Evaluating the Feasibility and Acceptability of a Digital Pre-Exposure Prophylaxis Navigation and Activation Intervention for Racially and Ethnically Diverse Sexual and Gender Minority Youth (PrEPresent): Protocol for a Pilot Randomized Controlled Trial

Background To end the HIV epidemic by 2030, we must double down on efforts to tailor prevention interventions to both young men who have sex with men and transgender and nonbinary youth. There is an urgent need for interventions that specifically focus on pre-exposure prophylaxis (PrEP) uptake in sexual and gender minority youth (SGMY) populations. There are several factors that impact the ability of SGMY to successfully engage in the HIV prevention continuum, including uptake of PrEP. Patient activation, having the knowledge, skills, and self-efficacy to manage one’s health, is an important indicator of willingness and ability to manage one’s own health and care autonomously. Patient navigation also plays an important role in helping SGMY access PrEP and PrEP care, as navigators help guide patients through the health care system, set up medical appointments, and get financial, legal, and social support. Objective This study aims to evaluate the feasibility and acceptability of a digital PrEP navigation and activation intervention among a racially and ethnically diverse sample of SGMY living in the Los Angeles area. Methods In phase 1, we will conduct formative research to inform the development of PrEPresent using qualitative data from key informant interviews involving PrEP care providers and navigators and working groups with SGMY. In phase 2, we will complete 2 rounds of usability testing of PrEPresent with 8-10 SGMY assessing both the intervention content and mobile health delivery platform to ensure features are usable and content is understood. In phase 3, we will conduct a pilot randomized controlled trial to evaluate the feasibility and acceptability of PrEPresent. We will randomize, 1:1, a racially and ethnically diverse sample of 150 SGMY aged 16-26 years living in the Los Angeles area and follow participants for 6 months. Results Phase 1 (formative work) was completed in April 2021. Usability testing was completed in December 2021. As of June 2023, 148 participants have been enrolled into the PrEPresent pilot randomized controlled trial (phase 3). Enrollment is expected to be completed in July 2023, with final results anticipated in December 2023. Conclusions The PrEPresent intervention aims to bridge the gaps in PrEP eligibility and PrEP uptake among racially and ethnically diverse SGMY. By facilitating the delivery of PrEP navigation and focusing on improving patient activation, the PrEPresent intervention has the potential to positively impact the PrEP uptake cascade in the HIV care continuum as well as serve as a model for the tailoring of PrEP interventions based on behavior-based qualifications for PrEP instead of generalized gender-based eligibility. Trial Registration ClinicalTrials.gov NCT05281393; https://clinicaltrials.gov/ct2/show/NCT05281393 International Registered Report Identifier (IRRID) DERR1-10.2196/50866

Overall Impact: This is a revised application to fund an R34 to develop and pilot a three component intervention to support uptake and adherence to PrEP among white, Black and Latino, young men who have sex with men (YMSM).The proposal will design an intervention with: 1) client-centered PrEP navigation, 2) patient activation; and 3) an mhealth platform to deliver intervention content.The final package, PrEP2Prevent, will be developed using formative research and work groups with young people; it will be piloted with 75 participants with three and six-month follow-up conducted to assess the following outcomes: PrEP use (via verified service use and prescription refill data) and adherence (using a biological outcome).Mediators will also be assessed.The results will inform powering and conduct of a full RCT.The proposal seeks to evaluate a combination of approaches that have strong potential for impact on the uptake of and adherence to PrEP.The focus on patient activation is novel and in this revised application well-justified.The study design is sound with a clearly laid out plan for achieving the study aims, which include conducting formative research, developing the intervention package through community-engaged methods, manualizing it and piloting the resultant program.The project is highly significant as well in that it focuses on a subpopulation in need of sustained and focused support in order to increase uptake of PrEP and reduce acquisition of HIV.The approach proposed is well-described integrating key intervention design components and a vigorous assessment of the feasibility and acceptability of the combination intervention.Overall the study investigators have addressed numerous critiques and suggestions of the previous review, although not all.The scientific premise is stronger, with the addition of background on the efficacy of patient activation and selfmanagement on various health outcomes.There continue to be some minor weaknesses that reduce overall enthusiasm for the project.The theoretical mechanisms of action of patient activation have been better described, but the proposal is still light on how this will be applied in the intervention content.How the intervention addresses uptake is still not well described, although the significance makes clear that a major gap remains between PrEP awareness and uptake; the focus of the intervention still appears to be on youth who are interested in or willing to take up PrEP.The description of how patient activation will locate and activate PrEP aware and eligible, but not interested YMSM is not addressed.The intervention still appears very much to be an uptake (among interested individuals) and adherence intervention.Nonetheless, if successfully executed the study will pave the way for a large clinical trial of the multicomponent intervention for high-risk, Black and Latino, urban, YMSM, which is significant and could have high impact on the field and the epidemic.

