Pre-exposure Prophylaxis (PrEP) taken as prescribed before HIV exposure is effective in preventing HIV infection among people exposed to HIV through sex or injection drug use [1]. The Ending the HIV Epidemic (EHE) initiative and the HIV National Strategic Plan 2021–2025 highlight PrEP as one of the key strategies to reduce new HIV infections [2,3]. It has been more than 10 years since the U.S. Food and Drug Administration (FDA) approved the first PrEP medication to prevent HIV transmission in 2012 [4]. Yet, there were still 36,136 HIV diagnoses in the U.S. in 2021; groups most affected are men (79%), gay, bisexual and other men who have sex with men (collectively referred to as MSM) (67%), Black/African American (hereafter referred to as Black) or Hispanic/Latino persons (59%), people aged 13 to 34 (56%), and those living in South (52%) [5]. Overall, PrEP prescriptions have been increasing among persons in the U.S. who could benefit, but still remain lower than the national goals [6,7]. Despite these increases, PrEP coverage is far from equal and substantial disparities persist among subgroups (e.g., Blacks and Hispanic/Latinos have lower rates of PrEP prescriptions than White persons). Identifying effective interventions for increasing PrEP use is important in reaching national HIV prevention goals.

To inform national prevention efforts, the U.S. Centers for Disease Control and Prevention’s (CDC’s) Prevention Research Synthesis (PRS) Project [8] has conducted an on-going evaluation of PrEP interventions since 2020. The PRS Project has been identifying evidence-based interventions (EBIs) and evidence-informed (EIs), collectively referred to as Best Practices, for increasing PrEP use and persistence in its Compendium, a compilation of effective HIV interventions [9]. The purposes of this study are to 1) summarize the characteristics of Best Practices for increasing PrEP use and persistence in the U.S. and 2) explore the research gaps based in the current PrEP behavioral intervention literature.

A protocol was registered in PROSPERO (CRD42021256460) [10]. Our report followed the guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRSIMA) Statement [11].

As of January 2023, there were 3,974 PrEP-related citations in the CDC PRS cumulative database (Figure 1). The majority were not behavioral interventions and excluded from our review. After we screened 266 full reports to assess for eligibility and excluded studies that did not report relevant outcomes, 24 eligible intervention studies were identified. Among the 24 studies, the majority of studies (n=14, 58%) were published in or after 2020. Sample sizes ranged from 10 to 29,262 with a median of 121 (interquartile: 54–316). Most (n=18, 75%) were conducted with sexually active MSM as defined by the authors [16–33] (Table 1). The majority of studies were RCTs (n=14, 58.3%) [16–18,20–22,24,26–28,30–32,34] while others were either pre-post studies (n=8, 33.3%) [19,23,29,33,35–38] or serial cross-sectional (n=2, 8%) [21,39].

Most common PrEP-related outcomes reported were PrEP medication adherence (n=12, 50%) [17,19,20,22,23,26–29,33,35,38]. Eight (33%) studies [19,22,26,28,29,32,33,40] used digital health technologies.

Of the 24 intervention studies, nine (37%) were determined to be Best Practices (4 EBIs [26,28,31,32] and 5 EIs [27,29,30,33,39]) (Table 2). The remaining studies (n = 15, 63%) did not meet Best Practices criteria (see appendix) because of either null/non-significant findings (n=14, 93%) [16–24,34–38] or small sample size (i.e., <25 per arm) (n=1, 7%) [41].

Given the importance of increasing PrEP prescription and use for EHE efforts, it is encouraging to have identified nine PrEP Best Practices in the United States to date. The nine Best Practices represent 37% of eligible PrEP interventions reviewed (i.e., 9 out of 24). More than half of Best Practices are mHealth interventions and conducted with MSM. No Best Practices were found for women, Hispanic/Latino persons, and persons who inject drugs (PWID). HIV continues to have a disproportionate impact on these populations and the PrEP coverage remains uneven [6,7]. These gaps call for additional research.

We offer observations from this systematic review and supplement our discussion by highlighting upcoming studies we obtained from the NIH Research Portfolio Online Reporting Tools (RePORTER) and what we have seen in Best Practices for other HIV outcomes (e.g., risk reduction, linkage to and retention in HIV care). First, three of four EBIs (i.e., iTAB, PrEPmate, M-Cubed) and two of five EIs (i.e., iTEXT, DOT Mobile App) use mHealth strategies. This finding aligns with the recently released recommendation by the Community Guide that digital PrEP interventions are effective for PrEP outcomes [42]. Our review findings also suggest that a longer intervention duration and bi-directional messaging may be important for improving PrEP outcomes such as adherence. Longer intervention periods may provide more time for intervention exposure to facilitate behavioral change and two-way messaging may help participants feel supported. An upcoming study, the PrEP-3D intervention, is a pharmacist-led PrEP program that uses mobile apps and bi-directional messages to improve PrEP use among MSM [43], which may contribute further knowledge about the effectiveness of pharmacist-led PrEP programs and bi-directional messaging.

