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OBJECTIVES: A proportion of HIV-infected children with advanced disease develop severe malnutrition soon after antiretroviral therapy (ART) initiation. We tested the hypothesis that systemic inflammation underlies the pathogenesis of severe malnutrition in HIV-infected children. DESIGN: Cross-sectional laboratory sub-study in 613 HIV-infected children initiating ART in Uganda and Zimbabwe. METHODS: We measured C-reactive protein (CRP), TNFα, IL-6 and soluble CD14 by enzyme-linked immunosorbent assay in cryopreserved plasma at baseline (pre-ART) and week-4 (children with severe malnutrition only). Independent associations between baseline biomarkers and subsequent hospitalization for severe malnutrition were identified using multivariable fractional polynomial logistic regression. RESULTS: Compared to children without severe malnutrition (n = 574, median age 6.3 years, median baseline weight-for-age Z-score -2.2), children hospitalized for severe malnutrition post-ART (n = 39, median age 2.3 years, median baseline weight-for-age Z-score -4.8) had higher baseline CRP (median 13.5 (IQR 5.5, 41.1) versus 4.1 (1.4, 14.4) mg/L; p = 0.003) and IL-6 (median 9.2 (6.7, 15.6) versus 5.9 (4.6, 9.3) pg/mL; p < 0.0001), but similar overall TNFα, sCD14 and HIV viral load (all p > 0.06). In a multivariable model, higher pre-ART IL-6, lower TNFα and lower weight-for-age were independently associated with subsequent hospitalization for severe malnutrition. Between weeks 0-4, there was a significant rise in CRP, IL-6 and sCD14, and fall in TNFα and HIV viral load in children hospitalized for severe malnutrition (all p < 0.02). CONCLUSIONS: Pre-ART IL-6 and TNFα were more strongly associated with hospitalization for severe malnutrition than CD4 count or viral load, highlighting the importance of inflammation at the time of ART initiation in HIV-infected children.

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