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AIDS:
doi: 10.1097/QAD.0b013e32835caad1
Clinical Science

A novel pharmacokinetic approach to predict virologic failure in HIV-1-infected paediatric patients

Bouazza, Naïma,b; Tréluyer, Jean-Marca,b,c,d; Msellati, Philippee; Van de Perre, Philippef,g,h; Diagbouga, Sergei; Nacro, Boubacarj; Hien, Hervéi; Zoure, Emmanuellej; Rouet, Françoisi; Ouiminga, Adamai; Blanche, Stephanea,c,k; Hirt, Déboraha,b; Urien, Saika,b,c

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Abstract

Objective: The objective of this study was to develop in children an HIV dynamic model able to predict simultaneously the viral load and CD4+ lymphocyte evolutions, and to take into account, through a composite inhibition score, the relative contribution of each drug of the combination efavirenz–didanosine–lamivudine and use this score as a predictor of treatment failure in a multidrug therapy.

Design: Open phase II trial (BURKINAME – ANRS 12103) registered in the ClinicalTrials.gov database (http://clinicaltrials.gov) with the no. NCT00122538.

Methods: Forty-nine children aged from 2.5 to 15 years were administered once-daily dose of lamivudine, didanosine and efavirenz. The three drugs effect was then characterized by a composite inhibition score combining the effect of each drug, according to their site and mechanism of action and their relative contribution.

Results: Efavirenz was the most potent antiretroviral and was responsible for 65% of the total effect, and then didanosine for 23% and lamivudine was the less potent with 12% of the total observed effect. An EC90 for efavirenz was determined (3.3 mg/l). AUC90 was estimated for lamivudine and didanosine: 8.4 and 1.5 mg h/l, respectively. The composite inhibition score was the best predictor of virologic failure compared with the concentrations of each drug taken independently [hazard ratio (HR) 0.6 per 10% increase, 95% confidence interval (CI) 0.41–0.88].

Conclusion: The relative contributions of three combined drugs were assessed on plasma viral load and CD4+ lymphocyte count kinetics in HIV-1-infected children. Pharmacokinetics targets have been suggested for lamivudine and didanosine. A composite inhibition score has been determined to be a high predictor of treatment failure in a multidrug therapy.

© 2013 Lippincott Williams & Wilkins, Inc.

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