PONE-D-19-26812

Beyond the Facility: An Evaluation of Seven Community-Based Pediatric HIV Testing Strategies and Linkage to Care Outcomes in a High Prevalence, Resource-Limited Setting

PLOS ONE

Dear Ms Sindelar,

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.

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Academic Editor

PLOS ONE

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Development (USAID), the ELMA Foundation, Elton John AIDS Foundation, and Viiv

Healthcare. No grant numbers were assigned for this project. None of the

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Additional Editor Comments (if provided):

The reviewers all agreed that this is a promising data-set. however they are also all in agreement that the manuscript as written currently is not technically sound. Please as you prepare a revision, use the STROBE Checklist to ensure that all important require element are included at the appropriate place.

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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: No

Reviewer #2: No

Reviewer #3: Yes

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

Reviewer #1: N/A

Reviewer #2: No

Reviewer #3: 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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

Reviewer #3: 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: There are three main issues I feel need to be addressed before I can commit to a full review of this paper:

1. Although the authors note that M-HIT was a collaborative effort among five partners, including the Lesotho MOH, all of the authors are from CHAI. Including the IPs and MOH in production may have assisted with the two more serious issues that need to be addressed below.

2. A description clearly describing the assent/consent process for the children included in this testing initiative is needed.

3. A clear description of the eligibility criteria for testing is needed to assess the results of the paper. Were children of HIV-negative mothers tested in this program? Were children tested without first assessing the status of the mother? There are situations in which that may be appropriate. However, it needs to be clearly described as it has a big impact on how we can assess the results. Please also comment on whether the eligibility criteria for testing is in line with Lesotho MOH policy or whether there was a deviation from standard practice for the purpose of this study.

Reviewer #2: Summary

This article by Sindelar et al, presents a large, unique, and important dataset from Lesotho and compares several different strategies for pediatric HIV testing in community-based settings. The dataset, drawn from a large collaborative implementation program, is valuable and compares head-to-head several strategies for pediatric testing which are often presented separately. As pediatric HIV testing continues to scale up in facilities for older children outside of PMTCT settings, critically examining the comparative effectiveness of different testing strategies is essential. In addition to considering testing coverage/uptake and yield, which are often the focus of case detection strategies, this paper also considers linkage to care and ART initiation, which makes it a valuable addition. However, there are numerous large methodologic issues in data interpretation, presentation, and contextualization that make the current version of the manuscript not scientifically sound. Revising the analysis and interpretation could transform this promising dataset into important lessons for those in the field of pediatric HIV testing. I enjoyed reading this paper and would look forward to reviewing a revision.

Major essential comments

1. Concepts of uptake of testing (proportion testing among those approached), testing yield (proportion testing positive among those testing), and relative numbers testing and testing positive between different strategies and age bands are reported inconsistently throughout manuscript (methods, results, discussion) but could be revised for clarity. Below are specific notes of where these concepts seem to be misinterpreted or inconsistently applied. Suggest reporting % uptake and % yield for each strategy, along with the already presented numbers testing and testing positive for each strategy. Further suggest adjusting these metrics to be per month to address differences in time period of data collection. Current reporting and comparisons are not scientifically valid.

a. Lines 134-138: suggest aligning these definitions of outcomes with the aforementioned % uptake, % yield, number tested, and number tested positive. Suggest providing numerator and denominator data (as appropriate) for each outcome. “Contribution of community-based testing…” is unclear as a metric. Does this mean the proportion of all children tested within the program that came from each strategy?

b. Line 160: unclear what testing volumes and identifications mean, but likely correspond to number tested and number testing positive; the terminology here differs from that mentioned earlier in the methods in lines 134-138. Suggest harmonizing even if my suggested terminology above is not your preferred terminology.

c. Lines 173-177: “MOCs tested and identified the highest number of children…contributed the smallest numbers in terms of overall children tested and identified, partly due to their shorter implementation timeframe”. Suggest adjusting all of the estimates to be per month of time, otherwise it is not a fair or valid comparison.

d. Lines 212-215: New data are introduced here (e.g. “index case testing which conducted over 80% of all tests on children”) and reflect new metrics that are not described in the results. Is this maybe referring to uptake of testing among those tested? The proportions given in this section do not add to 100%, so don’t seem to be relative contribution to numbers tested or yield. Also see lines 234-235 for 33% and 24% numbers which seem to be related.

