Clinic-Integrated Mobile Health Intervention (“JomPrEP” App) to Improve Uptake of HIV Testing and Pre-exposure Prophylaxis Among Men Who Have Sex With Men in Malaysia: Protocol for an Intervention Development and Multiphase Trial

Background Men who have sex with men (MSM) are disproportionately affected by the HIV epidemic in Malaysia and globally. Cross-cutting prevention strategies such as mobile health (mHealth), particularly smartphone apps, hold great promise for HIV prevention efforts among Malaysian MSM, especially when linked to HIV testing and pre-exposure prophylaxis (PrEP). Objective This study aims to adapt an existing app to create and test a clinic-integrated app (JomPrEP), a virtual platform to deliver HIV testing and PrEP services for MSM in Malaysia. Methods The JomPrEP project involves developing and testing an app-based platform for HIV prevention among Malaysian MSM and will be conducted in 2 phases. In phase I (development phase), we will adapt an existing mHealth app (HealthMindr) to create a new clinic-integrated app called “JomPrEP” to deliver holistic HIV prevention services (eg, HIV testing, PrEP, support services for mental health and substance use) among MSM in Malaysia. During phase II (testing phase), we will use a type I hybrid implementation science trial design to test the efficacy of JomPrEP while gathering information on implementation factors to guide future scale-up in real-world settings. Results As of September 2022, we have completed phase I of the proposed study. Based on a series of formative work completed during phase I, we developed a fully functional, clinic-integrated JomPrEP app, which provides a virtual platform for MSM in Malaysia to facilitate their engagement in HIV prevention in a fast and convenient manner. Based on participant feedback provided during phase I, we are currently optimizing JomPrEP and the research protocols for a large-scale efficacy trial (phase II), which will commence in January 2023. Conclusions Scant HIV prevention resources coupled with entrenched stigma, discrimination, and criminalization of same-sex sexual behavior and substance use hamper access to HIV prevention services in Malaysia. If found efficacious, JomPrEP can be easily adapted for a range of health outcomes and health care delivery services for MSM, including adaptation to other low- and middle-income countries. Trial Registration ClinicalTrials.gov NCT05325476; https://clinicaltrials.gov/ct2/show/NCT05325476 International Registered Report Identifier (IRRID) DERR1-10.2196/43318


PUBLIC HEALTH RELEVANCE:
The proposed research focuses on developing and prospectively testing the efficacy of a clinic-affiliated app (myCareLink) to deliver an integrated HIV prevention intervention in Malaysian MSM.We expect that this project will lead to the development of an innovative and culturally tailored app that will promote HIV testing and linkage to PrEP by addressing co-morbid psychiatric and substance use disorder (P/SUD) in Malaysian MSM.

CRITIQUE 1
Significance: 1 Investigator(s): 1 Innovation: 3 Approach: 2 Environment: 1 Overall Impact: This application proposes to develop and test the efficacy of a clinic-affiliated app (myCareLink) to deliver an integrated HIV prevention intervention that will promote HIV testing and linkage to PrEP and incorporates screening and support for underlying P/SUD in Malaysian MSM.The R21 phase will consist of 2 stages: 1) adaptation, expansion and refinement of an existing app, which will be integrated within the existing clinical care system.This will involve focus groups with MSM (n=25) and stakeholders (n=10) to theater test the existing app to develop an interactive prototype of the myCareLink app (alpha version).Then, the prototype will undergo usability testing (n=20), followed by the full development of the app (beta version); 2) Expanded Beta testing (n=50) of the myCareLink app will assess its usability and acceptability.The R33 phase will involve a Type 1 Hybrid Implementation Science Trial to evaluate the efficacy of myCareLink app vs. treatment as usual (TAU) in 268 Malaysian MSM for primary (HIV testing and PrEP uptake) and secondary (PrEP adherence and persistence) efficacy outcomes.Multi-level implementation outcomes will involve stakeholders' perspective of the relative advantage of myCareLink app over TAU, adaptability, perceived design quality and packaging, compatibility in the Malaysian context, interest in sharing the app with others and readiness for implementation.Research capacity strengthening between Yale and the University of Malaya will occur through collaborative learning between researchers at both institutions to promote expansion of mHealth research.• Central to this expanding HIV epidemic in MSM is condomless sex, STIs, and co-occurring psychiatric and substance use disorders (P/SUD), especially depression and amphetamine-type stimulant (ATS) use.
• Malaysia's HIV prevention gap are large for population due to stigma and criminalization of homosexuality and substance use, creating significant barriers to service.Therefore app-based screening and education can support reach of HIV and mental health care.
• Strategies that facilitate screening and prevention practices in a non-judgmental fashion are likely to increase access to evidence-based prevention like HIV testing and pre-exposure prophylaxis (PrEP), especially if screening and counseling addresses P/SUD.Introducing an innovative app-based platform to deliver holistic HIV prevention services represents a paradigm shift in HIV prevention since it can deliver effective prevention in a confidential, less-stigmatizing and convenient manner.
• High relevance for other LMICs and scalability for Malaysia Weaknesses 2. Investigator(s):

Strengths
• The PI has expertise in intervention adaptation, HIV and substance use prevention, clinical trials of HIV prevention and treatment, PrEP, mHealth, and a longstanding collaboration with researchers at the University of Malaya (UM) and Yale.
• interdisciplinary team has a strong track record working at the interface of the HIV prevention cascade, P/SUD, MSM and Malaysia's healthcare system.The team has led several efforts to develop and test various mHealth interventions for both prevention and treatment.
• The team (Drs.Altice, Kamarulzaman, Azwa, Wickersham, Anne, and the Malaysian AIDS Council) have had considerable success in changing public policy in Malaysia over the years by holding annual stakeholder meetings and presenting research findings.These meetings include both international (NIH, WHO, UNAIDS, UNODC, USAID, and Global Fund) and national (Ministry of Health, Ministry of Internal Affairs, NGOs, healthcare providers, researchers, etc.) stakeholders suggesting potential for policy influence.

Weaknesses
• none

Strengths
• use of a Type I hybrid implementation trial to obtain primarily efficacy outcomes with additional implementation guidance for the new app adoption and scale-up • incorporation of screening and guidance for co-morbid P/SUD in MSM needing HIV testing and PrEP delivery • app adaptation and deployment that addresses multiple levels of the HIV prevention cascade in a LMIC Weaknesses • use of apps for screening and guidance has been done, but facilitation of an express entry point to HIV testing and PrEP without direct contact with clinician is key to reducing stigma and barriers to care.

