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To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk.Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects.A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001).Amprenavir mean area under the curve over 12 h (AUC0–12 h) and concentration at 12 h (C12 h) (μg/ml) were, respectively, 42.7 μg × h/ml (range, 33.1–55.1) and 2.4 μg/ml (range, 1.4–3.2) in arm B and 17.4 μg × h/ml (range, 4.6–41.3) and 0.9 μg/ml (range, 0.2–2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P ≤ 0.0001). Lopinavir AUC0–12 h and C12 h were, respectively, 95.3 μg × h/ml (range, 60.3–119.3) and 6.3 μg/ml (range, 2.2–9.2) in arm A and 54.4 μg × h/ml (range, 23.5–112.2) and 3.0 μg/ml (range, 0.4–7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P ≤ 0.0008). Ritonavir exposure was not significantly different between arms.APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.