HIV infections among adolescents and young adults aged 13 to 24 years have more than doubled in the last 15 years, and these individuals represented 21% of the epidemic population (approximately 7100 infected youth) in the United States in 2018 [1-3]. Gay, bisexual, and transgender (GBT) youth represented up to 70% of new infections among youth in 2017. Among GBT youth, 37% were Black youth and 29% were Hispanic/Latino youth in terms of race/ethnicity, whereas 28% were White youth [3]. HIV also disproportionally impacts other marginalized youth, including those who are homeless, those who are incarcerated, those placed in foster care or other types of institutions, and those who engage in transactional sex [4-18]. Furthermore, there are geographic disparities in new HIV diagnoses. As reflected in the Ending the HIV Epidemic Initiative, southern states accounted for 52% of new HIV diagnoses in 2017 [19]. To stop HIV among adolescents, it is essential to routinely engage youth at the highest risk for HIV in prevention strategies and to achieve and sustain viral suppression in all youth living with HIV.

There are sequenced steps, referred to as the HIV treatment continuum and the HIV prevention continuum, that provide a metric for monitoring success toward ending the HIV epidemic. The first step in the HIV treatment continuum is to identify youth living with undiagnosed HIV infection. To achieve this, youth at high risk for HIV acquisition need to be tested for HIV every 3 months. However, 60% of youth living with HIV remain undiagnosed, and this is the highest rate in any age group [2]. Once diagnosed, the next steps are to ensure that youth living with HIV are linked to care, receive antiretroviral therapy (ART), and are regularly monitored so they can achieve viral suppression. ART, which is more effective and easier to take than before, improves quality of life and reduces early mortality. Furthermore, when youth achieve viral suppression, the risk of HIV transmission is reduced [9,10]. Impressively, about two-thirds (68%) of youth living with HIV are linked to care within 1 month of their diagnosis [13]. Among youth in care, 98% were prescribed antiretroviral therapy and 89% achieved viral suppression at 1 year [13]. However, less than half (34%-44%) of youth living with HIV are retained in HIV care for a year or more, and viral suppression among youth living with HIV is only about 16% at 5 years after diagnosis (compared with 58% among adults) [14,15], indicating that linkage to care is insufficient to achieve and sustain viral suppression [20].

Similar to the HIV treatment continuum, the HIV prevention continuum involves several key steps [21]. These include (1) access to health care; (2) regular HIV testing for youth at high risk, especially among GBT youth; (3) adoption of prevention strategies, such as condom use, pre-exposure prophylaxis (PrEP), and postexposure prophylaxis (PEP) for one time acute exposure; and (4) retention and adherence to these prevention strategies over time. Many youth, especially GBT youth, have limited access to health care. Approximately one in three GBT youth between 12 and 17 years of age do not receive preventive care, and one in three do not seek or receive care within a year of symptom onset for a health problem [16,18,22]. Youth who need PrEP are those least aware of and least likely to use PrEP [17,18]. Despite the demonstration of PrEP acceptability among GBT youth [23], PrEP utilization estimated from 2017 national data was only 9.4% among young men who have sex with men (MSM) compared with 19.9% among all MSM [24]. Although the proportion of health care providers prescribing PrEP in the United States has risen to 24%, differences in PrEP use between racial/ethnic groups remain, with a use percentage of 26% among eligible Black MSM versus 42% among White MSM [25]. Moreover, once initiated, PrEP adherence has been found to be suboptimal among young MSM, even when paired with tailored behavioral interventions [23,26].

In light of the suboptimal utilization of the treatment and prevention continua, the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) identified research gaps and defined five priority areas to guide its research agenda. The ATN is the only domestic research network (established in 2001) focused on youth at high risk for HIV and youth living with HIV (age 12-24 years). In this paper, we outline ATN’s research agenda for reducing new HIV infections among youth in the United States.

In this section, we describe each research priority area and highlight some of ATN’s efforts to address them. It is important to note that the ATN regularly reviews these research priorities to ensure that they continue to be responsive to scientific advances, changes in the epidemic of HIV, and emerging needs in the youth we serve.

