In 2021, there were approximately 960,000 people living with HIV in Brazil [1]. In recent studies, the HIV prevalence rate was estimated to reach approximately 23% among Brazilian gay men, bisexual men, and other men who have sex with men (MSM) [2] and surpass 30% among travesti and transgender women (TGW) in some cities [3,4]. Young MSM aged ≤30 years are among the few populations with an increasing number of new HIV infections in Brazil, whereas HIV incidence has stabilized in the overall population [2]. Since December 2017, oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) HIV preexposure prophylaxis (PrEP) have been freely available in Brazil through the national public health system (Sistema Único de Saúde [SUS]) [5]. As of October 2022, there were 566 health facilities across all Brazilian states providing oral PrEP to approximately 46,886 individuals [6]. Although 85% of current PrEP users in Brazil are MSM, PrEP use remains well below the initial projections [5].

Tenofovir-based oral PrEP has been effective in dramatically reducing population-level HIV incidence in multiple regions [7-11]. However, to realize the protective benefits of PrEP, individuals need to both initiate PrEP and remain on PrEP during periods of HIV vulnerability [12,13]. Among the individuals who initiated PrEP in the Brazilian SUS, discontinuation was common among MSM (approximately 40%) and TGW (>50%) [6]. PrEP Brasil, a daily oral PrEP demonstration study, found that although 74% of all participants had protective concentrations of tenofovir diphosphate at week 48, young participants and TGW participants had decreasing rates of protective drug concentrations throughout the study [14]. In addition, data from the ImPrEP study, which aimed to evaluate the feasibility of same-day PrEP initiation for MSM and TGW within the public health contexts of Brazil, Mexico, and Peru, identified lower PrEP adherence among TGW and individuals aged ≤30 years [15,16].

Owing to user adherence challenges, PrEP has not decreased HIV incidence among some population, particularly among populations with higher susceptibility (youth, racial and ethnic minorities, and TGW) [17-20]. Although HIV incidence in the ImPrEP study population was relatively low (0.85/100 person-years), it was higher among TGW, participants from Peru, those aged 18 to 30 years, Black or mixed-race participants, and those who were nonadherent to daily oral PrEP [15,16]. These disproportionately worse outcomes reinforce the potential of PrEP agents that do not require daily or planned oral dosing to increase their effective use among the most susceptible populations.

In multiple studies, reasons for discontinuing or never initiating daily oral PrEP include low HIV perceived risk, concerns about medication side effects, desire not to take a daily pill, stigma, competing life events, and challenges accessing the medication [13,21-23]. Long-acting PrEP agents may potentially address some of these concerns by providing consistent protection through infrequent, discrete administration, avoiding the need for daily adherence to an oral regimen and the related need for disclosure to sex partners and acquaintances [24].

Long-acting injectable cabotegravir (CAB-LA) is an integrase strand-transfer inhibitor, and its effectiveness for PrEP has been demonstrated in phase 2b/3 studies (HIV Prevention Trials Network [HPTN] 083 and HPTN 084) [25,26]. HPTN 083 was a double-blind double-dummy randomized controlled trial that assessed the effectiveness of CAB-LA for PrEP compared with oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) PrEP among 4566 cisgender MSM and TGW under high susceptibility to HIV. The blinded phase of the study showed the superiority of CAB-LA, with a 66% reduction in new infections in the cabotegravir arm compared with the active TDF and FTC arm. Similarly, HPTN 084 observed impressive reductions in HIV infections in the CAB-LA arm compared with the TDF and FTC arm among cisgender women in Africa, with an 89% reduction in new infections in the cabotegravir arm when compared with the active TDF and FTC arm. Data from both studies led to the regulatory approval of CAB-LA for HIV prevention in the United States, Australia, South Africa, Malawi, and Zimbabwe. Approval is currently being sought in numerous countries, including Brazil. In July 2022, a recommendation for CAB-LA PrEP was issued by the World Health Organization (WHO) [27].

Although it is reassuring that CAB-LA has demonstrated comparable effectiveness among youth, Black MSM, and TGW in large clinical trials, the advantages of bypassing daily adherence behavior may not be realized if individuals cannot access injectable PrEP or do not return for repeat injections. Implementation studies are needed to provide crucial information about how interventions that are proven efficacious under randomized clinical trial conditions can be optimized for delivery within real-world service settings. The ImPrEP CAB Brasil implementation study aims to generate critical evidence to inform national policies and program implementers about how injectable CAB-LA PrEP can be provided to MSM, nonbinary persons, and transgender persons within public health PrEP services in Brazil. Its implementation objectives are to describe the facilitators of and barriers to integrating CAB-LA into routine public health clinics and to evaluate whether a mobile health (mHealth) intervention optimizes decision-making on the best PrEP regimen among PrEP users and WhatsApp text messaging improves the uptake of and adherence to CAB-LA injection appointments. The primary clinical objective is to evaluate the effectiveness of CAB-LA PrEP in reducing the risk of HIV acquisition in a study cohort of participants in a context where participants can exercise choice in their HIV prevention method (injectable CAB-LA PrEP or daily oral PrEP).

The ImPrEP CAB Brasil (Figure 1) is an implementation study of CAB-LA PrEP among 1200 young adult (aged 18 to 30 years) sexual and gender minorities (SGMs) in 6 Brazilian cities: Rio de Janeiro, São Paulo, Manaus, Salvador, Florianópolis, and Campinas (Figure 2). Each participating site provides PrEP service as a part of the Brazilian SUS.

This is a type-2 hybrid implementation-effectiveness open-label cohort study with a convergent mixed methods approach (quantitative and qualitative). A type-2 hybrid design examines both effectiveness and implementation strategies within the same study [28]. The study will draw on selected implementation science constructs from the theoretical framework for acceptability (TFA) [29], the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework [30], and the framework of Proctor et al [31] to assess the implementation outcomes for the different study objectives outlined earlier. Relevant outcomes and their level of evaluation will include the following: acceptability at the individual health provider and participant levels, reach (choice and uptake) at the individual participant level, effectiveness at the individual participant level, implementation at the setting level (overall delivery), maintenance at the individual participant level, and feasibility at the setting level.

Individuals may participate in up to 4 different steps (Figure 3). In step 1, PrEP naive individuals who come to the study sites seeking PrEP will be exposed to education and counseling about HIV prevention and be informed of the availability of both oral and injectable PrEP. Half of the enrolled participants that tested negative for HIV will receive standard of care (SOC) prevention counseling, and the other half will be exposed to an mHealth education and decision support intervention in addition to SOC prevention counseling. Participants who choose to use injectable PrEP and with an undetectable HIV viral load will enroll in step 2 on the same day, whereas those who choose to use oral PrEP will be referred to the Brazilian Public Health PrEP program at the same clinic. Of the participants who enroll in step 2 and receive a CAB-LA injection, half will be randomized to receive a digital appointment reminder using WhatsApp (Meta Platforms, Inc; the most common messaging app in Brazil). Participants in step 2 who may decide to discontinue CAB-LA during the study follow-up will be invited to step 3 and switch to oral PrEP (TDF and FTC) or keep off PrEP with HIV and sexually transmitted infection (STI) monitoring and counseling for 1 year. Participants from either step 2 or step 3 who are diagnosed with an HIV infection during follow-up will be invited to be enrolled in step 4, where antiretroviral therapy (ART) effectiveness and ART resistance will be monitored for 1 year.

Participants will be included if they (1) are MSM, nonbinary person (assigned as male at birth), TGW, or transgender men; (2) are aged 18 to 30 years; (3) attend one of the study clinics looking for PrEP; (4) are CAB-LA and TDF and FTC PrEP naive; (5) are willing and able to provide written informed consent and adhere to the study requirements; (6) have nonreactive or negative HIV test results, including both third-generation HIV rapid tests and an undetectable HIV RNA at enrollment for individuals choosing injectable CAB-LA; (7) have no report of hepatic dysfunction; and (8) are willing to undergo all required study procedures. The full list of exclusion criteria is described in Multimedia Appendix 1. The study team will provide checklists to aid the site teams in accessing the inclusion and exclusion criteria.

The major clinical and implementation outcomes, levels of analysis, methods, and timing are described in Table 5.

Our major clinical outcome (primary analysis) will adopt an intent-to-treat approach and compare HIV incidence (and 95% CI) among individuals in the CAB-LA cohort with HIV incidence (and 95% CI) among individuals on daily PrEP within the Brazilian SUS. We will estimate the rate of HIV incidence with 95% CI in each group using Kaplan-Maier statistics. We will use a Cox proportional hazard model to assess the relative hazard (hazard ratio with 95% CI) between the 2 groups, overall and by site, age category, and gender.