2. In addition to defining and utilizing terms consistently as mentioned above, suggest harmonizing language about comparisons that are made and what they mean, and using precise language (e.g. avoid “significant” unless in the statistical sense, avoid terms like “incredibly effective” [line 216] if there is no comparison group or reference).

a. Line 214: Suggest not using significant unless these were statistically compared; later in discussion in lines 285-286 it says it was “not possible to compare between strategies” including community and facility-based.

b. Line 179-180: In several places, the article describes the proportion of children who were ages 5-14 among those who tested positive. While this is not an incorrect proportion to calculate, it cannot be interpreted as it is in the discussion to reflect prevalence or yield being higher in different groups. Suggest including the age breakdown among those children tested, not just those who test positive to identify whether yield differs between the groups. If n/N and % are included for each metric, all of the important absolute and relative comparisons can be made.

c. Lines 225-226: It’s not accurate to say that the greater number of children identified as positive using MOCs suggests that “children are more likely to receive HTC when it is provided alongside other health services”. That would be supported by a comparison of uptake between settings, not the relative number of positives between strategies.

d. Lines 239-242: It is not possible to evaluate the accuracy of the first sentence here about the contribution of CBT being relatively more than facility-based, as the authors do not present overall numbers in the results. This statement also contradicts other sections of the manuscript which say that facility based testing still has more positive children identified and higher uptake.

3. Linkage to care and ART initiation data are wonderful to see but should have a time period and window period in their definitions (e.g. linkage to care within 90 days after HIV diagnosis, or presented for scheduled visit within 30 days). Suggest revising lines 139-146 to include both, and also define how “active” was defined in determining who was retained.

4. Contextualizing these testing strategies more accurately and precisely within the peds testing literature in terms of uptake, yield, and linkage would help influence decision-making. For example, these data support what we’ve seen in other literature that index case and targeted testing strategies tend to have higher yield than “blanket” testing models, but the discussion in lines 225-252 lacks clarity in interpretation. There are important lessons on how to choose between these strategies, but they are not clearly presented.

5. Lines 203-204: This is a very important analysis that tests an important question of whether financial assistance/incentives/support modifies linkage to care. Given the sample size of positives in this study, it would be crucial to see the data or the point estimates and 95%CI for this analysis in order to conclude that there were no differences. Additionally, later in the paper we see that e-vouchers didn’t make it to families for a variety of reasons, some of which are reasonable to expect are random (e.g. mpesa registration issues) and others which would be expected to be related to the outcome of linkage (e.g. distance to clinic). Therefore, there is a clear potential for confounding (lines 266-267), which should be addressed and presented in this important analysis.

Minor important comments

1. Lines 107-108: suggest revision to “No sampling procedure was implemented as this program evaluation was conducted to evaluate routine implementation”. Implementation research or implementation science is a scientific discipline that often employs sampling procedures to test hypotheses, so would not be an accurate rationale for not including a sampling process.

2. Table 1: Unclear what the factors were that were used to determine “high risk of HIV infection”; would be crucial to define what those are and how they were identified and operationalized. With risk screening, a major barrier is often coverage of risk assessment, so would be good to comment on this.

3. Lines 162-164: Comparing time to linkage to care and ART initiation should be done using survival analysis (Cox proportional hazards regression, or some other version), not Wilcoxon’s rank sum (which is appropriate for comparing continuous time where all individuals have completed the outcome). Suggest revising the statistical test used to compare these. Did the authors perhaps intend to use a log rank test instead of a rank sum for survival data that do not have proportional hazards?

