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

Background Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug-drug interactions with antiretroviral therapy (ART) and safety in people living with human immunodeficiency virus (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-naive patients were randomized to dolutegravir- or efavirenz-based ART. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. HIV viral load was measured at week 24. Results Among 128 patients randomized, the median CD4 count was 191 cells/mm(3). The geometric mean ratio (GMR) for trough dolutegravir concentrations on higher- vs standard-dose rifampicin was 0.57 (95% confidence interval [CI], .34-.97; P = .039) and the GMR for mid-dose efavirenz was 0.63 (95% CI, .38-1.07; P = .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 = .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 = .063). Conclusions Compared with 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 toward faster sputum culture conversion. We demonstrated that high-dose rifampicin (35 mg/kg) reduced dolutegravir and efavirenz exposures without compromising virological suppression in patients with human immunodeficiency virus (HIV). High-dose rifampicin was well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion.

Automated summary

This study found that high-dose rifampicin can reduce the concentrations of dolutegravir and efavirenz in HIV patients without compromising virological suppression. It is well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion.