The Lancet, July 2021.
In 2012, bedaquiline and delamanid were the first new drugs approved for tuberculosis in more than 40 years. Both are oral and well-tolerated and intended to be used in patients who have drug-resistant TB. Historically, these individuals have had few treatment options and those regimens often included very toxic medicines. While bedaquiline and delamanid have a number of benefits, each drug modestly prolongs the QTc interval on the electrocardiogram (ECG). Because having a prolonged QTc can be a precursor to more serious cardiac toxicities (such as abnormal heart rhythms), the World Health Organization (WHO) recommended against using the two drugs together (as no one had carefully assessed the cardiac risk of doing so).
To address this knowledge gap, the randomized, controlled DELIBERATE trial (A5343), evaluated adding bedaquiline, delamanid, or both to background therapy in participants with multidrug resistant TB to accurately determine QTc effects of each drug alone versus together. ECGs were done frequently over the 24 weeks of treatment, in triplicate, and they were interpreted by an expert central reader. To be sure there were no adverse cardiac effects, early participants in the study were hospitalized and monitored carefully. A5343 found that adding delamanid to bedaquiline resulted in no more than additive QTc effects; no participants had grade 3 or 4 QTc events; and the study drugs were well-tolerated, including among people living with HIV. In exploratory analyses, eight-week sputum culture conversion was high in all groups and sustained in the combined treatment arm. These data suggest that co-administration of bedaquiline and delamanid among individuals with a normal QTc at baseline results in acceptable cardiac safety. Preliminary microbiology data were also encouraging in terms of treating drug-resistant TB. Based on these results, the WHO lifted their restriction on concurrent use of bedaquiline and delamanid, allowing them to be administered together among those patients who may need them the most.
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