Effect of HIV infection on plasma exposure to first-line TB drugs and target attainment in children.

BACKGROUND: Whether HIV infection adversely affects exposure to first-line TB drugs in children is debatable. It is also not known whether HIV infection increases the risk of plasma underexposure or overexposure to TB drugs. This study sought to address these questions.DESIGN/METHODS: Children on TB treatment were enrolled. After 4 weeks on therapy, blood samples were collected at pre-dose, 1, 2, 4, 8, and 12 h post-dose for pharmacokinetic analysis. Plasma drug exposure below and above the lower and upper bounds of the 95% confidence intervals of the reference mean for children were considered underexposure and overexposure, respectively. The effect of HIV infection on drugs exposure and risk of underexposure were examined using multivariate analysis.RESULTS: Of 86 participants (median age: 4.9 years), 45 had HIV coinfection. HIV coinfection was associated with lower pyrazinamide (PZA) and ethambutol exposures in adjusted analysis. Patients with TB-HIV coinfection were three times more likely to have PZA underexposure than those with TB only. Underexposure of rifampin was common irrespective of HIV coinfection status.CONCLUSIONS: HIV coinfection was associated with a higher risk for PZA underexposure in children. This effect should be accounted for in models and simulations to determine optimal PZA dose for children.

Adequacy of WHO weight-band dosing and fixed-dose combinations for the treatment of TB in children.

BACKGROUND: We examined whether the updated WHO weight-band dosing recommendations and fixed-dose combination tablets for the treatment of TB in children achieves recommended calculated dosages and adequate drug plasma exposure.DESIGN/METHODS: Children on first-line TB treatment per WHO guidelines were enrolled. Blood sampling at pre-dose, 1, 2, 4, 8, and 12 h post-dose after at least 4 weeks of treatment was performed. Drugs concentrations were measured using validated liquid chromatography tandem with mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Plasma drug exposure below the lower limit of the 95% confidence interval of the mean for children was considered low and above the upper limit was high.RESULTS: Of 71 participants, 34 (47.9%) had HIV coinfection. The median calculated dose for isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) was 10.0 (range 4.3-13.3), 15.0 (range 8.6-20.0), 30.0 (range 21.0-40.0), and 20.4 (range 14.3-26.7) mg/kg, respectively. Overall, most patients had under-exposure for RIF and PZA and over-exposure for INH and EMB. Drug dose and weight-for-age Z-score were associated with area under the curve from time 0-24 h for all drugs.CONCLUSIONS: Despite adherence to WHO dosing guidelines, low PZA and RIF plasma exposures were frequent in our study population. Higher than currently recommended dosages of RIF and PZA may be needed in children.