Engaging youth in interventions to increase their uptake, adherence, and retention with HIV treatment and prevention services poses great challenges but remains a critical research priority. It has long been known that community agencies and venues where youth congregate are fruitful settings for engaging youth [47,48]. Providing safe and affirming spaces where youth can receive culturally congruent support and services can promote engagement of HIV prevention and treatment services [49]. The importance of using text messages and social media platforms and apps for engaging and retaining youth is increasing [50-54]. Recent community mobilization programs, focused on addressing structural-level factors to improve HIV testing and prevention, yielded mixed results [55-57].

Leveraging and expanding this knowledge, ATN investigators have launched innovative studies that are examining social media–based strategies for engaging, recruiting, and retaining youth in research studies and testing technology-based interventions. For example, one current ATN project focuses on helping youth living with HIV secure jobs through vocational training to overcome socioeconomic barriers to health care [58]. ATN studies are focusing on how to more effectively reach youth with adaptations or novel delivery strategies of evidence-based interventions that are lower cost, more attractive, and more accessible, while having a greater impact on decreasing HIV transmission and acquisition, and increasing engagement and adherence to therapeutic and preventive interventions.

Implementation science research is one of the most important approaches for optimizing interventions and maximizing their impact on youth at high risk for HIV acquisition and youth living with HIV. The ATN employs innovative methods, such as implementation-effectiveness hybrids, to address effectiveness and implementation along the same timeline [59]. The portfolio of current ATN studies also includes interventions that were designed with dissemination in mind. They can be scaled rapidly, reduce the need to precisely replicate a manualized intervention, and focus on each youth’s personal risks, tailoring the work to address the variability that occurs across and between communities [60,61]. The studies also build on evidence-based interventions systematically assembled and disseminated by the Centers for Disease Control and Prevention (CDC), Substance Abuse and Mental Health Services Administration (SAMHSA), and Health Resources and Services Administration (HRSA) to identify the most robust intervention components for wider utilization and scale-up.

Although researchers have identified that adolescents prefer medical care that is local, integrated, quick, confidential, nonprejudicial, hassle-free, and inexpensive [62,63], this type of care is yet to become widely available. Lesbian, gay, bisexual, transgender, and queer (LGBTQ) youth face particular challenges in accessing and receiving culturally affirming health care services, as health care providers and others with whom youth interact in care settings may hold stigmatizing views of LGBTQ youth [64-66]. Such forms of stigma perpetuated by health care providers and others in clinical settings have been shown to be barriers to seeking health care, especially among transgender young people [67-69]. These challenges may be exacerbated for LGBTQ youth of color, as racism is a form of intersectional stigma that negatively impacts access to health care, especially for Black LGBTQ youth [65,70,71]. Clinical providers can play a pivotal role in promoting change within their organization, reducing stigma, and increasing youths’ engagement and progression through the HIV prevention and care continua. Health system and provider interventions can promote changes in practice as well as in care settings. For example, training medical, clerical, and administrative staff to be culturally responsive to GBT youth clients successfully transformed policies and protocols of a set of health care agencies [72]. Providing feedback on the perceived quality of a clinic’s care and services can also improve the quality of care and the services provided. For example, a current ATN project in iTech sends “mystery shoppers,” adolescent consumer advocates, to visit existing HIV testing sites to evaluate their HIV counseling and testing services according to a number of youth-focused dimensions. Testing sites receive informational reports that they can use to improve service delivery [73].

Despite the efficacy of PrEP and PEP in reducing HIV acquisition, some providers are reticent to prescribe these medications to youth because they are concerned about risk compensation (ie, adjusting one’s behavior according to the perceived level of risk), nonadherence, and ART toxicities [74,75]. Other providers have expressed concerns regarding prescribing PrEP and ART to substance users [76]. Clearly, provider-based interventions to promote PrEP and PEP are needed. Although several approaches for scaling up PrEP and PEP in youth have been developed [77,78], they are yet to be widely disseminated and some are yet to be rigorously evaluated. For instance, public health jurisdictions, such as the New York City Health Department, are using academic detailing, a strategy typically used by pharmaceutical companies that engages providers in their work setting, to efficiently educate providers about PrEP [79,80]. Interventions to help providers to deliver culturally affirming care to GBT youth are also needed. Although there are many text and web resources to promote the use of PrEP among primary care providers, the efficacy of these programs to improve practice and services for youth has not been fully evaluated [81-83]. TMI, one of the studies in Scale it Up, addresses this need.

