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Few studies have investigated metabolic complications in HIV-infected African children and their relation with inflammation.We compared baseline and changes in insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] and in markers of inflammation over 48 weeks, in a subset of antiretroviral therapy (ART)–naive Ugandan children from the Children with HIV in Africa-Pharmacokinetics and Adherence/Acceptability of Simple Antiretroviral Regimens trial randomized to zidovudine-, stavudine- or abacavir (ABC)–based regimen. Nonparametric methods were used to explore between-group and within-group differences, and multivariable analysis to assess associations of HOMA-IR.One-hundred eighteen children were enrolled, and median age (interquartile range) was 2.8 years (1.7–4.3). Baseline median HOMA-IR (interquartile range) was 0.49 (0.38–1.07) and similar between the arms. At week 48, median relative changes in HOMA-IR were 14% (−29% to 97%) in the zidovudine arm, −1% (−30% to 69%) in the stavudine arm and 6% (−34% to 124%) in the ABC arm (P ≤ 0.03 for all the arms compared with baseline, but P = 0.90 for between-group differences). Several inflammation markers significantly decreased in all study arms; soluble CD14 increased on ABC and did not change in the other 2 arms. In multivariate analysis, only changes in soluble CD163 were positively associated with HOMA-IR changes.In ART-naive Ugandan children, HOMA-IR changed significantly after 48 weeks of ART and correlated with monocyte activation.