Adapting Effective mHealth Interventions to Improve Uptake and Adherence to HIV Pre-Exposure Prophylaxis Among Thai Young Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial

Background Young men who have sex with men (YMSM) are the fastest-growing HIV-positive population worldwide. Thailand has the highest adult HIV seroprevalence in Asia; over 25% of men having sex with men in Bangkok are HIV positive. Pre-exposure prophylaxis (PrEP) is an efficacious HIV prevention strategy recommended for all at-risk individuals. PrEP is highly effective when taken as prescribed, but PrEP utilization rate has been low, and adherence is often inadequate. Objective We propose to develop and pilot a multicomponent, technology-based intervention to promote motivation to begin PrEP (“uptake”) and sustained adherence to PrEP among HIV-negative Thai YMSM. We will adapt an existing 2-session technology-delivered, motivational interviewing–based intervention to focus on PrEP use in YMSM in Thailand. The resulting intervention is called the Motivational Enhancement System for PrEP Uptake and Adherence (MES-PrEP). We will also develop motivational text messaging (MTM) to send two-way motivational messages to promote PrEP use. Methods The proposed study includes 3 phases. Phase 1 includes in-depth interviews with HIV-negative Thai YMSM and providers to explore barriers and facilitators of PrEP initiation and adherence, aiming to inform intervention content. Phase 2 consists of adapting and beta-testing MES-PrEP and MTM for functionality and feasibility using a youth advisory board of Thai YMSM. In Phase 3, we will conduct a pilot randomized controlled trial to evaluate the feasibility, acceptability, and preliminary efficacy of MES-PrEP and MTM to increase PrEP uptake and adherence among Thai YMSM. A total of 60 HIV-negative Thai YMSM who have not started PrEP and 60 YMSM who are on PrEP but not adherent to it will be randomized 2:1 to receive MES-PrEP and MTM (n=40) or standard PrEP counseling (n=20). The feasibility and acceptability of the intervention will be assessed through usage patterns and the System Usability Scale. The preliminary impact will be assessed by evaluating the proportion of PrEP initiation and level of adherence to PrEP. Participants will complete the assessments at baseline and at 1-, 3-, and 6-month postintervention. Biomarkers of adherence to PrEP and biomarkers of HIV and sexually transmitted infections will be collected. Results Recruitment for this study began in January 2022 for phase 1. Qualitative interviews were completed with 30 YMSM and 5 clinical providers in May 2022. Phase 3, the pilot feasibility and acceptability trial, began in July 2023. Upon project completion, we shall have developed a highly innovative mobile health intervention to support YMSM using PrEP, which will be ready for testing in a larger efficacy trial. Conclusions This study addresses a critical problem (ie, high HIV incidence and low PrEP use) among Thai YMSM. We are developing 2 potentially synergistic technology-based, theory-driven interventions aimed at maximizing PrEP use. The proposed project has the potential to make significant contributions to advancing HIV prevention research and implementation science. Trial Registration ClinicalTrials.gov NCT05243030; https://clinicaltrials.gov/ct2/show/NCT05243030 International Registered Report Identifier (IRRID) DERR1-10.2196/46435

1 R34 MH124081-01A1 3 HIBI WANG, B PUBLIC HEALTH RELEVANCE: Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV infection, yet rates of initiation and adherence are low and discontinuation rates are high in Thai YMSM, a high-risk population with HIV prevalence rate as high as 28.6%.This project will develop a technology facilitated intervention combining Motivational Enhancement System for PrEP Uptake and Adherence (MES-PrEP) and Motivational Interactive Text Messaging (MTM) to increase uptake of and sustained adherence to PrEP among HIV-negative, Thai YMSM.This study has potential to pave the way to the successful scale-up of PrEP implementation in Thailand.

CRITIQUE 1
Significance: 3 Investigator(s): 1 Innovation: 1 Approach: 3 Environment: 1 Overall Impact: This is a resubmission of an R34.MSM are 20 times as likely to be living with HIV than the general population.HIV prevalence among MSM in Thailand is nearly 30% with a particularly rapid rate of increase among youth 15-21 years.PrEP uptake and adherence is low among MSM.Barriers to initiating or staying on PrEP include low self-perceived risk, concerns of side-effects, drug use and HIV stigma.The goal of the application is to develop and pilot an intervention comprising a two-session computer-based motivational interview and motivational interactive text messaging to increase PrEP uptake and adherence among Thai HIV-negative MSM youth.Aim 1 will comprise 30 in-depth interviews with young MSM on PrEP and PrEP-naive to understand barriers and facilitators of PrEP.Aim 2 is to pilot test the adapted MES-PrEP among 120 young MSM (1/2 PrEP naïve and ½ on PrEP) with 1-month follow-up.Primary outcomes are PrEP uptake and adherence.After the first computerbased MI session, participants will receive daily text messages.After the second session, one month after the first, participants will receive weekly text messages until the last follow-up at month 6.Assessments will be at baseline, 1, 3 and 6-month interviews and comprise a survey as well as biomarkers that include DBS for PrEP adherence, STI and drug testing.The resubmission is highly responsive to the reviewers' comments that include increasing the sample size from 16 to 30 in-depth interviews in Aim 1, adding the socioecological model to incorporate structural and social-level factors, adding detail to the adaptation of the MESA platform, clarification of the size of the effect of MESA on ART adherence, and changing the exit interview from 6 to 1 month.Overall this is a very strong application led by an excellent investigative team.A moderate concern centers around the reality of addressing structural and social interventions through this intervention despite the addition of the SEM in the conceptual framework.As such, the inclusion of the SEM model seems more of a checking of a box rather than a commitment to addressing social and structural barriers.A few additional minor concerns are detailed below.

Strengths
• The rapidly expanding HIV epidemic among YMSM globally and in Thailand in particular (with an incidence of 12/100 PY in Bangkok) and the low rates of PrEP uptake and adherence underscore the need for interventions to increase PrEP use among HIV-negative young MSM.
• Truvada is available but underutilized in Thailand.An estimated 40% are currently on PrEP, and only 9.3% of Thai MSM who were offered PrEP started it.• 90% of YMSM in Thailand had a cell phone in 2014, and that number has likely increased.

Weaknesses
• Although the application now incorporates SEM into the conceptual framework, it's not clear how social and structural elements will actually be addressed in this intervention.The application mentions depression and stigma (both experienced at the individual level) as outcomes without explaining how these will be addressed from a societal or structural perspective.
• Although the application states that it is unlikely that LAI will be approved in Thailand, it's important to note the long-term vision for the intervention: how would the relevance of this intervention be affected by the presence of long-acting injectables in the Thai PrEP landscape.Could the intervention be adapted to LAI? Or would it be irrelevant for those on LAI? • Dr. Naar has used CIAS to develop an interactive MI session for sexual risk reduction for youth living with HIV.
• The MPI plan includes a reasonable resolution to potential conflicts (Dr.Stanton will resolve if a solution cannot be found).The MPIs have a history of collaboration as reflected on their publications.

Weaknesses
• None noted by reviewer

Strengths
• Combining a computer-based intervention and text messaging is innovative and particularly relevant to YMSM who are hard to reach but technologically savvy and receptive to this type of format.
• The ability to tailor both technology-based components of the intervention is novel.Both are interactive in the sense that content of the sessions and messages are dependent on prior responses from the participant.
• The addition of biomarkers is not new, but supports the validity of outcome measures.

