Title: Implementing oral (event-driven and daily) and long-acting Pre-exposure prophylaxis (PrEP) in mobile men in Sub-Saharan Africa

Design: A mixed method, multi-setting, multi-country, phase 3b, open-label, hybrid type 2 implementation and effectiveness randomized controlled trial (RCT). The trial will be carried out in 400 HIV negative men aged 18+ years in South Africa and Uganda. Men will be randomized 1:1 to either Group A: oral Tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) PrEP (event-driven or daily) or Group B: Long-acting injectable cabotegravir (CAB-LA) over 9-months. After 9-months participants from both groups will be offered choice of PrEP (oral TDF-FTC or CAB-LA) for a further 9-months, with the ability to change choice as required. Various strategies to support PrEP adoption, initiation, and persistence will be implemented, monitored, and reported on using a RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation science framework.

Treatment: CAB-LA or oral TDF-FTC Duration: 18 months

BACKGROUND HIV prevention pre-exposure prophylaxis (PrEP) has not been evaluated in men who mainly have sex with women and who may be at high risk of HIV acquisition due to high HIV prevalence in partners or particularly risky behaviours. Research to fill these data gaps is required to facilitate their inclusion in PrEP guidelines. Furthermore, with increasing PrEP options, recommendations to users and providers in high-burden / resource constrained settings is a key focus of the Sustainable Development Goal target to end AIDS by 2030. To date, HIV prevention research has largely focussed on adolescent girls and young women (AGYW) in low and middle income countries and men who have sex with men (MSM) in high income countries. Research on the user experience and choice of oral PrEP or CAB-LA PrEP amongst vulnerable heterosexual men is required.

Men consistently fare worse than women in levels of HIV testing and ART initiation with significant challenges in sub-Saharan Africa (SSA) for engagement and persistence in HIV treatment programmes well described. Despite this, heterosexual men represent the largest unaddressed gap in HIV services in SSA. Indeed, the failure of Treatment As Prevention trials (TASP) to show effect was in the main due to the failure to test and treat young men. Men who are mobile for work or through looking for work, are viewed by the WHO as a key population at high risk for HIV. As Africa's large youth bulge moves into young adulthood, the search for work and consequent mobile lifestyles will further increase.

In order to improve uptake, persistence, and effective use of all forms of PrEP, there is a need for simplified and differentiated delivery of PrEP that is person- and community-centred specifically for men. Effective use requires that all sex acts are covered by an effective prevention intervention such as PrEP. Given the importance of flexibility due to travel in this group, our hypothesis is that both oral PrEP (in particular, event-driven) and CAB-LA PrEP will be highly acceptable to men in two high-burden, resource limited, African countries, with high levels of effective use including persistence and coital coverage.

This is the first multi-country PrEP study for implementing both event-driven oral PrEP and Long-acting injectable cabotegravir (CAB-LA) in men in SSA (South Africa and Uganda). The programme will provide the evidence and cost-effectiveness analysis which is critical to decision making by African governments and donors on how to prioritise prevention resources and inform guidelines.

STUDY OBJECTIVES Effective use is defined as PrEP uptake and persistence, retention in care, and HIV exposure coverage with adequate drug tissue levels.

Overall Objective To assess effectiveness and implementation of CAB-LA and oral TDF-FTC (both daily and event driven) through comparison of uptake, retention in care, coital coverage, and participant choice

Primary Objective

1. Primary user effectiveness objective: To compare short term (9 months) and longer term (18 months) PrEP persistence patterns across different PrEP modalities (oral and injectable) amongst men who are mobile for work in South Africa and Uganda.
2. Primary implementation objective: To compare adoption (uptake and choice) across the different PrEP modalities (oral and injectable) amongst men who are mobile for work in South Africa and Uganda.

Adoption is defined as 1) uptake: do people accept and use the intervention they're randomised to, and 2) choice: based on the post-randomised period, i.e., months 9-18, what PrEP do they choose)

Secondary clinical objectives

1. To compare the effective coital coverage of oral daily/on-demand oral TDF-FTC versus CAB-LA
2. To describe the safety, tolerability and acceptance of all methods, as determined by self-reported adverse side effects, AEs and reasons for PrEP pause or discontinuation.

Secondary implementation objectives:

1. To understand the Reach of PrEP for mobile men and understand the barriers to and facilitators of uptake amongst those at risk who do and do not accept oral or LA PrEP.

