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. 2023 Jul 7;18(7):e0274031. doi: 10.1371/journal.pone.0274031

A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian adolescents: iCARE Nigeria treatment support protocol

Babafemi O Taiwo 1,*, Lisa M Kuhns 2,3, Olayinka Omigbodun 4,5, Olutosin Awolude 6,7, Kehinde M Kuti 7,8, Adedotun Adetunji 9, Baiba Berzins 1, Patrick Janulis 10, Sulaimon Akanmu 11, Oche Agbaji 12, Agatha N David 13, Akinsegun Akinbami 14, Abiodun Folashade Adekambi 15, Amy K Johnson 2,3, Ogochukwu Okonkwor 1, Bibilola D Oladeji 9, Marbella Cervantes 3, Olubusuyi M Adewumi 16, Bill Kapogiannis 17, Robert Garofalo 2,3
Editor: Joel Msafiri Francis18
PMCID: PMC10328338  PMID: 37418498

Abstract

Background

Nigeria is one of six countries with half the global burden of youth living with HIV. Interventions to date have been inadequate as AIDS-related deaths in Nigeria’s youth have remained unchanged in recent years. The iCARE Nigeria HIV treatment support intervention, a combination of peer navigation and SMS text message medication reminders to promote viral suppression, demonstrated initial efficacy and feasibility in a pilot trial among youth living with HIV in Nigeria. This paper describes the study protocol for the large-scale trial of the intervention.

Methods

The iCARE Nigeria-Treatment study is a randomized stepped wedge trial of a combination (peer navigation and text message reminder) intervention, delivered to youth over a period of 48 weeks to promote viral suppression. Youth receiving HIV treatment at six clinical sites in the North Central and South Western regions of Nigeria were recruited for participation. Eligibility criteria included registration as a patient at participating clinics, aged 15–24 years, on antiretroviral therapy for at least three months, ability to understand and read English, Hausa, Pidgin English, or Yoruba, and intent to remain a patient at the study site during the study period. The six clinic sites were divided into three clusters and randomized to a sequence of control and intervention periods for comparison. The primary outcome is plasma HIV-1 viral load suppression, defined as viral load ≤ 200 copies/mL, in the intervention period versus the control period at 48 weeks of intervention.

Discussion

Evidence-based interventions to promote viral load suppression among youth in Nigeria are needed. This study will determine efficacy of a combination intervention (peer navigation and text message reminder) and collect data on potential implementation barriers and facilitators to inform scale-up if efficacy is confirmed.

Trial registration

ClinicalTrials.gov number, NCT 04950153, retrospectively registered July 6, 2021, https://clinicaltrials.gov/.

Introduction

Since 2016, guidelines in Nigeria, Africa’s most populous country, have recommended antiretroviral therapy (ART) regardless of CD4 cell count for all people with HIV [1]. Effective ART suppresses HIV-1 replication, which curbs AIDS-related morbidity and mortality, limits viral transmission, and is essential to end the epidemic [2–4]. Youth in Nigeria have not benefited from ART as much as adults [5–8]. The United Nations defines youth as individuals aged 15–24, in recognition of the developmental risks to health and well-being of mid-to-late adolescence and young adulthood [9] and has called for their prioritization in national HIV treatment strategies [10]. An estimated 180,000 youth ages 15–24 are living with HIV in the country, with 23,000 new infections in 2020 [11]. Viral load suppression is estimated to be approximately 43% across age groups, however, it is significantly lower among youth and younger adults (aged less than 34 years) [12]. In 2020, an estimated 3,000 youth died of AIDS-related causes in Nigeria [11]. Effective interventions to promote ART adherence and suppression of HIV-1 viremia are needed to ultimately end the epidemic among vulnerable youth.

Peer support, which shifts supportive care to community-based and non-professional providers for efficient use of resources [13, 14], is recommended by the World Health Organization as a strategy that provides many benefits for youth across the HIV care continuum [15]. Peer support can also motivate and reinforce self-care and help to build self-efficacy for HIV treatment [15]. In addition, mobile technology-based strategies (mHealth) have emerged as a promising approach to deliver HIV-related interventions, particularly among youth, with a growing body of evidence suggesting efficacy [16–18]. Approaches using mHealth have the advantage of simple interfaces for users, accessibility anywhere mobile telephone signals and/or Wi-Fi are available, relative affordability, and have been promoted specifically to reach stigmatized and disenfranchised populations [19, 20]. An SMS text message reminder intervention, the Treatment Text intervention (TXTXT), developed by members of our research team has shown evidence of both feasibility and efficacy to promote ART adherence among youth with HIV in the United States (US) [21]. Based on social cognitive theory [22, 23], TXTXT is a bi-directional and personalized reminder intervention to promote medication adherence, which incorporates environmental cues to action and self-management support and feedback.

