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Several factors influence the antiviral response to antiretroviral therapy. In this pharmacokinetic and pharmacodynamic analysis, the relationship of drug exposure, demographics, and cotherapy measures to antiviral response in a cohort of largely treatment-experienced children treated with amprenavir and nucleoside reverse transcriptase inhibitors was examined. Multiple pharmacodynamic and demographic factors were examined, but only the minimum plasma concentration (Cmin)/protein-binding-adjusted 50% inhibitory drug concentration (IC50) ratio and whether individuals received 2 versus fewer than 2 nucleosides to which their viral isolates were susceptible were associated with the magnitude of the time-weighted average change in HIV-1 RNA log10 copies/mL from baseline (AAUCMB). In multivariate logistic regression analysis, only the Cmin/IC50 ratio was independently associated with having a ≥ 1 log10 AAUCMB decline. The probability in the study population of having a ≥1 log10 AAUCMB was 50% and 85% at Cmin/IC50 ratios of ≈ 1 and 4, respectively. Of the multiple factors examined, only the Cmin/IC50 ratio was a significant predictor of antiviral response in the first 8 weeks on amprenavir-containing combination antiretroviral therapy.