PONE-D-22-29453Factors associated with retention of mother-baby pairs in the elimination of mother-to-child transmission of HIV program in Kaberamaido district: a retrospective cohort study.PLOS ONE

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Additional Editor Comments :

Factors associated with retention of mother-bay pairs in the elimination of mother-to-child transmission of HIV program in Kaberamaido district: a retrospective cohort study

PONE-D-22-29453

This is an interesting study. The authors claim to have conducted a retrospective cohort study to 1) determine the levels of retention in care rates and 2) identify factors associated with the retention in care of mother-baby pairs along the eMTCT in a large district in Uganda. It is an example of how to use hospital-based registers to mount a follow-up study and provide long-term important outcomes.

However, there are so many issues:

1. Is it a cohort study? By definition, a cohort study requires a clear definition of exposure. Here there is no clear exposure. Yes, there is a follow-up and clear outcomes defined. Please fill out the STROBE checklist form (https://www.strobe-statement.org/checklists/) for cohort studies and annexes. By doing so the co-authors will improve the reporting.

2. The background needs some reorganization:

- The paragraph at lines 102 to 107 should come after the paragraph at lines 109 to 114.

- why citation 1 is followed by citations 10 and 11 in the first paragraph?

3. Lines 150 and 151 - the prevalence here is the overall population of adults, is itn´t? Please be specific.

4. Data abstraction procedures: please indicate the full list of variables and do not such lists with etc!

5. It is late already to correct this. The sample size formula is for just determining a proportion (typically in cross-sectional studies). It is not for looking for association analysis is done here.

6. Data analysis and Results:

- It is unclear from the description of the methods whether the authors ascertained the exact follow-up times for each child. That way it would be possible to show a Kaplan-Meier plot of retention

- A bit unusual. The follow-up time should be the age of the child because it is at 18 months old that we declare definitely negative or not. Right? Why did the authors decide to use some other follow-up time?

- The retention is estimated from your sample. Please include 95% confidence intervals. Put those as well in the abstract.

- The calendar time is ignored in this analysis. At least have the year of recruitment as one covariate to add to the model (inlcude it as dummy indicators).

- table 1:

infant age at recruitment please add more descriptives (mean, SD, range, quartiles and keep the dichotomized version as you have). Almost a third of children get to eMTCT past the recommend 8 weeks. We wonder if they do not reach 12 months (after the whole essential immunization for example). This could inform where to act to reduce these losses of opportunity.

Mothers' ART entry point the eMTCT subdivide (pre-natal, delivery, postdelivery?)

- lines 290 to 293: the average time spent by mother-baby pairs in eMTCT program. How this was computed? Does this account for the fact that there is right censoring time here?

- So the authors decided to study the association at 12 months and at 18 months of follow-up. There were only 19 events (people leaving the cohort) up to the 12th month of follow-up, and another 29 between the 12th and 18th months of follow-up. So for the 12 months, we do not see much when adjusted. Therefore, a) put the current tables 2 and 3 in the annexes. Then do one analysis using a discrete logistic survival model. In this model you have dummy indicators for 12 and 18 months and put the other variables as you have done. Do not include the viral load on the adjusted model.

- table 2:

Add a row for total pairs included

What is the definition for Viral load suppression here?

Only 232 mothers had a viral load ie adjusting for this variable you throw away 136 observations. I would recommend not to include this variable. Or do one analysis without this variable and move the current adjusted model with just 232 observations to supplementary materials.

- Figure 1: No need for the bars. Just the line is OK and please add confidence intervals.

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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

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

Reviewer #1: I Don't Know

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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: Yes

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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

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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: I do have some comments to be addressed:

1. What does EID mean? EID (in the abstract and introduction) may even be a universal acronym but it should be explained the first time it is used (which is only found at the study design section)

2. From how many records were selected the 368 records included in the analysis.

3. There is a way to know if there are differences between the pairs included in the analysis compared to those not included. Those not included with incomplete data could be the most missing and lost-to-follow up with a certain implication on the study results.

