Abstract
Implementation of pre-exposure prophylaxis (PrEP) to prevent HIV transmission is suboptimal in the United States. To date, the literature has focused on identifying determinants of PrEP use, with a lesser focus on developing and testing change methods to improve PrEP implementation. Moreover, the change methods available for improving the uptake and sustained use of PrEP have not been systematically categorized. To summarize the state of the literature, we conducted a systematic review of the implementation strategies used to improve PrEP implementation among delivery systems and providers, as well as the adjunctive interventions used to improve the uptake and persistent adherence to PrEP among patients. Between November 2020 and January 2021, we searched Ovid MEDLINE, PsycINFO, and Web of Science for peer reviewed articles. We identified 44 change methods (18 implementation strategies and 26 adjunctive interventions) across a variety of clinical and community-based service settings. We coded implementation strategies and adjunctive interventions in accordance with established taxonomies and reporting guidelines. Most studies focused on improving patient adherence to PrEP and most conducted pilot trials. Just over one-third of included studies demonstrated a positive effect on outcomes. In order to end the human immunodeficiency virus (HIV) epidemic in the U.S., future, large scale HIV prevention research is needed that develops and evaluates implementation strategies and adjunctive interventions for target populations disproportionately affected by HIV.
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Introduction
Pre-exposure prophylaxis (PrEP) to prevent HIV acquisition is highly effective, reducing risk of transmission from sexual intercourse by 99% and through injection drug use by 74% [1], and it is a central strategy of the Ending the HIV Epidemic (EHE) initiative in the U.S [2]. PrEP provision by clinicians and uptake by those who would potentially benefit, however, has been poor [3]; only around 25% of the 1.2 million Americans who are indicated have been prescribed PrEP [4]. Low PrEP provision among health care providers is due in part to barriers such as lack of awareness of PrEP, comfort discussing sexual activity with patients, and the purview paradox (i.e., the discordance in beliefs between HIV specialists and primary care providers on who should prescribe PrEP) [5]. Additionally, ongoing protection from HIV depends on adherence by the user to the medication regimen and other procedures over time [6, 7]. Furthermore, there are wide disparities in PrEP prescribing and use; for example, rates of PrEP prescription are lower, and rates of PrEP discontinuation are higher among individuals of color, young cisgender men who have sex with men, and transgender individuals [8,9,10,11].
Multilevel barriers contributing to the gaps and inequities in PrEP implementation and uptake are well documented [12]. In a comprehensive systematic review conducted in 2022 examining determinants (i.e., barriers and facilitators) of PrEP implementation, Li et al. cataloged approximately 2000 determinants across 286 distinct articles. Their findings revealed that two-thirds of these determinants were focused on the recipients of PrEP, with one-third focused on the delivery system. Common patient-level barriers included low awareness of PrEP, self-perception of being low risk for HIV, and competing health priorities that made integrating PrEP challenging. Although most patients indicated interest and willingness to use PrEP after hearing about it, they also indicated that mistrust in the health care system and stigma, as well as challenges navigating the health care system were prominent barriers to accessing PrEP. Among those who started using PrEP, particular barriers regarding consistent adherence to PrEP, included remembering to take pills daily, lack of social support, and needing to complete follow-up appointments to remain on PrEP. Regarding provider- and system-level barriers, lack of awareness, knowledge, discomfort, and resistance to PrEP were frequently cited, as well as financing, available resources, and lack of training. Moreover, primary care providers indicated that they did not see a large enough patient base to keep up to date with guidelines around high-quality PrEP care [12].
Meeting the EHE goal of increasing PrEP coverage to 50% by 2025 [2] will require a shift from focusing on barriers and facilitators toward identifying and evaluating strategies and interventions to capitalize on facilitators, surmount barriers, and ultimately scaling up to improve outcomes. This review aims to synthesize what is currently known about change methods to enhance PrEP implementation and use.
Change Methods to Enhance PrEP Implementation and Use: Implementation Strategies and Adjunctive Interventions
Implementation strategies are change methods aimed at system- and provider-level improvements that target implementation determinants (i.e., factors that influence the success of implementation) [13,14,15], and enhance implementation outcomes [16, 17]. Implementation outcomes are indicators of how well or how much a clinical program or practice is delivered by the health delivery system, and they include reach, adoption, fidelity, and sustainability [18, 19]. Implementation outcomes are distinct from clinical treatment outcomes, which focus on whether the treatment produced a desired change in health outcomes among patients. For PrEP, implementation strategies aim to raise awareness and improve adoption, implementation, and sustainment by prescribers [20] (e.g., health care professionals, pharmacists). Examples include training to enhance knowledge, skills, and resources needed to identify individuals indicated for PrEP, or adapting services to facilitate better access for patients–like same day prescriptions for individuals at the point of testing.
