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

高效抗逆转录病毒疗法(HAART)降低了艾滋病毒感染者的发病率和死亡率 全世界。然而，早期治疗失败(即世卫组织第3或4期疾病或前12个月死亡 在资源受限设置(RLS)下比在资源丰富设置下高3倍。早期治疗 衰竭与低CD4计数、低体重指数和贫血有关，但这些标记物是非特异性的 并可能反映晚期艾滋病毒、混合感染和/或营养不良。营养不良对人类健康的相对贡献 RLS的早期治疗失败尚不清楚。RLS中高达40%的成年人由于蛋白质-能量而营养不良， 缺铁或缺铁性贫血或其他与免疫功能障碍有关的微量营养素缺乏症 并增加发病率和死亡率。然而，这种营养不良对艾滋病毒感染者的意义 在RLS中启动HAART尚不清楚。除了免疫功能障碍，这种营养不良还与 肠道完整性受损，微生物移位和免疫活性增加。最近，慢性艾滋病毒感染 也与“肠道渗漏”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 基线营养不良预测RLS中HIV感染成人的早期治疗失败 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作用有关 导致全身免疫活性增强。为了解决我们的假设，我们将利用数据和 成人艾滋病临床试验小组正在进行的一项试验中收集的冷冻样本 (ACTG 5175)。这项由美国国立卫生研究院资助的研究正在评估HAART在8个国家的1571名HIV感染成年人中的疗效 RLS国家(非洲-3、亚洲-2、美洲-3)和美国。我们提出了三个具体目标：1) 确定基线微量营养素状况，并评估其与基线疾病阶段、人口统计学的关系 以及启动HAART的初治艾滋病毒感染者成人中易于测量的营养指数；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移位、免疫 激活，减少免疫恢复。我们的研究成功的可能性很高，因为我们的国际 该团队包括艾滋病毒、免疫学、统计学和营养学研究领域的负责人。为我们的研究提供数据和样本 来自美国国立卫生研究院资助的一项试验，该试验仍在进行中，但已完成登记。这将减少所需的时间 完成计划研究，优化成本效益。重要的是，我们的研究产生的数据将填补 在了解营养不良对RLS早期HAART结果的作用方面的关键知识差距。这样的数据 需要1)提供必要的证据来指导新试验的设计，以优化 RLS的HAART，那里艾滋病毒、早期治疗失败、粮食不安全和营养不良都很常见，以及2) 进一步深入我们对营养不良、免疫与传染病发病机制关系的认识。

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 enrolment. 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.