Please carefully address the reviewer's comments and suggestions.

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We look forward to receiving your revised manuscript.

Kind regards,

Patricia Evelyn Fast, MD, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

This paper applies a new analysis to the PENPACT-1 data, to investigate time to treatment interruption for Protease-Inhibitor-based vs NNRTI-based regimens over a 4 year period. The paper is well written and convincing. Two reviewers have provided valuable suggestions to improve the presentation of results.

In addition to addressing the reviewers' comments, please comment on whether important changes in the treatment regimens used, including the availability of palatable protease inhibitors have occurred during the years since the trial ended.

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When submitting your revision, we need you to address these additional requirements.

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2. Thank you for stating the following in the Competing Interests section:

"Although the authors have no financial competing interests for this manuscript, DEY has been an investigator on studies unrelated to HIV supported by Astellas, Chimerix, Merck, Pfizer, Viracor-Eurofins, Kansas City Area Life Sciences Institute, and the Marion Merrell Dow Fund; DEY was a founder and is an unpaid advisory board member for the non-profit Maipelo Children’s Trust/Cover the Globe, which provides HIV services in Botswana. The other authors report no conflicts of interests. "

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Absence of evidence is not evidence of absence so said the late great Doug Altman writing along with his longtime co-author Martin Bland back in 1985 in their great Statistics Notes series in the BMJ. The caution raised there, I think, applies somewhat to the well presented and succinct piece of work laid out in this mansuscript. The present study is based on an extended followup of a large trial that had an extensive geographical footprint looking at paediatric HIV within children aged 1 month through to just under 18 years. The parent trial was a 2x2 factorial study whose aim was to look at changes in viral load after 4 years. The present study looked to asesss whether tehre was a differenec in the timing of treatment disruption both at the end of the initial followup period which was 4 years and at the end of study at 6.5 years.

I have some issue with some of the wording and presentation of the data in lines 194 through 197. Specifically I would like to see 95% Confidence Intervals for all the estimates given ie the 66% and 83% on line 195, the 70% and 63% on line 197 and the estimates of 81% and 84% on line 212. I believe the term "treatment distruption probability" on lines 195 and 196 would be better put as eg "66% 95CI(LB,UB) had a treatment disruption" and on line 196 consider changing "At 4 years..." to something like "By four years 70% (95 CI(LB,UB) and 63%... had experienced at least one treatment disruption respectively".

Table 2 seems rather unnecessary given that all the information it contains already and fully exists within the text on lines 199-201 and 215-6.

I would suggest that a) given this is secondary analysis of pre-existing data and b) that this hints a little at a post-hoc power analysis, the last sentence of the results could be excised without any loss of import for this work.

Finally, I always find the use of a risk table (showing numbers at risk and events occuring within a time interval) under KM plots to be most helpful and would respectfully request that the authors consider adding these to their Figure 2.

Reviewer #2: The authors have not made the underlying data readily available; access is restricted to protect the privacy and confidentiality of the study participants. The authors have provided an institutional email address through which researchers can access the primary data. This is in line with the Plos data policy.

The authors need to clarify in the ethics statement why exemption from an IRB outside the USA was not sought for the secondary analysis.

Line 76, consider stating that '...children progress much faster to AIDS and death' rather than refer to HIV disease.

Line 78 implies that longer time on their initial regimen means greater efficacy. Please confirm whether there is any evidence that duration of treatment improves efficacy of ART; in the context you have used, it might be more appropriate to state that longer time on the initial regimen may result in greater effectiveness of ART.

Line 116; please confirm if block randomization was carried out with blocks based on the site of enrollment.

Line 124; it would be important to clarify what data was collected on the adherence questionnaires that were administered every 24 weeks and what data was collected during the other scheduled visits, or ad hoc as stated in line 122.

As it reads now, it implies that data on treatment disruptions for each drug were collected covering 3 days prior to every 24 week visit when the questionnaire was administered and barriers to adherence experienced in the 2 weeks prior to this visit. This is a very narrow window to collect this data over 4 years.

Line 146 implies that the adherence questionnaire was administered strictly every 24 weeks. As the visit schedule meant volunteers were seen at least once every 12 weeks, please clarify if it was permissible for an adherence questionnaire to e administered in the visit immediately following a 24 week visit when it was missed.

Lines 167 and 173; please confirm whether the classification of race was based on self-reporting at all sites.

Line 220; please confirm if the 25% of events reported, involved a substitution of either the PI or NNRTI or if these cases include instances of substitution of one or more of the NRTIs without interference with the administration of the PI or NNRTI in the regimen.

Line 221; please clarify if stoppage or suspension of the entire first line regimen resulted in starting the second line regimen in all cases. Please also specify how the group that had the first line regimen stopped differs from the group that had switches to a second-line regimen.

Table 3; Please clarify if caregiver requests were distinguished from adverse events. Please state in line 24 if the caregiver requests listed in the table were all those that were for reasons other than adverse events.

Line 332; please clarify in the methods section if the adherence questionnaire was standardized across study sites and age groups. The statement on line 332 implies that the questionnaires differed across sites and age groups.

Figure 1; what was the reason for volunteers who withdrew consent after initiation of ART?

There were more cases of withdrawal of consent in the NNRTI group than the PI group; please state whether any of these withdrawals were related to adverse events or issues of tolerability of the drugs?

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Greg Fegan

Reviewer #2: Yes: Vincent Muturi-Kioi

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Time to treatment disruption in children with HIV-1 randomized to initial antiretroviral therapy with protease inhibitors versus non-nucleoside reverse transcriptase inhibitors

PONE-D-20-04892R1

Dear Dr. Yin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Patricia Evelyn Fast, MD, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for your careful attention to the reviewers' comments.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Greg Fegan

Reviewer #2: Yes: Vincent Muturi-Kioi