In contrast to implementation strategies, which target determinants within the delivery system, adjunctive interventions are change methods that target recipients [19, 21]. Adjunctive interventions have been defined as change methods that target recipients (e.g., patients) of a health intervention and are designed to increase motivation, self-efficacy, or capacity for initiating, adhering to, complying with, or engaging with the health intervention [21]. Adjunctive interventions are supplementary methods that support a health intervention, like PrEP, to enhance its effectiveness in improving health outcomes [22, 23]. Moreover, they are distinguished from other change methods by their targets, outcomes, and causal processes. The outcomes and their target are distinct from implementation strategies; adjunctive interventions seek to improve innovation outcomes, which are defined as the success or failure of an innovation (e.g. PrEP) based on its impact on recipients [19]. Examples of adjunctive interventions for PrEP include digital tools and peer support programs that facilitate raising awareness among patients, as well as supports for those initiating and maintaining adherence to PrEP [24]. See Smith et al., 2024, particularly Table 1, for detailed distinctions between implementation strategies and adjunctive interventions and Fig. 1 for a decision tree for identifying different types of change methods [21]. Table 1 in this paper displays key implementation science terminology. Henceforth, the term change method will refer broadly to both implementation strategies and adjunctive interventions.
Gaps in the Literature
To date, there are no systematic reviews focused on cataloging and demonstrating the effectiveness of implementation strategies or adjunctive interventions used for PrEP in the U.S. One existing review identified the extent to which implementation science has been used broadly within HIV prevention or treatment research in the US [25], though this review required the use of implementation science language to be included, which likely excludes many studies testing approaches that would be considered implementation strategies in the implementation science field (e.g., testing educational approaches for clinicians). Another review identified interventions, some adjunctive, to enhance patient adherence to daily oral medications, which could be generalized to PrEP [26]. Three other reviews explored topics tangentially related to PrEP implementation and adherence; one focused on understanding reasons for non-adherence as well as methods for measuring adherence [27], and the other focused on re-engaging people living with HIV who are lost to follow-up [28]. Thus, our systematic review is the first to comprehensively examine the effectiveness of implementation strategies and adjunctive interventions related to PrEP in the U.S. Moreover, our review also identifies and links strategies and adjunctive interventions to the specific implementation outcomes being measured. In this study, our primary objective was to systematically categorize and evaluate the diverse change methods used to influence implementation outcomes (e.g., reach, adoption, fidelity, and sustainability) related to PrEP. By examining the effectiveness of these approaches, we aimed to provide insight into the successful integration of PrEP within various healthcare settings and among diverse populations of recipients.
Methodology
We conducted a broad database search between November 2020 and January 2021 of implementation studies along the HIV prevention and care continuum that were published during or after the year 2000. The search strategy is included in Supplemental File 1. The protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021233089). A total of 20,265 records were identified through a database search of Ovid MEDLINE, PsycINFO, and Web of Science [12]. The number of unique records was then reduced through deduplication, title and abstract screening, full-text review, and extraction of study- and sample-level data. All steps were completed using Covidence software [29]. The full protocol and initial inclusion criteria of all PrEP related implementation studies of the initial systematic review has been published elsewhere [12, 30]. Here, we report only the extraction and review process for categorizing the implementation strategies and adjunctive interventions evaluated within the sample of PrEP studies from the previous review.
Inclusion Criteria
To be included in this review, studies needed to evaluate a change method (i.e., either an implementation strategy targeting an implementation outcome at the system-level or an adjunctive intervention effecting individual patient-level behavior change). We excluded studies that (a) only described the development of a change method and did not evaluate its effect on an implementation outcome, (b) only assessed barriers and/or facilitators and did not implement a change method, or (c) created a mathematic model to simulate change but did not include implementing a change method.
Of the 286 articles related to PrEP, a first round of screening conducted by authors DL and BK identified 93 as potentially containing an evaluation of an implementation strategy or adjunctive intervention. These studies were tabulated in Microsoft Excel. A second round of eligibility screening was performed via paired consensus meetings by the coding team, composed of seven Masters- and PhD-level researchers familiar with HIV implementation research (JLM, NB, JPZ, AQ, AZ, VM, JV). A total of 44 studies were included in this analysis. Figure 1 displays the PRISMA and details of exclusion by number.