Strengths
• Use of IS framework and use of hybrid Type 1 design to test efficacy primarily and implementation secondarily.
• interdisciplinary team has a strong track record working at the interface of the HIV prevention cascade, P/SUD, MSM and Malaysia's healthcare system.The team has led several efforts to develop and test various mHealth interventions for both prevention and treatment.
• For R21, the team will adapt the existing app (HealthMindr) and expand and refine it to make culturally appropriate in the Malaysian context.The new, clinic-affiliated myCareLink app will be designed to deliver an integrated HIV prevention intervention that incorporates screening and guidance for co-morbid P/SUD in Malaysian MSM.The app will be developed in collaboration with Keymind, an experienced mobile app development company that has significant experience in building HIPAA-compliant apps, including HealthMindr.
• They will use the modified IM Adapt model to adapt the HealthMindr app to create the myCareLink app for optimal use in Malaysian MSM.The modified IM Adapt model consists of four sequential steps needs assessment, finding right intervention, theatre testing • Good procedures for R33 hybrid study • The team will form a multidisciplinary mHealth Capacity Building (MCB) Committee to increase the research capacity of faculty and students at UM and to expand their scope and experiences with research to include mHealth.Over the five years, the MCB committee will: a) assess challenges and opportunities for increasing mHealth research initiatives at UM; b) identify needs for programmatic changes or educational offerings related to mHealth; and c) formulate specific, realistic goals and a detailed action plan to achieve goals pertaining to mHealth capacity building.This platform is ideally situated to gather sufficient information to guide a future Fogarty Training program in mHealth across a number of diseases and guide LMIC scholars to submit Fogarty K01 applications.A key strength of this program is the longstanding collaboration between UM and Yale (over 15 years) and commitment to health equity in key populations with or at risk for HIV in Malaysia.This program fully aligns with UM's new mandate to build and strengthen its research capacity generally in the areas of mHealth and implementation science.
• The MCB committee will conduct several activities crucial to mHealth research capacity-building efforts between Yale and UM and will expand beyond the faculty at Yale and UM on this application.Drs.Ng and Altice are well-poised to bring scholars from both institutions together.UM currently has two Fogarty Training programs (HIV and Aging and Research Ethics) with another on HIV implementation science (Altice/Kamarulzaman MPIs) under review.These prior and ongoing successes speak to the potential for aligning research and collaboration between UM and Yale and translating it to future research and capacity building.UM has increased its international standing having risen from 151 in 2015 to 70 in 2020, attesting to its interest and ability in becoming a leader in research and training in the Asia Pacific region.Additionally, research activities proposed in this application will strengthen the mHealth research capabilities at UM by: a) fostering a collaborative partnership between UM's clinical, community health and health informatics entities; b) extending UM's domestic and international research network; and c) facilitating UM's partnership with academia, industry, and government for mHealth research.It is likely that the MCB committee will sustain itself under the UMeHI and maintain momentum and progress on mHealth capacity building even beyond the scope of this proposed project.

Weaknesses
• Mental health screening and education can be strengthened.PHQ-2 under detects depression for populations with mental health literacy • Messages for mental health have not been identified from evidence-based or it does not appear to be so.When will these messages get developed?Given the costly development of this contact, it may be better to adapt from existing tested mental health promotion.

Strengths
• longstanding relationships between Yale and University of Malaya with over 15 years of successful foreign collaborations and partnerships in medical and public health research for key populations, including MSM.  important factors, such quantifiable milestones, a data sharing plan, a data safety monitoring plan, and a well articulated plan to increase the mHealth research capacity at UM.

Strengths
• Addresses an important need in a high incidence population (Malaysian MSM) • Tackles the extra difficult step of finding and communicating with those who are not "out of the closet"

Weaknesses
• A major argument for the use of mHealth to communicate with key populations is the ability to maintain confidentiality.However, we the US government has purchased vast quantities of GPS data from cellphone companies.GPS data virtually eliminate the possibility of anonymity.In time, transmission of information via cellphone could become the *least* private way to communicate with health care providers.

Strengths
• The PI is an Associate Research Scientist (elsewhere referred to as a postdoctoral associate) in Yale's Dept of Infectious Diseases.She works with Frederick Altice, also at Yale, who is the PI on another application for this award.Although junior, Shrestha is accomplished, with publications stemming from research on mHealth applications and HIV in Malaysia.
• Shrestha's primary Malayan co-investigator has a good track record of conducting studies and publishing.He leads the eHealth agenda in University of Malaya to promote the use of ICT in improving health care.

Weaknesses
• None

Strengths
• The innovations they claim include adaptation of an existing app (HealthMindr), integration into existing clinic settings, and inclusion of P/SUD symptoms and needs.These innovations may also enhance the sustainability of the app, provided the other clinic personnel find it useful.• The steps of adaptation, implementation, and evaluation are appropriate and achievable.

Weaknesses
• The R33 phase includes a step in which participants share the app with nonparticipants, providing some insight into the acceptability among people not recruited face-to-face by the investigators.

