Viremia copy-years: measuring the effect of cumulative HIV burden on outcomes

描述(由申请人提供)：十多年来，血浆艾滋病毒病毒载量生物标记物已被证明在提供临床护理和进行艾滋病毒研究方面具有无价价值。虽然这个生物标记物是随时间连续测量的，但它在很大程度上是以横断面方式分析使用的，侧重于单个时间点的病毒载量测量(例如，治疗前或最近的测量)。虽然这些方法已经证明了病毒载量与关键临床结果有关的明确预后价值，但它们无法涵盖随着时间的推移个人累积的艾滋病毒负担，这可能与炎症和免疫激活有关，并有助于非艾滋病相关的发病率和死亡率。这项申请提出了一种新的、累积的血浆HIV RNA暴露测量方法，称为病毒血症复制年数。研究人员将估计在接受治疗的患者中开始抗逆转录病毒治疗(ART)后的累计艾滋病毒负担，并评估病毒血症复制年数对临床结果的影响。假设病毒血症复制年将产生可证明的独立预后价值，而不是传统的测量艾滋病毒病毒载量的横断面方法。2000年1月1日至2008年12月31日期间，将通过CFAR综合临床系统网络，对2000年1月1日至2008年12月31日期间开始抗逆转录病毒治疗的艾滋病毒感染者进行一项回顾性队列研究。具体目的是：制定一项衡量启动抗逆转录病毒疗法(目标1)的治疗后患者血浆艾滋病毒累积病毒载量暴露的指标--病毒血症复制年数(目标1)；评估患者社会人口学和临床特征与病毒血症复制年数之间的关系(目标2)；评估病毒血症复制年数对全因死亡率的影响，而不考虑治疗前和及时更新的病毒载量(目标3)。病毒血症复制年数的测量将用梯形法则(目标1)的时间加权总和来近似。将探索其他方法，包括在按时间的病毒载量散点图上替代使用Riemann和和核平滑器，以非参数方式定义曲线下的面积。将使用线性回归，将病毒血症复制年限作为目标2的因变量，并使用生存方法作为目标3的自变量。协变量选择将采用半贝叶斯方法，并将使用逆概率加权边际结构模型来解释因果路径上的混杂因素。发展一种具有明显独立预后价值的艾滋病毒病毒负荷累积测量方法，对于未来研究与炎症生物标志物、免疫激活和临床事件有关的病毒血症复制年数，以及对艾滋病毒护理患者中临床事件的风险分层具有重要意义。由于发达国家的患者越来越多地将艾滋病毒感染带入7岁和80岁，并经历了由非艾滋病决定的临床条件的发病率和死亡率，其中许多与炎症和免疫激活有关，因此开发一种新的测量方法来捕获累积的艾滋病毒病毒载量暴露是及时和可取的，并可能改变病毒载量在研究和实践中的作用。PHS 398/2590(09/04版，2006年4月4日重新发布)页面续格式页面 公共卫生相关性：艾滋病毒病毒载量衡量的是艾滋病毒携带者血液中的病毒数量。这项研究将开发一种新的方法来计算艾滋病毒携带者随着时间的推移血液中艾滋病毒的数量。这种新的艾滋病毒病毒载量测量方法可能会让医生更好地确定患者的死亡风险。

DESCRIPTION (provided by applicant): For over a decade, the plasma HIV viral load biomarker has proven invaluable for the provision of clinical care and the conduct of HIV research. Although this biomarker is measured serially over time, it has largely been used in a cross-sectional manner analytically, focusing upon viral load measurement at a single time point (e.g., pre-treatment or most recent measure). While such approaches have demonstrated clear prognostic value of viral load in relation to key clinical outcomes, they fail to capture an individual's cumulative HIV burden over time, which is likely to be related to inflammation and immune activation, and to contribute to non-AIDS related morbidity and mortality. This application proposes development of a novel, cumulative measure of plasma HIV RNA exposure referred to as viremia copy-years. The investigators will estimate cumulative HIV burden following antiretroviral therapy (ART) initiation in treatment-naove patients, and evaluate the effect of viremia copy-years on clinical outcomes. It is hypothesized that viremia copy-years will yield demonstrable independent prognostic value beyond traditional cross-sectional approaches to measuring HIV viral load. A retrospective cohort study of treatment-naove HIV-infected patients initiating ART between 1 Jan 2000 and 31 Dec 2008 will be conducted through the 9-site, nationally distributed, CFAR Network of Integrated Clinical Systems. The specific aims are to: Develop a measure of cumulative plasma HIV viral load exposure, viremia copy-years, among treatment-naove patients initiating ART (aim 1); Evaluate the relationship between patient sociodemographic and clinical characteristics and viremia copy-years (aim 2); and Estimate the effect of viremia copy-years on all-cause mortality independent of pre-treatment and time-updated viral load (aim 3). Measurement of viremia copy-years will be approximated with a time-weighted sum using the trapezoidal rule (aim 1). Other methods will be explored including alternative use of a Riemann sum and kernel smoothers on scatter plots of viral load-by-time to define the area under the curve non-parametrically. Linear regression will be used with viremia copy-years as the dependent variable for aim 2, and as an independent variable using survival methods for aim 3. A semi-Bayes approach to covariate selection will be employed, and inverse probability weighted marginal structural models will be used to account for confounders on the causal pathway. Development of a cumulative measure of HIV viral load burden with demonstrable independent prognostic value has implications for future studies of viremia copy-years in relation to inflammatory biomarkers, immune activation and clinical events, as well as for risk stratification for clinical events among patients in HIV care. As patients in developed countries are increasingly living with HIV infection into the 7th and 8th decades of life and experiencing morbidity and mortality from non-AIDS defining clinical conditions, many of which are associated with inflammation and immune activation, the development of a novel measure capturing cumulative HIV viral load exposure is timely and desirable, and may transform the role of viral load in research and practice. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: HIV viral load measures the amount of virus in the blood of someone with HIV. This research will develop a new way to calculate the quantity of HIV virus someone with HIV has in their blood over time. This new HIV viral load measurement may allow doctors to better determine a patient's risk for dying.