Biomarkers, Therapy, and Mortality in the Evolving HIV Epidemic

描述(由申请人提供)：这是一份NIAID为期5年的K01奖项的申请书，重点特别与NIAID的目标(非AI-04-033)有关，即在传染病和艾滋病流行病学和结果研究方面促进年轻科学家的职业发展。Bryan Lau博士将应用严格的流行病学和生物统计学方法来解决与当前艾滋病毒护理高度相关的三个主要研究目标。虽然有效的治疗大大降低了艾滋病毒的死亡率和发病率，但目前对优化治疗和死亡率结果变化的关切依然存在。目前的HIV治疗指南建议在CD4计数低于200个/ul时开始HAART方案，并考虑启动200至350个/ul之间的治疗指南。尽管治疗指南规定，超过200个/ul的人确实会进展为艾滋病和死亡。临床队列研究可能有助于解决与优化治疗和因治疗而发生的死亡率变化相关的问题。然而，临床队列研究有非结构化的访问时间表，允许个人潜在地自我选择更频繁地利用医疗保健，而“经典”队列个人以设定的时间间隔被跟踪。虽然经典的队列研究设计可能不能利用研究访问之间设定的间隔来获取最大程度的信息，因为间隔是任意的，并且不是基于卫生保健需求。这项研究项目的目标是：1)确定除了CD4计数和HIV RNA水平之外的生物标志物是否有可能被用于对需要开始治疗的个人进行进一步的靶向治疗，以及这些标志物是否可以用于监测治疗反应；2)量化自引入有效治疗以来特定原因死亡风险的变化；以及3)比较基于间隔的(经典的)和基于临床的队列研究结果的潜在差异。这些目标将通过利用两个正在进行的艾滋病毒队列来实现：约翰·霍普金斯艾滋病毒临床队列和艾滋病与静脉注射经验的联系(ALIVE)。这些目标具有重要的临床和公共卫生意义，因为个人可能更有针对性地开始治疗并监测治疗效果。此外，确定特定原因死亡率的变化可能有助于确定传统上可能不被认为与艾滋病毒有关的需要关注的潜在领域。K01将为刘博士提供受保护的时间，让他获得额外的指导研究经验、课程安排和参与与艾滋病毒相关的研讨会和其他论坛，这些将大大增强刘博士目前在生物统计学和流行病学方面的研究能力，使他能够对临床艾滋病毒研究中日益复杂的问题有深入的了解，并将这些学科整合到富有成效和独立的研究生涯中。

DESCRIPTION (provided by applicant): This is an application for a 5-year K01 award from NIAID with an emphasis particularly relevant to NIAID's goals (NOT-AI-04-033) of fostering the career development of young scientists in infectious diseases and AIDS epidemiology and outcomes research. Bryan Lau, Ph.D., will apply rigorous epidemiological and biostatistical methods to address three major research aims that are highly relevant to the current HIV care. While effective therapies have greatly reduced the mortality and morbidity due to HIV, current concerns regarding the optimization of therapy and the changes in mortality outcomes remain. Current therapeutic guidelines for HIV recommend initiating a HAART regimen at CD4 counts below 200 cells/uL and consider nitiating between 200 to 350 cells/uL Despite the therapeutic guidelines, individuals above 200 cells/uL do progress to AIDS and death. Clinical cohort studies may be useful for addressing questions related to optimization of therapy and the changes in mortality that have occurred due to therapy. However, clinical cohort studies have unstructured visit schedules allowing for individuals to potentially self-select for more frequent health-care utilization whereas the "classical" cohort individuals are followed at set time-intervals. Although classical cohort study designs may not capture the fullest extent of the information with a set interval between study visits as the interval is arbitrary and not based on health care needs. The goal of this research project is to: 1) determine whether biological markers other than CD4 counts and HIV RNA levels could potentially be used to further target therapy towards individuals that need to initiate treatment and whether these markers may be utilized in monitoring treatment response; 2) quantify the changes in cause-specific mortality risk since the introduction of effective therapies; and 3) to compare potential differences in results between interval-based (classical) and clinic-based cohort studies. These goals will be accomplished by utilizing two ongoing HIV cohorts: the Johns Hopkins HIV Clinical Cohort and AIDS Link to Intravenous Experience (ALIVE). These aims have important clinical and public health significance in that individuals may be better targeted for initiation of therapy and monitored for therapy effectiveness. Additionally, identifying changes in cause-specific mortality may help identify potential areas that require attention that may not traditionally be considered HIV-related. The K01 will provide the protected time for Dr. Lau to gain the additional mentored research experience, coursework, and involvement in HIV-related seminars and other forums that will substantially augment Dr. Lau's current research capabilities in biostatistics and epidemiology, enable him to gain an in-depth knowledge of the increasingly complex issues in clinical HIV research, and integrate these disciplines in a productive and independent research career.