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In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patients treated with genotypic-guided therapy.Patients failing combination therapy (HIV-1 RNA > 10 000 copies/ml, and at least 6 months of therapy with nucleoside analogues and 3 months with PI) were randomly assigned into two arms: control group (C) in which the treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation profiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chromatography. `Suboptimal' concentration (SOC) was defined as at least two PI plasma levels below 2 × IC95. Others were defined as `optimal' concentration (OC). Patients were categorized into four groups: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype); G4 (OC/genotype). An intent-to-treat analysis was performed with viral load as the primary endpoint.A total of 81 patients [mean age 39.7 ± 8 years, 59 men, 52.7% Centers for Disease Control and Prevention (CDC) stage C] were included in the pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, baseline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentration and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 32.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseline at month 6 were: −0.23 ± 0.29 log10 copies/ml (G1); −0.97 ± 0.28 (G2); −0.68 ± 0.37 (G3); −1.38 ± 0.20 (G4). Multivariate analysis showed PI plasma concentrations to be an independent predictor of HIV-RNA evolution (P = 0.017).Multiple parameters determine the response to antiretroviral therapy and causes other than the development of drug resistance should be considered in the setting of therapeutic failure. Suboptimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy.