The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis

Abstract

Purpose Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV. Methods Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n=209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks. Results The patients had a median age of 32 (range 19–55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment. Conclusion Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.

Low rifampicin concentrations in tuberculosis patients with HIV infection

“…In the 'Starting Tuberculosis and Antiretroviral Therapy' (START) trial (CAPRISA 001: NCT00091936) described previously, patients (n = 58) who had no prior history of TB, were randomized equally to receive integrated TB and HIV treatment (n = 29) or HIV treatment following the completion of TB treatment (n = 29) [16]. In both arms, ART comprised of once daily enteric-coated didanosine (400 mg for participants > 60 kg; 250 mg for participants < 60 kg), lamivudine 300mg and efavirenz 600mg, but if > 50kg and on TB treatment, then efavirenz 800mg was prescribed.…”

“…FDCs were dosed according to weight bands detailed in the TB control programme guidelines in effect at the time of the study. Accordingly, rifampicin dose was 450mg daily for five days a week in patients weighing < 50 kilograms (kg) or 600mg dosed daily five times a week in patients weighing 50 kg or more [16].…”

Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial

“…Nevirapine biotransformation pathways are more sensitive to induction than are those of efavirenz, and nevirapine-based regimens therefore have a greater risk of subtherapeutic NNRTI concentrations. [2][3][4][5] The reduction in nevirapine concentration is most pronounced during the fi rst 2 weeks of antiretroviral therapy, when it is typically prescribed at half dose (200 mg lead-in dose) to prevent hypersensitivity before a steady state concentration has been reached. 6 To avoid this problem, WHO guidelines recommend efavirenz rather than nevirapine for patients co-infected with HIV and tuberculosis.…”

Changes to antiretroviral drug regimens during integrated TB–HIV treatment: results of the SAPiT trial

“…The absence of clinically significant alteration of efavirenz plasma concentration when co-administered with rifampicin has been demonstrated [26,27]. Efavirenz has also been shown to have a lower risk of hepatotoxicity than nevirapine [25].…”