To conWrm and reWne associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV + ) youth and 80 HIV-1 seronegatives (HIV ¡ ) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration¸10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10-1,000 mIU/ mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). These immunogenetic relationships were all independent of nongenetic factors, including HIV-1 infection status and immunodeWciency. Alternative analyses conWned to HIV + youth or Hispanic youth led to similar Wndings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of diVerential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to eVective immune response to recombinant vaccines.

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.

Introduction Future HIV vaccine efficacy trials with adolescents will need to ensure that participants comprehend study concepts in order to confer true informed assent. A Hepatitis B vaccine trial with adolescents offers valuable opportunity to test youth understanding of vaccine trial requirements in general. Methods Youth reviewed a simplified assent form with study investigators and then completed a comprehension questionnaire. Once enrolled, all youth were tested for HIV and confirmed to be HIV-negative. Results 123 youth completed the questionnaire (mean age=15 years; 63% male; 70% Hispanic). Overall, only 69 (56%) youth answered all six questions correctly. Conclusions Youth enrolled in a Hepatitis B vaccine trial demonstrated variable comprehension of the study design and various methodological concepts, such as treatment group masking.

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 þ T cell count above 350 cells=mm 3 . 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 þ 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.