Bienczak, A; Denti, P; Cook, A; Wiesner, L; Mulenga, V; Kityo, C; Kekitiinwa, A; ... McIlleron, H; + view all Bienczak, A; Denti, P; Cook, A; Wiesner, L; Mulenga, V; Kityo, C; Kekitiinwa, A; Gibb, DM; Burger, D; Walker, AS; McIlleron, H; - view fewer (2016) Plasma efavirenz exposure, sex, and age predict virological response in HIV-infected African children. JAIDS Journal of Acquired Immune Deficiency Syndromes , 73 (2) pp. 161-168. 10.1097/QAI.0000000000001032.

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Abstract

BACKGROUND: Due to insufficient evidence in children, target plasma concentrations of efavirenz are based on studies in adults. Our analysis aimed to evaluate the paediatric therapeutic thresholds and characterise the determinants of virological suppression in African children. METHODS: We analysed data from 128 African children (aged 1.7-13.5 years) treated with efavirenz, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 36 months. Individual pharmacokinetic measures (C12h, C24h and AUC0-24) were estimated using population-pharmacokinetic modelling. Cox multiple failure regression and multivariable fractional polynomials were used to investigate the risks of unsuppressed viral load associated with efavirenz exposure and other factors amongst 106 initially treatment-naïve children, and likelihood profiling used to identify the most predictive pharmacokinetic thresholds. RESULTS: The risk of viral load >100 copies/mL decreased by 42% for every 2-fold increase in efavirenz mid-dose concentration (95% CI: 23-57%; p<0.001). The most predictive PK thresholds for increased risk of unsuppressed viral load were: C12h 1.12 mg/L (HR=6.14; 95% CI: 2.64-14.27), C24h 0.65 mg/L (HR=6.57; 95% CI: 2.86-15.10), and AUC0-24 28 mg[BULLET OPERATOR]h/L (HR=5.77; 95% CI: 2.28-14.58). Children over 8 years old had a more than 10-fold increased risk of virological non-suppression (p=0.005); among children under 8 years old boys had a 5.31 times higher risk than girls (p=0.007). Central nervous system AEs were infrequently reported. CONCLUSIONS: Our analysis suggests the minimum target C24h and AUC0-24 could be lowered in children. Our findings should be confirmed in a prospective paediatric trial.

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