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.