Strengths
• The ubiquitous nature of cell phones in Thailand make this a feasible intervention for YMSM.
• The steps to adapt MESA and develop MES-PrEP and MTM (following ADAPT-ITT) are reasonable, thoughtful and thorough (Aim 1); • Outcome measure of feasibility and acceptability are appropriate along with preliminary efficacy outcomes: PrEP uptake and adherence.
• The addition of SEM expands the scope beyond the individual and incorporates social and structural context into the study.
• DBS for PrEP adherence, STI testing and drug testing are biomarkers that strengthen the validity of self-reported outcomes • Use of CIAS technology that is flexible and easily programmed by clinicians for MI sessions.
The latter feature makes it scalable and sustainable over time.
• Both computer-based components are tailored to the individual participants: MI is interactiveeach session is unique based on participant's responses; text messages are based on content from individual MES-PrEP including readiness to take PrEP, and PrEP adherence.
• The Youth Advisory groups and clinical providers will both be involved in developing content of the MI sessions and text messages ensuring content that is both population and clinically appropriate.
• Preliminary studies support this study: with MESA reducing viral load among youth living with HIV on ART in a large RCT and high levels of acceptability among participants.

Weaknesses
• While SEM is added to the framework, it's unclear how the structural concepts themselves will be operationalized.
• Drug use is mentioned as a barrier to PrEP uptake and adherence but not discussed in the application (type of drugs, prevalence, how the intervention will address it).
• Acceptability and feasibility are measured from the perspective of participants; however it would be helpful for future studies and scale-up to understand acceptability and feasibility from the implementers perspectives including providers and clinicians who have may have to re-program the platforms based on evolving information.
• STIs are secondary outcome measures but the rationale for including them are never addressed.
• It is unclear why TGW or TGM youth are not included in this study.Overall Impact: The purpose of this revised R34 is to adapt an MI-based electronic agent intervention to deliver a 2-session PrEP uptake and adherence intervention for young (16-25) Thai men who have sex with men in Bangkok.This is a well-written and highly responsive revised application.The study team is highly experienced and the environment is strong.The scientific premise of the proposed intervention is strong and the combination of the electronic MI-based agent and tailored text messages is innovative.There were some minor weaknesses in the approach, but overall the description of the phases of the study (including the interviews in Phase 1, adaptation in Phase 2, and the pilot RCT in Phase 3) is very thorough.Overall, this is a strong application with several addressable minor weaknesses.

Strengths
• Rates of HIV infection among young men who have sex with men (YMSM) are disproportionately high and rates of HIV among Thai MSM are estimated to be 20-30%.There is a clear need for innovative interventions addressing HIV in Thai MSM.
• PrEP is an effective prevention tool, but willingness to take PrEP among Thai MSM is low (~40%) and only 9.3% of Thai MSM who were offered PrEP started it.There is clearly a need for more robust PrEP interventions that target uptake and maintenance on PrEP in Thailand.
• Smartphone use in Thailand is very high and therefore the SMS component of the proposed intervention may be scalable if shown to be effective.
• The ability for the computer software that runs the agent to be tailored easily to different contexts may make it highly scalable.
• The scientific premise of the study is strong.The investigators directly addressed concerns about data speed, the potential impacts of approval of long-acting injectables, and how they would better understand mechanisms preventing uptake and adherence.

Weaknesses
• A relatively minor concern is that the MI agent can only be viewed in the clinic and therefore this may limit its potential scalability.

Investigator(s):
Strengths • Dr. Wang (PI/PD) is an epidemiologist and has been involved for a decade in HIV prevention and treatment research in Thailand.He was involved with adapting MI-based intervention for HIV-positive Thai youth, which is the basis of the proposed study.He is well qualified to serve as an MPI for the proposed work.
• Dr. Phanuphak (MPI) is the Chief of Prevention and the Chief of Search at the TRCARC) and has extensive experience in conducting clinical research, including overseeing 3 PrEP studies in Thailand currently.
• Dr. MacDonell (co-I) is a developmental and pediatric psychologist and has expertise in HIV behavioral intervention and the use of technologies for MI-based intervention.
• Dr. Sadasivam (co-I) is a computer engineer with expertise in technology-facilitated behavioral intervention.
• Dr. Rongkavilit (co-I) is a physician and clinical researcher with expertise in HIV medicine and behavioral research in Thailand.
• The team is supported by expert consultants in MI (Dr.Naar) and international HIV intervention research (Dr.Stanton).
• Some of the team members have a history of collaboration.

