Dear Dr Devine,

Thank you for submitting your manuscript entitled "Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: a cost-effectiveness analysis using a transmission model" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by an academic editor with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Jun 05 2023 11:59PM.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Katrien Janin, PhD

Senior Editor

PLOS Medicine

Dear Dr. Devine,

Thank you very much for submitting your manuscript "Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: a cost-effectiveness analysis using a transmission model" (PMEDICINE-D-23-01515R1) for consideration at PLOS Medicine.

We do apologise for the delay in you receiving feedback on your manuscript. Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, we are not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. We cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Oct 20 2023 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Katrien Janin, PhD

PLOS Medicine

plosmedicine.org

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Comment from the Academic Editor:

The reviewers were generally positive about the paper and its suitability for PLOS Medicine. They provided a number of suggestions for the authors to address in their revision and I believe the clarifications, corrections, and further information would improve the paper or be valuable information for future readers of the paper.

Requests from the editors:

GENERAL:

Your manuscript has been assessed by four reviewers whose reports can be found below. As you will see from the comments, the reviewers have raised a number of concerns that need addressing. Please carefully revise the manuscript to address all comments raised.

For in-text reference, citations are placed within square parentheses and should precede punctuation as follows, e.g see line 29 “…. 17.6 million United States Dollars (US$) in 2017 [3].’ Please check and amend throughout.

Please provide 95% CIs and p values for all results were appropriate, check and amend throughout. For p values, please report these as p<0.001 and where higher as p=0.002 or p=0.050. Suggest reporting statistical information for clarity in the following format: ‘x’; (95% CI [‘y’,’ z’] p<0.001).

STUDY DESIGN:

i) For the ​​economic evaluation part of your manuscript, please report your economic analysis according to the appropriate study design provided at http://www.equator-network.org/?post_type=eq_guidelines&eq_guidelines_study_design=economic-evaluations&eq_guidelines_clinical_specialty=0&eq_guidelines_report_section=0&s= and provide the relevant completed checklist. In the checklist please include sufficient text excerpted from the manuscript to explain how you accomplished all applicable items.

ii) For the transmission model, we ask for inclusion of specific items, derived from Geoffrey P Garnett, Simon Cousens, Timothy B Hallett, Richard Steketee, Neff Walker. Mathematical models in the evaluation of health programmes. (2011) Lancet DOI:10.1016/S0140-6736(10)61505-X.

Please ensure all the items listed below are included with your manuscript. Please review the list below and confirm/revise as necessary:

(i) Please provide a diagram that shows the model structure, including how the disease natural history is represented, the process and determinants of disease acquisition, and how the putative intervention could affect the system.

(ii) Please provide a complete list of model parameters, including clear and precise descriptions of each parameter, together with the values or ranges for each, with justification or the primary source cited, and important caveats about the use of these values noted.

(iii) Please provide a clear statement about how the model was fitted to the data.

(iv) For uncertainty analyses, please state the sources of uncertainties quantified and not quantified.

(v) Please provide sensitivity analyses to identify which parameter values are most important in the model. Uncertainty estimates seek to derive a range of credible results on the basis of an exploration of the range of reasonable parameter values. The choice of method should be presented and justified.

(vi) Please discuss the scientific rationale for this choice of model structure and identify points where this choice could influence conclusions drawn. Please also describe the strength of the scientific basis underlying the key model assumptions.

ABSTRACT:

For the abstract, please structure the abstracts along the following 3 headings: Background, Methods and Findings, Conclusions. (Currently there are separate headings for Methods and Findings sections). Please remove all other subheaders.

Abstract Background: Provide the context of why the study is important. The final sentence should clearly state the study question.

Abstract Methods and Findings:

Please quantify the main results with 95% CIs and p values. In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

Abstract Conclusions:

Please interpret the study based on the results presented in the abstract, emphasizing what is new without overstating your conclusions.

AUTHORS SUMMARY:

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Ideally each sub-heading should contain 2-3 single sentence, concise bullet points containing the most salient points from your study.

In the final bullet point of ‘What Do These Findings Mean?’ Please include the main limitations of the study in non-technical language.

ACKNOWLEDGMENTS/ DECLARATIONS

Please remove all statements apart from acknowledgements, author contributions and abbreviations from the end of the main manuscript and include these only in the relevant parts of the manuscript submission form. Funding, competing interest, and data availability will be compiled as metadata. The ethics declaration should be included in your method section.

