Impact of Malnutrition on HIV Treatment Failure in Resource-Limited Settings

资源有限环境中营养不良对艾滋病毒治疗失败的影响

• 批准号: 7806498
• 负责人: Amita Gupta
• 金额: $ 65.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-16 至 2013-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806498
• 关键词: AIDS clinical trial group; Acute-Phase Reaction; Address; Adult; Africa; Age; Albumins; Americas; Anemia; Anti-Retroviral Agents; Asia; Biochemical Markers; Body mass index; C-reactive protein; CD14 gene; CD4 Lymphocyte Count; Carotenoids; Cells; Cessation of life; Chronic; Clinical; Communicable Diseases; Country; Data; Data Analyses; Data Set; Developing Countries; Disease; Disease Progression; Early treatment; Enrollment; Equation; Ethnic Origin; Extravasation; Failure; Food; Funding; Future; Gender; Grant; HIV; HIV Infections; Height; Hemoglobin; Highly Active Antiretroviral Therapy; Immune; Immune System Diseases; Immune system; Immunity; Immunologics; Immunology; Infection; Inflammatory; International; Intestines; Iron; Iron deficiency anemia; Knowledge; Low Prevalence; Malnutrition; Measures; Memory; Micronutrients; Modeling; Morbidity - disease rate; Nutritional; Nutritional Study; Outcome; Parents; Participant; Pathogenesis; Patients; Persons; Proteins; Public Health; Regimen; Relative (related person); Resources; Role; Sampling; Selenium; Specimen; Staging; Statistical Methods; T-Lymphocyte; Time; Treatment Failure; Treatment outcome; United States; Upper arm; Vitamin A; Weight; Work; case control; cohort; cost; cytokine; demographics; design; immune activation; immune function; indexing; insight; microbial; micronutrient deficiency; mortality; public health relevance; restoration; statistics; success; therapy outcome; treatment response

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has reduced morbidity and mortality in HIV-infected persons worldwide. However, early treatment failure (i.e. WHO stage 3 or 4 illnesses or death during the first 12 months of HAART) is >3-fold higher in resource limited settings (RLS) than in resource-rich settings. Early treatment failure is associated with low CD4 count, low body mass index, and anemia, but these markers are nonspecific and could reflect advanced HIV, co-infections, and/or malnutrition. The relative contribution of malnutrition to early treatment failure in RLS is unknown. Up to 40% of adults in RLS are malnourished due to protein-energy, iron or iron-deficiency anemia, or other micronutrient deficiencies, which are associated with immune dysfunction and increased morbidity and mortality. However, the significance of this malnutrition in HIV-infected persons initiating HAART in RLS is unclear. In addition to immune dysfunction, this malnutrition has been associated with impaired gut integrity, increased microbial translocation and immune activation. Recently, chronic HIV infection has also been associated with a "leaky gut" and systemic immune activation. High levels of immune activation result in impaired immune restoration with HAART and HIV disease progression. Therefore, we hypothesize that baseline malnutrition is predictive of early treatment failure among HIV-infected adults in RLS and that early treatment failure is related to the synergistic deleterious effects of HIV and malnutrition on gut mucosal integrity leading to increased systemic immune activation. To address our hypotheses, we will utilize data and cryopreserved samples collected as part of an ongoing trial conducted by the Adults AIDS Clinical Trial Group (ACTG 5175). This NIH-funded study is evaluating the efficacy of HAART among 1571 HIV-infected adults in 8 RLS countries (Africa-3, Asia-2, Americas-3) and the United States. We propose three specific aims:1) To characterize baseline micronutrient status and assess its relationship to baseline disease stage, demographics and simple-to-measure nutritional indices among treatment-na¿ve HIV-infected adults initiating HAART; 2) To assess whether specific measures of baseline malnutrition are independent predictors of early treatment failure. 3) To determine whether malnutrition and treatment failure are associated with microbial translocation, immune activation, and reduced immune restoration. Our study has a high likelihood of success because our international team includes leaders in HIV, immunology, statistics and nutrition research. Data and specimens for our study come from a NIH-funded trial that is ongoing but has completed enrollment. This will reduce the time needed to complete the planned studies and optimize cost-efficiency. Importantly, data generated from our study will fill a critical knowledge gap in the understanding the role of malnutrition on early HAART outcomes in RLS. Such data are needed to 1) provide necessary evidence to guide the design of new trials that will optimize the benefits of HAART in RLS, where HIV, early treatment failure, food insecurity, and malnutrition are all common, and 2) further our insights on the relationship between malnutrition, immunity and infectious disease pathogenesis. PUBLIC HEALTH RELEVANCE This work is important for public health because HIV and malnutrition are leading causes of morbidity and death in developing countries. In this project, we will estimate the burden of malnutrition among persons with advanced HIV starting antiretroviral treatment in developing countries, examine the relationship between baseline malnutrition and HIV treatment outcomes, and explore whether malnutrition causes HIV treatment failure by causing damage to a patient's intestinal tract, leading to leakage of the intestinal tract and chronic activation of the immune system. These studies will provide important insights about the impact of malnutrition on HIV treatment response and will therefore guide future efforts to optimize treatment for persons with both malnutrition and HIV.