Data Extraction and Coding Procedures
Virtual, synchronous training and refinement occurred over seven, hour-long sessions between June and September 2022. Training involved reviewing the codebook and operational definitions for codes, practice coding, discussion, and further codebook refinement. Due to the complexity of coding, each article was coded by two independent coders, and consensus was reached for each article. If consensus could not be reached, a third reviewer with expert knowledge and experience with implementation strategies (authors JDS and DHL) adjudicated. Once consensus was achieved for each article, two authors (JLM and JDS) audited all the coding to discuss any discrepancies and make final determinations. Coding took place from December 2022 through July 2023. The coding scheme was developed by authors JLM, DHL, NB, AZ, AQ, JPZ, BK, and JDS through an iterative refinement process. All data was collected directly from publication-available information. First, articles were separated into two primary categories: (a) strategies for PrEP implementation or (b) adjunctive intervention(s), as determined by the target of the change method (delivery system vs. patient), the outcomes assessed, and the change method’s function (support delivery vs. uptake/use) [21]. Full codebooks with operational definitions are included as Supplemental Files 2 and 3. Overall, our codebooks were developed to capture all of the data elements needed to properly specify and replicate change methods in implementation science based on established reporting guidelines [16, 18]. Moreover, implementation outcomes were coded given that they are the most proximal outcomes associated with change methods, such as implementation strategies [31]. We also developed codes seeking to better understand for whom and under what conditions certain change methods are effective.
Implementation Strategies
For studies evaluating implementation strategies for PrEP, the following codes were used: (a) strategy structure, which delineated the discrete practices or components of strategies used to effect implementation outcomes. For studies that included a bundle of strategies, a hierarchical structure was given to the bundle, with a row for each discrete strategy that was included within; (b) the Expert Recommendations for Implementing Change (ERIC) compilation, which identifies 73 discrete implementation strategies categorized into 9 domains based on conceptual similarity [32, 33]; (c) the measured implementation outcome(s) associated with PrEP implementation [18]; (d) study design [34]; (e) whether the strategy was effective at impacting implementation outcomes (criteria detailed in Supplemental File 2), (f) the priority population(s) the strategy targets, and (g) the setting in which the implementation strategy was used. In addition, we developed a code capturing whether the study had a health disparities or health equity focus; this code was informed by literature on measuring equity [35,36,37]. It involved classifying the study as (a) not having a health disparities or equity focus; (b) identifying a health disparity through the study, (c) conducting an implementation trial solely among a priority population or within a particular community as defined by the Centers for Disease Control and Prevention (CDC) [38], or (d) comparing the effectiveness of a strategy between a CDC priority population and a general population.
Finally, there are several characteristics of implementation strategies that are important to capture to operationally define them, permit replication, and identify core features that promote generalizable lessons about the impact they have on implementation outcomes. Proctor and colleagues (2013) provided reporting guidelines for strategy specification that include (a) the actor (i.e., who delivers the strategy); (b) action(s) (i.e., what are the specific actions, steps, or processes that need to be delivered); (c) action target (i.e., where and to whom the strategy is delivered); (d) temporality (i.e., when the strategy is delivered); (e) dose (i.e., intensity); (f) implementation outcome (i.e., implementation outcome(s) likely to be affected by each strategy); and (g) justification (i.e., empirical, theoretical, or pragmatic justification for the choice of implementation strategy) [16]. Raters coded their confidence with whether the elements of strategy specification were present on a 4-point scale across each category (0 = not present; 1 = minimal confidence, high inference; 2 = moderate confidence, moderate inference, 3 = completely confident, no inference).
Adjunctive Interventions
For studies evaluating an adjunctive intervention for PrEP and in a parallel to implementation strategy coding, we coded: (a) the adjunctive intervention structure (i.e., core practices or principles and associated elements and intervention activities) [39], (b) the measured innovation outcome(s) [19] (i.e., indicators of PrEP being successfully taken up, adhered to, and maintained by PrEP recipients); (c) whether the adjunctive intervention was adequately specified, (d) whether the adjunctive intervention was effective, (e) the priority population(s) receiving the adjunctive intervention, (f) the setting, and (g) whether the intervention had a health disparities or health equity focus. Consistent with the defining characteristics of adjunctive interventions, the outcomes targeted were recipient-level behaviors, most commonly uptake of and adherence to PrEP.
Additionally, we employed multiple behavior change frameworks. The Theoretical Domains Framework (TDF) [40, 41] was used to categorize the individual level processes involved in health behavior change, which the adjunctive interventions target [21]. Each core intervention component was coded using one or more of the 14 TDF domains. For each TDF code, a confidence rating on a three-point scale was used, wherein “1” was coded as least confident, “2” indicated moderate confidence, and “3” indicated high confidence that the components described in the paper matched the TDF domain used. The TDF domain was also mapped onto the COM-B framework. COM-B is a related behavior change framework designed to link intervention functions to one of three mechanisms of behavior change, namely capability (made up of physical and psychological capability), opportunity (made up of social and physical opportunity), and motivation (made up of automatic and reflective motivation) [42]. Literature linking COM-B and TDF guided the mapping procedure [40]. All studies were double coded by JLM, NB, and JPZ and consensus meetings were held for each study.
Results
Of 93 manuscripts identified via extraction, K = 44 were included in the review (see Fig. 1 for exclusion reasons). There were k = 18 studies coded as evaluating implementation strategies and k = 26 evaluating adjunctive interventions. A list of all included study citations is included in Supplemental File 4 Implementation strategy and adjunctive intervention results are reported separately.
Implementation Strategies
A total of 122 discrete implementation strategies for PrEP were identified across 18 studies. All studies included a bundled or multicomponent strategy (i.e., more than one discrete strategy packaged and used together). On average, ~ 6 discrete strategies were used in each study (min = 1, max = 16). Regarding strategy effectiveness, eight (44%) were rated as having a positive effect, five (28%) had a mixed effect, and five (28%) were rated as “not applicable” due to a lack of comparison or baseline condition for which to determine effectiveness. No studies were identified as having null or negative effect. Study-level data associated with implementation strategies are displayed in Table 2.
Setting and Demographics
Studies took place in a variety of settings: clinical settings (including sexual health clinics, Veterans Administrations, community health centers, health departments, and academic hospitals; k = 9), pharmacies (k = 3), community-based settings (including community-wide initiatives, and community-based organizations; k = 3), family planning service centers (k = 2), syringe services centers (k = 1). The recipient (i.e., patient or client) population served by these studies were mostly among the general population at risk for HIV and indicated for PrEP (k = 10). The next largest group were cisgender gay, bisexual, or other men who have sex with men (GBMSM) (k = 6), each of the following were included in two studies: Black/African American individuals, cisgender women, and people who inject drugs; and the following were targets of one study: transgender individuals, veterans, and Latinx/Hispanic individuals. Some studies involved more than one priority population in their sample.
Study Design and Stage of Research
Most studies used a within-site design (k = 13), four were observational studies, and one used a between-site design. There were no studies that used a configurational comparative design or a within-and-between site design. Regarding the stage of research, 13 conducted pilot trials and five tested/trialed strategies. No studies compared strategies, and none of the studies were self-described as hybrid implementation–effectiveness studies [43].
Implementation Outcomes
There were 27 implementation outcomes measured across the 18 studies. The most frequently measured implementation outcome was reach (n = 12), followed by adoption (n = 9), and PrEP fidelity (n = 6). No studies measured costs or sustainment/sustainability. Antecedent outcomes (i.e., potential predictors of implementation outcomes: knowledge and awareness of PrEP, and strategy acceptability, appropriateness, and/or feasibility) were measured in five studies. Other notable outcomes beyond our a priori categories included provider-level ratings of strategy acceptability and usability, patient-level engagement with the implementation strategy, and HIV positivity rates.
Implementation Strategy Coding
Of the 73 possible discrete ERIC strategies, 41 were used (56% coverage). Table 3 displays the total usage of ERIC strategies across all studies as well as the presence of each unique domain used in a given study. The most common ERIC strategy domain employed across studies was Train and Educate Stakeholders (n = 31, 25%), followed by Develop Stakeholder Interrelationships (n = 20, 17%) and Use Evaluative and Iterative Strategies (n = 17, 14%). The least used ERIC domains were Provide Interactive Assistance (n = 1, < 1%) and Utilize Financial Strategies (n = 3, 3%). There were no strategies within the Adapt and Tailor to Context domain. Some strategy domains were used in multiple studies. Train and Educate Stakeholders was present in 15 (83%) studies, followed by Develop Stakeholder Interrelationships (n = 11, 61%), and Engage Consumers and Support Clinicians (n = 9, 50%).