Comments from the reviewers:

Reviewer #1: This is a well-written cost-effectiveness study that makes a single point in an important country for relapsing malaria. Tafenoquine is a better choice (more cost effective) than reasonable assumptions for the current primaquine regimen. As the authors mention in the discussion, the analysis shifts when higher dose primaquine regimens are used, but so do the risks. This study should encourage the Brazilian government to continue its phased roll out of tafenoquine to eliminate vivax malaria in hopes that further practical information will be gained from actual field data for use in other countries / situations. PLOS states that it also gets statistical reviews for its papers, which is good as although the numbers seem reasonable to me, they need to be examined by an outside statistician.

Reviewer #2: This is an innovative and interesting article which uses mixed methods to provide robust input to a proven model. It provides guidance as to the use of new technology that seems appropriate for policy action. I think it would help the reading public to have a bit more explanation of two areas that are mentioned but to my mind could be more complete. First a more complete review of the semi-quantitative device utilized including country of origin and cost

as well as explicit use parameters i.e. training needed and if there are other requirements to make it operational. Introducing new technology is always a tricky process and the application of implementation science principles might be suggested.

A second observation that could greatly impact implementation is the mentioned compliance with treatment once cases have been identified. This may require more costly behavioral change programs which do not seem to be reflected in the model. Perhaps a suggestion as to how roll out might be effected given model results and use would be useful to policy makers.

In all a good and interesting article worthy of publication.

Reviewer #3: The authors have produced a clear and well written paper to assess the cost effectiveness of rolling out Tafenoquine following G6PD screening vs primaquine for the treatment of vivax malaria in Brazil.

There are three minor comments:

1. While the dynamic transmission model paper is published elsewhere, because the CEA is based on it, it is necessary for the reader to understand the assumptions made for future interventions in the baseline scenario. The transmission model baseline projections should be described in the methods section. This will provide the reader with context for understanding geographical differences in CEA results.

2. No information was given on treatment access and how it may differ geographically. If the scenarios assume passive treatment only, then differences in treatment access will impact the analysis.

3. A section should be added to the discussion on the key sources of variation in the dynamic transmission model and how it impacts the CEA sensitivity analysis and results. It was unclear whether the n random draws from the cost parameter distributions were applied to m transmission model baseline simulations to result in n x m iterations. Please elucidate.

Reviewer #4: See attachment

Michael Dewey

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachments

Attachment

Submitted filename: price.pdf

Dear Dr. Devine,

Thank you very much for re-submitting your manuscript "Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: a cost-effectiveness analysis using a transmission model" (PMEDICINE-D-23-01515R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by the reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns, or like an extension.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org. For editorial questions, please feel free to contact me directly on kjanin@plos.org 

We look forward to receiving the revised manuscript by Dec 05 2023 11:59PM.   

Sincerely,

Katrien Janin, PhD

Senior Editor 

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Comments from the Editors:

Thank you for fully addressing our previous comments

We just have a very minor remark, regarding references.

Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

For online references (e.g see reference 26 and 27), please use the following format: [accessed on 2 Apr 2021] instead of [cited 2020 10 Nov]. For reference 26, I noticed the presence of a double ‘;’

Please double check your references and amend as needed.

We having given 5 working days to return the manuscript to us, but in your case please feel free to submit much sooner if that suits you. We look forward to issuing the editorial acceptance for you.

------------------------------------------------------------

Comments from Reviewers:

Reviewer #2: Much improved version which seems to respond to all of the reviewer comments.. i did notice that there was no reference to IRB approval which given the nature of the research may be acceptable i.e. secondary data etc.

i believe that the researchers could constructively add a paragraph on how these results might be interpreted by ph practitioners and or what other complementary research would be needed and or beneficial to using the results.

Reviewer #4: The authors have addressed all my points.

Michael Dewey

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr Devine, 

On behalf of my colleagues, I am pleased to inform you that we have agreed to publish your manuscript "Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: a cost-effectiveness analysis using a transmission model" (PMEDICINE-D-23-01515R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper !

Sincerely, 

Katrien G. Janin, PhD 

Senior Editor 

PLOS Medicine