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EFFECT OF ANTITUBERCULOSIS THERAPY ON THE PHARMACOKINETICS OF EFAVIRENZ IN CHILDREN
Awewura Kwara1, Hongmei Yang2, Sampson Antwi3, Anthony Enimil3, Fizza S. Gillani4, Anima M. Sarfo3, Antoinette Ortsin3, Albert Dompreh3, Lubbe Wiesner5, Charles A. Peloquin1
1University of Florida, Gainesville, FL, USA,2University of Rochester, Rochester, NY, USA,3Komfo Anokye Teaching Hospital, Kumasi, Ghana,4Brown University, Providence, RI, USA,5University of Cape Town, Cape Town, South Africa
Efavirenz-containing antiretroviral therapy (ART) is the preferred regimen in children older than 3 years receiving rifampin-containing antituberculosis (anti-TB) therapy. To date, there is limited data on the drug-drug interactions between efavirenz and 4-drug anti-TB therapy in children. We hypothesized that at the population level, efavirenz plasma concentrations in TB/HIV co-infected children who are treated with the maximized weight-based efavirenz dosage during anti-TB treatment will be comparable to concentrations in HIV-infected children receiving ART alone.
ART-naïve HIV-infected children aged 3 – 14 years old were enrolled and given ART regimen consisting of efavirenz (10-13.9kg – 200 mg; 14-24.9kg – 300mg; 25-39.9kg – 400 mg and > 40Kg – 600 mg) per WHO recommended weight-band dosing, plus zidovudine 180 - 240 mg/m2 and lamivudine 4 mg/kg twice daily. For the TB/HIV co-infected patients, anti-TB treatment using the new WHO recommended TB drug dosages for children was started immediately upon TB diagnosis and ART started within 2 to 8 weeks of TB therapy. Blood samples were collected at times 0, 2, 8, 12 and 24 hours post-dose after 4 weeks of ART in both arms. Efavirenz concentrations in plasma were measured using validated LC/MS/MS assays and pharmacokinetic parameters calculated using noncompartmental analysis. Pharmacokinetic parameters were compared by rank sum test.
Of the 72 patients, 38 (53%) had TB coinfection. Children with TB coinfection compared to those with HIV infection alone were younger, had lower body weight and height but received a higher efavirenz dose (median, 15 mg/kg vs. 13 mg/kg, P = 0.008). TB/HIV co-infected patients had significantly lower efvairenz Cmax, Cmin and AUC0-24h compared to those with HIV alone (see table below). The proportion of children with efavirenz Cmin < 1 µg/mL (considered subtherapeutic) was also higher among those with TB/HIV coinfection than those with TB alone (47.4% vs. 17.6%, P = 0.008).
This is the first study to investigate effect of first-line anti-TB drug regimen using new higher drugs dosages on efavirenz pharmacokinetics in children. Unlike the findings of adults and prior pediatric studies, 4-drug anti-TB therapy in the co-infected children was associated with significant reduction in efavirenz plasma exposure and trough concentrations. The effect of anti-TB treatment on long-term HIV treatment outcome in TB/HIV co-infected children need to be evaluated.