Among the 122 coded discrete implementation strategies, conduct ongoing training was employed 10 times, followed by make training dynamic, which was employed nine times. Next were intervene with patients/consumers to enhance uptake and adherence and obtain formal commitments, each coded six times, and develop educational materials, create new clinical teams, facilitate relay of clinical data to providers, and prepare patients to be active consumers were each employed five times. There were 32 ERIC strategies that were not used.
We created additional strategies that were not adequately captured by the ERIC taxonomy, namely, alter or create new workflows, defined as, “evaluate current workflow and create new one(s), or adapt existing workflows as needed to best accommodate the targeted innovation,” which was added to the Change Infrastructure domain and was used three times. Examples of this strategy included, “designing a pharmacy-based PrEP workflow that would complement the busy pharmacy during operating hours” [44]. Integrate services, defined as “integrate a new service with an existing one (e.g., incorporate PrEP into an existing psychosocial intervention)” was added but not assigned to a domain and was used six times. An example of this strategy was integrating HIV PrEP services within a syringe services program [45]. Finally, dissemination strategies, defined as the targeted distribution of information and materials to a specific public health or clinical practice audience [46, 47], were also coded separately and used three times. A list of all discrete implementation strategies assigned to each study with associated ERIC coding are available in Supplemental File 5.
For bundled strategies (i.e., multifaceted or multicomponent strategies packaged together), the most common combination of three strategy domains were Develop Stakeholder Interrelationships with Train and Educate Stakeholders and with Use Evaluative and Iterative Strategies (n = 5); and Develop Stakeholder Interrelationships with Train and Educate Stakeholders, and with Support Clinicians (n = 5). The most common combination of 4 strategies used together was Use Evaluative and Iterative Strategies, Develop Stakeholder Interrelationships, Train and Educate Stakeholders, and Support Clinicians (n = 4).
Strategy Specification
Regarding reporting guidelines to strategy specificity, on average, coders rated their confidence level as M = 2.37 for Actor, M = 2.37 for Action, M = 2.1 for Temporality, and M = 2.0 for Dose. Coders rated that 95% of studies justified why the strategy was chosen.
Health Equity
Regarding the extent to which the study had a health disparities or health equity focus: six (33%) did not have a health disparities or equity focus; four (22%) identified a health disparity through the study; seven (39%) conducted an implementation trial among a CDC priority population or within a particular community experiencing disparity; and one (6%) study compared the effectiveness of a strategy between a CDC priority population and general population.
Adjunctive Interventions
A total of 26 studies examined adjunctive interventions to improve PrEP uptake, adherence, or engagement. On average, authors described the adjunctive intervention having 5 discrete intervention components in each study (min = 1, max = 13). Regarding effectiveness, eight (31%) were rated as having a positive effect, 11 (42%) had a mixed effect, one study was rated as having a null effect (4%), and one study had a negative effect (4%). There were five studies rated as “not applicable” due to a lack of comparison or baseline condition to assess effectiveness. Just over half (k = 15, 58%) described implementation strategies used to support the uptake or use of the adjunctive intervention, though only three studies collected an implementation outcome associated with the adjunctive intervention (e.g., implementer fidelity) [48,49,50]. The other 42% only described the effectiveness of the adjunctive intervention and did not examine its implementation. Study-level data for each adjunctive intervention is displayed in Table 4.
Setting and Demographics
Studies took place in a variety of settings: clinical settings (including sexual health clinics, Veterans Administrations, community health centers, and academic hospitals; k = 12), community-based sites (k = 5), research offices (k = 2), a PrEP counseling center (k = 1), and internet settings, which included digital, electronic, or mobile device interventions (n = 6). The recipient (i.e., patient, client) population served by the adjunctive interventions were mostly GBMSM (k = 23). The next largest group were Black/African American individuals (k = 12), followed by adolescent men (k = 8) and cisgender women (k = 6). Studies including transgender individuals and Latinx/Hispanic individuals each were represented in three studies. One study included people who use drugs (PWUD). Some studies involved more than one priority population in their sample.
Study Design
Most studies were controlled or uncontrolled pilot trials (k = 15); followed by randomized controlled trials (RCTs; k = 5); then observational/naturalistic studies, longitudinal analyses of single cohorts, or pre-implementation assessments (k = 5); and one quasi-experimental, 2-arm study.