It is anticipated that there will be an average follow-up of 1.5 years per person with at least 75% retention each year (N=1350 person-years of follow-up) and that incidence will be higher than that observed in HPTN 083 in Latin America (0.60 per 100 person-years). If the observed incidence is approximately 50% higher than that observed in HPTN 083, the study will be able to estimate an incidence of 0.85 (95% CI of 0.47-1.42) per 100 person-years (Table 6). If the observed incidence is approximately twice as high as that observed in HPTN 083, then the study will be able to estimate an incidence of 1.18 (95% CI of 0.72-1.82) per 100 person-years. If the comparison group is of similar size, then the incidence would need to be 2.2 to 2.5 times higher to observe statistically significant differences between CAB-LA and oral PrEP. However, if the comparison group is 3 times larger, then the incidence would need to be 2 to 2.2 times higher to observe statistically significant differences between CAB-LA and oral PrEP.

To reach the primary implementation objective, we will report descriptive statistics (numbers, proportions, and medians) of Likert-scale responses to the TFA constructs (affective attitude, burden, ethicality, intervention coherence, opportunity costs, and perceived effectiveness and self-efficacy) among health care providers.

The study protocol and informed consent forms were reviewed and approved by the Evandro Chagas National Institute of Infectious Diseases (INI), Fundação Oswaldo Cruz (Fiocruz) institutional review board (August 25, 2022; #CAAE 59166522.7.1001.5262) and the Research Ethics Review Committee at the WHO with respect to scientific content and compliance with applicable research and human participants’ regulations. The protocol, site-specific informed consent forms, participant education and recruitment materials, and any requested documents and their subsequent modifications were also be reviewed and approved by the ethical review bodies responsible for the oversight of the research conducted at each of the study sites. Informed consent will be obtained in 2 study steps. In step 1, consent will be obtained from participants who visit the site looking for PrEP. In step 2, the participants will provide consent for the use of injectable CAB-LA PrEP. This study may be paused or stopped at any time by the local institutional review board or the study’s principal investigator.

ImPrEP CAB Brasil is the first study to evaluate CAB-LA PrEP implementation in Latin America. Latin America is one of the regions where PrEP scale-up, as well as the reduction of inequalities in PrEP access, is most needed. We hereby describe the study protocol, providing details of the study’s objectives, procedures, outcomes, and statistical analysis to aid researchers from Brazil, Latin America, and other regions during CAB-LA implementation within public health systems.

To date, no clinical or implementation results are available for injectable PrEP with CAB-LA in real-life settings. We expect the acceptability of CAB-LA in Brazil to be high. Data from a web-based survey and descriptive choice experiment have shown that injectable PrEP was preferred over other PrEP modalities in Brazil [35-37]. Our results regarding PrEP choice among individuals seeking PrEP in health units will increase this body of evidence. For instance, in the field of contraception, the increased availability of options and informed decision-making in the choice of contraception have improved the uptake and persistence of the methods used [38]. It is likely that expanding the method options for PrEP will similarly improve uptake and persistence.

Our study will also contribute to the expansion of the knowledge on the best HIV testing algorithm to be implemented in low- and middle-income countries when using CAB-LA for PrEP, which is a major need.

This study is coordinated by INI-Fiocruz, an internationally recognized research institution and the leading reference center in Latin America for infectious diseases. INI-Fiocruz has been working closely with the Brazilian Ministry of Health (BMOH), the Pan American Health Organization, Unitaid, and the WHO to address evidence gaps and identify key learnings to inform the introduction of injectable CAB-LA PrEP among the most susceptible populations. The INI-Fiocruz team has extensive experience in engaging SGMs in demand creation, providing HIV combination prevention services that foster PrEP uptake and retention and advocating for enhanced HIV prevention policies [39,40]. In addition to being a recognized academic institution, INI-Fiocruz is the largest HIV prevention and treatment center in Rio de Janeiro, Brazil, with over 1000 SGMs tested per year [41]. The INI-Fiocruz study team was responsible for planning, designing, and implementing the PrEP Brasil study [14], which provided critical evidence to support the BMOH in the incorporation of PrEP as a public health policy. The team also coordinated the ImPrEP study, which provided information for PrEP surveillance in Brazil, and PrEP implementation in Mexico and Peru [16].

This study is poised for informing policy makers, building public health staff capacity, and creating environments for successfully implementing the proposed prevention strategies in collaboration with the BMOH. Moreover, we expect the mHealth component to be highly acceptable and possibly implemented within the Brazilian public health system.

The ImPrEP CAB Brasil study will contribute to the generation of valuable information to inform the design of programmatic strategies for implementing CAB-LA PrEP in Brazil, maximizing the public health impact of PrEP in reducing HIV incidence among young SGMs in Brazil, Latin America, and other countries in the Global South.