The iCARE Nigeria initiative includes both an HIV treatment support intervention and an HIV testing promotion intervention (parallel combination interventions). Herein, we describe the treatment support intervention of iCARE Nigeria (iCARE-Treatment), which incorporates locally adapted peer navigation and TXTXT to directly support youth living with HIV and promote viral suppression and is being tested via the UG3/UH3 mechanism, funded by the US National Institutes of Health (NIH). In the UG3 pilot phase of the study, which was completed prior to the initiation of the protocol described herein, iCARE-Treatment was piloted in a 48-week pre-post trial; participants (N = 40) were 50% male, mean age 19.9 years (range = 15–24), and 55% perinatally infected. Viral suppression (defined as viral load ≤ 200 copies/mL) was 35% at baseline and increased to 68% at 24 weeks and 60% at 48 weeks. These increases correspond to an odds ratio (OR) = 14.0 (p < .001) and OR = 6.0 (p = 0.013), at 24 and 48 weeks, respectively. Participants reported high satisfaction, with 100% indicating that they were satisfied/mostly satisfied with the intervention and 100% would refer a friend to receive it [24].

Study objectives

The purpose of this study is to assess the efficacy of iCARE-Treatment, a combination peer navigation and text message medication reminder intervention, on viral suppression among youth living with HIV, aged 15–24. Secondary objectives are to assess intervention effects on ART adherence and retention in HIV care.

Materials and methods

Design

The protocol described herein is presented following the SPIRIT guidelines with related checklist (Fig 1). This study is a randomized stepped wedge trial among six clinical sites in Nigeria. A cluster-randomized design was chosen over individual-level randomization to eliminate the threat of contamination across intervention and control conditions at each site, given the social aspects of the peer navigation intervention. We chose a stepped wedge cluster randomized design because it allowed all participants to receive the intervention and has logistical advantages of staggering training and intervention launch between clusters over time, so that limited resources can be used strategically. The sites were divided into three clusters consisting of one, three, and two sites respectively. The Cluster 1 sites include the Infectious Disease Institute of the College of Medicine, University of Ibadan (IDI/CoMUI); Cluster 2 sites include Lagos State University Teaching Hospital (LASUTH), Lagos University Teaching Hospital (LUTH), Nigerian Institute of Medical Research (NIMR); and Cluster 3 sites include Jos University Teaching Hospital (JUTH) and Olabisi Onabanjo University Teaching Hospital (OOUTH). In addition, IDI/CoMUI and LASUTH have 1 and 3 affiliate clinics linked to the sites, respectively, and LUTH, NIMR, JUTH and OOUTH have 2 each. The study duration of 96 weeks consists of four 24-week periods, which include control (pre-intervention), intervention, or follow-up (post-intervention) conditions. Per the stepped wedge design (Fig 2), there are three different sequences: 1) two 24-week intervention periods then two follow-up periods (no control period); 2) one 24-week control period followed by two intervention periods then one follow-up period; 3) two 24-week control periods followed by two intervention periods (no follow-up period). Thus, each sequence includes 48 continuous weeks of the iCARE-treatment intervention, which consists of peer navigation and support combined with daily text message medication reminders (TXTXT). The control and follow-up periods are observational, with collection of data only, while receiving standard care. Study enrollment and data collection began in April of 2021 and all data are expected to be completed by September of 2023.

Fig 1. SPIRIT checklist.

Fig 1

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Fig 2. iCARE study schema.

Fig 2

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Ethical approval

This protocol has been approved by the Institutional Review Boards of Northwestern University (STU00214317-CR0001), Ann & Robert H. Lurie Children’s Hospital of Chicago, College of Medicine, University of Ibadan/University College Hospital; Lagos State University Teaching Hospital, Lagos University Teaching Hospital, Nigerian Institute of Medical Research; Jos University Teaching Hospital and Olabisi Onabanjo University Teaching Hospital respectively, with a waiver of parental permission for participation of minors (aged 16–17). Current protocol version: March 11, 2022. Any modifications to the protocol are submitted to and approved by the IRBs of Record prior to implementation. Spontaneously reported adverse events and unintended effects of the trial are tracked by the study Principal Investigators and reported to the IRBs of Record. Study participants complete a written informed assent or consent process prior to participation in research activities. This study is monitored by a Data Safety and Monitoring Board (DSMB), the composition of which may be obtained from the study Principal Investigator at the lead institution. The trial will be suspended or stopped if recommended by the DSMB and the study investigators, in consultation with the study sponsor, determine that, in their clinical opinion, there are risks to participants for continuation.

Identification and recruitment of participants

Participants were recruited from youth patients at each clinical site. Individuals were eligible if they were: (a) living with HIV, (b) a registered patient at a clinical site, (c) aged 15 to 24 years (emancipated or with parental permission if aged 15), (d) on ART for at least three months and (e) able to understand and read basic English, Hausa, Pidgin English or Yoruba, (f) willing and able to provide informed assent or consent, and (g) intending to remain a patient in the study clinic during the study period (up to 96 weeks). Individuals were excluded if they were: (a) unable to provide informed assent or consent; (b) aged 15 years and are not emancipated or do not have parental permission for participation.