Outcomes
A total of 32 innovation outcomes were identified (i.e., indicators of PrEP being successfully taken up, adhered to, and maintained by PrEP recipients [19]). The most frequently studied outcome was PrEP adherence (n = 16), followed by uptake (n = 10), and maintenance/persistence (n = 6). Other antecedent outcomes were identified, including knowledge and awareness of PrEP (n = 7), PrEP acceptability (n = 3), PrEP appropriateness (n = 3), and PrEP feasibility (n = 1). In addition, adjunctive intervention acceptability, appropriateness, and/or feasibility by recipients and/or providers was coded 11 times. Provider fidelity to adjunctive intervention delivery was assessed in three studies. Other notable outcomes beyond our a priori categories included participant intentions to continue to use PrEP, whether PrEP was ever used, and participant engagement in other risky behaviors.
Categorization by TDF and COM-B
Of the 14 TDF domains, Knowledge was the most used (n = 51), followed by Environmental Context and Resources (n = 40), Behavioral Regulation (n = 29), and Beliefs about Capabilities (n = 27). The least coded domains were Optimism (n = 1) and Reinforcement (n = 3), and Intentions and Emotion were each coded six times. Average confidence ratings for TDF (scale = 0–3) coding across all studies was 2.04 (range = 1.5–3).
Of the six COM-B sub-categories, the most commonly used was Psychological Capability (n = 24), followed by Reflective Motivation (n = 21), and Physical Opportunity (n = 20). Social Opportunity and Physical Capability were each coded 11 times, and Automatic Motivation was used eight times. A breakdown of the number of TDF and COM-B codes used are included in Table 5, and full details of TDF and COM-B codes used for each study and core adjunctive intervention component are provided in Supplemental File 6.
Specification
Given that they are important for replication, we coded the extent to which the actor, action, and dose were adequately described for each adjunctive intervention on a four-point scale (0–3). Average ratings for actor M = 1.73, action M = 2.12, dose M = 2.39. Coders rated that 92% of studies justified why the adjunctive intervention was chosen.
Health Equity
Regarding the extent to which the study had a health disparities or health equity focus: all (100%) had either a health disparities or equity focus; six (23%) identified a health disparity through the study; 18 (69%) conducted an implementation trial among a CDC priority population or within a particular community experiencing disparity; and one (4%) study compared the effectiveness of a strategy between a CDC priority population and a general population.
Discussion
In this review, we systematically identified 44 studies evaluating implementation strategies and adjunctive interventions used to effect implementation and innovation outcomes associated with PrEP across all U.S.-based published studies. We classified implementation strategies that targeted the health system according to an established compilation [32, 33] and adjunctive interventions according to the TDF [40, 41] and the COM-B taxonomies [42]. Our findings indicate that more studies examined change methods at the recipient level (adjunctive interventions) to improve uptake, adherence, and persistence in PrEP rather than strategies targeting the health system and focusing on reach, adoption, fidelity, and sustainment of PrEP implementation. This finding aligns with research identifying determinants, which have largely focused on identifying barriers and facilitators at the individual recipient level regarding uptake and use of PrEP [12] and not those related to implementers or implementing systems.
Most studies in this review were in the early stages of evaluating strategies or adjunctive interventions, with nearly two-thirds conducting pilot trials. This finding aligns with a recent review of NIH-funded HIV implementation projects, which found that most studies were in the implementation preparation phase [51]. Moreover, no studies in this review conducted hybrid effectiveness-implementation trials, which focus more heavily on testing and evaluating the impact of implementation strategies. Therefore, future projects that conduct larger, adequately powered implementation or hybrid trials are warranted to deepen our scientific knowledge of how to influence structural change and improved implementation of PrEP.
The majority of studies had either a health disparities or health equity focus, but this focus was more prevalent in studies evaluating adjunctive interventions than those evaluating implementation strategies. Given the existing disparities in PrEP prescribing and use [52], it is crucial that future research places a strong emphasis on promoting equity. This can be achieved, for example, by ensuring healthcare providers have comprehensive knowledge about the appropriate indications and circumstances for PrEP use, actively encouraging discussions about PrEP and working toward destigmatizing its use. Moreover, healthcare organizations and systems should adapt their services, integrate new approaches, and make necessary adjustments to their structure and procedures to ensure equitable access to PrEP.
