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

病毒血症复制年：衡量累积艾滋病毒负担对结果的影响

• 批准号: 8074986
• 负责人: MICHAEL J MUGAVERO
• 金额: $ 19.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074986
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adherence; Age; Anti-Retroviral Agents; Area Under Curve; Biological Markers; Blood; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Caring; Cessation of life; Characteristics; Clinical; Clinical Data; Clinical Research; Cohort Studies; Data; Demographic Factors; Developed Countries; Development; Diagnosis; Disease; Enrollment; Event; Exposure to; Fibrin fragment D; Future; HIV; HIV Infections; Health; Immune system; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Laboratories; Life; Life Experience; Linear Regressions; Malignant Neoplasms; Measurement; Measures; Methods; Modeling; Morbidity - disease rate; Myocardial Infarction; Observational Study; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Plasma; Principal Investigator; Probability; Prognostic Factor; Protease Inhibitor; RNA; Regimen; Research; Research Personnel; Resources; Risk; Ritonavir; Role; Site; Stratification; Structural Models; Sum; Survival Analysis; System; Test Result; Time; Update; Viral; Viral Load result; Viral load measurement; Viremia; Virion; Virus; Weight; antiretroviral therapy; base; clinical care; clinical practice; cohort; follow-up; hazard; immune activation; interest; medication compliance; mortality; non-nucleoside reverse transcriptase inhibitors; novel; prognostic; programs; research in practice; research study

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.

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对于提供临床护理和开展HIV研究具有非常宝贵的价值。尽管该生物标志物随时间连续测量，但其主要以横截面方式分析使用，集中于单个时间点的病毒载量测量（例如，治疗前或最近的措施）。虽然这些方法已经证明了病毒载量与关键临床结果相关的明确预后价值，但它们未能捕获个体随时间的累积HIV负担，这可能与炎症和免疫激活有关，并导致非AIDS相关的发病率和死亡率。本申请提出开发一种新的血浆HIV RNA暴露的累积测量方法，称为病毒血症拷贝年。研究者将评估初治患者开始抗逆转录病毒治疗（ART）后的累积HIV负荷，并评估病毒血症拷贝年对临床结局的影响。据推测，病毒血症拷贝年将产生明显的独立预后价值超出传统的横断面方法来测量HIV病毒载量。 将通过9个研究中心、全国分布的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ART的未经治疗的HIV感染患者进行回顾性队列研究。具体目标是：在开始ART治疗的初治患者中，开发一种累积血浆HIV病毒载量暴露量（病毒血症拷贝年）的测量方法（目标1）;评价患者社会人口统计学和临床特征与病毒血症拷贝年之间的关系（目标2）;估计病毒血症拷贝年对全因死亡率的影响，与治疗前和时间更新的病毒载量无关（目标3）。病毒血症拷贝年的测量将使用梯形法则（目的1），通过时间加权和近似计算。将探索其他方法，包括在病毒载量-时间散点图上交替使用黎曼和和核平滑器，以非参数化方式定义曲线下面积。将使用线性回归，将病毒血症拷贝年作为目标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解释因果途径的混杂因素。 开发一种具有明显独立预后价值的HIV病毒载量累积测量方法，对未来研究病毒血症拷贝年与炎症生物标志物、免疫激活和临床事件的关系，以及对HIV护理患者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感染艾滋病毒进入第七和第八个十年，并经历非艾滋病定义的临床病症的发病率和死亡率，其中许多与炎症和免疫激活有关，开发一种新的测量方法捕获累积的艾滋病毒载量暴露是及时和可取的，并且可能改变病毒载量在研究和实践中的作用。PHS 398/2590（2004年9月修订，2006年4月重新印发） 公共卫生相关性：HIV病毒载量测量HIV感染者血液中的病毒量。这项研究将开发一种新的方法来计算艾滋病毒携带者血液中的艾滋病毒数量。这种新的HIV病毒载量测量方法可以让医生更好地确定患者的死亡风险。