The Effect of Rifampicin on the Plasma and Intracellular Pharmacokinetics of Tenofovir Alafenamide Fumarate in Participants with HIV-associated Tuberculosis

Background: Rifampicin reduces plasma tenofovir and intracellular tenofovir diphosphate (TFV-DP) concentrations when co-administered with tenofovir alafenamide fumarate (TAF). Standard-dose TAF with rifampicin still provided higher TFV-DP concentrations than tenofovir disoproxil fumarate (TDF) in a healthy volunteer study, but this interaction has not been assessed in people with HIV-associated tuberculosis. Setting: Open label, three-period pharmacokinetic study in participants with HIV-1 on tenofovir based ART (plus emtricitabine and efavirenz) in the maintenance phase of weight-based tuberculosis therapy. Methods: Concentrations of intracellular peripheral blood mononuclear cell TFV-DP and plasma tenofovir were measured during three treatment periods: 1) TDF 300 mg daily and rifampicin (TDF + RIF), 2) TAF 25 mg daily and rifampicin (TAF + RIF), and 3) TDF without rifampicin post-completion of tuberculosis therapy (TDF–NoRIF). Twenty-four hour area under the concentration-time curves (AUC 0-24h ) were estimated, and geometric mean ratios (GMR) with 95% confidence intervals were calculated to compare concentrations. Results: Eighteen participants were enrolled: median age of 42 years; 56% male. The TFV-DP AUC 0-24h GMRs comparing the TAF + RIF treatment period with the TDF + RIF and TDF–NoRIF periods were 5.46 (4.26 to 7.00) and 5.23 (3.71 to 7.37), respectively. Plasma tenofovir AUC 0-24h GMR was 0.08 (0.06 to 0.09) and 0.07 (0.06 to 0.09) when comparing TAF + RIF with the TDF + RIF and TDF–NoRIF periods, respectively. Conclusions: When combined with rifampicin, ART containing standard-dose TAF resulted in higher TFV-DP concentrations than TDF-based ART in participants with HIV-associated tuberculosis, supporting its use with rifampicin-containing tuberculosis therapy.