The reviewed studies suggest several promising implementation strategies for increasing PrEP implementation. One approach involves utilizing comprehensive PrEP educational training modules aimed at healthcare providers, which has proven effective in enhancing PrEP awareness and knowledge [53]. More focused, equity informed training programs also showed promise [54]. Decision aids, risk calculators, and automated reminders developed to support provider decision-making when providing PrEP care were effective [55, 56]. Multiple studies included in this review described efforts to integrate PrEP services into existing settings, such as family planning and reproductive health [57, 58], syringe service programs [45], and within pharmacies [59, 60]. Finally, other large-scale strategies such as collective impact have been employed that seek to unify municipal organizations toward a common goal [61]. All of the change methods described in this paragraph are consistent with the definition of implementation strategies as they primarily target the health delivery system, and not patients.
Healthcare professionals can also employ adjunctive interventions such as medication reminders, adherence counseling, and routine follow-up appointments. Medication reminders, which may come in the form of mobile apps, text messages, or phone calls, serve to reinforce the importance of daily PrEP usage and help patients establish a consistent routine [62,63,64]. Adherence counseling and follow-up support can provide personalized guidance, addressing individual barriers to consistent PrEP usage and offering strategies for overcoming them [48, 65, 66]. Digital tools, like mobile apps and websites, can offer accurate and up-to-date information on PrEP, allowing users to make informed decisions and providing contingency management supports [67]. Finally, tailored, peer navigation and social support programs can provide an additional layer of social and emotional support that encourages PrEP uptake and adherence and fosters open dialogue about HIV prevention within at-risk communities [49, 68, 69]. All of the change methods described in this paragraph are consistent with the definition of adjunctive interventions as they target patients.
Limitations and Future Directions
Our findings should be interpreted with some caution. Despite the availability of a variety of implementation strategies and adjunctive interventions, only 16 (36%) studies were rated as having a positive effect on primary outcomes. There were 11 (24%) that were unable to be rated, given that the stage of research did not allow for an effectiveness evaluation, which indicates that many of the available change methods are yet to be evaluated with an adequately powered sample and/or with a comparison group.
Additionally, the ERIC compilation used for coding strategies did not always allow for perfect fit with the strategies found in our sample, leaving some strategy components left uncoded, and the need for our team to create new strategies. Moreover, we found ERIC to insufficiently categorize informatics-related approaches, such as workflow creation and integration, clinical decision support, and EMR-based implementation strategies. This led to us creating new codes, such as alter or create new workflows to capture these types of strategies. Frequently, PrEP services were often integrated within existing services, but we did not find an ERIC strategy that reflected this approach. Future research may be needed that expands ERIC to include new technologies developed by informaticists and among HIV researchers.
Most change methods included gay and/or bisexual MSM as the targeted recipient population broadly (62%) followed by Black/African American individuals (31%); with relatively few targeting adolescents (16%), Latinx or Hispanic individuals (16%), cisgender women (11%), transgender individuals (9%), or people who use or inject drugs or substances (7%); therefore, additional research is needed that focuses on other CDC priority populations, with particular emphasis on intersectionally marginalized populations. We hope that this review will spur on additional reviews that further demonstrate which implementation strategies or adjunctive interventions work for whom and under what circumstances.
Adjunctive interventions require a greater focus on implementation. To have maximum public health impact of PrEP, implementation strategies that increase supply and adjunctive interventions that increase demand and use are equally needed. Because HIV risk disproportionally affects communities that experience other forms of structural and social inequities, adjunctive interventions that help individuals use and adhere to the medication are essential for achieving PrEP efficacy. However, adjunctive interventions themselves often have additional implementation considerations, and just over half of the adjunctive intervention papers in our review described implementation strategies related to their implementation. Future research on PrEP adjunctive interventions should not only evaluate their effect on PrEP-related outcomes but also place them in the context of implementation strategies that may differ from those strategies used for PrEP.
We used simple criteria to determine whether change methods were effective, that is, whether study authors reported benefit based on change among primary implementation outcome(s) for the target population or setting. As noted above, most studies included in this review identified as a pilot or feasibility study and lacked a control group, thus limiting confidence in the validity of the results and our ability to recommend these strategies for wide dissemination within the practice community. It is our expectation, however, that implementation research focusing on PrEP will be more rigorous and yield more generalizable results worth disseminating to the wider practice community. As additional research comes to fruition, more stringent criteria that considers validity and direction of implementation effects as well as other critical dimensions of implementation research (i.e., strategy specification) [16, 70] will be valuable to evaluate the effectiveness of implementation strategies.