Randomization

After the completion of initial enrollment, clusters were randomized to a sequence. We felt that cluster randomization via the stepped wedge design was reasonable in this case because the restricted age range and similar settings (university-based healthcare setting) were expected to make the clusters relatively homogenous. The random assignments were generated by a computerized random number generator by the Statistician (PJ). Randomized sequences were concealed from participants and study staff until enrollment was completed. Clusters 2 and 3 were randomized to the sequence with one or two initial control periods (data collection only), respectively, followed by two intervention periods. In order to run interim analyses by cluster and step, the statistician will not be blinded during statistical analyses.

Cluster 1 was not randomized but began the intervention at the point of enrollment, which was purposeful as this was a test site for the original UG3 pilot trial of the intervention and thus had staff ready and trained to begin the intervention at the start of the study period. The final sequence of the four 24-week periods in each cluster is shown in Fig 2. A two-day training was conducted with investigators and staff of clusters 2 and 3 after their initial control period (s), immediately prior to intervention deployment (staggered by start date). This was then followed by intensive step-down trainings at each cluster site with all staff and peer navigators (including alternate/replacement peer navigators), to prepare them to deliver the intervention.

Description of the intervention period: iCARE-Treatment

The iCARE-Treatment intervention includes peer navigation and daily text message medication reminders. After assessment of the participant’s needs and development of an action plan, peer navigators make at least one contact (in-person or phone) every two weeks with participants to support goals of the action plan. Peer support is designed to be dynamic and flexible, with support provided via text message, WhatsApp message, and phone calls and includes accompaniment to the clinic, assistance with medication pick-up, and other health-related appointments, as needed. Peer navigators also work with the study coordinator, project manager and investigators to facilitate referrals to mental health and other services and provide general peer support. Peer navigators are selected based on recommendations from their HIV care providers. Requirements for this role include living with HIV and being virologically suppressed in the prior 12-month period (or the last available viral load measurement), clinically stable according to their physician’s subjective assessment, and aged 18–30 years. Age range and other targeted attributes of peer navigators are informed by findings from formative research conducted in youth and other stakeholders prior to the UG3 pilot study. Based on findings from the UG3 adaptation and pilot study [25], we expected to match each peer navigator to 4–5 study participants with salient shared characteristics, such as gender, age group, residential location, education level, religion, and other social characteristics (e.g., marital status, motherhood). Peer navigators receive a monthly stipend to cover cost of transportation and telephone/text messaging plus honorarium for their time. The total amount provided as stipend is based on results of our preparatory stakeholder engagement activities and consistent with local standards.

The text message reminder intervention is an mHealth intervention using the TXTXT platform, designed and tested with evidence of efficacy in our prior work in the US [21, 26]. This intervention includes a youth-centered, personalized, and bidirectional set of three daily messages to support adherence. The daily text messages include a personalized initial medication reminder that coincides with the participant’s chosen time to take their antiretroviral regimen, followed by a second message 15 minutes later, asking whether they took their medication, with a request for reply (“yes” or “no”). An encouraging third automated message, from our text message library, is then triggered by their reply. Both the initial and follow-up messages are chosen by each youth and personalized to reflect content meaningful to them. To protect confidentiality, messages are worded in a way that would not reveal the participant’s HIV status if read by a third party. In the UG3 study, youth living with HIV worked with study staff to adapt the text message library to ensure it contained expressions understood and commonly used by youth locally. The text messages are delivered via the Dimagi Commcare platform (https://www.dimagi.com/commcare/). Participants use their own phones for text messaging; however, a phone is provided to participants who do not have access to a phone, which is anticipated to be less than 20% of participants. Participants also receive 100 Nigerian Naira per week during the intervention period to cover the (minimal) costs of text messages (i.e., “airtime”).

Control period

During the pre-intervention control periods, study participants receive standard-of-care (SOC) adherence counseling only. In Nigeria, per national guidelines [27], SOC adherence counseling includes a readiness assessment at initiation of ART to emphasize both the benefits of medication adherence and also the consequences of poor adherence, including virological failure; the development of a patient-centered adherence strategy, and on-going monitoring. Two consecutive viral load test results above 1000 copies/mL, at least 3 months apart, triggers enhanced adherence counseling which includes exploration of specific barriers to adherence and development of an adherence intervention plan with follow-up at 3-month intervals.

Follow-up period

This is the post-intervention period when daily text messaging and protocol-specified peer navigation are discontinued, and participants return to standard care.