Weaknesses
• The means of strengthening capacity for mHealth research is vague, amounting to collaboration between the researchers.Beyond collaboration they mention forming a capacity building committee, but they don't say what the functions or goals of the committee will be.

Strengths
• Centre of Excellence for Research in AIDS (CERiA) at the University of Malaya Medical Centre has an established record for HIV-related research in Malaysia.
• The Yale Schools of Medicine and Public Health provide a strong and experienced support infrastructure for this study.

Strengths
• A rationale is provided for each milestone

Weaknesses
• It isn't clear whether the milestones in section C.4. apply to the end of the R21 phase or the R33 phase, or a mixture of the two.
• The milestones are not quantitative.

Strengths
• The study should be achievable in the time provided.• Not applicable Resubmission:

Protections for Human Subjects:
• Not applicable Renewal: • Not applicable Revision: Overall Impact: New HIV infections are increasingly concentrated among key populations such as MSM.However, access to HIV testing, linkage to care, and pre-Exposure Prophylaxis (PrEP) remain low among MSM in LMIC including Malaysia.This is a well written and well-researched proposal that presents a mHealth system, called myCareLink, an 'app' that will deliver an integrated HIV prevention intervention that will promote HIV testing and linkage to PrEP.The innovation is to incorporate screening and support for underlying psychiatric and substance use disorders.The proposed mHealth intervention will be adapted to the cultural context and tested in a trial compared to 'treatment as usual'.Preliminary work by the investigators qualitative interviews with MSM in Malaysia indicated preferences for interfacing with 'apps' rather than health professionals to access HIV testing, PrEP, counseling services.By combining support for HIV testing, uptake for PrEP and mental health in a single 'app' accessible to MSM, myCareLink system has real potential to make a scalable breakthrough advance in a very difficult Problem in LMICs.If successful, the proposed is likely to yield relatively high public health impact.

Strengths
• HIV incidence in Malaysia is increasing in MSM, especially where stigma and discrimination are high • Demonstrates prior research to support premise of the study that HIV testing and PrEP scale-up for HIV is the most effective and cost-effective strategy to reduce HIV transmission, especially in MSM • HIV testing is a critical barrier in MSM population in Malaysia-less than 50% had HIV tested in past 12 months • Presents evidence that mHealth is a cost-effective strategy to reach stigmatized and hard-toreach populations, like MSM, and linking them to care.

Weaknesses
• None

Strengths
• The PI has expertise in intervention adaptation, HIV and substance use prevention, clinical trials, PrEP, mHealth, and a longstanding collaboration with researchers at the University of Malaya (UM) and Yale.
• PI has demonstrated experience in proposed area of research in MSM, with several peerreviewed scientific publications • PI has successfully obtained internal funding to conduct substantial preliminary research work on the same topics in the US and Malaysia • integration of the app into existing clinical care settings to facilitate an "Express" entry point for HIV testing and PrEP delivery (PrEPxpress) to reduce direct contact between MSM and clinicians

Weaknesses
• None

Strengths
• Provided a strong and thorough overview of the approach informed by preliminary studies • The methods and procedures for developing and adapting the existing mHealth App and expected results are well-described in a systematic way (R21) • (R33) A robust Type 1 implementation trial design will be use to assess efficacy of the intervention compared to treatment as usual.
• Procedures of recruitment, randomization and analysis are clearly described • Plans to minimize bias from contamination across groups are presented • Appropriate measures to minimize risks related to privacy and security are specified

Weaknesses
• Self-reported HIV testing as a primary outcome raises some concerns of bias, especially in the case of self-testing.
• No description of potential sources of data on HIV testing as primary outcome

Strengths
• The collaborating institution have well-established infrastructure and a longstanding history of research partnership, which will provided an excellent environment for the success of the project.

Strengths
• The steps clearly described in the exploratory R21 phase and the three milestones proposed are conceivable and make logical sense linking to the R33 phase that will likely support the successful transition and completion of the overall project.