Given the small number of included articles in this study, we did not examine whether the number or type of ERIC strategies used were tied to greater or lesser impact on implementation strategy effectiveness, nor did we examine whether the number of combination of TDF/COM-B domains impacted adjunctive intervention effectiveness. Although prior research has suggested that multicomponent interventions and implementation strategies likely have a greater impact on outcomes than discrete strategies [71,72,73], further research that identifies which components or combinations of strategies and adjunctive intervention components are associated with larger effects are needed. Moreover, there were no comparative (i.e., head-to-head) implementation strategy trials. Research designs such as factorials and Sequential, Multiple Assignment, Randomization Trials (SMART) [74] provide viable options to identify what works, for whom, and under what conditions.
We did not conduct a risk of bias assessment among included studies. Given that the vast majority of studies involved pilot or feasibility trials, we had a limited number of RCTs (k = 5) of which to evaluate for bias. As the state of the literature advances and more RCTs are conducted, risk of bias assessments will be appropriate. Finally, we only included peer-reviewed literature indexed in a major database, which introduces publication bias [75].
Conclusion
Broad scale, successful implementation of PrEP requires a comprehensive approach that addresses barriers and facilitators for both people in need of PrEP and organizations providing PrEP services [76]. Implementation strategies and adjunctive interventions should be tailored to the needs of different populations and must focus on increasing access to PrEP services by providing it in convenient locations, providing education and support for people to ensure they are adhering to PrEP, promoting positive attitudes towards PrEP use, and addressing HIV-related stigma to achieve successful outcomes [20]. Effective implementation strategies and adjunctive interventions that focus on raising awareness and uptake for PrEP are critical in reaching those at greatest risk for HIV and reducing overall transmission rates [77]. By addressing barriers and leveraging innovative solutions, these efforts can ensure that more individuals are engaged in PrEP care and benefit from its HIV prevention potential.
Data Sharing
We systematically reviewed D&I research on PrEP implementation and built a public dashboard that transfers knowledge to researchers and implementers. The first review explored the determinants of PrEP implementation [12]. Although systematic reviews provide value to the growing field of HIV D&I science by identifying areas of concentrated knowledge and gaps, they are not in themselves innovative. To address this issue, we created a public, interactive dashboard to explore the results of these systematic reviews. The dashboard allows users to examine more than 1,900 determinants of PrEP implementation, coded by CFIR, from 239 peer-reviewed articles [14, 15, 19]. This tool was developed using user-centered design principles and organizes results at the (1) paper level, with filtering enabled by year, priority population, study participants, setting, and US region, and (2) determinant level, with filters by CFIR constructs, valence, and data collection method. Using the results of the current review on strategies that address implementation strategies, the dashboard was updated including the results presented here displaying 18 studies coded as implementation strategies and 26 as adjunctive interventions. This update allows users to explore results at the (3) strategy categorization level, coded by ERIC [32] and at the (4) adjunctive intervention level, coded by COM-B framework [39, 40]. Users can export results, allowing analyses of subsets of results and identification of implementation strategies by context. The dashboard can be accessed via https://hivimpsci.northwestern.edu/dashboard/.
Data Availability
We included supplemental files of our codebook, which includes operational definitions of codes. The systematic review dashboard, which a portion of our studies were drawn from is freely available at https://hivimpsci.northwestern.edu/dashboard/. Additional data is available from the authors upon request.
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Funding
This work was supported by a supplement grant to the Third Coast Center for AIDS Research, an NIH-funded center (P30 AI117943; PI: D’Aquila; Supplement PIs: Mustanski & Benbow). J.D. Smith was supported by the CIRCL-Chicago Implementation Research Center (UG3 HL154297) and the Utah Clinical and Translational Science Institute (UM1 TR004409). James Merle was supported by a training grant from the National Library of Medicine (T15LM007124; PI: Eilbeck). JPZ and az’s time was supported by a training grant from the National Institute of Mental Health (T32MH130325; PI: Newcomb). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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BM, DL, NB, and JDS conceived of the paper. DL and BK performed the literature search. JLM, DL, BK, JPZ, AQ, AZ, VM, and JV conducted the screening for inclusion and contributed to the coding. JLM performed the data analysis and synthesis. All authors drafted and/or critically revised the work.
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Merle, J.L., Benbow, N., Li, D.H. et al. Improving Delivery and Use of HIV Pre-Exposure Prophylaxis in the US: A Systematic Review of Implementation Strategies and Adjunctive Interventions. AIDS Behav 28, 2321–2339 (2024). https://doi.org/10.1007/s10461-024-04331-0
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DOI: https://doi.org/10.1007/s10461-024-04331-0