4. The major limitation of the study is the inclusion criterion "On the other hand, clients with incomplete/missing information, clients transferred from other health facilities and clients not in the EID/ART register were excluded from the study", which may have led to a about estimation of results.

5. Improve formatting and capitalization

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PONE-D-22-29453R1Factors associated with retention of mother-baby pairs in the elimination of mother-to-child transmission of HIV program in Kaberamaido district: a retrospective cohort study.PLOS ONE

Dear Dr. ODONGO,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 07 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Orvalho Augusto, MD, MPH

Academic Editor

PLOS ONE

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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. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

This report is very relevant as it documents retention rates at 12 and 18 months in the eMTCT (elimination mother-to-child transmission) program somewhere in Uganda. Since the last version there were improvements. There are a few shortcomings:

1. Study design. Be careful with the meaning of the word cohort. Indeed, the authors might have a cohort of mother-children pairs who entered in the eMTCT program and were followed up to 12-18 months. But that alone does not mean it is a cohort (the epidemiologic analytical study) study because a comparison group is not described. Remember in epidemiologic terms an exposure means at least 2 levels (exposed or not exposed) ie. at least a control group (no exposure) must be defined. Which is not the case here. The authors stated in the response to the previous round of comments that "babies being exposed to HIV infection from their mothers" is the exposure. Where is the comparator of such a group? In fact, the analysis never produces an association between retention and "being registered in the eMTCT program". Ok?

Because of this, I suggest changing the title and removing any designation of cohort study here. You may say something like "longitudinal analysis" or "cohort of mother-babies" etc…

2. It is still a bit unclear what is the definition to enter the cohort here. Line 184 says "HIV-positive mother-baby pairs enrolled in the eMTCT program from 1st January 2013 to 31st December 2018". When is this event? At PCR sample collection?

3. About the association analysis:

- Please note Cox in "Cox proportional hazard regression" is a name. Please write with capital "C".

- Usually there are 3 time scales to deal in a cohort analysis. The age (child and mother ages), the follow up time and calendar time. The authors i) dealt with the ages (mother age is used for adjustment; child age is homogeneous so OK to ignore for now); ii) the follow up time [which the Cox PH uses, so OK]; iii) Calendar time should not be ignored. For example, the test and treat introduction in 2016 might have changed how and/or characteristics of mother-baby pairs going to eMTCT, and also could affect the retention. Therefore calendar time could be a confounder here. It would be OK to just add dummy indicator of the year the mother-baby entered in the eMTCT. Also add in the table 1 the year of when the pair entered in the eMTCT.

4. Do not only "excel" in line 255. It is "Microsoft excel" and please add a citation and version.

5. Line 247 mentions viral load. Of whom? Of the mother or of the child?

6. Figure 2.

- I apologize to the authors that I made them change the time scale to age. Please return to follow up time (in months).

- Add please add below the plot the risk set size.

7. Figure 1:

- The totals do not add up. This is because we need a box showing the 368 who entered the analysis. So between the 457 and the 368 there were 89 removed.

8. The 89 who where excluded due to incomplete data represent 19.5% of all potential mother-baby pairs. Please, add a comparison of the 89 and 457.

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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 #2: (No Response)

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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 #2: Partly

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

Reviewer #2: Yes

**********

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 #2: Yes

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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 #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 #2: The manuscript reports on the very important topic of elimination of mother to child transmission of HIV in Uganda. It focuses on retention of mother-baby pairs, which is critical for the success of any EMTCT program. The manuscript is generally well written; however, the authors may wish to address the following:

Abstract: Line 41-42. The authors may wish to specify that the statistics reported in this sentence are for Uganda.

Introduction: Lines 106-107. please add a reference to the transmission risk of 20-25% referred to in this sentence.