4. Line 164-165: For the negative binomial regression, suggest including a bit more information on the model itself and how it accounted for the varying length of time at each setting, and how it incorporated facility-based testing. Unclear as is. Additionally, suggest rechecking model results in lines 187-193, which do not reflect what would be expected based on the yield of each testing strategy.

5. Line 249: related to above, important to include in this sentence that the linkage to care intervention included provision of financial assistance, which is not standard in many settings.

6. New data are introduced on lines 227-230. This is really important and valuable information that sheds light on implementation challenges. Should be included in methods and results as data, not in discussion.

7. Glad to see the acknowledgement of need to have cost data in lines 294-295!!! This is really notably missing from the pediatric HIV testing literature and is a crucial decision-making factor for MOH. Suggest that authors consider writing a follow-up paper that documents any cost data they have, even if only number of staff members required to be employed to reach these numbers.

Discretionary comments

1. Abstract: suggest clarifying time period for linkage and ART initiation and suggest providing N and n for the yields.

2. Figure 1 and text do not match one another in terms of concepts being explained and relevant denominators.

3. Line 198: what were the treatment guidelines for children during this period of time and could the time to ART initiation be confounded by the changes in guidelines that are mentioned in the discussion?

4. Lines 204-206: Interesting finding about ART initiation and e-vouchers; suggest explaining why this might exist in discussion in lines 258-262.

5. Lines 219-220: While I agree that community-based testing likely does identify children earlier in their disease progression than facility-based testing, the present manuscript doesn’t have data to support this; suggest rephrasing this sentence to point more to other literature instead of stating as a lesson from these data.

6. Lines 221-224: there are many studies in this space, several systematic reviews and broader synthesis papers, and global datasets and national surveys that support this point. Suggest including additional information to contextualize more broadly.

7. Line 250: who is the reference group for this?

8. Line 256: There are systematic reviews about the effect of financial assistance on linkage; suggest offering a broader review of this literature to more appropriately contextualize.

9. Line 263: not possible to evaluate how recent the data in this reference are as ref is missing; were the data before the era of test and treat all? That could explain gaps. If mixed, suggest restricting to time period of post test and treat so that there shouldn’t be a gap.

10. Line 274: why were children “lost”? this is a large proportion and could influence estimates of linkage and treatment and retention.

11. Line 280: ANC services? HIV services?

Reviewer #3: Abstract:

• Instead of saying “Majority of children identified were…” include the exact proportion of children identified

• It may be better to put the number of children diagnosed rather than 9% of the overall number of people as the paper is about paediatric testing

• Abstract doesn’t mention of the 7 strategies, however these where in the title of the paper?

• Was ART initiated and dispensed in the community for the duration of the follow up period? May need to clarify in the abstract where ART was dispensed. Title and abstract implies that ART was dispensed in community settings.

• Line 33 are “enrolled” children the same as those children diagnosed?

Introduction

1. Line 81: What year is this data from?

2. The introduction would benefit form mention of subsequent linkage to care concerns of community-based HIV testing strategies

3. The introduction outlies in great detail the barriers to testing and HIV testing gaps among children but does not bring forth any evidence of how community-based HIV testing could bridge this gap? Has previous work on community-based testing for children been done in other settings? Has this been effective?

4. The introduction provides a lot of data on ART coverage, however, is there is any data of HIV testing coverage in the age group? What is covered of early infant diagnosis in Lesotho or the region? Or PMTCT coverage? This data will be useful to give context for the testing gaps that exist if available.

5. Line 81: the prevalence is 2.1% among children of what age range?

6. Line 90: is there a reference to M-HIT anywhere? A protocol? This would be helpful for additional context to the study

Methods

7. Is this paper presenting M-HIT or a subcomponent of M-HIT? It may be important to clarify that this paper is focusing on apart of M-HIT and clearly demarcate which part. This is not clear.

8. Line 104 that says the testing strategies were focused on rural areas is contradictory to the rest of the section. Are Maseru and Leribe rural areas?