描述（由适用提供）：高度活跃的抗逆转录病毒疗法（HAART）降低了全球HIV感染者的发病率和死亡率。但是，在资源有限的环境（RLS）中，早期治疗失败（即，在HAART的前12个月内谁患有3或4阶段的疾病或死亡）比资源丰富的环境高3倍。早期治疗失败与低CD4计数，低体重指数和贫血有关，但是这些标记是非特异性的，可以反映晚期HIV，共同感染和/或营养不良。营养不良对RLS早期治疗失败的相对贡献尚不清楚。由于蛋白质能量，铁或铁缺乏贫血或其他微量营养素缺乏，RLS中多达40％的成年人营养不良，这与免疫功能障碍以及发病率和死亡率增加有关。但是，这种营养不良在RLS中引发HAART的HIV感染者中的重要性尚不清楚。除了免疫功能障碍外，这种营养不良还与肠道完整性受损，微生物易位增加和免疫激活有关。最近，慢性HIV感染也与“肠道漏水”和全身免疫激活有关。高水平的免疫激活导致HAART和HIV疾病进展的免疫疾病受损。因此，我们假设基线营养不良可以预测RLS中HIV感染的成年人的早期治疗失败，并且早期治疗失败与HIV和营养不良对肠粘膜完整性的协同有害影响有关，从而导致全身免疫激活增加。为了解决我们的假设，我们将利用数据和冷冻保存样本作为成人AIDS临床试验组正在进行的试验的一部分（ACTG 5175）。这项由NIH资助的研究正在评估HAART在8个RLS国家（非洲3，Asia-2，Americas-3）和美国的1571名HIV感染的成年人中的有效性。我们提出了三个具体目标：1）表征基线微量营养素状态并评估其与基线疾病阶段，人口统计学和备受衡量的营养指数的关系 - 对艾滋病毒感染的成年人发起了HAART； 2）评估基线营养不良的特定测量是否是早期治疗失败的独立预测指标。 3）确定营养不良和治疗衰竭是否与微生物易位，免疫激活和免疫菌群减少有关。我们的研究很有可能成功，因为我们的国际团队包括艾滋病毒，免疫学，统计和营养研究领域。我们研究的数据和标本来自正在进行的NIH资助试验，但已完成入学。这将减少完成计划研究所需的时间并优化成本效益。重要的是，我们的研究产生的数据将填补了解营养不良在RLS早期HAART结果的作用方面的重要知识差距。需要此类数据1）提供必要的证据来指导新试验的设计，以优化HAART在RLS中的好处，其中HIV，早期治疗失败，食物不安全感和营养不良都是常见的，2）进一步进一步了解营养不良，免疫学和感染性疾病病原体之间的关系。公共卫生相关性这项工作对公共卫生很重要，因为艾滋病毒和营养不良是发展中国家发病和死亡的主要原因。在该项目中，我们将估计患有艾滋病毒晚期艾滋病毒的患者的营养不良燃烧在发展中国家开始抗逆转录病毒治疗，检查基线营养不良与艾滋病毒治疗结果之间的关系，并探索营养营养不良是否通过对患者的肠道造成肠道损害而导致HIV治疗，从而导致肠道肠道和肠道肠道渗透和肠道肠道系统的泄漏。这些研究将提供有关营养不良对HIV治疗反应的影响的重要见解，因此将指导未来的努力，以优化营养不良和HIV患者的治疗。