TY - JOUR
T1 - Decreased dolutegravir and efavirenz concentrations with preserved virological suppression in patients with TB and HIV receiving high-dose rifampicin
AU - Sekaggya-Wiltshire, Christine
AU - Nabisere, Ruth
AU - Musaazi, Joseph
AU - Otaalo, Brian
AU - Aber, Florence
AU - Alinaitwe, Lucy
AU - Nampala, Juliet
AU - Najjemba, Letisha
AU - Buzibye, Allan
AU - Omali, Denis
AU - Gausi, Kamunkhwala
AU - Kengo, Allan
AU - Lamorde, Mohammed
AU - Aarnoutse, Rob
AU - Denti, Paolo
AU - Dooley, Kelly E
AU - Sloan, Derek J
N1 - Funding: This publication was produced as part of the SAfety and EFficacy in high-dose RIFampicin trial, which is part of the European and Developing Countries Clinical Trials Partnership-2 (EDCTP2) Programme supported by the European Union (grant TMA2016CDF-1580). Additional support was provided by a Global Challenges Research Fund award from the Scottish Funding Council, administered via the University of St. Andrews.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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.
AB - 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.
KW - TB-HIV
KW - High-dose rifampicin
KW - Antiretroviral therapy
KW - Dolutegravir
KW - Efavirenz
U2 - 10.1093/cid/ciac585
DO - 10.1093/cid/ciac585
M3 - Article
SN - 1058-4838
VL - 76
SP - e910-e919
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 3
ER -
