Long term outcomes in drug resistant tuberculosis with Bedaquiline, Pretomanid and varying doses of Linezolid.

OBJECTIVES

Assess the effectiveness of bedaquiline, pretomanid and linezolid (BPaL) regimens with varying doses and duration of linezolid at the end of 48 weeks post treatment among drug resistant tuberculosis (DR TB) patients.

METHODS

Multicentric pragmatic randomized clinical trial in which BPaL regimens were given for 26 weeks for pulmonary pre extensively drug resistant tuberculosis (PreXDR TB); bedaquiline, pretomanid and linezolid 600 mg for 26 weeks (arm1), structured dose reduction arms with linezolid dose reduction from 600 to 300 mg after nine weeks (arm2) and 13 weeks (arm3). Participants were followed up for recurrence-free cure up to 48 weeks post-treatment. Whole genome sequencing in sputum samples at baseline and recurrence differentiated relapse and reinfection.

RESULTS

Of 403 enrolled, 378 were included for the modified intent-to-treat analysis based on baseline sputum culture positivity and sensitivity to medications in the study regimen. Among them, 331(88%) had recurrence-free cure at the end of 48 weeks of post-treatment follow-up; arm1:112(87%), arm2:110(88%), arm3:109(88%). Overall, 14 (12 bacteriological and 2 clinical) recurrences (arm1-four, 2-six and 3-four) occurred; 11 recurrences occurred within 24 weeks after treatment completion; four out of 11 within the first 12 weeks. Of the 10 paired sputum samples available at baseline and recurrence for comparison of lineages, there were two reinfections and eight relapses.

CONCLUSION

Structured dose reduction arms had comparable recurrence free cure rates as linezolid 600 mg arm when given along with bedaquiline and pretomanid for 26 weeks in PreXDR TB. Most of the recurrences occurred within the first six months.