highlight the development in SVR -rates  
 
Discussion:  
 The main reason for lower c osts in DAA treatment is the discounts given by pharmaceutical 
companies in Brazil. As effectiveness is higher in DAAs and further costs are lower (due to 
discounts) it is not surprising that new DAA treatments are "cost -saving" compared to prior 
standard treatment. In other countries and scenarios this might not be the case as costs for 
DAA regimens are higher than the standard of care. In these cases more comprehensive 
health economic techniques must be applied (e.g. long -term cost -effectiveness studies)  
 It should be clarified that adverse events usually occur in interferon -containing regimens.  
 Some other regimens which have been approved should be also mentioned (SOF/VEL, 
PTV/r/OMV+DSV, GRZ/ELB)  
 Further it should be clarified that new treatment eval uated are not generally cost -saving 
compared to older treatments and this is only the case for Brazil due to the high discounts.  
 As the conclusion could be drawn only for the Brazilian context, information on cost and 
cost-effectiveness studies for other  countries (e.g. USA, GB, …) should be referenced. Many 
studies show that new treatment is cost -effective, but not cost saving. That must be clarified.  
As a general recommendation, the article should stronger focus on the analysis and determination 
of the  guideline based costs. Given the high discounts on DAA treatments conclusions for the 
Brazilian context are obvious.  
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.  
 
Yes 
 
Are the conclusions drawn adequately supporte d 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, please spe cify 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 complet e 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, write 'I declare that I have no competing interests' 
below.  If your reply is y es to any, please give details below.  
 
Research funding by AbbVie, Gilead, Janssen -Cilag. Travel -Support by Roche.  
 
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 manu script 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 Access Creative Commons  
CC-BY license ( http://c reativecommons.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 j ournal  
Reviewer ’s report  
 
Title: Micro -costing analysis of guideline -based treatment by direct -acting agents: the real -life 
case of hepatitis C management in Brazil  
 
Version: 0 Date: 19 May 2017  
 
Reviewer: Jona Stahmeyer  
 
Reviewer's report:  
 
The article "Treatment by direct -acting agents might be cost -saving: the real -life case of hepatitis 
C management at a public national reference healthcare institute in Brazil" describes an 
interesting topic. Especially in middle and lower income countries treatment of hepatitis C is 
aggravated by high costs of antiviral treatment, especially interferon -free regimens. The authors 
present the case of Brazil in their study. Although this is a highly relevant topic there are some 
structural and context -related aspects which have to be taken into account.  
 
General considerations:  
 The authors focus on two aspects of HCV -treatment: (1.) use of transient elastography (TE) 
and (2.) newly introduced antiviral treatment and associated total treatment costs of Brazilian 
guideline -based treatment  
 These aspects should be clearly separated. Even if TE has facilitated determination of  liver 
cirrhosis, these techniques are of minor importance given recent developments in antiviral 
treatment. It should be highlighted that these non -invasive methods could provide an accurate 
determination of liver fibrosis/cirrhosis at lower risk for the patients compared to biopsy.  
 The article should mainly focus on the calculation of guideline -based treatment costs 
including the different regimens which are analyzed. In the introduction, it should be 
mentioned that high discounts are given by pharmaceu tical companies in Brazil.  
 
Introduction:  
 It is doubtful if TE techniques can reduce the burden. The disease burden could be primarily 
decreased by effective antiviral treatments, but TE facilitates determination of liver cirrhosis 
and could be used large -scale.  
 Aspects of TE and antiviral treatments should be clearly separated.  
 The authors state that few studies have estimated the costs of TE and alternative methods. 
One reason for this is that these costs are negligible compared to antiviral tr eatment. Further 
there are standardized fees in most healthcare systems. For example, costs in Great Britain 
are about 50 GBP and in Germany costs range between 50€ -100€.  
 The authors state that the aim of the analysis is to give information if TE and DAA treatment 
is cost -saving. The authors must state a comparator as savings can usually occur in 
comparison with an alternative treatment strategy. If TE is cheaper than bio psy, it might be 
cost-saving for determination of liver -cirrhosis (nevertheless sensitivity and specific could be 
taken into account). Further treatment with new DAAs could be cost -saving compared to 
non-treatment or alternative treatment options. Usually Markov -model are used to calculate 
cost-effectiveness.  
 
