Effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis

Abstract

Background and objectives: Nevirapine-containing antiretroviral therapy (ART) and rifampicin-based antitubercular therapy are commonly co-administered in Africa, where nevirapine is often the only available non-nucleoside reverse transcriptase inhibitor. Rifampicin induces the metabolism of nevirapine, but the extent of the reduction in nevirapine concentrations has varied widely in previous studies. We describe the steady-state pharmacokinetics of nevirapine during and after antitubercular therapy in South African patients.Methods: Sixteen patients receiving ART including standard doses of nevirapine were admitted twice for intensive pharmacokinetic sampling: during and after rifampicin-based antitubercular therapy.Results: Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 [90% confidence interval (CI) 0.49-0.79] for C max , 0.64 (90% CI 0.52-0.80) for area under the curve up to 12 h (AUC 0 -12 ) and 0.68 (90% CI 0.53 -0.86) for C min . Nevirapine C min was subtherapeutic (<3 mg/L) in six patients during antitubercular therapy (one of whom developed virological failure) and in none afterwards. There was no correlation between rifampicin concentrations and the degree of nevirapine induction assessed by the proportional change in nevirapine concentrations between the two admissions. The ratio of nevirapine AUC 0 -12 to the AUC 0 -12 of its 12-hydroxy metabolite was significantly lower in the presence of antitubercular therapy, consistent with induced metabolism.Conclusions: Nevirapine concentrations were significantly decreased by concomitant rifampicin-based antitubercular therapy and a high proportion of patients had subtherapeutic plasma concentrations. Further study in African patients is required to determine the implications for treatment outcomes.

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

“…A noncompartmental analysis of part of this study, including intensively sampled TB/HIV-coinfected patients (up to 12 h after nevirapine administration), has been reported earlier [17].…”

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.…”

Immunologic and Virologic Responses to Nevirapine Based Antiretroviral Therapy (ART) Among HIV-tuberculosis Co-infected Ugandan Children on Rifampicin Based Anti-tubercular Treatment

“…19 Both adult and paediatric studies done in Africa, Thailand and India have shown varying levels of the effect on NVP plasma levels as a result of the drug-drug interaction during concomitant use of a rifampicin containing anti-TB regimen and a NVP based ART regimen. [4][5][6]8,[20][21][22][23] An intensive pharmacokinetic study of standarddose NVP with and without rifampicin in South African adults found sub-therapeutic NVP levels in 6 of 16 patients during rifampicin dosing. 8 A pharmacokinetic sub analysis conducted on 20 of the children in this study as reported by Barlow Mosha et al also found that NVP trough concentration was significantly reduced in children who received rifampicin and NVP concurrently.…”

“…[4][5][6] Adult studies have demonstrated that the drug interaction between NVP and rifampicin results in decreased levels of NVP that may be suboptimal for complete viral suppression. 7,8 We conducted a retrospective analysis to compare the immunologic and virologic response to NVP based ART regimen among HIV-TB Co-infected Ugandan children on rifampicin based anti-TB treatment compared to those on ART alone.…”