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

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）降低了全世界艾滋病毒感染者的发病率和死亡率。然而，在资源有限的环境中，早期治疗失败（即在HAART治疗的头12个月内出现世卫组织3期或4期疾病或死亡）比在资源丰富的环境中高出5至3倍。早期治疗失败与低CD4计数、低体重指数和贫血有关，但这些标记是非特异性的，可能反映晚期艾滋病毒、合并感染和/或营养不良。营养不良对RLS早期治疗失败的相对影响尚不清楚。由于蛋白质能量、铁或缺铁性贫血或其他微量营养素缺乏，高达40%的RLS成年人营养不良，这与免疫功能障碍和发病率和死亡率增加有关。然而，这种营养不良在RLS中启动HAART的hiv感染者中的意义尚不清楚。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“漏肠”和全身免疫激活有关。高水平的免疫激活导致HAART和HIV疾病进展的免疫恢复受损。因此，我们假设基线营养不良可以预测感染艾滋病毒的成人RLS患者的早期治疗失败，并且早期治疗失败与艾滋病毒和营养不良对肠道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。为了验证我们的假设，我们将利用成人艾滋病临床试验组（ACTG 5175）正在进行的一项试验中收集的数据和冷冻保存的样本。这项由美国国立卫生研究院资助的研究正在评估8个RLS国家（非洲-3、亚洲-2、美洲-3）和美国的1571名艾滋病毒感染者的HAART疗效。我们提出了三个具体目标：1)在开始HAART治疗的未接受治疗的艾滋病毒感染成人中，描述基线微量营养素状况并评估其与基线疾病阶段、人口统计学和简单测量的营养指标的关系；2)评估基线营养不良的具体指标是否是早期治疗失败的独立预测因素。3)确定营养不良和治疗失败是否与微生物易位、免疫激活和免疫恢复降低有关。我们的研究有很高的成功可能性，因为我们的国际团队包括艾滋病毒、免疫学、统计学和营养学研究的领导者。本研究的数据和标本来自美国国立卫生研究院资助的一项正在进行但已完成登记的试验。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，从我们的研究中产生的数据将填补理解营养不良对RLS早期HAART结果的作用的关键知识空白。需要这些数据来1)提供必要的证据来指导设计新的试验，以优化HAART在RLS中的益处，其中艾滋病毒，早期治疗失败，粮食不安全和营养不良都很常见；2)进一步了解营养不良，免疫和传染病发病机制之间的关系。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。在这个项目中，我们将估算发展中国家开始抗逆转录病毒治疗的晚期艾滋病患者的营养不良负担，研究基线营养不良与艾滋病治疗结果之间的关系，并探讨营养不良是否会通过对患者肠道造成损害，导致肠道渗漏和免疫系统的慢性激活而导致艾滋病治疗失败。这些研究将为营养不良对艾滋病毒治疗反应的影响提供重要见解，因此将指导未来优化营养不良和艾滋病毒感染者的治疗。

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.