Study assessments

Participants are consented by study staff at the enrollment visit and complete interviewer-administered computerized study assessments at each visit, at 24-week intervals, captured in REDCap (see Table 1 for full schedule of activities). Study consent includes permission for use of participant data and samples for future studies. The longitudinal module of REDCap with survey queue and scheduling modules is used for both survey data collection and entry of data from case report forms, anchored to the enrollment date. All study data are securely stored at Northwestern University in a limited access database by study ID. All hard copy participant information (e.g., study checklists, consent forms) are securely stored at each study site in locked file cabinets with limited access. Study enrollment and data collection procedures are monitored annually by contractual arrangement with a third-party monitor, arranged by the study sponsor.

Table 1. iCARE Nigeria treatment intervention schedule of activities.

Pre-intervention (Control Sites) Baseline (Intervention Phase) Intervention Week 24- Intervention Phase Week 48 –Intervention Phase Post-intervention
Informed consent X X
Blood draw for viral load X X X X Xa
Blood draw for CD4 count Xb Xb
Blood draw for future studies (stored; virologic resistance testing and other studies) X X X X
Adherence Assessment: Dried Blood Spot (DBS), Pharmacy Pick-up Records Abstraction [28, 29], Self-Report [30] X X X X Xc
Computer Assisted Personal Interviewing Questionnaires d X X X X
Implementation Assessment e X X X X X
Cost Assessment f X X X X X
SMS + Peer Navigation Baseline through week 48
SMS Text Initiation X
Peer Navigation Enrollment X
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a Per medical chart abstraction of standard of care viral load quantification

b CD4 quantification will be performed only at the first study visit (either pre-intervention in Jos, Lagos, Sagamu), or baseline (in Ibadan)

c Medical records abstraction only (no self-report, no DBS)

d Computer assisted personal interviewing (CAPI): Demographic Characteristics, HIV treatment knowledge [31], HIV medication self-efficacy [32], HIV stigma [33], depressive symptoms [34], alcohol and drug use [35], intervention satisfaction and acceptability [36]

e RE-AIM framework implementation strategies [37], contextual factors from the Consolidated Framework for Implementation Research (CFIR) [38].

f Includes abstraction of cost data from site administrative records and through interviews with stakeholders

Primary outcome

Viral load suppression is defined as plasma viral load < 200 copies/mL. Blood for viral load quantification is collected via venipuncture at each study visit. Viral load quantification is performed at study laboratories using real-time HIV-1 COBAS® assay (Roche Molecular Systems, Inc.) with a lower detection limit of 20 copies/mL.

Secondary outcomes

Retention in HIV care is defined as at least two medical visits in a 24-week study period [39], with clinic visits abstracted from the medical record. ART adherence is measured via self-report, pharmacy records, and quantification of antiretroviral drug levels in dried blood spots (DBS). Self-reported adherence is measured as 30-day adherence on a visual analogue scale (VAS) of 0 to 100 [30]. Pharmacy records are captured as part of routine care in the electronic medical record. Drug pick-up adherence based on medication possession ratio (MPR) will be calculated from pharmacy records [28, 29], using drug pick-up records over each 24-week period, as total number of days’ supply obtained including the last fill, divided by number of days between first fill and last day of the observation window [40]. Five 50μL blood spots are collected on protein saver cards (DBS) for measurement of antiretroviral drug levels. The samples are dried out at room temperature for 24 hours, then sealed tightly with desiccant and a humidity indicator, and stored at -20 degrees Celsius until analysis. Clinic visit and pharmacy records are abstracted from medical records onto case report forms and entered in REDCap. Both VAS and MPR values will be evaluated as dichotomous indicators of ≥90% adherence (good) or < 90% adherence (poor) [41].

Statistical analysis

Several data quality checks will be conducted prior to analysis, including analysis of descriptive statistics and graphic plots to detect appropriate range of variables and to detect missing data or invalid cases. All data are stored in a password-protected network server with daily back-up. For descriptive statistics, percentages will be presented for dichotomous outcomes (e.g., viral suppression vs. non-suppression) and means will be presented for continuous outcomes (e.g., medication adherence). Similarly, changes between intervention and control periods will be summarized via odds ratios. Generalized estimating equations (GEE) will be used to account for multiple observations of participants. A binomial distribution and logit link function will be used to evaluate the statistical significance of the intervention effect (i.e., difference in viral suppression between intervention and pre-interventions periods), while controlling for secular trends in the outcomes over time and accounting for cluster with fixed effects. This analysis will follow the principles of intention-to-treat analysis and will be evaluated by examining the statistical significance of the regression coefficient for the intervention on the primary outcome. For differences in viral load suppression, we will compare intervention and control periods at the end of the intervention period, i.e., 48 weeks. Data collected during the follow-up period will be analyzed to explore the durability or “post-dose effect” of the intervention.

Sample size calculation

With a small to moderate within cluster correlation (ICC = 0.10) and moderate individual autocorrelation (0.50), this analysis will have adequate power (power = 0.945) to detect an OR of 1.5 in the proportion of participants achieving viral suppression with at least 90 participants per site. Our effect size estimate is conservative given that the iCARE UG3 pilot trial findings (OR = 14.0) was not randomized and not controlled. Findings from our prior randomized trial of text messaging on medication adherence (a related outcome) among YLH in the United States suggested an effect size of OR = 2.12 (95% CI 1.01–4.45).