9. Table 1: The different testing strategies are unclear in their current format. It may be useful if there was some expansion to these as the title of the paper is an evaluation of the 7 strategies and they therefore should play a major role in the paper. E.g. *Targeted testing: what was the selection criteria for a child who is high risk? Where are the venues described? Schools? Shopping complexes? Community halls?

*The relationship between facility index testing, door to door testing and door to door index testing is not clear. If testing is offered for all household members in facility index testing, how then do you index an individual in the same household become an index when everyone in that household has been tested already?

10. Line124: This appears as another intervention in addition to just community-based testing leading to ART initiation i.e. another motivator (economic) was provided which may have resulted in the subsequent high linkage and retention rates.

11. Line 137: Please consider rewording to “Diagnosing children unknown HIV”. Identifying implies that the testing may have been done prior to you finding the child.

12. 138: You would need a denominator to quantify this i.e. your denominator would be total number of children tested in each district (community and facility), however, this is not presented in the results?

13. Line 145: Describing the expected ART visits in the 3 months may be useful in order for the reader to understand how many times a client would have come within the 3 months e.g. are they just supposed to come to the clinic once in the 3 months to be classified as retained?

14. What is the justification of only 3-month retention given that ART is a lifelong treatment?

Results

1. Line 172: It would make more sense to present the yield of HIV for each testing strategy as each testing strategy was not implemented for the same amount of time. That would make a better argument for cost effectiveness of each strategy. As a stand-alone this figure is not presenting that much additional data aside from the breakdown in diagnosis by age in the different testing strategies. It may be better presented in a table that presents additional demographic information such as Gender of the children.

2. Is additional demographic information such as gender available? This would useful to add to the paper

3. Line 196: What happened to the other children that were not enrolled? What was the reason for non-enrolment? Do we know if they were subsequently linked to care as including the non-enrolled in the denominator would affect the linkage to care proportion significantly?

4. Line 204: why are there no results shown? As noted above this result is critical in understanding weather or not the e-voucher impacted linkage to care.

Discussion

1. Line 248: the timely client follow-up support is not previously defined? How was this different from facility care?

2. Line 247: it will be best if the proportion of children lost be included in the results as mentioned above. How was “lost” defined? Is this that there was no record of them at the clinic when you followed up? If so that may be better categorised as “not linked to care”? Again, the follow up procedure between diagnosis to linkage should be clearly described in the paper.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Chido Dziva Chikwari

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Attachments

Attachment

Submitted filename: Reviewer Comments Plos.docx

PONE-D-19-26812R1

Beyond the Facility: An Evaluation of Seven Community-Based Pediatric HIV Testing Strategies and Linkage to Care Outcomes in a High Prevalence, Resource-Limited Setting

PLOS ONE

Dear Ms Sindelar,

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.

We would appreciate receiving your revised manuscript by Mar 14 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable 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. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled '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.

We look forward to receiving your revised manuscript.

Kind regards,

Marcel Yotebieng, M.D., MPH, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

We have heard back from reviewers. though they all appreciate the effort that was put in the revision, there are still major issues to clarify.

Regarding reviewer #3 comment about the results of HIV testing of the mother, I agree with him/her that "Omitting or not reporting on the status of the mother limits the generalizability and usefulness of the results presented". Please if where ever the HIV status of the mother is known, report it. otherwise address this as a limitation in the discussion

I also agree with reviewer #2 on the need to check the consistency of the results including the negative binomial model.

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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 #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: 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: Partly

Reviewer #2: Partly

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: 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: Yes

Reviewer #2: Yes

Reviewer #3: 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 #1: Yes

Reviewer #2: Yes

Reviewer #3: (No Response)

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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: Thank you for submitting this revised paper. There is important information being presented and I think that with revision, this paper may be suitable for publication. However, I feel there is one central design flaw that still needs to be addressed. It is unclear to me why the authors of this study would not have ascertained and then reported on the status of the mother of the children being tested through these community based strategies. For PITC, when children are sick and in a health facility, it makes sense for both clinical and practical reasons for the children to be tested directly, regardless of the status of the parent. This is not the case for the testing of healthy children in a community based setting. Testing children of HIV-negative mothers, as seems likely to have been done in this program, is not efficient, as the results of this study clearly show. Testing all children is appropriate for a population based survey like the PHIAs. But that is not what is being reported on here. This paper is looking at practical strategies that countries can implement for community based case finding of children. Omitting or not reporting on the status of the mother limits the generalizability and usefulness of the results presented. Unless this is addressed clearly, I cannot recommend this paper for publication.

