The recent large-scale introduction of antiretroviral therapy (ART) among persons living with HIV/AIDS (PLWHA) in sub-Saharan Africa, while lifesaving for many, has been attended by a high early mortality rate. It is probable that the high prevalence of malnutrition in the region, worsened by HIV disease, is a factor in both early mortality and overall ART outcomes. Previous studies in PLWHA in resource-constrained settings have reported poorer outcomes in persons with nutritional deficiencies in the absence of ART, but none has documented longitudinal, within-person effects of ART on nutritional status or of nutritional status on ART outcomes. We have initiated a pilot study to examine whether the refeeding syndrome (RS), which has been observed in multiple settings in which severely cachectic or marasmic patients are treated and fed, contributes to the early deaths. In November 2006 we began recruiting 200 patients who are starting ART at a clinic supported by the University of Alabama at Birmingham's (UAB) Centre for Infectious Disease Research in Lusaka, Zambia (CIDRZ) and who exhibit high risk for early ART mortality (CD4+ count < 50 cells/<L or body mass index [BMI] < 16 kg/m2). We are conducting targeted symptom reviews, physical examinations, and dietary recalls 6 times in the first 3 months of ART, and measuring serum levels of phosphate, potassium, magnesium, glucose, and albumin. To date, 12% of subjects have met our criterion for RS at 1 or more visits; 4 of 19 cohort mortalities had RS; and 5 subjects with RS survived after phosphorus supplementation. R21 funding will enhance our study significantly and cost- efficiently by enabling us to monitor many additional outcomes in this already-recruited population. In stored serum samples we will measure additional metabolic analytes (sodium, chloride, bicarbonate, urea nitrogen, and creatinine), selected micronutrients (ferritin for iron status, folic acid, vitamins A, B12, and E, and selenium), and inflammatory markers (C-reactive protein and 1-1-acid glycoprotein) before and during ART. We will extend the study with visits at 6 and 12 months and will analyze the nutrient contents of the dietary recalls. This will enable us to diagnose RS more definitively by distinguishing it from disorders of hydration and electrolytes, to document the effects of ART on food and nutrient intakes, and to detect effects of micronutrient deficiencies and fluxes on outcomes in the first year of ART. The results will guide the design of intervention trials to address metabolic and nutritional issues, to reduce early ART mortality and improve ART outcomes in resource-constrained settings. PUBLIC HEALTH RELEVANCE: The introduction of antiretroviral therapy (ART) among persons with HIV/AIDS in sub- Saharan Africa, many of whom are undernourished, has been attended by a surprisingly high early mortality rate. This project aims to examine the influence of metabolic and micronutrient status on ART outcomes in a population in Lusaka, Zambia who are at high risk for early ART mortality. Future intervention trials will address these metabolic and nutritional issues, to reduce early ART mortality and improve ART outcomes in resource-constrained settings.