Background. Low body mass index (BMI) at antiretroviral therapy (ART) initiation is associated with early mortality, but the etiology is not well understood. We hypothesized that low pretreatment serum phosphate, a critical cellular metabolism intermediate primarily stored in skeletal muscle, may predict mortality within the first 12 weeks of ART. Methods. We prospectively studied 352 HIV-infected adults initiating ART in Lusaka, Zambia to estimate the odds of death for each 0.1？mmol/L decrease in baseline phosphate after adjusting for established predictors of mortality. Results. The distribution of phosphate values was similar across BMI categories (median value 1.2？mmol/L). Among the 145 participants with BMI 18.5？kg/m2, 28 (19%) died within 12 weeks. Lower pretreatment serum phosphate was associated with increased mortality (odds ratio (OR) 1.24 per 0.1？mmol/L decrement, 95% CI: 1.05 to 1.47; ) after adjusting for sex, age, and CD4+ lymphocyte count. A similar relationship was not observed among participants with BMI ≥18.5？kg/m2 (OR 0.96, 95% CI: 0.76 to 1.21; ). Conclusions. The association of low pretreatment serum phosphate level and early ART mortality among undernourished individuals may represent a variant of the refeeding syndrome. Further studies of cellular metabolism in this population are needed. 1. Introduction Early mortality in the initial 90 days after antiretroviral therapy (ART) initiation is strikingly high among persons with low body mass index (BMI < 18.5？kg/m2) compared to those with normal BMI [1–4]. While a greater incidence of opportunistic infections and more advanced immunosuppression likely contributes to increased mortality in undernourished patients [5, 6], the loss of metabolically active tissue may negatively impact a range of critical physiologic processes and also contribute to these early deaths [7–9]. Skeletal muscle mass, a major reservoir of bioavailable phosphate, is reduced early in HIV-associated weight loss, and among HIV-uninfected persons chronic undernutrition is associated with a reduction in mitochondrial enzyme activity which rapidly normalizes with nutritional support [10–12]. Prior studies of malnourished prisoners-of-war and chronically ill hospital patients found that rapid depletion of serum phosphate after aggressive feeding disrupts electrolyte homeostasis and can induce cardiac and pulmonary complications and death—a condition termed refeeding syndrome [13–16]. We hypothesized that a similar syndrome resulting from increased metabolic demand for phosphate-dependent cellular metabolism
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