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.
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.
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