Strengths
• The subpopulations of focus are at very high risk for HIV acquisition.
• PrEP access, uptake and adherence is suboptimal for Black and Latino YMSM, although white YMSM are now included in this revised application.
• The revised application explains why transgender individuals are not included.
• PrEP is effective and barriers to uptake and adherence must be identified and addressed through in order to reach national HIV prevention goals • The successful development of the intervention would offer an important model for US cities and YMSM.

Weaknesses
• The role of PrEP stigma is not well described.
• A major gap in the PrEP cascade is between eligibility and interest and intention to access.The data presented suggests that good portions of YMSM are aware of PrEP, but are not using it.Driving demand for PrEP by raising risk perception, addressing stigma and discrimination may 1 R34 DA046361-01A1 4 HIBI KIPKE, M be where the work is needed, and not necessarily increasing access among those who seek PrEP.
• Self-management and patient activation have been used in conditions where there is a diagnosis; needing PrEP is not exactly the same.

Strengths
• PI is a senior leader in the HIV prevention field and experienced investigator with a strong track record of directing interdisciplinary research teams, NIH funding, complex research studies and reporting results in peer-reviewed publications.
• Highly experienced, interdisciplinary investigative team brings extensive and relevant expertise to project (e.g., population health, medical care, intervention development and testing, mhealth and technology science research, etc.) • Appropriate balance of experienced senior investigators in required areas of expertise, which span various areas.
• Revised application adds significant strength in intervention design, with the addition of Bauermeister adding to the team considerably.

Weaknesses
• Patient navigation is not particularly innovative 4. Approach:

Strengths
• Although there are a lot of moving parts in this proposal, they are linked together in a way that makes sense and one builds on the next.The visual of the roadmap is helpful in indicating the process and structure of the work.
• The number of groups and group members of the "working groups" is now clear and seems adequate to the task.
• Again, how the formative research will clarify how patient activation "works" in the navigation and mhealth components is just not that well specified.
• The expansion of the working groups significantly increases confidence that the intervention design will be grounded in the real lives of the focal populations • Stigma is mentioned and how the intervention might address it is described, albeit briefly.

Weaknesses
• The navigation component will address concrete and material needs, but the description of how this will happen is not very detailed; referrals will be made, but will the navigators be trained in case management and have the experience needed to do this effectively?
• PrEP stigma is not assessed in the pilot evaluation measures.
• The proposal indicates that it will develop a culturally relevant intervention, but there is little in the description of the formative research that addresses culture.

Strengths
• All sites involved have excellent environments to conduct the research described.• The applicants have addressed many of the concerns of the reviewers, although there remain some concerns.Overall Impact: This is a revised application from Los Angeles Children's Hospital.The PI is an experienced researcher in HIV and youth.The proposed study will develop, implement and evaluate a theoretically-driven intervention to address these barriers and promote PrEP uptake and adherence using an existing mHealth platform.The proposed study has a number of strengths.It proposes an innovative approach to developing an intervention to improve the use of PrEP, and it has a with a talented team of investigators.There are also a number of weaknesses.It is not clear whether the project is planning to create a program for YMS overall, or three programs adapted for different ethnic groups.The general aim seems to be the former, but the methods seem oriented to the latter.A number of aspects of the approach are unclear or unwieldy, which seems likely to handicap the operation of the research.On balance, the research seems a fine idea but needs more clarity and focus.

