Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin

Abstract

Background Higher doses of rifampicin may improve treatment outcomes and reduce the duration of TB therapy, but drug-drug interactions with anti-retroviral therapy (ART) and safety in people living with HIV have not been evaluated. Methods This was a randomized open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily dose rifampicin. ART treatment naïve patients were randomized to dolutegravir- or efavirenz-based ART, whilst those already on ART continued existing medications. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. Sputum was collected for mycobacterial culture collected at week 8, and plasma for HIV viral load at Week 24. Results Among 128 patients randomized, the median CD4 count was 191cells/mm3. Geometric mean ratio (GMR) for trough dolutegravir concentrations on higher vs. standard-dose rifampicin was 0.57 [95%CI: 0.34-0.97, p = 0.039] and GMR for mid-dose efavirenz was 0.63 [0.38-1.07, p = 0.083]. There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs. 14.0%, p = 0.901), as was the incidence of drug-related grade 3-4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higher-dose rifampicin (18.6% vs. 37.0%, p = 0.063). Conclusions Compared to standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well-tolerated among people living with HIV, and associated with a trend towards faster sputum culture conversion.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

“…It has been long suspected that this induction capacity was maximal with standard rifampicin doses ( 11 – 13 ). A recent study has shown that a high dose of rifampicin (35 mg/kg daily) reduced the trough concentrations of dolutegravir (a substrate of UDP glucuronosyltransferase (UGT) 1A1 and CYP3A4) and mid-dose concentrations of efavirenz (a substrate of CYP2B6) by 43% and 37%, as compared to 10 mg/kg rifampicin ( 14 ). No loss of virological control of HIV was observed in participants with dolutegravir or efavirenz concentrations below target thresholds, but the study was not powered to assess virologic efficacy ( 14 ).…”

“…High-dose rifampicin (35 mg/kg) does not affect the exposure to isoniazid, pyrazinamide, and ethambutol, compared to standard-dose rifampicin ( 5 ). In a recent study, patients receiving high-dose rifampicin (35 mg/kg) exhibited reduced plasma exposures to the anti-retroviral drugs dolutegravir and efavirenz as compared to patients receiving standard-dose rifampicin ( 14 ). However, the drug interaction potential of high rifampicin doses remains unknown for all other drugs.…”

Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial

“…Additionally, studies are exploring the potential use of high-dose rifampicin (up to 35 mg/kg) for children [ 36 , 37 ]. These developments may result in higher exposure to rifampicin and, as a consequence, a larger decrease in dolutegravir levels, as observed in adults [ 38 ].…”