Adolescent Trials Network Research Articles

Short-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load Suppression

This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on/3 days off) in adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV/AIDS Interventions and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal/early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies/ml plus a preentry value below 200 copies/ml and an entry CD4+ T cell count above 350 cells/mm3. Of the 32 subjects enrolled, 12 (37.5%) had confirmed viral load rebound >400 copies, with 18 subjects (56%) coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4+ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV.

The child and adolescent psychiatry trials network (CAPTN): infrastructure development and lessons learned

BackgroundIn 2003, the National Institute of Mental Health funded the Child and Adolescent Psychiatry Trials Network (CAPTN) under the Advanced Center for Services and Intervention Research (ACSIR) mechanism. At the time, CAPTN was believed to be both a highly innovative undertaking and a highly speculative one. One reviewer even suggested that CAPTN was "unlikely to succeed, but would be a valuable learning experience for the field."ObjectiveTo describe valuable lessons learned in building a clinical research network in pediatric psychiatry, including innovations intended to decrease barriers to research participation.MethodsThe CAPTN Team has completed construction of the CAPTN network infrastructure, conducted a large, multi-center psychometric study of a novel adverse event reporting tool, and initiated a large antidepressant safety registry and linked pharmacogenomic study focused on severe adverse events. Specific challenges overcome included establishing structures for network organization and governance; recruiting over 150 active CAPTN participants and 15 child psychiatry training programs; developing and implementing procedures for site contracts, regulatory compliance, indemnification and malpractice coverage, human subjects protection training and IRB approval; and constructing an innovative electronic casa report form (eCRF) running on a web-based electronic data capture system; and, finally, establishing procedures for audit trail oversight requirements put forward by, among others, the Food and Drug Administration (FDA).ConclusionGiven stable funding for network construction and maintenance, our experience demonstrates that judicious use of web-based technologies for profiling investigators, investigator training, and capturing clinical trials data, when coupled to innovative approaches to network governance, data management and site management, can reduce the costs and burden and improve the feasibility of incorporating clinical research into routine clinical practice. Having successfully achieved its initial aim of constructing a network infrastructure, CAPTN is now a capable platform for large safety registries, pharmacogenetic studies, and randomized practical clinical trials in pediatric psychiatry.

Patient-Related Risks for Nonadherence to Antiretroviral Therapy among HIV-Infected Youth in the United States: A Study of Prevalence and Interactions

Adherence continues to be a major barrier to successful treatment with highly active antiretroviral therapy (HAART) for HIV-infected individuals. HIV-infected adolescents and young adults face a lifetime of treatment with HAART. Often, individuals who struggle with adherence to HAART face multiple barriers that would therefore impact on the success of any single modality intervention. Thus, we conducted a cross-sectional, observational study to determine the prevalence of personal barriers to adherence and to identify associations between these barriers in HIV-infected subjects, 12 to 24. We studied the following personal barriers to adherence: mental health barriers, high/low self-efficacy and outcome expectancy, and the presence of specific structural barriers. There were 396 subjects infected after age 9 recruited from sites from the Adolescent Trials Network for HIV/AIDS Interventions or the Pediatric AIDS Clinical Trials Group. Of the 396 subjects, 148 (37.4%) self-identified as nonadherent. No significant differences were found between adherent and nonadherent subjects for the presence of mental health disorders. Adherence was significantly associated with all but one structural barrier. Both self-efficacy and outcome expectancy were higher among adherent versus nonadherent subjects (p < 0.0001). Grouping subjects according to low self-efficacy and outcome expectancy for adherence, adherence differed according to the presence or absence of mental health disorders and structural barriers (p < 0.0001). Our data suggest that adolescents have significant rates of non-adherence and face multiple personal barriers. Adherence interventions must address multiple barriers to have the maximum chance for positive effects.