Strengths
• Young men who have sex with men (YMSM) are an important group in the HIV epidemic, as they continue to have high rates of new HIV infections and relatively low use of PrEP.
• If this project achieves its aims, it can develop a promising adaptation (or adaptions) of PrEP for YMSM.

Weaknesses
• The current application includes three target groups of YMSM African Americans, Hispanic Whites, and Non-Hispanic Whites -with what appears to be separate plans for both qualitative and quantitative analyses for each of them, without sufficiently specifying how (or if) the various results will be combined in the end.It is not clear if it is the goal to have a single PrEP, or three PrEP protocols designed for each of the groups.

Strengths
• There is a multidisciplinary team headed by an experienced research leader Dr. Kipke, who also serves as co-director of the Southern California CTSI.
• Co-investigators include adolescent medicine expert Marvin Belzer wo provides feedback ion PrEP guidelines and cultural anthropologist Katrina Kubicek, who verses the formative research Phase 1 of the study.
• Consultants include pharmacologist Angela Kashuba, whose lab analyzes dried blood spots for PrEP adherence, Joseph Baumeister, who consults on intervention development and evaluation, and Kate Muessig, a health behavior interventionist who will assist in the qualitative analyses.

Weaknesses
• It is difficulty to sort through the potential overlapping roles of the various leaders, consultants, subcontractors, and staff.

Strengths
• It is innovative to integrate mHealth services with patient navigation in the service of enrolling and helping YMSM to succeed in PrEP.
• The project will integrate a number of mHealth services in the PrEP2Prevent intervention.
• Using patient activation as a central concept seems to fit the YMSM population very well and is innovative.

Weaknesses
• None Noted

Strengths
• The intervention, called PrEP2Prevent, will provide PrEP navigation and support to help youth access services to address their basic needs (e.g., food, housing, safety) and engage youth in each step of the PrEP care continuum.
• The PrEP2Prevent will include a major focus for patient navigation, which seems important for the young population.Another emphasis is emphasizing patient activation, which can help youth grow to represent their needs rather than relying on others to provide the impetus.A third emphasis is using technology support, which fits better with the young population than it would for an older clientele.

Weaknesses
• It is not clear what the primary and secondary dependent variables are.The distinction between feasibility and acceptability is not clearly stated, nor are the component measures clearly provided."Feasibility" is defined as "at least 50% of individuals used the platform on average greater or equal to twice a week…", but this is a narrow operational definition.There is no definition of "acceptability" provided.• Expectations of the technological aspects may be unrealistic.For example, the CAB noted that low PrEP uptake may be related to patients needing to enter a clinic, and providing these services online would address this barrier.But online services may have the same problem with waiting lists, and at some point the client needs to be seen physically.
• Many aspects of the study seem unwieldy.For example, six working groups will be formed (3 ethnicity groups in PrEP or not in PrEP) to carry out some of the formative research, and this seems a substantial load: 6 groups x 4-6 sessions each, for 6-8 YMSM.It isn't clear how the results will be analyzed given the magnitude of the data, and it is not clear how the results will be synthesized across the groups.
• It would be helpful to include a section in the Approach recognizing limitations of the research, problems anticipated, and strategies to minimize problems.Such a section could better demonstrate awareness of potential drawback.• The Saban Research Institute is responsible for providing administrative support for research at CHLA, and all its PIs are members of the USC faculty.

Environment
• University of North Carolina provides support for Dr Hightow-Weidman and consultant Dr.
Muessig, as well as analysis of laboratory tests under the supervision of Dr. Kashuba's laboratory.
• Two technology companies are also subcontractors, one will use focus group results to create a final mHealth design, and the other will use that design to create a desktop and/or mobile app for the YMSM clients as well as a research dashboard.

Weaknesses
• It is not very clear from the proposal what whether TSRI is a part of CHLA, vice-versa , or if they are independent of each other.Likewise what University of Southern California contributes to the study, if it does.
• While the team approach is useful, there are also many organizations and individuals to be coordinated in conducting the research.

