Analytic Methods for HIV Treatment and Co-Factor Effects

这项建议的主要目的是进一步发展分析观测数据的新方法 艾滋病毒感染者的基础和随机试验，以及这些方法在获得的数据中的应用 在随机和观察性研究中，试图帮助回答重要的开放性实质性问题， 关于HIV相关疾病的治疗和病程。所提出的方法是基于 (i)一类新的因果模型的估计，包括结构嵌套模型，边际模型， 结构模型（MSM），直接效应结构嵌套模型，连续时间结构嵌套模型， 和最优机制结构模型（SNM）。许多新方法从根本上说是“流行病学”的 因为它们需要关于时间依赖性混杂因素的数据，即，结果的风险因素， 预测随后使用研究药物或辅因子的治疗。 特别是，我们计划进一步开发最佳制度的国家监测机制和动态的国家监测机制，以帮助确定 开始HAART治疗和改变HAART方案的最佳时间，作为受试者CD4的函数 计数、HIV RNA、临床病史，以及基因型或表型耐药检测结果（如果可用）。 我们的方法将与指导分析和再分析的目标，与合作者，数据的发展 来自HSPH的HIV因果共移植多人艾滋病队列研究，妇女跨部门 HIV研究，瑞士HIV队列研究，蛋白酶抑制剂时代的后果研究 （SCOPE）、儿科晚期结局方案（PACTG 219）和ALLRT研究。 相关性（参见说明）： 观察的方法被用来回答紧迫的因果问题，不能或尚未 在随机试验中研究。特别是，我们正在开发最好的方法来确定 在HIV感染受试者中启动HAAART治疗的最佳CD4和HIV RNA水平， 一旦对初始HAART方案产生耐药性，则是改变治疗的最佳时间。

The principal aim of this proposal is to further development of new methods for analyzing observational data bases and randomized trials of HIV-infected persons and the application of these methods to data obtained in randomized and observational studies in an attempt to help answer important open substantive questions concerning the treatment and course of HlV-related disease. The proposed approaches are based either on (i) the estimation of new classes of causal models which include structural nested models, marginal structural models (MSMs), direct effect structural nested models, continuous time structural nested models, and optimail regime structural models (SNMs). Many of the new methods are fundamentally "epidemiologic" in that they require data on time-dependent confounding factors, that is, risk factors for outcomes that also predict subsequent treatment with the drug or cofactor under study. In particular, we plan to further develop optimal regime SNMs and dynamic MSMs to help detemnine the optimal times to start HAART therapy and to change HAART regimens as a function of a subject's CD4 count, HIV RNA, clinical history, and, where available, results of genot^lc or phenotypic resistance testing. Our methods will be developed with the goal of directing analyzes and reanalyzes, with collaborators, of data from the HIV Causal Colioboration at HSPH . the Multicenler AIDS Cohort Study, The Women's Interagency HIV Study, The Swiss HIV Cohort Study, The Study of The Consequences of Protease Inhibitor Era (SCOPE), Pediatric Late Outcomes Protocol (PACTG 219) and the ALLRT study. RELEVANCE (See instructions): Observational methods are used to answer pressing causal questions that cannot be or have not yet been studied in randomized trials. In particular we are developing methods that are the best available to determine the optimal CD4 and HIV RNA levels at which to initiate HAAART therapy in HIV infected subjects and the optimal time to change therapy once resistance to a initial HAART regime has developed.