Effectiveness and Cardiac Safety of Bedaquiline-Based Therapy for Drug-Resistant Tuberculosis: A Prospective Cohort Study

Abstract

Background Bedaquiline improves treatment outcomes in patients with rifampin-resistant TB (RR-TB) but prolongs the QT-interval and carries a black-box warning by the U.S. Food and Drug Administration. The World Health Organization recommends that all patients with RR-TB receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac safety has not been published. Methods We conducted an observational cohort study of RR-TB patients from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, including electrocardiograms (ECGs) performed in triplicate at four time points during bedaquiline therapy. Participants were followed until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT-prolongation, defined as any QTcF>500 ms or an absolute change from baseline (△ QTcF) >60 ms. Results We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant (XDR) TB. Most participants (97%) received concurrent clofazimine. 74% of participants were cured or successfully completed treatment, and outcomes did not differ by HIV status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase of 23.7 (SD 22.7) ms from baseline to month 6. Four participants experienced a QTcF>500 ms and 19 experienced a △QTcF>60 ms. Older age was independently associated with QT-prolongation. QT-prolongation was neither more common nor severe in participants receiving concurrent lopinavir-ritonavir. Conclusions Severe QT-prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close QT-monitoring may be advisable in older patients.

Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis

“…We conducted a prospective observational study to measure the intracellular concentrations of bedaquiline in PBMCs. We enrolled a subset of participants from the PROBeX study—an observational cohort study of patients in South Africa with RR-TB on bedaquiline-containing regimens ( 41 ). Bedaquiline was dosed at 400 mg daily for the first 14 days, followed by 200 mg three times weekly for an additional 22 weeks.…”

Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study

“…The parent PROBeX study recruited 195 adults with known HIV status and culture-confirmed RR-TB who were initiating treatment with a bedaquiline-containing regimen between April 2016 and March 2018. 22 During the study period local treatment guidelines recommended an 18- to 24-month regimen. Linezolid was provided at a dose of 600 mg daily, with reduction to 300 mg daily at the discretion of treating clinicians if toxicity developed.…”

The pipeline of new molecules and regimens against drug-resistant tuberculosis

“…Safety concerns related to QT prolongation require ECG monitoring during therapy [27] , [28] . Clinical experience has demonstrated that the drug is generally well tolerated with severe QT prolongation being uncommon and adverse events leading to discontinuations being rare, also in the combination with delamanid [29] , [30] , [31] . Bedaquiline analogs that are in early clinical development will hopefully have less cardio-dysrhythmic side effects ( Table 2 ).…”