Reviewer #2: Summary of revised paper

This article from Sindelar et al has been substantially and meaningfully revised to address reviewer comments. Analyses have been redone and presented in clearer ways and more context has been given. Despite all of these well-conducted revisions, some major internal inconsistencies remain in this paper that would need to be addressed for it to be scientifically accurate. Additionally, there are several cases where easily identifiable and very relevant literature was not able to be found by the authors, which diminishes the sense that a careful detailed eye was applied to other areas of revision within the paper.

Major essential comments

1. Table 2 does not include the number of children who tested positive, which makes it impossible to check many of the subsequent analyses. Below are specific items to address to allow the paper to be accurately evaluated:

a. The authors’ revised “Objectives” section is great. However, the columns in Table 2 do not match their objective, which states that comparison will be done between # tested, # tested positive, and proportion tested positive (yield). The table shows a new proportion that was not previously described and is not well interpreted in the text, and fails to include the number who tested positive in each of the categories. Suggest adding this column. The authors suggest this was omitted because of word count or space restrictions; in this case, I’d suggest removing the column showing the proportion in the column to the left of yield.

b. Related to the previous comment, when I tried to back calculate the number of positives in each of the strata (as suggested by the authors in their response letter), the presented yields did not make sense. For example, the stated yield for D2D Index testing is 0.66% with a denominator of 229 children; if 1 child had tested positive, the yield would have been 0.437%; if 2 had tested positive, it would have been 0.873%; neither of these is the reported 0.66%. I checked several numbers across this table and all suggested either incorrect math or rounding errors. Suggest adding the column with the number of people who tested positive and then rechecking all proportions listed in the paper.

2. It is not possible to fully evaluate the accuracy of the negative binomial regression that the authors present. Despite the changes made in this revision, I still have concerns about the accuracy of this analysis. While the authors tried to address this concern in the revision by noting for D2D Index that 4.95 translates to 0.50, which is close to the 0.66% presented, that logic does NOT hold for the Targeted (2.23 vs 0.63%) and the Facility Index testing (1.34 vs 0.66%). Additionally, if this model was used to adjust for differences in time spent using each approach, we would not expect these numbers to be comparable. Overall, this statistical analysis cannot be evaluated for accuracy and appropriateness until the number of positive individuals is included in Table 2 and the proportions of yield are revised to be accurate.

3. The authors suggest that despite extensive literature review, there were no studies identified that addressed the impact of incentives on linkage to care. I’ve provided a number of articles that were identified using the search terms, “incentive linkage to care HIV” in PubMed. Even if these are not perfectly aligned to what the authors were searching for, it is inappropriate to present the results of this incentive analysis without contextualizing it in any of the incentives literature:

A Conditional Economic Incentive Fails to Improve Linkage to Care and Antiretroviral Therapy Initiation Among HIV-Positive Adults in Cape Town, South Africa.

Maughan-Brown B, Smith P, Kuo C, Harrison A, Lurie MN, Bekker LG, Galárraga O.

AIDS Patient Care STDS. 2018 Feb;32(2):70-78. doi: 10.1089/apc.2017.0238.

Financial Incentives for Linkage to Care and Viral Suppression Among HIV-Positive Patients: A Randomized Clinical Trial (HPTN 065).

El-Sadr WM, Donnell D, Beauchamp G, Hall HI, Torian LV, Zingman B, Lum G, Kharfen M, Elion R, Leider J, Gordin FM, Elharrar V, Burns D, Zerbe A, Gamble T, Branson B; HPTN 065 Study Team.