Second, Black persons, especially MSM, are disproportionally affected by HIV. Increasing PrEP access and use in these communities with unmet needs is essential, but the results for culturally tailored interventions to improve PrEP initiation/uptake for Black persons are mixed. One Best Practice is the PrEP Counseling Center which was conducted with young Black MSM (i.e., the ages of 16–25 years old) and consisted of a personalized comprehensive PrEP counseling session with a staff member who identified as a Black MSM and had extensive outreach and counseling experience related to HIV prevention and PrEP needs [30]. Two other culturally tailored interventions evaluated in this review (EnPrEP and Passport to Wellness) [17,18] did not show evidence of improving PrEP initiation/uptake among Black persons. They implemented culturally-informed, peer-based and client-centered peer support or support groups led by a peer navigator [17,18]. EnPrEP and Passport to Wellness included older populations while the PrEP Counseling Center focused on young Black MSM. One upcoming study by Arnold and colleagues is implementing Acceptance and Commitment Therapy PrEP (ACTPrEP), a culturally-tailored intervention for young Black MSM [40]. The intervention is based on the modified social ecological model of HIV infection risk that acknowledges multilevel domains such as individual (e.g., perception of HIV risk), social and sexual networks (e.g., stigma), community (e.g., lack of medical services), and public policy (e.g., cost of care). A PrEP navigator will be addressing barriers by promoting awareness and engagement in behaviors to improve PrEP uptake, persistence, and adherence. More culturally tailored interventions to address barriers to PrEP uptake and use are warranted to better understand what strategies work for different populations.

Third, the majority of Best Practices are for MSM although the current U.S. Public Health Services PrEP clinical practice guideline recommends to inform all sexually active adults and adolescents about PrEP and prescribe PrEP to people who request it, even if they do not report sexual or drug-injection practices that may put them at risk of acquiring HIV [44]. Populations that warrant attention are Hispanic/Latino persons, PWID, and women of color, especially Black women. An upcoming study in NIH’s RePORTER focuses on young Hispanic/Latino MSM and aims at improving PrEP use by reducing intersectional stigma for HIV testing and PrEP uptake [45]. For PWID, we identified one study but the study was not included in this review due to lack of pre-intervention data [46]. The study found feasibility and high acceptability of the bio-behavioral community-friendly health recovery program integrated in HIV prevention intervention to improve PrEP adherence. A more rigorous evaluation with comparison or pre-post data is encouraged.

Fourth, we identified only one Best Practice from peer-based interventions. Three studies (i.e., EnPrEP, Passport to Wellness, PrEP Peer Leaders) [17,18,24] that used peer-based support did not meet the PRS Best Practice criteria due to non-significant intervention effects. Among the three studies, EnPrEP was conducted in person to improve PrEP initiation and use while Passport to Wellness and PrEP Peer Leaders were done remotely to increase adherence. However, the CDC’s PRS project has identified 31 peer-based Best Practices to improve various HIV-related outcomes such as increasing consistent condom use [47,48], increasing HIV testing [49], and improving HIV care outcomes [50–55]. HIV peer navigation services is one of the public health practices for the EHE’s Treat Pillar (https://www.cdc.gov/hiv/effective-interventions/treat/index.html). The null results of peer-based PrEP interventions call for more research. One upcoming study is evaluating the effectiveness of mobile peer support interventions to reduce sexually transmitted infections among Black MSM PrEP users [56]. Another upcoming peer-based support intervention is intended to improve PrEP adherence and retention in PrEP care among youth MSM ages 18–29 years [57]. The findings from these upcoming studies will provide additional evidence of peer-based interventions for improving PrEP outcomes.

Fifth, almost all of the nine Best Practices utlized community engagement in the various stage of the intervention: seven reported community engagement in the development of interventions [26–29,31,32,39]; eight engaged communities when designing/developing the intervention content and how best to deliver the intervention [26–29,31–33,39]; and three implemented community engagement in the implementation of the intervention and included important community representatives [30,32,39]. EBIs involved the community by conducting focus groups of PrEP candidates to revise text messages [26], implementing preliminary qualitative reserch prior to the start of the actual study to get feedback from participants [31], or utilizing input from community members to tailor an existing HIV prevention app for the PrEP intervention [32]. Engaging the community when developing, designing, and implementing PrEP interventions may be key for effectiveness.

This review has several limitations. First, we only include published studies or those that have been accepted for publication in peer-reviewed journals. We may be missing non-published interventions. Second, PRS criteria for identifying Best Practices primarily focus on internal validity. Evidence related to external validity, clinical significance, implementation, cost, and population-level impact warrant further examination. Third, one of the Best Practices criteria requires having statistically significant findings. Some studies may have failed this criterion due to a lack of power from having a small sample size. Fourth, due to different intervention strategies and participant characteristics, comparing interventions can be challenging. However, this limitation might be mitigated as more studies become available for synthesis.

Despite the limitations, strengths of this review include using well-established systematic review procedures and evaluation criteria to identify Best Practices for PrEP use and adherence. This review also found research gaps for several populations disproportionately affected by HIV, including Black persons, Hispanic/Latino persons, PWID, and women of color. More research is also needed to explore how to effectively implement mHealth in various settings and gather evidence on peer support, and how to implement the Best Practices for PrEP in real world settings and evaluate their effectiveness. All Best Practices mentioned in this review are listed in the PRS Compendium [8]. Health care and prevention programs providers can use the Best Practices identified in serving their communities to help reach national goals for preventing HIV.