Weaknesses
• Quantifiable measures are not presented to form a basis for guidance, for example no measure of extend of integration of myCareLink in clinical settings Footnotes for 1 R21 TW011665-01; PI Name: Shrestha, Roman # Ad hoc or special section application percentiled against "Total CSR" base.
NIH has modified its policy regarding the receipt of resubmissions (amended applications).See Guide Notice NOT-OD-18-197 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-197.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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The behavioral interventions are based on appropriate behavioral theories

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No mention of a data sharing agreement between Yale and UM Authentication of Key Biological and/or Chemical Resources: Not Applicable (No Relevant Resources)

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Has assembled a strong team of investigators with extensive experience with mHealth behavioral interventions, implementation science, including the conduct of Hybrid Trials.•Collaboration with an experienced mobile app development company that has significant experience in building HIPAA-compliant apps New app-based platform to deliver holistic HIV prevention services represents a paradigm shift in HIV prevention since it can deliver effective prevention in a safe, confidential, lessstigmatizing and convenient manner.
Subjects: Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable Inclusion Plans: Applicable Only for Human Subjects research and not IRB Exemption #4.• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: • For NIH-Defined Phase III trials, Plans for valid design and analysis: Scientifically acceptable • Inclusion/Exclusion Based on Age: Distribution justified scientifically or possible overlap identified: 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: 'S NOTES: At the end of the discussion, the review panel wondered if the human subjects would have sufficient protection for mental health.
Numerous strengths,15 year track record of successful research and capacity building of University of Malaysia.Screening and health promotion app can help patients overcome stigma and barriers to receiving direct care.The R21 and R33 are well thought out.The team is expansive with longstanding record of working together and impacting policy in malaysia.Development of app is iterative, involving end user feedback throughout.Good integration of implementation science to inform development.Can improve mental health screening and health promotion aspects of the intervention.
1. Significance:Strengths• Malaysia's HIV epidemic is rapidly expanding with recent evidence suggesting accelerated sexual transmission, especially in MSM: 10% in 2008 to 54% in 2016.

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Centre of Excellence for Research in AIDS (CERiA) at the University of Malaya Medical Centre (proposed research site in Malaysia), CERiA has longstanding ties with the Ministry of Health, Ministry of Prisons, WHO, USAID, and World Bank.Moreover, we are collaborating with the HIV Unit at the University of Malaya Medical Centre (UMMC), the Red Clinic, the PT Foundation, and the Malaysian AIDS Council (serves as an umbrella organization to support and coordinate the efforts of non-governmental organizations working on HIV/AIDS issues in Malaysia) to deliver seamless and integrated HIV prevention services as well as guidance for psychiatric and substance use disorders, while ensuring sustainability and further expansion of the myCareLink app.
Weaknesses• Not clear how new content will be integrated into app which can be a milestone 1Study Timeline: (

Specific to applications designated clinical trial on the electronic cover sheet)
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable Inclusion Plans: Applicable Only for Human Subjects research and not IRB Exemption #4.

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For NIH-Defined Phase III trials, Plans for valid design and analysis:• Inclusion/Exclusion Based on Age: Distribution justified scientifically

Resource Sharing Plans: Acceptable Authentication of Key Biological and/or Chemical Resources:
Not Applicable (No Relevant Resources)

Budget and Period of Support:
Overall Impact: In adaptation of an existing app for reaching and advising Malaysian MSM, there are experienced researchers and supportive environments.The methods for much of the study are appropriate and well thought out.However, the investigators do not adequately address a number of

Inclusion Plans: Applicable Only for Human Subjects research and not IRB Exemption #4.
A pdf with the plan is mentioned, but I did not have access to it o

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For NIH-Defined Phase III trials, Plans for valid design and analysis: Scientifically acceptable• Inclusion/Exclusion Based on Age: Distribution justified scientifically