Primary study data will be analyzed as soon as possible after the end of data collection, with study findings disseminated in peer-review public health journals.

Discussion

We describe herein the design of a stepped wedge trial of the iCARE-Treatment intervention, a combination of peer navigation and text message reminders to promote viral suppression among youth living with HIV in Nigeria, aged 15–24 years. The intervention draws on evidence-based intervention approaches that we adapted to the Nigerian context through broad stakeholder input in the formative stage of study design. Following the pre-post pilot trial in the UG3 phase of this study with evidence of initial efficacy and feasibility, we sought to extend the evidence from the UG3 to a much larger sample in the UH3 study described herein. The design of this UH3 study has several additional strengths, including inclusion of youth living with HIV in multiple states and regions of Nigeria, using a practical stepped wedge design that ensures every cluster receives the intervention, and incorporating a combination of evidence-based intervention approaches.

iCARE-Treatment is among the first interventions to be tested in a rigorous trial of sufficient size to detect effects on ART outcomes in youth. Effective interventions are needed urgently, particularly in a country like Nigeria that has met none of the key metrics recommended by Joint United Nations Programme on HIV/AIDS (UNAIDS) for measuring progress in reducing the public health threat of HIV [11, 42]. Illustratively, AIDS-related deaths from 2010 to 2020 fell by only 28% compared to the target of 75% decline [11]. Since youth are known to fare worse than older persons on the cascade of HIV care [43, 44], interventions like iCARE-Treatment are needed to improve viral suppression in youth; sustained viral suppression is the gateway to lower morbidity and mortality and elimination of viral transmission [45–47]. In designing this UH3 trial, our team is mindful of the need to understand potential barriers to broad adoption and scale-up of the iCARE-Treatment intervention should the results from the UG3 pilot be replicated in the UH3 study. As such, we intend to collect data on potential implementation barriers and facilitators, including cost implications, during the UH3 study and provide public health collaborators and policy makers with a comprehensive summary of evidence at the end of the study.

Supporting information

S1 File

(DOCX)

Click here for additional data file. (393KB, docx)

Acknowledgments

We would like to thank members of the iCARE team at all study sites for their contribution to the study protocol and procedures.

Data Availability

No datasets were generated or analyzed during the current study. All relevant data from this study will be made available upon study completion.

Funding Statement

This publication was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (https://www.nichd.nih.gov) of the National Institutes of Health under Award Number UH3HD096920. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health under award number UH3HD096920 to BT and RG. The funding source has no role in the original design of this study, analysis and interpretation of data, or decision to submit results.

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Decision Letter 0

Joel Msafiri Francis

13 Dec 2022

PONE-D-22-22897A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian Adolescents: iCARE Nigeria treatment support protocolPLOS ONE

Dear Dr. Kuhns,

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 Jan 27 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Joel Msafiri Francis, MD, MS, PhD

Academic Editor

PLOS ONE

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1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

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2. Thank you for stating the following in the Acknowledgments Section of your manuscript: 

This publication was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number UH3HD096920. 

However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 

This publication was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (https://www.nichd.nih.gov) of the National Institutes of Health under Award Number UH3HD096920. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health under award number UH3HD096920 to BT and RG. The funding source has no role in the original design of this study, analysis and interpretation of data, or decision to submit results.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 

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5. We note that the original protocol file you uploaded contains a confidentiality notice indicating that the protocol may not be shared publicly or be published. Please note, however, that the PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution.

Therefore, we ask that you please seek permission from the study sponsor or body imposing the restriction on sharing this document to publish this protocol under CC BY 4.0 if your work is accepted. We kindly ask that you upload a formal statement signed by an institutional representative clarifying whether you will be able to comply with this policy. Additionally, please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed.

6. 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.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have read with interest this submission whose intention seems to publish the protocol of a future cluster randomized trial based on a previous smaller pilot study investigating the same intervention.

Although this type of submission should be encouraged it also represents a stage at which the trial design might be questioned by external reviewers. I have the following requests of clarifications:

Major points

1. The timing is unclear. When is time 0 likely to be for the earliest cluster to enter the study and over which time-span is the RCT planned to occur?

2. Primary endpoint. A HIV-1 COBAS® assay (Roche Molecular Systems, Inc.) with a lower detection limit of 20 copies/mL is going to be used to measure viral load. Unclear why a threshold d of 200 copies is used to establish viral suppression instead. Also unclear from Table 1 whether blood will be drawn after control periods and follow-up periods. These viral loads are crucial for the comparison with the values measured after intervention.

