Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the ViradaptStudy

Objective: In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patien ts treated with genotypic-guided therapy. Methods: Patients failing combination therapy (HIV-1 RNA > 10 000 copies/ml , and at least 6 months of therapy with nucleoside analogues and 3 months w ith PI) were randomly assigned into two arms: control group (C) in which th e treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation p rofiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chroma tography. 'Suboptimal' concentration (SOC) was defined as at least two PI p lasma levels below 2 x 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. Results: A total of 81 patients [mean age 39.7 +/- 8 years, 59 men, 52.7% C enters for Disease Control and Prevention (CDC) stage C] were included in t he pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, ba seline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentrat ion and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 3 2.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseli ne at month 6 were: -0.23 +/- 0.29 log(10) 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 evoluti on (P = 0.017). Conclusion: Multiple parameters determine the response to antiretroviral th erapy and causes other than the development of drug resistance should be co nsidered in the setting of therapeutic failure. Suboptimal concentrations o f PI limit the response to antiretroviral therapy. Therapeutic drug monitor ing of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy. (C) 2000 Lippincott Williams & Wilkins.