Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment.

Background: The M2 metabolite of bedaquiline causes QT-interval prolongation, making electrocardiogram (ECG) monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for 6-month bedaquiline treatment. Methods: Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF. Established nonlinear mixed-effects models were fitted to pharmacokinetic and ECG data. In a virtual patient population, QTcF values were simulated for scenarios with and without concomitant clofazimine. ECG monitoring strategies to identify patients who need to interrupt treatment (QTcF > 500 ms) were explored. Results: One hundred seventy patients were included, providing 1131 bedaquiline/M2 plasma concentrations and 1702 QTcF measurements; 2.1% of virtual patients receiving concomitant clofazimine had QTcF > 500 ms at any point during treatment (0.7% without concomitant clofazimine). With monthly monitoring, almost all patients with QTcF > 500 ms were identified by week 12; after week 12, patients were predominantly falsely identified as QTcF > 500 ms due to stochastic measurement error. Following a strategy with monitoring before treatment and at weeks 2, 4, 8, and 12 in simulations with concomitant clofazimine, 93.8% of all patients who should interrupt treatment were identified, and 26.4% of all interruptions were unnecessary (92.1% and 32.2%, respectively, without concomitant clofazimine). Conclusions: Our simulations enable an informed decision for a suitable ECG monitoring strategy by weighing the risk of missing patients with QTcF > 500 ms and that of interrupting bedaquiline treatment unnecessarily. We propose ECG monitoring before treatment and at weeks 2, 4, 8, and 12 after starting bedaquiline treatment.

Evaluating the Efficacy of an Online Learning Tool for EEG Teaching: A Prospective Cohort Study.

OBJECTIVE: To determine the effectiveness of a 6-month, interactive, multimodal, Web-based EEG teaching program (EEGonline) in improving EEG analysis and interpretation skills for neurologists, neurology residents, and technologists, particularly in resource-limited settings. METHODS: Between June 2017 and November 2018, 179 learners originating from 20 African countries, Europe, and the United States were registered on the EEGonline course. Of these, 128 learners (91% African) participated in the study. Pre- and postcourse multiple choice question (MCQ) test results and EEGonline user logs were analyzed. Differences in pre- and posttest performance were correlated with quantified exposure to various EEGonline learning modalities. Participants' impressions of EEGonline efficacy and usefulness were assessed through pre- and postcourse satisfaction surveys. RESULTS: Ninety-one participants attempted both pre- and postcourse tests (71% response rate). Mean scores improved from 46.7% ± 17.6% to 64.1% ± 18%, respectively (p < 0.001, Cohen d 0.974). The largest improvement was in correct identification of normal features (43.2%-59.1%; p < 0.001, Cohen d 0.664) and artifacts (43.3%-61.6%; p < 0.001, Cohen d 0.836). Improvement in knowledge was associated with improved subjective confidence in EEG analysis. Overall confidence among postcourse survey respondents improved significantly from 35.9% to 81.9% (p < 0.001). Lecture notes, self-assessment quizzes, and discussion forums were the most utilized learning modalities. The majority of survey respondents (97.2%) concluded that EEGonline was a useful learning tool and 93% recommended that similar courses should be included in EEG training curricula. CONCLUSIONS: This study demonstrated that a multimodal, online EEG teaching tool was effective in improving EEG analysis and interpretation skills and may be useful in resource-poor settings.

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

BACKGROUND: Bedaquiline improves treatment outcomes in patients with rifampin-resistant (RR) tuberculosis but prolongs the QT interval and carries a black-box warning from the US Food and Drug Administration. The World Health Organization recommends that all patients with RR tuberculosis 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 patients with RR tuberculosis from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, which included obtaining electrocardiograms in triplicate at 4 time points during bedaquiline therapy. Participants were followed up until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT interval prolongation (QT prolongation), defined as any QT interval corrected by the Fridericia method (QTcF) >500 ms or an absolute change from baseline (ΔQTcF) >60 ms. RESULTS: We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant tuberculosis. Most participants (97%) received concurrent clofazimine. Of the participants, 74% were cured or successfully completed treatment, and outcomes did not differ by human immunodeficiency virus status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase (standard deviation) of 23.7 (22.7) ms from baseline to month 6. Four participants experienced a QTcF >500 ms and 19 experienced a ΔQTcF >60 ms. Older age was independently associated with QT prolongation. QT prolongation was neither more common nor more 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 monitoring of the QT interval may be advisable in older patients.