Methods:  
 Please explain the activity -based costing method in more detail. In this equivalent to the 
micro or macro -costing approach? (Drummond et al. 2005. Methods for The Economic 
Evaluation of Health Care Programmes)  
 
Results:  
 The authors should focus on guideline -based treatment costs  
 Were costs for liver biopsy also calculated with the ABC approach? It is stated that biopsy is 
cheaper than TE, which is surprising as invasive methods are u sually more expensive (e.g. 
US, GB and Germany). A direct cost comparison is only reasonable if the same costing 
method is applied.  
 Treatment costs for different regimens should not be stated in costs per pill, but in weekly 
costs and total costs per tre atment course as this is the most relevant aspect comparing 
different treatments  
 The paragraph on the literature review regarding real -world efficacy should be extended to 
highlight the development in SVR -rates  
 
Discussion:  
 The main reason for lower c osts in DAA treatment is the discounts given by pharmaceutical 
companies in Brazil. As effectiveness is higher in DAAs and further costs are lower (due to 
discounts) it is not surprising that new DAA treatments are "cost -saving" compared to prior 
standard treatment. In other countries and scenarios this might not be the case as costs for 
DAA regimens are higher than the standard of care. In these cases more comprehensive 
health economic techniques must be applied (e.g. long -term cost -effectiveness studies)  
 It should be clarified that adverse events usually occur in interferon -containing regimens.  
 Some other regimens which have been approved should be also mentioned (SOF/VEL, 
PTV/r/OMV+DSV, GRZ/ELB)  
 Further it should be clarified that new treatment eval uated are not generally cost -saving 
compared to older treatments and this is only the case for Brazil due to the high discounts.  
 As the conclusion could be drawn only for the Brazilian context, information on cost and 
cost-effectiveness studies for other  countries (e.g. USA, GB, …) should be referenced. Many 
studies show that new treatment is cost -effective, but not cost saving. That must be clarified.  
As a general recommendation, the article should stronger focus on the analysis and determination 
of the  guideline based costs. Given the high discounts on DAA treatments conclusions for the 
Brazilian context are obvious.  
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.  
 
Yes 
 
Are the conclusions drawn adequately supporte d 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, please spe cify 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 complet e 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, write 'I declare that I have no competing interests' 
below.  If your reply is y es to any, please give details below.  
 
Research funding by AbbVie, Gilead, Janssen -Cilag. Travel -Support by Roche.  
 
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 manu script 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 Access Creative Commons  
CC-BY license ( http://c reativecommons.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 j ournal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Micro -costing analysis of guideline -based treatment by direct -acting agents: the real -life 
case of hepatitis C management in Brazil  
 
Version: 0 Date: 19 May 2017  
 
Reviewer: Jona Stahmeyer  
 
Reviewer's report:  
 
The article "Treatment by direct -acting agents might be cost -saving: the real -life case of hepatitis 
C management at a public national reference healthcare institute in Brazil" describes an 
interesting topic. Especially in middle and lower income countries treatment of hepatitis C is 
aggravated by high costs of antiviral treatment, especially interferon -free regimens. The authors 
present the case of Brazil in their study. Although this is a highly relevant topic there are some 
structural and context -related aspects which have to be taken into account.  
 
General considerations:  
 The authors focus on two aspects of HCV -treatment: (1.) use of transient elastography (TE) 
and (2.) newly introduced antiviral treatment and associated total treatment costs of Brazilian 
guideline -based treatment  
 These aspects should be clearly separated. Even if TE has facilitated determination of  liver 
cirrhosis, these techniques are of minor importance given recent developments in antiviral 
treatment. It should be highlighted that these non -invasive methods could provide an accurate 
determination of liver fibrosis/cirrhosis at lower risk for the patients compared to biopsy.  
 The article should mainly focus on the calculation of guideline -based treatment costs 
including the different regimens which are analyzed. In the introduction, it should be 
mentioned that high discounts are given by pharmaceu tical companies in Brazil.  
 
