Purpose

RFA: -

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD),
National Institute on Drug Abuse (NIDA), and National Institute of Mental Health (NIMH)

Purpose

The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) has the capacity for developing and conducting selected behavioral, community-based translational, prophylactic, therapeutic, microbicide and vaccine trials based on and adding to the information developed through the Adolescent Medicine HIV/AIDS Research Network (11) and the earlier years of the Adolescent Medicine Trials Network (21).

The primary mission of the ATN is to conduct research, both independently and in collaboration with existing research networks and individual investigators, in HIV-infected and HIV-at-risk pre-adolescents, adolescents, and young adults up to age 25 years. Prevention research, not the development of antiretroviral therapy trials, remains a large focus of research for pre-adolescents. Much of the research activity of the ATN focuses on collaboration with the Clinical Trials Networks supported by other institutes of the National Institutes of Health (NIH), including but not limited to the Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute (NCI) through coordination of research.

The ATN brings expertise and resources to collaborative protocol development that ensures feasible and acceptable study design as well as experience in recruiting and retaining this unique population. This initiative calls for a broad array of intervention studies aimed at the primary, secondary, and tertiary prevention of HIV infection in pre-adolescents, adolescents, and young adults at clinical sites and in their surrounding communities. These include pilot phase and formative studies as well as selected larger efficacy level interventions, with appropriate collaboration from other networks when needed. Comparative effectiveness and operational research, including program evaluation research, may also be conducted when necessary and feasible. This network designs, develops, and conducts multiple common clinical trials as well as pertinent formative and translational research studies collaboratively or independently when needed. The ATN strives to bring the required numbers of subjects into rigorously designed common protocols and thus address pressing research questions in youth more quickly than individual centers acting alone.

Background

An estimated 1.2 million new HIV infections occur among 15 to 24 year olds annually in the world, a number that represents a staggering 45% of all annual new infections. Each day another 3, young people are newly infected. In the US, the HIV incidence rate in youth is among the highest with 34% of all new infections occurring among 13-29 year olds in 6. These infections are disproportionately distributed among ethnic/racial minorities and men who have sex with men (MSM), with 62% of new infections among African-American and Hispanic populations and 53% of new infections among MSM in 6. These groups are also unique compared to all others in that longitudinal trends of infection over the last decade have continued to increase. The relative disproportion of youth (60-80%) who are unaware of their infection compared to adults (25%) is also alarming. Adding to these are significant numbers of HIV positive children, infected from birth, and entering adolescence with its attendant developmental issues. Recent CDC guidelines for routine HIV testing across the US are increasing the numbers of people identified with undiagnosed HIV infection. However, establishing a durable linkage to care, an activity associated with improved outcomes, remains an elusive challenge for many providers. Linkage to care is defined as a medical assessment by a licensed medical practitioner occurring within 6-12 months since diagnosis followed by at least one, if not more, similar additional medical assessments in the ensuing 3-6 month period and thereafter. This issue is of particular relevance among vulnerable populations like youth, who encounter many more obstacles and challenges than adults.

The ATN is the first clinical research group to address the particular challenges and unique clinical management demands of HIV-infected adolescents and the prevention needs of at-risk youth through common protocols. The ATN has undertaken studies to interrupt HIV transmission in uninfected youth. The Connect-to-Protect® (C2P) Program has established and continues to develop the primary prevention infrastructure called for in an NIH-Community Consultation (January 11-12, 1) on what racial and ethnic minority youth and their caregivers will require to accept HIV prevention vaccine research. This is expected to buttress the foundation for research efforts on other primary biomedical prevention modalities including microbicides and pre-exposure prophylaxis (PrEP) among this vulnerable population. The C2P program has been successfully implemented at all ATN sites across the US and Puerto Rico, and preliminary evidence shows that community mobilization (engagement in prevention efforts) has effected positive changes in behaviors, which are ultimate determinants of HIV transmission and acquisition.

Secondary prevention studies examine ways to preserve health in HIV-infected populations, including management strategies like earlier initiation of highly active antiretroviral therapy (HAART) with subsequent de-intensification, vitamin D supplementation to mitigate renal and bone co-morbidities associated with HAART, and the evaluation of human papillomavirus (HPV) immunization safety and immunogenicity. Studies are needed in key areas: effects of HIV infection and of HAART on neurocognitive and other neurologic outcomes; long-term effects of newer therapies administered during growth and sexual maturation periods; adolescent-specific HIV pathogenesis; and the potential for immune recovery mediated by therapeutic vaccines or immune-based therapies. As more effective agents are used widely to treat HIV disease in youth, improved survival may permit serious non-AIDS events (SNAEs) associated with ongoing immune dysregulation and activation to emerge. These include malignancies, particularly those resulting from co-infection with HPV, hepatitis B virus (HBV) or hepatitis C virus (HCV), cardiovascular and central nervous system events, as well as renal and hepatic diseases. Relevant studies on immunopathogenesis and therapeutic strategies to address these possible co-morbidities are needed. Furthermore, as efforts increase to identify youth with unknown HIV infection, interventions to address the needs of newly diagnosed youth will be important. Studies that address co-morbidities with HIV infection such as mental health disorders and substance abuse issues are also of paramount importance.

