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HIV病毒载量生物标志物已被证明在提供临床护理和开展HIV研究方面具有不可估量的价值。虽然这种生物标志物是随时间连续测量的，但它主要以横断面方式分析使用，侧重于单个时间点的病毒载量测量（例如，预处理或最近的测量）。虽然这些方法已经证明了与关键临床结果相关的病毒载量的明确预后价值，但它们无法捕捉到一个人随着时间的推移累积的艾滋病毒负担，这可能与炎症和免疫激活有关，并导致非艾滋病相关的发病率和死亡率。本应用提出了一种新的、累积的血浆HIV RNA暴露测量方法，称为病毒血症复制年。研究人员将评估未接受治疗的患者开始抗逆转录病毒治疗（ART）后的累积艾滋病毒负担，并评估病毒血症复制年对临床结果的影响。假设病毒血症复制年将产生可证明的独立预后价值，超越传统的横断面方法来测量HIV病毒载量。一项针对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未接受治疗的艾滋病毒感染者的回顾性队列研究将通过全国分布的9个站点的CFAR综合临床系统网络进行。具体目标是：在开始抗逆转录病毒治疗的未接受治疗的患者中，制定一种累积血浆HIV病毒载量暴露（病毒血症复制年）的测量方法（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之间的关系（目标2）；估计病毒血症复制年对不依赖于治疗前和时间更新病毒载量的全因死亡率的影响（目标3）。病毒血症复制年的测量将使用梯形规则（目的1）用时间加权和来近似。将探讨其他方法，包括在病毒随时间负载的散点图上使用黎曼和和核平滑的替代方法，以非参数地定义曲线下的面积。线性回归将使用病毒血症复制年作为目标2的因变量，并使用生存方法作为目标3的自变量。将采用半贝叶斯方法进行协变量选择，并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。开发具有可证明的独立预后价值的HIV病毒载量负担累积测量方法，对未来研究与炎症生物标志物、免疫激活和临床事件相关的病毒血症复制年，以及HIV护理患者临床事件的风险分层具有重要意义。随着发达国家越来越多的艾滋病患者感染到生命的第7和第8个十年，并经历非艾滋病定义的临床疾病的发病率和死亡率，其中许多与炎症和免疫激活有关，开发一种捕捉累积HIV病毒载量暴露的新方法是及时和可取的，并可能改变病毒载量在研究和实践中的作用。小灵通398/2590 （Rev. 09/04，重新发布4/2006）页延续格式页

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.