Weaknesses
• None noted by reviewer

Strengths
• The use of an electronic agent to deliver MI is innovative in the context of PrEP uptake and adherence among Thai MSM • The pairing of the MI agent with regular 2-way text messaging is innovative.

Weaknesses
• None noted by the reviewer.

Strengths
• Well articulated study aims.
• The theoretical grounding of the intervention in IMB and MI is well described and is consistently applied throughout the intervention and assessment.
• The use of the ADAPT-ITT model for adaptation is a strength.
• The study builds off of prior work by this study team demonstrating their ability to successfully carry out similar projects.
• Providing mobile devices to participants who may not have one is a strength.
• Clear description for how interviews in Phase I will inform intervention adaptation.
• The adaptation process is thoroughly described.
• The control condition is appropriate and the 2:1 randomization was justified.• Clear plan for linking participants who test positive for HIV or syphilis to care.
• The scientific rigor of the proposed study is high.

Weaknesses
• The section on the PrEP cascade that seemed to imply that the stages of change model was also driving intervention development.
• It was unclear whether participants had to opt into receiving text messages after the first month.
• Only interviewing 20 participants for the exit interviews is a missed opportunity to get more feedback on the intervention from more participants.
• The quantitative acceptability measures could be more robust, as the SUS is fairly narrow in what it assesses.
• It wasn't clear where some of the measures (e.g., Decisional Balance for PrEP Use) were sourced.

Strengths
• The University of Massachusetts Medical School -which houses the Population and Quantitative Health Sciences Department -is a strong research environment to oversee the operational and financial aspects of the proposed study.
• The Institute of HIV Research and Innovation has substantial resources to oversee the day-today operations of the proposed study in Thailand.
• UCSF and Wayne state are appropriate environments to oversee the work being done by the co-Is at those institutions.

Weaknesses
• The recruitment clinics seem like they may be excellent sources for participants, however the recruitment and retention plan is not particularly well articulated.

Strengths
• The timeline is tight, but the investigators are highly experienced.
• Study team organization is clear.

Weaknesses
• The recruitment and retention plan are not very specific about procedures that will be used and the success of those procedures in prior studies.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections • Risk adequately described and ways to mitigate those risks considered.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
1 R34 MH124081-01A1 10 HIBI WANG, B Acceptable • Identification and addressing AEs and SAEs described.

Inclusion Plans:
• 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 Based on Age: Distribution justified scientifically • Inclusion of 16-17 year old children.Enrollment limited to men, with no discussion of whether transgender men will be included.Could be strengthened by rationale for excluding transwomen.Race/ethnicity will reflect local population.

Vertebrate Animals:
Not Applicable (No Vertebrate Animals)

Resubmission:
• Highly responsive to prior critiques.

Applications from Foreign Organizations:
• Notes how this study, if successful, can serve as a global model for HIV prevention of at-risk groups in LMICs.Overall Impact: Applicants propose to adapt existing interventions to support PrEP uptake and adherence in young Thai MSM.This is a high-risk population, and there is a need for scalable interventions to support improved uptake.The proposal has several strengths, including a strong clinical setting, a strong research team, and a well-defined set of outcomes from the pilot RCT.Enthusiasm is somewhat limited by a suggestion that clinicians could modify the intervention platform, which would decrease rigor; by preliminary data on MESA that were presented a year and a half ago but never published; and by a suggestion that some steps of the ADAPT-ITT approach will be skipped through a preemptive choice of the intervention to modify.The proposal to use a well-understood framework to guide the selection and adaptation of the intervention but preempt that framework to choose the investigators' own intervention without a systematic process compromises the value of using the framework.