JAMA Intern Med. 2017 Aug 1;177(8):1083-1092. doi: 10.1001/jamainternmed.2017.2158.

Economic strengthening for HIV testing and linkage to care: a review of the evidence.

Swann M.

AIDS Care. 2018;30(sup3):85-98. doi: 10.1080/09540121.2018.1476665. Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699403/

Economic strengthening for HIV testing and linkage to care: a review of the evidence.

Swann M.

AIDS Care. 2018;30(sup3):85-98. doi: 10.1080/09540121.2018.1476665. Review.

A combination intervention strategy to improve linkage to and retention in HIV care following diagnosis in Mozambique: A cluster-randomized study.

Elul B, Lamb MR, Lahuerta M, Abacassamo F, Ahoua L, Kujawski SA, Tomo M, Jani I.

PLoS Med. 2017 Nov 14;14(11):e1002433. doi: 10.1371/journal.pmed.1002433. eCollection 2017 Nov.

High-Yield HIV Testing, Facilitated Linkage to Care, and Prevention for Female Youth in Kenya (GIRLS Study): Implementation Science Protocol for a Priority Population.

Inwani I, Chhun N, Agot K, Cleland CM, Buttolph J, Thirumurthy H, Kurth AE.

JMIR Res Protoc. 2017 Dec 13;6(12):e179. doi: 10.2196/resprot.8200.

Investigating interventions to increase uptake of HIV testing and linkage into care or prevention for male partners of pregnant women in antenatal clinics in Blantyre, Malawi: study protocol for a cluster randomised trial.

Choko AT, Fielding K, Stallard N, Maheswaran H, Lepine A, Desmond N, Kumwenda MK, Corbett EL.

Trials. 2017 Jul 24;18(1):349. doi: 10.1186/s13063-017-2093-2.

Voucher incentives improve linkage to and retention in care among HIV-infected drug users in Chennai, India.

Solomon SS, Srikrishnan AK, Vasudevan CK, Anand S, Kumar MS, Balakrishnan P, Mehta SH, Solomon S, Lucas GM.

Clin Infect Dis. 2014 Aug 15;59(4):589-95. doi: 10.1093/cid/ciu324. Epub 2014 May 6.

Minor

1. In table 1, D2D Index testing should be relabeled as a targeted strategy. Any strategies that use an index to identify individuals for testing, or apply any other approach for risk stratification among individuals or risk to influence selection of sites is targeted, not blanket testing.

2. The authors clarified that “active” in care is defined as having one or more visits after ART initiation. It is not clear whether this took into consideration the number of visits that one SHOULD have had. For example, a child who had 2 visits after ART initiation, but was expected based on time elapsed to have had 9, should likely be classified as lost to follow up or not retained, but using the authors’ described definition would still be considered active. This approach systematically overestimates retention, which is not scientifically appropriate.

3. The analysis in lines 274-6 should include a statistical comparison and p-value.

4. There is mismatch between Table 2 and Figure 1. Figure 1 still has “Facility-based” as a category, which is not presented in Table 2 and seems strangely high.

5. There is still new data presented in the discussion of this manuscript, which should not happen in a scientific manuscript. The authors state that the data were not presented in the results section because the sample used in the survey was not representative; this is not a reasonable reason for introducing new data in the discussion, unless those data have already been published elsewhere (in which case they should be referenced).

6. The authors were not able to find any papers about linkage to care in the pre or post test and treat era. Here are some papers for consideration from PubMed. Also consider finding the pediatric specific paper from the SEARCH trial. Some include adult populations, but can be included to contextualize:

Predictors of timely linkage-to-ART within universal test and treat in the HPTN 071 (PopART) trial in Zambia and South Africa: findings from a nested case-control study.

Sabapathy K, Mubekapi-Musadaidzwa C, Mulubwa C, Schaap A, Hoddinott G, Stangl A, Floyd S, Ayles H, Fidler S, Hayes R; HPTN 071 (PopART) study team.

J Int AIDS Soc. 2017 Dec;20(4). doi: 10.1002/jia2.25037.

