Dear Mr Banstola,

Thank you very much for submitting your manuscript "Effectiveness of ongoing single dose Rifampicin post-exposure prophylaxis (SDR PEP) implementation under routine programme conditions – an observational study in Nepal Impact assessment of single dose Rifampicin post-exposure prophylaxis" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

Dear Dr. Banstola and colleagues,

The reviewers and I found your manuscript to be important and worthwhile contribution on an important topic. There are specific requests to clarify the presentation made by Reviewer 2, in particular. Please address the ethical issues found in the reviews. Please add a study-specific protocol (referred to in the Methods, in addition to Ref 8) as a supplementary file and add a viable hyperlink, if available, to the protocol. As well as possible, please address the concerns in the detailed critique by Reviewer 3.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

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[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

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Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Paul J. Converse

Academic Editor

PLOS Neglected Tropical Diseases

Elsio Wunder Jr

Section Editor

PLOS Neglected Tropical Diseases

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Dear Dr. Banstola and colleagues,

The reviewers and I found your manuscript to be important and worthwhile contribution on an important topic. There are specific requests to clarify the presentation made by Reviewer 2, in particular. Please address the ethical issues found in the reviews. Please add a study-specific protocol (referred to in the Methods, in addition to Ref 8) as a supplementary file and add a viable hyperlink, if available, to the protocol. As well as possible, please address the concerns in the detailed critique by Reviewer 3.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: This is a very well-conducted study of great interest. The report is well-written.

Reviewer #2: - The sample size is sufficient to ensure adequate power to address authors' hypothesis

- However, some additional analysis could have been made:

o Page 8, Figure 1: is the decrease in leprosy incidence significant? “the decline is most evident in the Morang district” sentence should be replaced by a sentence given the incidence rates and the comparison between those from the different districts.

o Table 2: p-value should ne mentioned in order to easily identify the differences between the districts.

o Table 4: some p-value are 0.00 or 0.000, please clarify

- Page 6:

o the dosage of RIF should be mentioned,

o the possibility that people from one district travel in another should be discussed as this might interfere with the way to contract leprosy

- Page 7: could the authors comment on the contact average par case that seems very high (i.e. 23) in comparison to literature and also specify the nature of their relationship, as it was shown previously that single-dose rifampin offered significant protection for only neighbors of neighbors plus social contacts (reference 7).

- Page 10: regarding the diagnosis methods: the authors should clearly specify that the diagnosis was only based on clinic and provide some evidence that the abilities of the leprosy confirmation teams working in each district to diagnose leprosy were similar.

Reviewer #3: (No Response)

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The results are clearly presented.

Reviewer #2: - Tables and figures:

o it should be clearly indicated which districts represent the comparator and the intervention groups in all tables and figures

o there are many small tables, it should be possible to merge some of them (e.g. Tables 2 and 3, Tables 4 and 5)

- Page 6: a map of Nepal highlighting the districts would be highly appreciated

- “discussion”:

o page 16: the first sentences of the discussion should be replaced by more quantitative statements, the same can be said for the sentence “The individual protective effect of SDR-PEP is clear” page 19.

o given the results section, is not straightforward to see where the “protective effect of 72%” come from

o page 18: the authors should also comment on the risk of drug resistance selection in leprosy by given a single drug

Reviewer #3: (No Response)

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The Conclusions are fullt supported by the data presented.

Reviewer #2: Please refer to the above sections

Reviewer #3: (No Response)

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: The Introduction is a very clear summary of current knowledge and practice in regard to post-exposure prophylaxis (PEP) for leprosy. I suggest adding a sentence about retrospective case-finding and PEP, which was done in Cambodia, with good results. This is probably a useful way to enhance the effect of PEP at the start of an intensive PEP programme. See: "Preventing leprosy with retrospective active case finding combined with single-dose rifampicin for contacts in a low endemic setting: results of the Leprosy Post-Exposure Prophylaxis program in Cambodia. Cavaliero, et al, Acta Tropica, 2021.

A second point relates to cases in children, which are regarded as a reasonable proxy for the level of transmission in a community. In Figure 1 of the current paper, the overall incidence rate of leprosy in each of the four districts is presented. If available, I would like to see the same Figure replicated to show the incidence in children under 15 years of age. Since there were only 123 incident cases in the study, the numbers may be too low to reach any conclusion, but it is an indicator that should be watched closely.

Reviewer #2: Page 4: the authors should provide a table summarizing the design, number of cases and main findings of the PEP trials already published together with their one study

Reviewer #3: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: High quality study and paper.

Reviewer #2: This study represents an enormous piece of work given the challenges of such clinical trials, especially among population whose socioeconomic status is predominantly low (poor and ultra-poor) and when the follow-up needs to be long as for leprosy. Therefore, I believe that after the modifications requested this paper deserves to be published, as it will add valuable data regarding PEP implementation in the leprosy field.

Reviewer #3: (No Response)

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Reviewer #1: Yes: Paul Saunderson

Reviewer #2: No

Reviewer #3: No

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Attachments

Attachment

Submitted filename: PLOSNTD PNTD-D-24-01153 review final.docx

Attachment

Submitted filename: PLOS NTD PNTD-D-24-01153 note to editor.docx

Dear Mr Banstola,

We are pleased to inform you that your manuscript 'Effectiveness of ongoing single dose Rifampicin post-exposure prophylaxis (SDR PEP) implementation under routine programme conditions – an observational study in Nepal Impact assessment of single dose Rifampicin post-exposure prophylaxis' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Paul J. Converse

Academic Editor

PLOS Neglected Tropical Diseases

Elsio Wunder Jr

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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Dear Dr. Nand Lai Banstola,

Thank you for your careful and painstaking responses to the reviewers comments. Congratulations on the acceptance of your paper for publication in PLoS Neglected Tropical Diseases.