Weaknesses
• The description of the MI platform mentions that the software might be reprogrammed by researchers, clinical staff or clinicians to address different behaviors or contexts.But it is not clear how decisions about changes to the software would be made or documented, and how the impact of the intervention would be assessed if the intervention is changed (or changeable) by clinicians during the study.If it is the intention that the intervention could be expanded when new therapies are approved (e.g., long acting injectable PrEP), this could be a plus, but as described, having clinicians or clinical staff change the app to target new health behaviors is problematic.
• The preliminary data presented on MESA are from a small number of participants, and data on efficacy presented are from an abstract presented a year and half ago and not subsequently published (based on a search conducted for recent publication at the time of review).It is speculative to rely on data from a conference presentation that has not been peer reviewed and is not available for review to endorse a major component of the intervention approach.Although preliminary data are not required for this mechanism, MESA is described as a successful intervention, and having stronger data to support this assertion would make the proposal stronger.
• ADAPT-ITT suggests relying on data from phase 1 to choose which intervention to adapt, but the proposal states that MESA has already been selected based on prior work with MSM.If the framework is to be used meaningfully, it seems odd to go in with a decision made about what the best intervention to adapt is, without following the earlier steps or considering other interventions for adaptation.If the applicants want to use a subset of the ADAPT-ITT process by skipping steps 1-2, this should be stated.
• The stages of change model seems to be an awkward addition conceptually to the PrEP cascade discussion, and really isn't integrated into the rest of the proposal.
• The SUS is a very limited assessment of usability in terms of identifying actionable revisions; qualitative data would strengthen the actionable assessment usability and how to improve it.

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Dr. Wang (PI) has a strong track record of HIV research in Thailand, including the adaptation of the MI-based intervention for Thai youth living with HIV.Dr. Phanuphak (MPI) is Chief of Prevention has extensive experience with clinical trials (including HPTN) and has 3 ongoing PrEP trials.• The team is well rounded with Dr. Boudreaux providing expertise in HIV prevention interventions; Dr. MacDonnell provides expertise in development and pediatric psychology, Dr. Naar has expertise in MI and Dr. Stanton on intervention research.Dr. Sadasivam is a computer engineer with extensive expertise in developing technology-facilitated behavioral health interventions.

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Thai MSM are at high risk for HIV infection• Scalable tools to increase PrEP uptake and adherence are a critical need• Adapting existing approaches is a time-saving approach to develop culturally appropriate intervention approachesWeaknesses• Data on low uptake and persistence presented are mostly US data; unclear if these are the same critical issues in Thai MSM2.Investigator(s):Strengths• Dr. Wang is well qualified to lead the proposed work• Dr. Phanuphak is well qualified to serve as a dual PI and oversee research activities • Consultants are well positioned to support the study team.The intervention with Thai YMSM is innovative Weaknesses • Use of DBS to measure PrEP adherence is not innovative 4Preliminary data on MI are compelling • Appropriately phased plan for development of content, production of intervention components and pilot RCT • YAB will provide critical input into the development of the intervention • Use of ADAPT-ITT model is appropriate and provides a good framework for the adaptation • The development of SMS content from the interview context is a strong approach • Mediation analyses using SEM are important supplemental analyses

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The TRC and RSAT clinics are very strong settings for the proposed research • UMass, Wayne State and UCSF are strong institutional settings Weaknesses • None noted by reviewer 1 Clear measures for acceptability and feasibility are proposed • Biological measure for PrEP adherence is a strength, and detailed information about the proper storage and handling of the specimens to assure accuracy of testing Weaknesses • None noted by reviewer Protections for Human Subjects: Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable Inclusion Plans: • 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 Based on Age: Distribution justified scientifically THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES: PROTECTION OF HUMAN SUBJECTS: ACCEPTABLE

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Development of a technology-based intervention offers advantages in reach, cost, anonymity and therefore scalability.

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University of Massachusetts Medical School and the Thai Red Cross AIDS Research Center (the Men's Health Clinic and Tangerine Community Health Center) are outstanding research to oversee the administrative and operational aspects of this study respectively.The Thai Red Cross AIDS Research Center is an HPTN site with extensive experience with complicated and rigorous clinical trials that are used for FDA filings. environments

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For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable• Inclusion/Exclusion Based on Age: Distribution justified scientifically• unclear why trans/nonbinary persons are not included