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.
aEA 3620, Université Paris Descartes, Sorbonne Paris Cité
bUnité de Recherche clinique, AP-HP, Hôpital Tarnier
cCIC-0901 Inserm, Cochin-Necker
dService de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Saint-Vincent-de-Paul, Université Paris – Descartes, Sorbonne Paris Cité, Paris
eUMI 233, IRD-Université de Montpellier I-Université de Yaoundé 1, Montpellier
fINSERM U 1058
gUniversité Montpellier 1
hCHU Montpellier, Département de bactériologie-virologie et Département d’Information Médicale, Montpellier, France
jService de Pédiatrie, CHU Sourô Sanou, Bobo Dioulasso, Burkina Faso
kUnité d’Immunologie, Hématologie et Rhumatologie Pédiatriques, AP-HP, Hôpital Necker Enfants Malades, Paris, France.
Correspondence to Naïm Bouazza, Unité de Recherche Clinique, Hôpital Tarnier, 89 rue d’Assas, 75006 Paris, France. Tel: +33158412884; fax: +33158411183; e-mail: firstname.lastname@example.org
Received 14 March, 2012
Revised 23 October, 2012
Accepted 15 November, 2012
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).