Tertiary prevention studies are needed to restore ill HIV-positive youth to full or better function. All HIV-infected youth are faced with social and physical developmental challenges of puberty that make coming to terms with chronic illness, complex drug regimens, and disclosure to peers an intensely more complicated endeavor. There are few innovative adolescent-specific studies to improve treatment adherence and to prevent or minimize the negative consequences of HIV infection, particularly during the critical developmental periods of adolescence. The ATN is systematically evaluating the major difficulties adolescents have with adherence to antiretroviral regimens. Special attention is needed for the emerging behavioral problems of perinatally-infected adolescents who experience all of the socio-behavioral difficulties of their sexually-infected peers, but also face unique clinical management problems given past multiple drug regimen failures. The ATN is addressing these special needs through studies designed with chronic disease specialists and collaborations with other AIDS clinical trials networks.

The ATN's current agenda needs to be sustained and expanded to meet the emerging needs of this population. The ATN has been able to identify, develop, and implement a broad research agenda consisting of formative and adaptive behavioral research studies, community-based epidemiologic needs assessments, and therapeutic pilot studies and trials. NICHD, National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH) intend to work with ATN investigators to further the HIV research agenda for American youth in three major ways: (1) by meeting the clinical management and behavioral needs of HIV-infected youth, (2) by further strengthening and developing the community-based primary prevention infrastructure that might support HIV preventive biomedical clinical trials, including vaccines, microbicides, PrEP and integrated biomedical and behavioral trials, and (3) by collaborating with the Centers for Disease Control and Prevention (CDC) and their local health department grantees to improve the identification, linkage and engagement to care of youth with undiagnosed HIV infection. To accomplish these goals fully, NICHD, NIDA, and NIMH will coordinate the development of the ATN's research agenda and the use of its available resources with the Clinical Trials Networks supported by the Division of AIDS, NIAID and the NCI.

Scope

This initiative calls for a broad array of interventional studies, conducted collaboratively and independently when needed, aimed at the primary, secondary, and tertiary prevention of HIV infection in pre-adolescents, adolescents, and young adults at the trials units associated with the network. A significant portion of these youth will include populations that are medically disenfranchised, of low socio-economic status and/or of racial/ethnic minority constituency (e.g., African-American and Hispanic youth, substance abusing youth, etc.).

Studies on all three prevention levels should be interdisciplinary collaborations to address the complexity of the population and co-occurring health problems, such as sexually transmitted disease infection, alcohol and substance abuse (including levels and patterns of use), and mental, psychiatric and neurocognitive disorders. Behavioral, biomedical, and integrated modalities should be considered in the context of available infrastructure and utilizing the unique capabilities of the network. Research that employs an integrated biomedical and behavioral approach is encouraged where possible.

Primary prevention studies will focus on efforts to interrupt HIV transmission in uninfected populations. This will be accomplished by establishing a community-based primary prevention infrastructure that will be able to support clinical trials evaluating HIV preventive vaccines, microbicides, PrEP and other biomedical modalities as part of its menu of prevention strategies tailored for youth at greatest risk for HIV infection or transmission. These strategies include, but are not limited to, interventions in the following areas:

evaluation of the ATN's C2P Program, a model of community mobilization and effective partnering with community-based organizations and neighborhood stakeholders;
development and evaluation of individual, dyad, or group based primary prevention interventions that make optimal use of the unique ATN structure;
evaluation of key elements in the successful translation of efficacious behavioral programs into community implementation;
evaluation of models to assess the impact of different recruitment approaches and informational modalities on prevention trial participation and of models to promote engagement in research;
evaluation of theoretically-based behavioral interventions relevant to youth facing co-occurring health risks, including sexually transmitted disease, substance use, and mental disorders;
development and evaluation of multilevel, combination HIV prevention interventions for youth that result in sustained risk reduction;
evaluation of the acceptability and uptake of biomedical prevention modalities (e.g., vaccines, microbicides, PrEP, rapid testing) and their impact on adherence to HIV risk reduction guidelines;
utilizing ATN’s C2P primary prevention infrastructure, evaluation of interventions and programs implemented independently and collaboratively with CDC to improve identification of youth with undiagnosed HIV infection as a means of preventing secondary transmission events;
utilizing ATN’s C2P primary prevention infrastructure for the development and evaluation of novel primary prevention interventions, including those which leverage the structural features of this infrastructure;
integration of existing programs for primary prevention or treatment of drug abuse and other negative health and mental health outcomes among youth to reduce risk for HIV acquisition;
implementation of enhanced linkage to care interventions and programs for youth with HIV made possible through ongoing program evaluation and refinement, employed independently and collaboratively with CDC to prevent further secondary transmission.

Secondary prevention studies examine behavioral and therapeutic interventions, ideally at earlier stages of infection, in order to preserve health and function toward preventing disease progression in HIV-infected populations. These include, but are not limited to, studies in the following areas:

evaluation of interventions and programs implemented independently and collaboratively with CDC to improve identification of youth with undiagnosed HIV infection, ideally at earlier stages of infection and particularly among populations of racial and ethnic minority;
evaluation of enhanced linkage to care interventions and programs for youth with HIV implemented independently and collaboratively with CDC to preserve health and prevent disease progression;
evaluation of the effects of HIV infection and of HAART on neurocognitive and other neurologic outcomes including among behaviorally infected youth, a setting that is ideal for the study of events in early HIV disease;
tailoring interventions (prevention, adherence, etc) to the level of neurobehavioral functioning among youth living with HIV;
clinical evaluation of therapies to exploit the immunologic resilience of recently-infected youth;
clinical trials to optimize the efficacy and minimize the long-term untoward effects including the neurobehavioral, cardiovascular, metabolic, bone and renal outcomes of current and new antiretroviral agents;
clinical trials to elucidate mechanisms of HIV related and/or HAART associated SNAEs and to evaluate prevention and/or treatment modalities for such co-morbidities among youth;
clinical trials to evaluate prevention or treatment modalities for HIV-related or exacerbated co-infections and cancers;
pharmacokinetic and pharmacogenetic studies of current and novel antiretroviral agents, including studies of interactions with other commonly used medications such as contraceptive agents in youth populations;
utilizing recent findings from developmental neuroscience to tailor interventions to the level of neurobehavioral functioning among youth living with HIV;
interventions to evaluate programs for anticipatory guidance to perinatally-infected youth to delay sexual initiation and optimize sexual health, prevent alcohol and substance abuse, improve mental health, and develop life skills;
interventions to evaluate programs to promote responsible sexual behavior among HIV-infected youth to prevent HIV transmission to others, including risk reduction interventions to reduce transmission of HIV;
interventions to prevent HIV transmission, with attention to mental health and substance use problems, including screening and referral for treatment, and interventions to address chronic and episodic substance use;
evaluation of programs designed to promote or optimize antiretroviral drug adherence in youth, including but not limited to, interventions that focus on technology development.
evaluation of programs designed to promote or optimize antiretroviral drug adherence in youth, including interventions to address substance use problems affecting treatment adherence by screening and referral of youth who are either episodic or chronic substance users;

Tertiary prevention studies evaluate strategies to restore ill HIV-positive adolescents and young people to full or better function. These studies include, but are not limited to, the following areas:

the effective management of adolescents presenting very ill, as well as the management of young people with dwindling therapeutic options;
evaluation of the efficacy of system- or organ-specific therapies in immune compromised adolescents;
the assessment of the impact of both HIV infection and its therapy on the life-decisions of young adults with respect to relationships, education, employment, and child-bearing with the development of theory-based interventions;
evaluation of integrated treatment approaches incorporating psychological, medical and ancillary services care, including medical and mental health services, substance abuse treatment, case management, school and housing support, job training, and legal advice, when needed;
evaluation of neurocognitive functioning and ways to restore or prevent further loss of neurocognitive functional capacity by improving treatment adherence, management of risk behavior, and enhancing performance in developmentally important contexts such as work and school.

Organizational Components and Responsibilities

The ATN consists of the Adolescent Medicine Coordinating Center (ACC), the Data and Operations Center (DOC), and 14 Adolescent Medicine Trials Units (ATUs). The AMLG is comprised of three subgroups to implement the research agenda (Therapeutics, Behavior, and Community Prevention). Current ancillary groups include the Study Coordinator Group, the Community (Connect-to-Protect) Coordinators Group, the Community Advisory Board, Data and Safety Monitoring Board(s) (DSMB), and the Ethics Advisory Panel. ATN Network governance and coordination is provided by an Executive Committee, comprised of the Principal Investigator and Project Director of the ACC, the Vice Chair(s) for any AMLG subgroup, the Principal Investigator and Project Director of the DOC, the Chair and Vice Chair of the Adolescent Medicine Trials Units Principal Investigators, and the NICHD Project Scientist. Other NIH scientists, Chairs and Vice Chairs of ancillary clinical and community coordinator groups, and the staff person of the Community Advisory Board serve as non-voting ad hoc members. The Executive Committee enforces the established policies and procedures of the ATN.