3. Unclear why the statistical unit in the trial are the 3 clusters and not the clinical site. If I understood well ultimately Cluster 2 will be equivalent to sequence 2 and Cluster 3 to sequence 3. It would make more sense to me that each site (apart from site #1 for which I appreciate the rationale for being allocated deterministically to sequence 1) have equal chance to be allocated either to sequence 2 or sequence 3. In general, there the need to clarify the advantages of such a cluster trial randomisation as opposed to individual participants randomisation.

4. It is not uncommon that at least one statistician in the trial team is not blind to the randomisation. The justification given (the complexity of the analysis) is however unusual. I assume that the authors mean that one statistician will remain un-blind to be able to produce interim analysis reports by clusters and sequence. Please clarify.

5. More details are needed to describe the creation of randomisation schedules. What kind of randomisation will be employed? The number of clusters available is limited and therefore simple forms of randomization may not achieve balance between intervention and control arms at either the cluster- or participant-level.

6. Unclear why such a small OR of 1.5 was used to calculate statistical power. The pilot study indicates that the magnitude of the effect is likely to be a lot larger and up to 14-fold difference. Also unclear how the individual correlation (r=0.5) and cluster-correlation (r?? <0.5) estimates are coming from.

7. Statistical analysis section is quite short and has little details/clarity. Because of the use of GEE methods my understanding is that the strategy will be compared only within clusters (so that each participant act as his/her own control). Will be any comparison between sequences? If so, what is going to be the approach to analysis? Clusters can be considered independent and therefore GEE should not be needed.

8. The trial is going to be costly. I am not an expert in the field but is there a plan to evaluate whether the possible benefit in terms of increased number of youths with a suppressed viral load as a consequence of the intervention is going to be cost-effective? There is only a hint to this possible analysis in the last paragraph of the Discussion.

9. One of the possible advantages of publishing a trial protocol is aiming to pre-register the study with a journal prior to data collection/collation, to avoid publication bias and limit researcher degrees of freedom. Authors should clarify whether this is an intent as it would strengthen the submission.

Minor points

1. Wording is fairly confusing with some of the sentences phrased in the future ‘it is anticipated that…’ ‘participants will be….’ ‘quality checks will be conducted’ ‘data will be analysed’ etc. vs. others which are placed in the past (like the trial has actually already occurred) e.g. ‘Cluster 1 was not randomised’ ‘participants were recruited’ etc. Suggest phrasing is standardised throughout.

2. Lines 90-96. Form the way the paragraph is structured, it is not obvious at first reading that these are the results of a separate pilot study and not those produced by preliminary data of the current protocol.

3. Line 95. Please indicate exact p-value instead of <0.05.

Reviewer #2: The authors present a description of the methods for a cluster randomized stepped wedge trial of an intervention to increase viral suppression on HIV-1 antiretroviral treatment targeted towards youth. The protocol is clear and well written and is presented in a manner that others could replicate. I have no substantive edits for the authors. Thanks for following the SPIRIT guidelines.

Minor comment:

Based on the results of the pilot, it would appear the trial is overpowered if the target is 1.5 times the odds of viral suppression comparing pre to post implementation. The authors might want to consider what is a clinically important increase in viral load suppression (although anything up from the baseline in the 30's would be better) rather than the 1.5 which would not result viral suppression levels that are beneficial at a the target population level.

It appears the population for the intervention is all youth regardless of mode of acquisition of HIV infection. Do the authors anticipate any difference in response to the intervention by youth who were perinatally infected versus infected as adolescents or young adults?

**********

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: No

Reviewer #2: No

**********

[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.

PLoS One. 2023 Jul 7;18(7):e0274031. doi: 10.1371/journal.pone.0274031.r002

Author response to Decision Letter 0

10 May 2023

Please include the following items when submitting your revised manuscript:

1. 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'.

2. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

3. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

Journal Requirements:

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

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

RESPONSE: We have revised the headings and subheadings to conform to the required style.

2. Thank you for stating the following in the Acknowledgments Section of your manuscript:

This publication was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number UH3HD096920.

However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

This publication was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (https://www.nichd.nih.gov) of the National Institutes of Health under Award Number UH3HD096920. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health under award number UH3HD096920 to BT and RG. The funding source has no role in the original design of this study, analysis and interpretation of data, or decision to submit results.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

RESPONSE: We have removed the funding information from the acknowledgements statement and the funding statement that you have on file is correct.

3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

RESPONSE: We have moved the ethics statement to the last paragraph of the methods section.

4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

RESPONSE: There are no SI files included in this submission.

5. We note that the original protocol file you uploaded contains a confidentiality notice indicating that the protocol may not be shared publicly or be published. Please note, however, that the PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution.

Therefore, we ask that you please seek permission from the study sponsor or body imposing the restriction on sharing this document to publish this protocol under CC BY 4.0 if your work is accepted. We kindly ask that you upload a formal statement signed by an institutional representative clarifying whether you will be able to comply with this policy. Additionally, please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed.