Material and Methods>Study area. Line 153. The authors indicate here that the study was carried out in 5 health facilities in Kaberamaido district. In line 157-158, they indicate that 8 health facilities are providing HIV/AIDS services in the district; and in lines 184-185, the authors state that all HIV-positive mother-baby pairs in the district were enrolled. Is the data presented in the manuscript from 5 or 8 health facilities? Can the authors clarify this in the METHODS section?

The authors should try to provide additional information about the study health facilities. For example, how many of these facilities were health centers and how many were hospitals? What routine PMTCT services are offered in these facilities. When is the first PCR? when is the second PCR?

Line 154-169: The authors have provided valuable information about Kaberamaido district. Please cite the source of this information.

Material and Methods>Study Design: Line 180. The follow-up time for the cohort is 24 months. At what point does this follow-up start? is it during pregnancy? At delivery? or some other time? Please clarify. The RESULTS indicate that follow-up ends when the baby is 18 months of age; how do the authors reconcile the 18 months with the 24 months stated here?

Materials and Methods>Sample size determination. The formula used is appropriate for a prevalence study, not this kind of study. This should specifically be mentioned in the limitations.

Materials and Methods>Data abstraction procedures. Line 221-222. The sentence here appears incomplete. Edit it.

Measurement of variables. Line 247-248; Define viral suppression.

Line 249-251. Here, the time of Nevirapine initiation is categorized as before or after 24 hours, but in the RESULTS section, Table 1, Nevirapine prophylaxis is categorized as before or after 72 hours. Be consistent in your definition and categorization of this variable.

DISCUSSION: Line 355-357. TASO-Soroti is mentioned here for the first time without defining it! What does TASO do? What support do they provide to the health facilities? The authors should describe TASO and the kind of work they do in the METHODS section. It is hard to follow the argument in the DISCUSSION without clear understanding of the work done by this organization.

Line 369-372; Health system strengthening by Implementing Partners is given as a possible explanation for the high retention. A brief description of these health system strengthening activities should be written in the METHODS section to give the reader a better understanding of the study setting and routines. To mention this late in the DISCUSSION makes it difficult for the reader to follow the explanations given.

Line 381: LTFU is mentioned here and in Table 2. Please write it in full at first mention.

Line 424-429: The statements here seem to suggest that the authors attempted to reduce misclassification of loss to follow-up by calling participants to determine true outcomes. Participants who could not be traced by phone were left out of the study because of resource limitations (line 428-429). This raises a number of questions. The study was designed to use secondary data from routine facility records, how is it that you added primary data collected through phone interviews? If the phone interviews were carried out for the purpose of collecting research data, did the participants provide any consent? Why did the authors leave out participants who could not be traced? Shouldn't they have been classified as lost to follow-up?

Line 437-439: The message in this sentence is not clear. The sentence is probably incomplete.

Table 3>Viral load status. This appears to be the only significant variable in the adjusted model. It would be important to know at what point these viral load results were obtained. Are these results of tests carried out during pregnancy, post-natal period or at any time during study follow-up? How did you define suppression in instances where some participants have 2 or more viral load results in the course of study follow-up? If a test carried out in pregnancy showed viral suppression and later in the post-natal period a subsequent test showed non-suppression or vice-versa, how were these results categorized? Can you clearly define these categories in the METHODS section.

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Reviewer #2: No

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Factors associated with retention of mother-baby pairs in the elimination of mother-to-child transmission of HIV program in Kaberamaido district: a retrospective cohort study.

PONE-D-22-29453R2

Dear Dr. ODONGO,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Orvalho Augusto, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This manuscript has improved. Few minor issues:

Line 70 (in the abstract) change multivariate to multivariable.

Lines 292./293 and 300 add "hazards" so the name of the model becomes "Cox proportional hazards".

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 #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 #2: Yes

**********

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

Reviewer #2: Yes

**********

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 #2: Yes

**********

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 #2: Yes

**********

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 #2: (No Response)

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Reviewer #2: No

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