PrEP, PEP, and treatment as prevention have become important biomedical interventions that can either protect youth from becoming infected or ensure longer life and higher quality of life for youth living with HIV [9,84,85]. The first trials of PrEP (tenofovir plus emtricitabine) in 15- to 21-year-old youth at high risk for HIV infection, conducted by the ATN, demonstrated that PrEP offered high levels of protection for youth who were adherent and did not identify safety concerns [26,86,87]. Concerns related to long-term adherence to daily oral therapy has led researchers to examine the efficacy of long-acting antiretroviral agents, particularly injectable formulations of ART, which are currently being evaluated in phase III studies with adults, and broadly neutralizing antibodies, which are currently in phase IIb testing [88-90]. To help ensure that these novel formulations are approved for youth, the ATN is collaborating with the HIV Prevention Trials Network (HPTN) to examine the acceptability, tolerability, and adherence to injectable cabotegravir in youth. Because of its experience navigating the ethical, legal, and regulatory issues associated with the participation of youth in trials of biomedical interventions, the ATN has and will continue to play a pivotal role in advancing biomedical prevention efforts for youth [91,92].

HIV vaccine research and the development of immune-based and topical microbicidal–based therapies are other promising biomedical interventions [93-97]. Basic and clinical scientists have made major developments in knowledge about HIV reservoirs and interventions for an HIV cure, although attempts to achieve a cure have been unsuccessful to date [98,99]. One of the studies in the CARES U19 focuses on treatment of acutely infected youth, comparing their viral reservoirs over time to those of youth with established infections who were treatment naive. This project will provide important data on developmentally linked immunological processes associated with early and sustained viral suppression. Additionally, there has been an improved understanding of the role of the mucosal microbiome, semen exposure, and STIs in the risk of HIV acquisition and transmission [100]. The most futuristic approaches are studies of gene editing, which look to either eliminate the CCR5 gene or mutate the HIV virus successively so that it is no longer robust and easily transferable [101]. When these interventions are ready for testing, the ATN is well positioned to initiate trials of these biomedical studies in collaboration with researchers conducting trials with adults.

Technology use is ubiquitous among adolescents; thus, its power and reach can be harnessed for interventions targeting each stage of the prevention and care continua. Technology offers unique opportunities to recruit, engage, and retain adolescents in research through provision of tailored messages, inclusion of game-based elements, and delivery of personalized theory-based intervention components and health content [102]. Given that more than 96% of youth aged 18 to 29 years in the United States have smartphones and regularly use the internet for a variety of activities, interventions delivered through the internet and mobile phones are highly acceptable to youth [103,104]. Although the costs for initial start-up and development of technology-based interventions are high, once developed, the associated costs of adaptation and dissemination are more moderate. It is not surprising that the number of researchers developing and testing internet- and app-based HIV interventions is rapidly increasing. Unfortunately, these efforts are not well coordinated, and there is a proliferation of similar apps or websites that fail to make novel contributions or address unanswered questions [105,106].

Each ATN U19 program (iTech, CARES, and Scale it Up) is developing and evaluating innovative technology–based interventions across the HIV prevention and care continua. iTech focuses on the evaluation of technologically oriented and youth-oriented interventions, with each project utilizing mobile technologies, including apps, mobile-optimized websites, and online video counseling. The apps within iTech are tailored to the population addressed (eg, seronegative youth and youth living with HIV), the targeted health outcome (eg, PrEP uptake or adherence, engagement with health care, and viral suppression), and the technology platform utilized. iTech will foster the identification of the specific features across apps that are most used and most useful for specific populations. Using a harmonized set of technology-focused metrics and paradata for evaluation and cost-effectiveness analyses, iTech represents a coordinated effort that will allow for more impactful technology-based interventions. For example, one of its projects is a three-arm, randomized, controlled trial that is testing the efficacy of P3 (Prepared, Protected, emPowered), a novel, theory-based mobile app to promote PrEP adherence through social networking and gamification. This app utilizes game mechanics (rewards and unlocking app features) and social networking/peer support to also improve retention in PrEP clinical care and PrEP persistence among GBT youth [107].