RESPONSE: The study sponsor does not prohibit or restrict publication of the protocol. The confidentiality statement appears in the protocol to prevent publication without permission. In the cover letter for this resubmission, we have granted permission for the publication of the protocol. We have also uploaded a clean copy of the protocol with the confidentiality notice removed.

6. 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.

RESPONSE: We have reviewed the reference list to ensure that it is complete and correct.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

Reviewer #2: Yes

________________________________________

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

________________________________________

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

________________________________________

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

________________________________________

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

________________________________________

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have read with interest this submission whose intention seems to publish the protocol of a future cluster randomized trial based on a previous smaller pilot study investigating the same intervention.

Although this type of submission should be encouraged it also represents a stage at which the trial design might be questioned by external reviewers. I have the following requests of clarifications:

Major points

1. The timing is unclear. When is time 0 likely to be for the earliest cluster to enter the study and over which time-span is the RCT planned to occur?

RESPONSE: Study enrollment and data collection began in April of 2021 and all data collection is expected to be complete by September of 2023. We have added this statement to the design section on p.6.

2. Primary endpoint. A HIV-1 COBAS® assay (Roche Molecular Systems, Inc.) with a lower detection limit of 20 copies/mL is going to be used to measure viral load. Unclear why a threshold d of 200 copies is used to establish viral suppression instead. Also unclear from Table 1 whether blood will be drawn after control periods and follow-up periods. These viral loads are crucial for the comparison with the values measured after intervention.

RESPONSE: The threshold of 200 copies/mL was chosen because this is the cut-off used to define virologic failure clinically. Plasma viral load values between 20 and 200 are thought to represent release of non-replicating viral particles that is not indicative of antiretroviral treatment failure. Consistent with this, undetectable viral load is defined as viral load below 200 copies/mL in the undetectable = untransmissible tenet (i.e., U=U). Blood will be drawn at all follow-up visits in both the control and follow-up periods.

3. Unclear why the statistical unit in the trial are the 3 clusters and not the clinical site. If I understood well ultimately Cluster 2 will be equivalent to sequence 2 and Cluster 3 to sequence 3. It would make more sense to me that each site (apart from site #1 for which I appreciate the rationale for being allocated deterministically to sequence 1) have equal chance to be allocated either to sequence 2 or sequence 3. In general, there the need to clarify the advantages of such a cluster trial randomisation as opposed to individual participants randomisation.

RESPONSE: To clarify, clusters 2 and 3 did have equal chance of allocation to sequences 2 and 3, respectively. In terms of advantages, the stepped wedge trial in this case had logistical advantages in that training and intervention launch were staggered, which allowed for limited resources to be used strategically. We have added this information to the manuscript on p.6, design section.

4. It is not uncommon that at least one statistician in the trial team is not blind to the randomisation. The justification given (the complexity of the analysis) is however unusual. I assume that the authors mean that one statistician will remain un-blind to be able to produce interim analysis reports by clusters and sequence. Please clarify.

RESPONSE: Yes, exactly. We have revised the narrative to include specific detail on why the statistician is not blind to analyses, given their role in running interim analyses by cluster and step.

5. More details are needed to describe the creation of randomisation schedules. What kind of randomisation will be employed? The number of clusters available is limited and therefore simple forms of randomization may not achieve balance between intervention and control arms at either the cluster- or participant-level.

RESPONSE: The randomization scheme was a simple cluster-level randomization, given the pragmatic nature of the design. We felt this was a reasonable choice given that the restricted age range and similar setting (university-based healthcare setting) were expected to make the clusters relatively homogenous. We have added this language to the randomization section on p.7.

6. Unclear why such a small OR of 1.5 was used to calculate statistical power. The pilot study indicates that the magnitude of the effect is likely to be a lot larger and up to 14-fold difference. Also unclear how the individual correlation (r=0.5) and cluster-correlation (r?? <0.5) estimates are coming from.

RESPONSE: The OR=1.5 was chosen because the pilot trial was a non-randomized and non-controlled trial with a very small sample size. Our prior randomized trial of effect of text messaging on medication adherence (a related outcome) among youth living with HIV in the US found an effect size of 2.12, with a 95% CI of 1.01 – 4.45 (see PMID: 26362167).

Therefore, we chose an effect size that we felt would be as conservative as possible given the stepped wedge design. We added additional details on the cluster level correlation to the power section. Cluster correlation (ICC = 0.10) was based on prior cluster randomized trials of viral suppression interventions which generally find cluster level ICCs of 0.05 to 0.15. Individual autocorrelation were chosen based on high rates of autocorrelation among individuals in prior studies. We also note that power estimates are only marginally impacted by these parameters and, given the current estimate of power and conservative estimate for the effect size, these assumptions do not substantially impact the overall evaluation of the statistical power of the study.