High levels of retention in care with streamlined care and universal test and treat in East Africa.

Brown LB, Havlir DV, Ayieko J, Mwangwa F, Owaraganise A, Kwarisiima D, Jain V, Ruel T, Clark T, Chamie G, Bukusi EA, Cohen CR, Kamya MR, Petersen ML, Charlebois ED; SEARCH Collaboration.

AIDS. 2016 Nov 28;30(18):2855-2864.

Only adults: Understanding the Time Needed to Link to Care and Start ART in Seven HPTN 071 (PopART) Study Communities in Zambia and South Africa.

Seeley J, Bond V, Yang B, Floyd S, MacLeod D, Viljoen L, Phiri M, Simuyaba M, Hoddinott G, Shanaube K, Bwalya C, de Villiers L, Jennings K, Mwanza M, Schaap A, Dunbar R, Sabapathy K, Ayles H, Bock P, Hayes R, Fidler S; HPTN 071 (PopART) study team.

AIDS Behav. 2019 Apr;23(4):929-946. doi: 10.1007/s10461-018-2335-7.

7. The reasons given for no voucher being received are related to distance, which could also be associated with linkage, serving as a confounder. This needs to be mentioned in the limitations section and interepreted.

Reviewer #3: The is a well written paper which provides useful data with potential to influence HTC policy for children and adolescents, an area which is often neglected. The authors have adequately responded to reviewer comments and it is my recommendation that this paper be accepted for publication.

I have no additional comments.

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Reviewer #3: Yes: Chido Dziva Chikwari

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PONE-D-19-26812R2

Beyond the Facility: An Evaluation of Seven Community-Based Pediatric HIV Testing Strategies and Linkage to Care Outcomes in a High Prevalence, Resource-Limited Setting

PLOS ONE

Dear Ms Sindelar,

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Additional Editor Comments (if provided):

Sorry for the delay getting back to you on this. I have had a phone discussion with Reviewer #1 about their concern. the yield to the testing is low and it is important for country program and other funding agencies, to clearly understand who was tested. if as stated only “Children of HIV-negative mothers were not tested under the M-HIT project”, it is important to made this clear and maybe separate children tested in this strategy from other blanket testing strategy.

This is a very large testing effort.

[Note: HTML markup is below. Please do not edit.]

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Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #4: (No Response)

**********

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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

Reviewer #2: Partly

Reviewer #4: Yes

**********

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Reviewer #1: N/A

Reviewer #2: No

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: No

**********

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Reviewer #2: Yes

Reviewer #4: Yes

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Reviewer #1: Thanks for the response to my concern. The authors have stated that “Children of HIV-negative mothers were not tested under the M-HIT project”, which is a really important statement. What it implies is that the M-HIT project had a system for screening for the exposure status of children and then directing their testing based on that screening process. This statement implies that they had a way of determining whether the mother was HIV infected or HIV-negative. The authors need to provide more detail on this as it would be crucial for other countries and programs to understand how they managed this as they design their own community testing programs. The actual data collection form and SOP should be provided. It would also be essential if the authors have it to provide information on how many mothers were screened, how many were infected versus negative, as well as how many children had a deceased mother or a status unknown mother.

I am still concerned about whether in fact all or even a majority of the children were HIV-exposed and eligible for testing and that concern is based on the numbers. According to the text an average of 2433 were done per month over 30 months which would total to 72,990 tests in 2 districts in Lesotho. This number is discrepant to the MHIT Testing Strategies Dataset provided which has a total of 406,983 test (46% in children would give roughly 187,000. I didn’t go through to sort it to get the exact number, but the authors need to double-check this discrepancy). Regardless of which number is correct, both would be very high for a testing strategy that was restricted to HIV-exposed children. To give a sense of expected numbers see exercise below utilizing numbers from Spectrum. According to this exercise, there are only roughly 150,000 exposed children in all of Lesotho. Using the numbers given in the text (72,990), the authors propose that they have tested half this number in just two districts. The yield seen in this study is less than what would be expected if you just tested all children in the general population at random, which is not what the authors have stated was done in this program.

