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

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.

Short-term virological efficacy, immune reconstitution, tolerance, and adherence of once-daily dosing of didanosine, lamivudine, and efavirenz in HIV-1-infected African children: ANRS 12103 Burkiname.

Access to antiretroviral therapy (ART) and routine laboratory monitoring are limited for HIV-1-infected children from sub-Saharan Africa. This trial conducted in Bobo-Dioulasso, Burkina Faso, aimed to describe the biological efficacy, tolerance, and adherence of the combination of didanosine, lamivudine, efavirenz in once-daily administration among eligible HIV-1-infected children. From February 2006 to November 2007, 51 HIV-1-infected children aged from 30 months to 15 years and eligible for ART were enrolled in a phase II open clinical trial with follow-up visits every 3 months. HIV-1 genotype testing was performed in children with plasma viral load (PVL) >1000 copies per milliliter after ART initiation. Children were followed for a median of 13.4 months [interquartile range (IQR) 12.8-14.2]. At enrollment, median CD4 count was 8% (IQR = 4.5-12). PVL was 341,032 (IQR = 127,838-761,539) copies per milliliter. At 12 months, median CD4 increased significantly by +15% (P < 10(-3)), and median PVL decreases significantly by -290,500 copies per milliliter (P < 10(-4)). Hemoglobin and platelets counts increased significantly by +1.05 g/dL (P < 10(-5)) and 108,500 cells per milliliter (P < 10(-3)), respectively. Based on pill count, mean yearly adherence was 97.3%, and 48% of the children had an adherence rate ≥ 95% at the four quarterly visits. Adherence was better for girls than for boys independently of other sociodemographic variables or markers of HIV disease progression. Drug-resistant mutations were found in 11 children (21.6%). This once-daily drug combination is associated with excellent virological efficacy, immune reconstitution, and good adherence. However, the high prevalence of drug resistance mutations is a matter of concern.

Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial.

OBJECTIVE: To assess 12-month survival, pharmacokinetics, immunologic and virologic efficacy, tolerance, compliance and drug resistance in HIV-infected children in Bobo-Dioulasso, Burkina Faso, receiving once-daily highly-active antiretroviral therapy as a combination of didanosine (DDI), lamivudine (3TC) and efavirenz (EFV). METHODS: In the ANRS 12103 open phase II trial, HIV-infected children were examined at inclusion and monthly thereafter. CD4+ T-lymphocyte (CD4) count, plasma concentration of ribonucleic acid (RNA) of human immunodeficiency virus type 1 (HIV-1) and haematologic and biochemical parameters were measured at baseline and every trimester. HIV-1 resistance testing was performed in case of viral escape. Drug plasma concentrations were determined with high-performance liquid chromatography. FINDINGS: From February 2006 to November 2007, 51 children (39% girls) with a mean age of 6.8 years were enrolled and treated for 12 months. At baseline, Z scores for mean weight-for-age and mean height-for-age were -2.01 and -2.12, respectively. Mean CD4% was 9.0. Median plasma HIV-1 RNA viral load was 5.51 log(10) copies per millilitre (cp/ml). Two children (3.9%) died and another 11 (22%) suffered 13 severe clinical events. At month 12, mean WAZ had improved by 0.63 (P < 0.001) and mean HAZ by 0.57 (P < 0.001). Mean CD4% had risen to 24 (P < 0.001). Viral load was below 300 RNA cp/ml in 81% of the children; HIV resistance mutations were detected in 11 (21.6%). CONCLUSION: The once-a-day combination of DDI + 3TC + EFV is an alternative first-line treatment for HIV-1-infected children. Dose adjustment should further improve efficacy.

Is the recommended once-daily dose of lamivudine optimal in West African HIV-infected children?

We aimed in this study to describe lamivudine concentration-time courses in treatment-naïve children after once-daily administration, to study the effects of body weight and age on lamivudine pharmacokinetics, and to simulate an optimized administration scheme. For this purpose, lamivudine concentrations were measured in 49 children after at least 2 weeks of didanosine-lamivudine-efavirenz treatment. A total of 148 plasma lamivudine concentrations were measured, and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Children were divided into two groups, according to their pharmacokinetic parameters, thanks to tree regression analysis. For each patient, the area under the curve was derived from estimated individual pharmacokinetic parameters. Different once-daily doses were simulated in each group, to obtain the same exposure in children as the mean effective exposure in adults (8.9 mg/liter.h). A two-compartment model in which the slope of distribution is assumed to be equal to the absorption rate constant adequately described the data. Parameter estimates were standardized for a mean standard body weight using an allometric model. Children were then divided into 2 groups according to body weight: CL/F was significantly higher in children weighing less than 17 kg (1.12 liters/h/kg) than in children over 17 kg (0.95 liters/h/kg; P=0.01). The target mean AUC of 8.9 mg/liters.h was obtained with a 10-mg/kg once-daily lamivudine (3TC) dose for children below 17 kg; the recommended dose of 8 mg/kg seems to be sufficient in children weighing more than 17 kg. These assumptions should be prospectively confirmed.

Is the recommended dose of efavirenz optimal in young West African human immunodeficiency virus-infected children?

We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (Cmin and Cmax, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold Cmin (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C(min)s below 1 mg/liter. A significantly higher percentage of children with C(min)s of >1.1 mg/liter or AUCs of >51 mg/liter x h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C(min)s between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

Didanosine population pharmacokinetics in West African human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatment.

Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (Cmax), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and Cmax (P < or = 0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter x h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.