Research on Children Yielding Valuable Clinical Information

Research on Children Yielding Valuable Clinical Information

PD-1 and PDL-1 expression in patients with chronic HIV-1 infection: relationship to CD4%, immune activation and antiretroviral therapy (ART) (46.22)

Abstract In chronic HIV-1 infection, CD8 T-cell exhaustion is linked to an increased expression of programmed death molecule (PD-1), a negative regulator of activated T cells. We investigated the relative expression of PD-1 and its ligand PD-L1 in T cells and monocytes of HIV-1 infected patients at different time points of ART. In healthy controls (n=3), &amp;lt;10%of CD4 or CD8 T cells expressed PD-1; in comparison, expression of PD-1 was increased (P&amp;lt;0.05) in treatment naïve patients (n=9) in both CD4 and CD8 T cells. In patients, PD-1 expression on CD4 T cells was correlated with activation marker, HLA-DR (P=0.0004) and inversely related to percentage of CD4 T cells (P=0.0004). Percentage of cells expressing PD-L1 was significantly higher in monocytes (CD14+) versus CD4 T cells and CD8 T cells (P&amp;lt;0.05). Culture of PBMC with cytokines IL-2, IL-7 and IL-15 for 6 days in vitro resulted in increased expression of PD-1 and PD-L1 in CD4 and CD8 T cells, coupled with increased expression of Ki67 and HLA-DR in 3 ART naïve patients. ART was associated with a trend towards decreasing PD-1 expression. We conclude that PD-1 and PDL-1 interaction contributes to CD4 T cell loss in a state of chronic immune activation associated with HIV-1 infection. Supported in part by the “The International Maternal Pediatric Adolescent AIDS Clinical Trials Network of the National Institute of Allergy and Infectious Diseases” (UOI-A141089 and N01-HD-3-3345) and Institutional support.

Partnership Selection and Formation: A Case Study of Developing Adolescent Health Community-Researcher Partnerships in Fifteen U.S. Communities

Purpose This study describes the partner selection process in 15 U.S. communities developing community-researcher partnerships for the Connect to Protect® (C2P): Partnerships for Youth Prevention Interventions, an initiative of the Adolescent Trials Network for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) Interventions. Methods Each site generated an epidemiological profile of urban youth in their community, selected a focus population and geographic area of youth at risk for HIV, conducted a series of successive structured interviews, and engaged in a process of relationship-building efforts culminating in a collaborative network of community agencies. Results Sites chose as their primary target population young women who have sex with men (n = 8 sites), young men who have sex with men (n = 6), and intravenous drug users (n = 1). Of 1162 agencies initially interviewed, 281 of 335 approached (84%) agreed to join the partnership (average 19/site). A diverse array of community agencies were represented in the final collaborative network; specific characteristics included: 93% served the sites’ target population, 54% were predominantly youth oriented, 59% were located in the geographical area of focus, and 39% reported provision of HIV/STI (sexually transmitted infection) prevention services. Relationship-building activities, development of collaborative relationships, and lessons learned, including barriers and facilitators to partnership, are also described. Conclusions Study findings address a major gap in the community partner research literature. Health researchers and policymakers need an effective partner selection framework whereby community-researcher partnerships can develop a solid foundation to address public health concerns.

Calibration and validation of an oral fluid‐based sensitive/less‐sensitive assay to distinguish recent from established HIV‐1 infections

Sensitive/less-sensitive (S/LS) serum-based serologic methods have been developed to measure human immunodeficiency virus (HIV) incidence by distinguishing recent from established infections. Such methods require venipuncture. The goal of this study was to develop an alternative to serum-based S/LS testing using oral fluid (OF) as the testing medium. Serum/OF pairs were collected from 342 patients attending 15 Adolescent Trials Network (ATN) clinical sites. The sera were tested with the use of the dilutional Vironostika (DV; Biomerieux, Durham, NC) S/LS assay (DV(SOD=1.0)) as the reference against which an OF LS assay was calibrated using 40 of the OF pairs. Receiver operating characteristic (ROC) curve analyses pinpointed the OF LS test parameters that maximized concordance with the serum-based DV. Validation of the calibrated OF LS included testing of the remaining 302 serum/OF pairs. During calibration the maximum concordance with the DV was 95.2% and 89.5% for 21 recent and 19 established samples, respectively, at a 1:50 OF sample dilution and an optical density (OD) cutoff of 0.280. When applied to the validation sample set (N=302), the concordance was 73.6% for the recent samples and 89.6% for the established samples. The OF LS assay showed a good concordance with the serum-based reference S/LS assay. It presents an alternative to invasive specimen collection, and has the potential for increasing test compliance in young subjects. However, because of the uncertainty of the performance characteristics of the serum-based S/LS assay with which it was compared, further validation of the OF LS using seroconversion sample pairs is needed.

