Decreased dolutegravir and efavirenz concentrations with preserved virological suppression in patients with TB and HIV receiving high-dose rifampicin

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 [95% CI, 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.