Systemic exposure to rifampicin in patients with tuberculosis and advanced HIV disease during highly active antiretroviral therapy in Burkina Faso

Abstract

Low plasma concentrations of rifampicin, an essential antituberculosis drug, have been reported particularly among HIV co-infected persons. In a prospective, longitudinal study we measured rifampicin systemic exposure at different timepoints during highly active antiretroviral therapy (HAART). From May 2006 to April 2007, 16 tuberculosis (TB)/HIV co-infected patients were enrolled in Ouagadougou, Burkina Faso. All patients received fixed dose combinations of rifampicin, isoniazid, pyrazinamide and ethambutol under direct observation and HAART, consisting of a fixed dose combination of stavudine, lamivudine and nevirapine. Rifampicin concentrations during the dosing interval were determined by HPLC at three different timepoints: (i) after 2 weeks of TB therapy and before starting HIV therapy (T0); (ii) after 4 weeks of combined therapy (T1); and (iii) after 10 weeks of combined therapy (T2). The median values of the area under the curve (AUC(0-24)) of rifampicin increased by 39% at T1 (15.69 μg · h/mL; P = 0.01) and by 83% at T2 (20.65 μg · h/mL; P = 0.001) compared with T0 (11.28 μg · h/mL). Similar variations were observed for the median C(max) at T0 (2.24 μg/mL) compared with T2 (2.83 μg/mL; P = 0.003). However, none of the subjects had C(max) levels >8 μg/mL at either T0 or T2. Rifampicin systemic exposure increased during combined TB and HIV therapy, possibly due to increased drug absorption or decreased oral clearance, but remained invariably low in this population. Studies to define the C(max) rifampicin concentrations, which are associated with a significantly increased risk of treatment failure, are urgently warranted.