Snapshots for May 2006

Snapshots for May 2006

A unified web-based Query and Notification System (QNS) for subject management, adverse events, regulatory, and IRB components of clinical trials

Even after intensive review, interpretative questions, ambiguities, contradictions, or errors, will arise once the protocol is scrutinized by site IRBs and implemented at sites. This will occur despite preparation and implementation of site protocol training, and provision of well crafted case report forms for the reporting of clinical and laboratory evaluations and adverse events. Since many staff are involved in each protocol, site investigators or study coordinators might direct protocol queries, participant management, or IRB queries to different network participants, resulting in inconsistent responses. It is important to establish a response mechanism that ensures consistent responses and their systematic documentation. For reporting of adverse events, and the submission of or documentation of completion of regulatory requirements, an easily accessible and structured communications system is also required. This paper describes the development and implementation of a user-friendly web-based query and notification system (QNS) for subject management, adverse events, regulatory, and IRB components. This system was created in the Adolescent Trials Network for HIV/AIDS Interventions (ATN), using existing web based tools with minor modifications and minimal cost. The query and notification system is interactive and allows for free flow of information among the site coordinators and both the protocol teams and the regulatory group. The process of the system is transparent to users at the sites, although its use and maintenance is controlled by Data Operations Center staff, to assure that ATN requirements for review and approval are met. This results in consistency of and timeliness of responses to queries, timeliness and accuracy of adverse event reporting and the ability for the data operations center regulatory staff to provide notification of pending or delinquent regulatory submissions.

Challenges to conducting HIV preventative vaccine trials with adolescents.

It is estimated that 10.3 million people aged 15-24 are living with HIV infection/AIDS worldwide, with 7000 new infections occurring each day. Many of these infections occur during the adolescent years. These rates of infection make adolescents an important target for research in primary prevention. Currently, preparations are under way by the National Institutes of Health-supported HIV networks--the Adolescent Trials Network, the Pediatric AIDS Clinical Trials Group, and the HIV Vaccines Trials Network--for phase 1/2 HIV vaccine trials involving adolescents in the United States. Identifying the challenges to conducting HIV vaccine trials with this population is a crucial component of these preparations. Challenges to HIV vaccine trials with adolescents were identified by reviewing previous vaccine research for adolescents and HIV infection in adolescents and speaking with experts in HIV/AIDS and adolescent medicine. Adolescents (typically those younger than 18 years of age) are minors and fall under ethical and regulatory safeguards for their participation in clinical research including parental permission. Adolescents may not appropriately perceive personal risk, posing challenges for informed consent as well as prevention counseling during a trial. Safety and immunogenicity studies of adolescents are likely to be required by the US Food and Drug Administration before vaccine approval for this population. Early identification and subsequent follow-up of high-risk adolescents are problematic. Vaccine-induced seropositivity may present potential barriers to military service, employment, marriage, and acquiring health insurance. The age at optimal immunization, particularly for girls in some countries, may be during preadolescence. The successful completion of HIV vaccine trials with adolescents must address these challenges both in the United States and internationally. This report addresses relevant background information, identifies the issues surrounding HIV vaccine trials with adolescents, discusses what progress has been made, and addresses plans and implications for the implementation of these trials.

The Child and Adolescent Psychiatry Trials Network (CAPTN)

The current generation of clinical trials in pediatric psychiatry often fails to maximize clinical utility for practicing clinicians, thereby diluting its impact. To attain maximum clinical relevance and acceptability, the Child and Adolescent Psychiatry Trials Network (CAPTN) will transport to pediatric psychiatry the practical clinical trials model widely used in other areas of medicine. CAPTN, a collaborative effort of the Duke Clinical Research Institute and the American Academy of Child and Adolescent Psychiatry, will conduct large, simple "practical" trials that provide generalizable answers to important clinical questions without bias. "Large" in this case means the random allocation of thousands of patients in hundreds of clinical centers to different treatments as they are delivered in community settings. "Simple" means that the number and type of data elements (and, hence, subject and investigator burden) is small and straightforward so as not to discourage provider or patient participation and to maximize the number of subjects per dollar spent. With 200 to 400 child and adolescent psychiatrists each participating in two or three practical clinical trials over 4 years, CAPTN promises to advance both the evidence base and research capacity in child and adolescent psychiatry.

Principles from clinical trials relevant to clinical practice: Part II.

Principles from clinical trials relevant to clinical practice: Part II.