Strengths
• Timeline is reasonable.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections • All men; justified scientifically.Race: Three groups will be included in approximately the same proportion, although the inclusion enrollment report is not very clear.

Vertebrate Animals:
Not Applicable (No Vertebrate Animals)

Resubmission:
• The prior review comments views praised the study's significance, research team, and innovation and commented that the work built on approaches that have strong potential for impact on the uptake and adherence of PrEP.
• But the reviewers were critical of many aspects including: 1) limiting participants to African Americans and Non-Hispanic whites, not including transgender participants, and not justifying why the study is restricted to men; 2) not adequately describing the theoretical mechanisms of action of patient activation or the contact delivered via Lifespeed; 3) "conducting a LOT" of formative research that is not well described; 4) not explaining how the intervention addresses stigma; 5) the cost of the intervention, particularly Lifespeed; 6) not clarifying what the study's primary and secondary variables are or the dependent variables, while including a large number of key study variables and not defining the key variables of "acceptability" or "feasibility"; and 8) not addressing cost measurement or tracking.The revision is responsive to some of the critiques, and it clearly indicates in the proposal in bold burgundy what changes were made.Many of the prior problems remain.Overall Impact: This revised R34 study by a PI from the Children's hospital of Los Angeles proposes an intervention to increase uptake of and adherence to PrEP among young men who have sex with men.As this group has some of the highest HIV incidence and prevalence in the US, it addresses a significant issue.The innovation is somewhat limited as the projects proposes to adapt a previously developed intervention (for African American MSM) to a new target population (young MSM).The main contribution of the project seems to be the direct targeting of patient activation.This is overall a strong application, with an appropriate responsiveness to the reviewer comments on the original submission, except for a key concept (patient engagement with technology) that is increasingly being recognized as a potential barrier for the implementation of mHealth interventions.NIH has modified its policy regarding the receipt of resubmissions (amended applications).See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-074.html.The impact/priority score is calculated after discussion of an application by averaging the overall scores (1-9) given by all voting reviewers on the committee and multiplying by 10.The criterion scores are submitted prior to the meeting by the individual reviewers assigned to an application, and are not discussed specifically at the review meeting or calculated into the overall impact score.Some applications also receive a percentile ranking.For details on the review process, see http://grants.nih.gov/grants/peer_review_process.htm#scoring.

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It also adds new technology firms with considerable experience in mhealth and app development • High level of support from Co-Investigators and collaborating clinical and community-based sites as demonstrated in letters of support Weaknesses Integrating mhealth with patient navigation and patient activation is innovative.

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Detailed and clearly laid out for an ambitious project Weaknesses • None Noted Protections for Human Subjects: Acceptable Risks and/or Adequate Protections • well described plan Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable • well described Inclusion of Women, Minorities and Children: • Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically Biological and/or Chemical Resources: Not Applicable (No Relevant Resources) Budget and Period of Support:

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Children's Hospital of Los Angeles (CHLA) is a strong home base for the study, and the PI has a key role there as Director of Research.Dr. Kipke is also the founder of CHLA's Community, Health Outcomes, and Intervention Research (CHOIR) Program.

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Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not acceptable • Inclusion/Exclusion of Children under 18: Including ages <18; justified scientifically

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Team of investigators with extensive NIH funding experience and expertise in key areas for the application • Appropriate effort levels of investigators Weaknesses Patient activation seems to be a novel construct for intervention Weaknesses • Adapts an intervention previously developed by the PI to a slightly altered population 4Does not take potential obstacle of patient (dis)engagement into account • No cut-offs for feasibility / acceptability thresholds given 5. Environment: Strengths • The academic and community-partner sites provide an excellent environment to carry out the study Weaknesses Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion of Children under 18: Including ages <18; justified scientifically largely responsive, yet the important potential problem of patient engagement pointed out in the original critique not addressed 1 DA046361-01A1; PI Name: Kipke, Michele D.

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For NIH-Defined Phase III trials, Plans for valid design and analysis: Not acceptable • Inclusion/Exclusion of Children under 18: Including ages <18; justified scientifically Many measures are indicated, but there is not a clear conceptualization or measurement model to guide what is needed.