Numbers for Lesotho from Spectrum 2018 and 2019

General Population= 2,049,311

Population <15= 651,743

Estimated <15 exposed to HIV= 151,649 (calculated as mothers needing PMTCT per year x .95x 15 years)

Estimated <15 HIV-infected= 12,134

Prevalence<15= 12,143/651,743=

<15 HIV+ on ART= 8,499

<15 HIV+ not on ART= 3,635

Expected Yield General Population Testing= 3,635/651,743= 0.6%

Expected Yield HIV Exposed Restricted Testing= 3635/151,649= 2.4%

Perhaps, I have made an error in my calculations. I would love to hear back from the authors on this. I must again emphasize the primary importance of describing clearly how the children in this study came to be tested for the downstream interpretation of these results and the generalizability of the findings to other programs and countries.

Reviewer #2: Thank you for making revisions to this paper. All but the following two points were sufficiently addressed in the most recent submission.

The modeled number of positive children analysis is still not clear, even when compared to the newly presented number of children tested. I suggest removing it from the manuscript as it does not add additional insight about how to prioritize testing strategies.

While the evouchers were sent by mobile phone, and therefore getting to the health facility was not a problem in receiving money, the authors still state that "remote locations" was associated with network failures and accounted for some evouchers not being received; "remote locations" is also likely associated with distance to a clinic and therefore likelihood of linkage to care. Given this potential for confounding, a note should be added to the limitations to qualify this.

Reviewer #4: 1) It is unclear how “positive yield” was defined and calculated. Take Table 2 Adults category as an example. In the first row, Tested positive (30.80) / Tested (1182) = 2.60%, which is the positive yield shown in the table. But how the All M-HIT positive yield was calculated, as 17.40 / 2327 = 0.75%, which does not equal to 3.73%.

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Beyond the Facility: An Evaluation of Seven Community-Based Pediatric HIV Testing Strategies and Linkage to Care Outcomes in a High Prevalence, Resource-Limited Setting

PONE-D-19-26812R3

Dear Dr. Sindelar,

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.

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Marcel Yotebieng, M.D., MPH, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

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: Partly

Reviewer #2: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

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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

Reviewer #2: Yes

Reviewer #4: No

**********

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: Yes

Reviewer #2: Yes

Reviewer #4: 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: Thank you to the authors for clarifying the eligibility criteria. I think that was really important. A couple of more comments:

1) Can you please double-check the total number of tests? According to the text an average of 2433 were done per month over 30 months which would total to 72,990 tests in 2 districts in Lesotho. This number is discrepant to the MHIT Testing Strategies Dataset provided which has a total of 406,983 test (46% in children would give roughly 187,000).

2) I think it would be useful in the conclusion to mention that all children were tested regardless of exposure status per the Know Your Status Policy. What the authors have shown is that there are clearly missed children that can be identified in these community based settings. But what policymakers need to know now is if there can be a more efficient process of identifying them than what was presented in this paper. To make this paper more relevant, I would encourage the authors to at least present that question. There are several groups working on this. In Zim, there has been symptom based screening efforts. What I think will be more effective is using exposure status- i.e. only test kids if mother is positive, deceased, or unavailable. This can be assessed quickly and will dramatically improve yield. CHAI from Malawi presented on such an approach at AIDS 2020. I am sure the authors also from CHAI are aware of this work and it might be good to reference it.

PEE1431 - "Right under our nose": A simple screening tool to identify HIV-positive children outside of the PMTCT program at outpatient departments in Malawi

Speaker

Anna Tallmadge, Clinton Health Access Initiative

Session Name

E-posters Track E

Room

Poster Channel - Track E

Reviewer #2: (No Response)

Reviewer #4: My comments were addressed and I have no further comment.

My comments were addressed and I have no further comment.

My comments were addressed and I have no further comment.

My comments were addressed and I have no further comment.

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Reviewer #1: No

Reviewer #2: No

Reviewer #4: No