Safety and efficacy of exposure to bedaquiline−delamanid in multidrug-resistant tuberculosis: a case series from France and Latvia

Abstract

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) represent a therapeutic challenge [1]. Two anti-TB agents, bedaquiline and delamanid, have been recently approved for the treatment of MDR/XDR-TB. Bedaquiline has a terminal half-life of 5.5 months, in contrast with the short half-life of delamanid (38 h). Both drugs increase the QTcF (Fridericia-corrected QT) interval, although no clinically significant cardiac events have been reported in patients treated with one of these drugs [2, 3]. The clinical trials that led to approval of bedaquiline and delamanid tested these drugs by adding one of them, for a duration of 24 weeks and 6-8 months, respectively, to optimised background [2, 3]. To date, only six cases treated with the bedaquiline−delamanid combination have been reported, mostly presenting interim results [4-6]. The World Health Organization (WHO) recommends to use these drugs for a standardised duration of 24 weeks, the concomitant use of bedaquiline and delamanid being restricted to patients with "no other therapeutic options". Otherwise, it is recommended to start the two drugs sequentially after a washout period of 6 months, when switching from bedaquiline to delamanid, and 5 days, when switching from delamanid to bedaquiline [7]. We report the results of exposure to concomitant and sequential treatment with bedaquiline and delamanid, including treatment courses beyond 24 weeks, as part of multidrug MDR/XDR-TB regimens. A multicentre case series was established including patients who started treatment for culture-proven MDR-TB from January 1, 2013 to August 31, 2015, and were exposed to the bedaquiline−delamanid combination for ⩾30 days. Participating centres were three hospitals in the Paris region, France (Bligny, Pitié-Salpêtrière and Bichat), and the Riga East University Hospital in Riga, Latvia. Exposure to bedaquiline and delamanid was defined as the sum of: 1) days of concomitant treatment; and 2) days of exposure to one drug after stopping it, as defined by washout period, while taking the other one (sequential treatment). Standard definitions of MDR/XDR-TB and WHO treatment outcomes were applied. Time to sputum culture conversion was measured from treatment start to the first of two consecutive negative sputum culture results. Treatment regimens were tailored for each patient in agreement with WHO guidance: concomitant or sequential treatment with bedaquiline and delamanid was used to provide regimens with at least four effective drugs to patients with resistance or intolerance to second-line drugs. Bedaquiline and delamanid treatment courses were prolonged beyond 24 weeks according to criteria presented elsewhere [8]. Individualised treatment oversight was provided by the French and Latvian TB Consilia. Adequate treatment monitoring, including periodic ECGs as recommended, and pharmacovigilance were implemented. Treatment was usually started under inpatient, and then continued under outpatient care. Seriousness of adverse events was defined according to the US Na...

QT prolongation and cardiac toxicity of new tuberculosis drugs in Europe: a Tuberculosis Network European Trialsgroup (TBnet) study

“…These findings support published results [8][9][10] and recent data from a Phase III clinical trial testing Dlm versus a placebo [11]. In addition, a relevant proportion of physicians used the new drugs for treatment for more than 6 months [12,13] and in combination with QT-interval prolonging agents [14,15]. Limitations of this study include retrospective data collection, the analysis of aggregate data, incomplete coverage of the WHO Europe region with over-representation of Western Europe, bias linked to surveys which may lead to underestimating the number of events and the absence of sudden death in the questionnaire.…”

Concurrent, Prolonged Use of Bedaquiline and Delamanid for Multidrug-Resistant Tuberculosis

“…This case report represents the first incident in which a patient with pulmonary MDR-TB was treated concurrently with Bdq and Dlm beyond 24 weeks in Korea. These observations are consistent with recent studies conducted outside of Korea, including several reports describing patients treated with one or both drugs for more than 24 weeks, as necessary [6][7][8]. No seri-ous adverse events were reported in these cases.…”

Management of Multidrug-Resistant Tuberculosis

“…5 Over 40 adult patients with MDR/XDR-TB have been reported who have received bedaquiline and delamanid concurrently. [84][85][86][87] The combination appears effective and well tolerated, with few reports of QTc intervals > 500 millisecond. In some of these reports, patients were treated for greater than the recommended 6 months and tolerated the medications well.…”

“…In some of these reports, patients were treated for greater than the recommended 6 months and tolerated the medications well. 84,86,87 As these two drugs are often used in patients with few treatment options, extending the duration of use beyond 6 months is recommended in these settings. 69…”