Introduction:  
 It is doubtful if TE techniques can reduce the burden. The disease burden could be primarily 
decreased by effective antiviral treatments, but TE facilitates determination of liver cirrhosis 
and could be used large -scale.  
 Aspects of TE and antiviral treatments should be clearly separated.  
 The authors state that few studies have estimated the costs of TE and alternative methods. 
One reason for this is that these costs are negligible compared to antiviral tr eatment. Further 
there are standardized fees in most healthcare systems. For example, costs in Great Britain 
are about 50 GBP and in Germany costs range between 50€ -100€.  
 The authors state that the aim of the analysis is to give information if TE and DAA treatment 
is cost -saving. The authors must state a comparator as savings can usually occur in 
comparison with an alternative treatment strategy. If TE is cheaper than bio psy, it might be 
cost-saving for determination of liver -cirrhosis (nevertheless sensitivity and specific could be 
taken into account). Further treatment with new DAAs could be cost -saving compared to 
non-treatment or alternative treatment options. Usually Markov -model are used to calculate 
cost-effectiveness.  
 
Methods:  
 Please explain the activity -based costing method in more detail. In this equivalent to the 
micro or macro -costing approach? (Drummond et al. 2005. Methods for The Economic 
Evaluation of Health Care Programmes)  
 
Results:  
 The authors should focus on guideline -based treatment costs  
 Were costs for liver biopsy also calculated with the ABC approach? It is stated that biopsy is 
cheaper than TE, which is surprising as invasive methods are u sually more expensive (e.g. 
US, GB and Germany). A direct cost comparison is only reasonable if the same costing 
method is applied.  
 Treatment costs for different regimens should not be stated in costs per pill, but in weekly 
costs and total costs per tre atment course as this is the most relevant aspect comparing 
different treatments  
 The paragraph on the literature review regarding real -world efficacy should be extended to 
highlight the development in SVR -rates  
 
Discussion:  
 The main reason for lower c osts in DAA treatment is the discounts given by pharmaceutical 
companies in Brazil. As effectiveness is higher in DAAs and further costs are lower (due to 
discounts) it is not surprising that new DAA treatments are "cost -saving" compared to prior 
standard treatment. In other countries and scenarios this might not be the case as costs for 
DAA regimens are higher than the standard of care. In these cases more comprehensive 
health economic techniques must be applied (e.g. long -term cost -effectiveness studies)  
 It should be clarified that adverse events usually occur in interferon -containing regimens.  
 Some other regimens which have been approved should be also mentioned (SOF/VEL, 
PTV/r/OMV+DSV, GRZ/ELB)  
 Further it should be clarified that new treatment eval uated are not generally cost -saving 
compared to older treatments and this is only the case for Brazil due to the high discounts.  
 As the conclusion could be drawn only for the Brazilian context, information on cost and 
cost-effectiveness studies for other  countries (e.g. USA, GB, …) should be referenced. Many 
studies show that new treatment is cost -effective, but not cost saving. That must be clarified.  
As a general recommendation, the article should stronger focus on the analysis and determination 
of the  guideline based costs. Given the high discounts on DAA treatments conclusions for the 
Brazilian context are obvious.  
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.  
 
Yes 
 
Are the conclusions drawn adequately supporte d 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, please spe cify 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 complet e 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, write 'I declare that I have no competing interests' 
below.  If your reply is y es to any, please give details below.  
 
Research funding by AbbVie, Gilead, Janssen -Cilag. Travel -Support by Roche.  
 
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 manu script 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 Access Creative Commons  
CC-BY license ( http://c reativecommons.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 j ournal  
assistant