Drug-resistant tuberculosis treatment

Regarding PICO question 9 (MDR/RR-TB, 2019) (use of bedaquiline and delamanid together), 
the analyses yielded adjusted odds ratios of 1.6 (95% CI: 0.5–5.4) for treatment success versus 
treatment failure, 0.8 (95% CI: 0.3–2.1) for treatment success versus death, 1.2 (95% CI: 0.6–2.5) for 
treatment success versus failure or death, and 0.6 (95% CI: 0.3–1.1) for treatment success versus all 
unfavourable outcomes. With regard to adverse events, among the 92 patients receiving bedaquiline 
with concomitant delamanid during treatment in the endTB observational study (total exposure of 
1095 person-months), two bedaquiline-related adverse events and delamanid-related adverse events 
occurred (combined rate: 0.46 per 100 person-months of exposure). This rate was comparable to 
the rates among people receiving bedaquiline alone (0.41 per 100 person-months of exposure) and 
delamanid alone (0.68 per 100 person-months of exposure). Two drug-related serious adverse events 
occurred among the 92 patients receiving concomitant bedaquiline and delamanid, one attributed 
to each drug (combined rate: 0.09 per 100 person-months of exposure). The rate of these events 
was lower than the rates of drug-related serious adverse events among patients receiving either of 
these drugs alone (bedaquiline, 0.28; delamanid, 0.39). No fatal drug-related events occurred among 
patients receiving bedaquiline and delamanid
concurrently.
QTcF measures among people receiving bedaquiline and delamanid increased by an average of 15 ms 
(from 398 ms to 413 ms) from measures taken before or at the time of first receipt of concurrent 
bedaquiline and delamanid use, to the end of the first month. In subsequent months of exposure, the 
mean QTcF measures were similar to those at the end of the first month (range: 404–420 ms). QTcF 
prolongation of more than 500 ms was rare, occurring in only one patient in month 7 of concomitant 
exposure. Drug-related cardiac adverse events were infrequent, occurring in only two of 92 people 

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Recommendations 
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exposed to concomitant bedaquiline and delamanid (rate: 0.2 per 100 person-months). Only one 
drug-related cardiac serious adverse event occurred (rate: 0.1 per 100 person-months). No fatal 
drug-related cardiac events occurred among the 92 people exposed to bedaquiline and delamanid 
concurrently. 
In the endTB observational study overall (n=1094), there were two fatal drug-related cardiac events 
(sudden deaths attributable to QT prolongation); also, another patient experienced a cardiac arrhythmia. 
Both of the deaths occurred among patients receiving bedaquiline, clofazimine, capreomycin and 
p-aminosalicylic acid (but not moxifloxacin or delamanid); in both patients, hypokalaemia was present. 
These patients were not included in the analysis related to this PICO question because they did 
not meet the criteria for inclusion according to the predefined statistical analysis plan. However, 
recognizing that these estimates of serious adverse events were absolute and not relative, the panel 
felt that this additional evidence was important for close monitoring in the future, when the final data 
of the endTB observational study become available. 
The GDG agreed that there was insufficient evidence to assess the efficacy or effectiveness of 
concomitant use of bedaquiline and delamanid, given that there were only 84 patients in the 
intervention group and the data did not lend themselves to a meaningful analysis for the secondary 
comparator (extended use of delamanid alone) because the populations were too different to allow 
for the matching that is usually carried out. This precluded a formal recommendation on the efficacy 
or effectiveness of concomitant use of bedaquiline and delamanid; however, the GDG concluded 
that a statement on safety could be made. This information is included in