2. To describe adoption:

   1. To identify characteristics of men who adopt oral PrEP versus CAB-LA
   2. To describe patterns of use of daily, on-demand, and long-acting PrEP amongst different groups of mobile men.

3. To understand the implementation of on-demand and long-acting PrEP for mobile men amongst service providers to inform scale-up.

   1. To understand the feasibility and fidelity of delivering on-demand and long-acting PrEP in different settings.
   2. To describe how on-demand and long-acting PrEP are delivered in practice.
   3. To describe the service-level needs to implement on-demand and long-acting PrEP.
   4. To evaluate acceptabiltiy and implementation of antibody based monitoring HIV status for CAB-LA.

4. To assess the total and average cost of oral PrEP and CAB-LA in South Africa and Uganda under study conditions from the provider perspective (Maintenance).

Exploratory objectives

1. To describe HIV incidence across the two PrEP modality arms
2. To describe any evidence of HIV drug resistance mutations in participants who acquire HIV infection whilst using PrEP across the two PrEP modality arms.
3. To describe persistence in care of those diagnosed HIV infected at screening.
4. To describe body mass index (BMI) and blood pressure across both arms.

STUDY DESIGN We will use a hybrid effectiveness implementation type 2 trial to evaluate the initial implementation (scale-up) phase of CAB-LA as a PrEP option in men who are mobile for work in South Africa and Uganda with a high burden of HIV. This is a Phase 3b, open label, hybrid type 2 study with co-primary aims of effective use and implementation.

This is a mixed method, multi-setting, multi-country randomized controlled trial (RCT), carried out in South Africa and Uganda to compare persistence in care for oral PrEP and CAB-LA in mobile men, which will inform PrEP implementation in men. Mobile men aged 18+ years, will be recruited from outreach settings in South Africa and Uganda. Those testing HIV negative (target sample size, n=400) will be randomized into 2 groups: Group A will receive oral TDF-FTC PrEP (using either event-driven or daily) and Group B will receive CAB-LA over 9-months. After 9- months participants from both groups will be offered choice of PrEP for a further 9-months, with the ability to change choice as required. Switch PrEP options will be monitored. Those receiving oral PrEP will be able to choose between event-driven and daily PrEP with the emphasis on coital coverage by PrEP.

Implementation Framework: The project utilises the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance) to evaluate MOBILE MEN's PrEP delivery preferences and patterns of use.

Participants will be supported in taking PrEP and the social science and implementation science data collection will feedback findings in real time, on the ways to facilitate men to maximise their adherence to PrEP.

Healthcare providers will be trained to deliver oral (daily and event driven) and injectable PrEP, develop services which are mobile men friendly- non-judgemental, timing and location appropriate for men.

Data will be collected in Uganda and South Africa.

Recruitment settings:

A decentralized model of care for recruitment and persistence in ongoing study will be developed whereby study visits will be conducted through mobile and outreach clinics. Demand creation for PrEP will take place through a community engagement campaign and peer outreach activities prior to the study starting, whereby men in the communities are exposed to PrEP educational materials and encouraged to visit community and public health sites to access sexual health services, including PrEP. Potential participants will be provided with educational information about each of the PrEP products through both the enrolment visit and as part of a community-wide demand creation campaign which precedes the study.

Inclusion Criteria:

1. Able and willing to provide informed consent
2. Aged 18 years and above on the day of screening
3. Willing to have a HIV test and receive the test results
4. Male at birth
5. In the past 6-months has travelled for work or to find work and spent at least one night away from home for work related purposes.
6. Available for follow up for the duration of the study

Exclusion Criteria:

1. Known HIV infection
2. Confirmed HIV-positive test result, indeterminate HIV test result, and/or signs and symptoms of an acute HIV infection
3. Body weight less than 35Kg at baseline
4. Allergy to any of the study products
5. Medical, social or other condition that, in the opinion of the site investigator, would interfere with the conduct of the study or safety of the participant (e.g., provided by self-report, or found upon medical history and examination or in available medical records)
6. Use of contraindicated medications: Medication for tuberculosis (Rifampin, rifapentine) or anticonvulsants (Carbamazepine, oxcarbazepine, phenobarbital, phenytoin)
7. Other reasons at the discretion of site investigator for unsuitability for study inclusion

The team is committed to open access data. The results of the study and anonymized data sets will be published in open access peer-reviewed journals and data repositories.