In contrast, CARES adopted low-cost, scalable, device-agnostic platforms that are utilized across all subpopulations and outcomes, with a focus on personalizing risk messages within platforms. Personalized messaging will be the same regardless of the delivery format (text message, phone call, and video chat). CARES interventions combine text messages and peer-support chat rooms with more traditional counseling methods. The CARES approach focuses on messages and probes, which address the following core functions of behavioral change: establish a framework for change, convey necessary information, build self-management skills, address barriers, and provide tools and support. Scale It Up is conducting an effectiveness trial, called SMART, of an intervention comparing text messaging and cell phone support to improve HIV medication adherence among youth living with HIV. Youth are recruited and enrolled online, using social media and app-based approaches. Across all ATN projects, the opportunity to provide a tailored suite of technology-based tools is a useful and innovative way to engage youth at high risk or youth living with HIV to improve HIV-related prevention and treatment outcomes (Table 1).

Actionable policies are optimally derived from and shaped by data. Fortunately, many of the recent state and federal policy shifts in the United States reflect the belief that youth should be empowered to advocate and take individual responsibility for their health. Some of these shifts include expanding minors’ authority to consent to health care, including care related to sexual activity and STIs, HIV testing and treatment, and the constitutional right to privacy regarding a minor’s decision to obtain contraceptives [108].

Most states today have a policy requiring some form of HIV education. Federally funded school-based HIV prevention programs typically do not address issues related to GBT youth and thus are not relevant for these youth [109,110]. For instance, many state-supported abstinence-only programs exclude discussions of same-gender sexuality (eg, State Abstinence Education Grant Program). Furthermore, the efficacy of such programs to reduce STI incidence and HIV prevalence has not been established since the majority of evaluations were not powered to detect changes in biological outcomes. A recent meta-analysis of school-based interventions reported that only one of seven programs reduced STI incidence and none decreased HIV incidence [111]. Thus, rigorous evaluation of multilevel school-based programs is being considered as a future ATN research priority.

Evidence on the relationship between school climate and hate crimes should be used to inform and create policies to monitor the increase and levy consequences for discriminatory acts against marginalized groups such as GBT youth. Similarly, policies to create safe spaces for GBT youth and monitor the success of engaging GBT youth and other youth at high risk for HIV acquisition should also be enacted [112]. There is evidence that in jurisdictions with more affirming LGBTQ school climates, these youth reported fewer days of episodic drinking and fewer drinking days at school [113]. The ATN is gathering and disseminating data to policy makers, public health officials, and other officials to make informed decisions and implement efficacious HIV prevention and treatment models for US youth. The Community-Engaged Dissemination and Implementation Research (CEDI) Workgroup is working in collaboration with ATN members to translate their evidence-based research findings for dissemination and implementation in clinic and community settings, and to inform policy and advocacy for delivery of care. Another example is the work being conducted by the ATN Modeling Core, which is developing a detailed health policy mathematical model to monitor and evaluate HIV in adolescents and young adults. The Modeling Core is using a novel approach to microsimulation modeling of HIV disease progression, patterns of care, and treatment outcomes, and applying innovative statistical methods to populate the model with data about patterns of health care, HIV viral load trajectories, and ART derived from completed ATN studies and other national studies. This model will be used to evaluate the potential clinical and economic impacts of ATN intervention trials to support medication adherence, retention in care, and improved clinical outcomes for youth living with HIV and inform decision makers [114,115].

While the current ATN agenda focuses on community and provider interventions that are acceptable to youth and scalable at the national level, the network’s structure is nimble enough to allow for additional high-priority studies generated internally within the network and/or in collaboration with other networks, agencies, and outside investigators. The EHE identified several focus and geographical areas where ATN investigators and research programs can contribute [27]. Taking the EHE focus areas into consideration, the network solicited research studies in 2019 that included a focus on (1) conducting assessments that use an implementation science framework, (2) expanding ongoing efforts in EHE geographic areas to reach underserved youth, or (3) building connections with health departments and other community-based partners in EHE geographic areas.

New projects resulting from this allow the network to increase its youth research portfolio in focused EHE geographic areas where ATN is currently not represented and to contribute to efforts to end the HIV epidemic. The ATN will continue to regularly review its priorities and launch new studies in response to changing needs, scientific advances, and epidemiological shifts in HIV incidence.