7. Statistical analysis section is quite short and has little details/clarity. Because of the use of GEE methods my understanding is that the strategy will be compared only within clusters (so that each participant act as his/her own control). Will be any comparison between sequences? If so, what is going to be the approach to analysis? Clusters can be considered independent and therefore GEE should not be needed.

RESPONSE: The GEE approach is used to control for the correlation of viral suppression across multiple observations of the same individuals over time while a fixed effect will be used to account for the effect of cluster. The main outcome is the difference in viral suppression between periods during the intervention compared to those not during the intervention, using a fixed effect for observation periods to control for secular trends in viral suppression. We have modified the analysis description to clarify these points.

8. The trial is going to be costly. I am not an expert in the field but is there a plan to evaluate whether the possible benefit in terms of increased number of youths with a suppressed viral load as a consequence of the intervention is going to be cost-effective? There is only a hint to this possible analysis in the last paragraph of the Discussion.

RESPONSE: Yes, we received supplemental funding to do a cost effectiveness analysis following completion of the trial. Because the focus of this manuscript is on the primary efficacy findings, details of the cost effectiveness evaluation are not included.

9. One of the possible advantages of publishing a trial protocol is aiming to pre-register the study with a journal prior to data collection/collation, to avoid publication bias and limit researcher degrees of freedom. Authors should clarify whether this is an intent as it would strengthen the submission.

RESPONSE: Data collection in this study is on-going, thus this protocol manuscript will not be published prior to data collection. However, this manuscript is a more detailed version of the clinicaltrials.gov protocol registration, which was submitted in parallel with the start of the study.

Minor points

1. Wording is fairly confusing with some of the sentences phrased in the future ‘it is anticipated that…’ ‘participants will be….’ ‘quality checks will be conducted’ ‘data will be analysed’ etc. vs. others which are placed in the past (like the trial has actually already occurred) e.g. ‘Cluster 1 was not randomised’ ‘participants were recruited’ etc. Suggest phrasing is standardised throughout.

RESPONSE: The differences in tense reflect whether or not the activity has occurred. The manuscript has been reviewed to ensure that the tenses used reflect actual initiation (or not) of the activities described.

2. Lines 90-96. Form the way the paragraph is structured, it is not obvious at first reading that these are the results of a separate pilot study and not those produced by preliminary data of the current protocol.

RESPONSE: We have revised line 91 of the manuscript to make it clear that the UG3 phase of the study was completed prior to the initiation of the protocol described in this manuscript.

3. Line 95. Please indicate exact p-value instead of <0.05.

RESPONSE: Exact p-values have been added as suggested.

Reviewer #2: The authors present a description of the methods for a cluster randomized stepped wedge trial of an intervention to increase viral suppression on HIV-1 antiretroviral treatment targeted towards youth. The protocol is clear and well written and is presented in a manner that others could replicate. I have no substantive edits for the authors. Thanks for following the SPIRIT guidelines.

Minor comment:

Based on the results of the pilot, it would appear the trial is overpowered if the target is 1.5 times the odds of viral suppression comparing pre to post implementation. The authors might want to consider what is a clinically important increase in viral load suppression (although anything up from the baseline in the 30's would be better) rather than the 1.5 which would not result viral suppression levels that are beneficial at a the target population level.

RESPONSE: The OR=1.5 was chosen because the pilot iCARE UG3 trial was a non-randomized and non-controlled trial with a very small sample size. Our prior randomized trial of effect of text messaging on medication adherence (a related outcome) among youth living with HIV in the US found an effect size of 2.12, with a 95% CI of 1.01 – 4.45 (see PMID: 26362167).

It appears the population for the intervention is all youth regardless of mode of acquisition of HIV infection. Do the authors anticipate any difference in response to the intervention by youth who were perinatally infected versus infected as adolescents or young adults?

RESPONSE: In our prior trial of text messaging on medication adherence in the U.S. and in the UG3 iCARE pilot trial, we did not find significant differences among vertically versus horizontally infected youth. However, we expect to explore these potential moderation effects in this trial as well.

________________________________________

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Reviewer #1: No

Reviewer #2: No

________________________________________

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Decision Letter 1

Joel Msafiri Francis

31 May 2023

A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian Adolescents: iCARE Nigeria treatment support protocol

PONE-D-22-22897R1

Dear Dr. Kuhns,

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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Kind regards,

Joel Msafiri Francis, MD, MS, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have addressed my comments. I think the effect size used in the sample size calculation is still too conservative given the use of an odds ratio as the measure of effect but the authors have adequately addressed my question.

**********

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.

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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 #2: No

**********

Acceptance letter

Joel Msafiri Francis

29 Jun 2023

PONE-D-22-22897R1

A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian Adolescents:  iCARE Nigeria treatment support protocol

Dear Dr. Kuhns:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Joel Msafiri Francis

Academic Editor

PLOS ONE

Associated Data

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    Supplementary Materials

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    Submitted filename: Response-to-review_draft_17April2023.docx

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    Data Availability Statement

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