Drug-resistant tuberculosis treatment

PICO question 9 (MDR/RR-TB, 2019) (use of bedaquiline and delamanid together). To analyse 
treatment success, failure, relapse and death for the concurrent use of bedaquiline and delamanid, 
the data were derived from the same cohort of patients from the endTB observational study that 
informed PICO question 7. However, in this dataset, only 92 patients received both medicines together 
for any period of time, and even fewer started bedaquiline and delamanid at the same time and within 
the first month of treatment (n=35). Another three patients were receiving concomitant bedaquiline 
and delamanid by the end of the first month of treatment, bringing the total number to 38. The 
remaining 57 patients started the two medicines more than 30 days apart and were therefore not 
included. Additional data sources comprised a cohort of 100 patients treated with bedaquiline in 
Mumbai, India (from an MSF-supported project), of whom 86 received some form of concomitant 
treatment with bedaquiline and delamanid during therapy; 62 of these 86 initiated the two medicines 
within 30 days of each other, and 46 of these 62 began both medicines during the first month of their 
treatment episode. The total intervention population therefore comprised 84 patients: 38 from the 
endTB observational study cohort and 46 from the Mumbai dataset. Due to the limited data available, 
the sources of data for the comparator populations were derived from the endTB observational 
study, and the datasets from Belarus, Mumbai, and Uzbekistan. There were inadequate numbers of 
patients available in the IPD for any meaningful analyses (n=4 patients who received bedaquiline and 
delamanid together). The primary comparison group included 401 patients (n=302 from the endTB 
observational study, n=82 from the Belarus dataset, n=17 from the Uzbekistan dataset and n=0 from 
the Mumbai dataset). These patients initiated bedaquiline within the first month of treatment and did 
not receive bedaquiline beyond 6 months duration. The secondary comparison group was derived 
from the endTB observational study and comprised 102 patients who received delamanid within the 
first month of treatment and who did not receive an extended duration of delamanid. No patients in 
the datasets from Belarus, Mumbai or Uzbekistan received delamanid for this duration. The median 
duration of concurrent use of bedaquiline and delamanid among the 84 patients in the intervention 
group was 18.5 months (IQR: 9 months, 21 months). 
Additional data presented included safety data from the DELamanId Bedaquiline for ResistAnt 
TubErculosis (DELIBERATE) trial (AIDS Clinical Trials Group A5343). The DELIBERATE trial is a randomized, 
open-label, three-arm pharmacokinetic and safety trial conducted at study sites in South Africa and 
Peru. Eligible patients were aged 18 years or more, with pulmonary MDR-TB (or rifampicin mono-
resistance) receiving treatment for MDR-TB, but without clofazimine, and with moxifloxacin replaced 
by levofloxacin and a baseline corrected QT interval by Fredericia (QTcF) of less than 450 ms. In 
addition to the MDR-TB treatment regimen with the conditions described above, the regimens used 
in the three study arms comprised: the addition of bedaquiline 400 mg once daily for 2 weeks, then 
200 mg thrice weekly for 22 weeks; the addition of delamanid 100 mg twice daily for 24 weeks; and 
the addition of both bedaquiline and delamanid. The primary objective of the trial was to compare 
the mean change from baseline in QTcF (averaged over weeks 8–24) when bedaquiline and delamanid 
were co-administered with the mean change observed when each drug was administered alone. 
In addition to the data reviewed for PICO questions 8 and 9, the GDG was provided with and reviewed 
data from a study in South Africa on the use of bedaquiline during pregnancy. This observational 
cohort study included information from 108 pregnant women with rifampicin-resistant TB (RR-TB) 
who were recruited from one MDR/RR-TB referral hospital in South Africa between January 2013 and 
December 2017. As part of their MDR/RR-TB regimen, 58 women received bedaquiline; they were 
compared to 50 women who had no bedaquiline in their regimen. The women in this study gave 
birth to 109 live infants, of whom 49 had bedaquiline exposure in utero and 60 had no bedaquiline 
exposure in utero. Clinical assessments were carried out at 2, 6 and 12 months after birth to document 
infant outcomes. The main objective of the study was to document treatment, pregnancy and infant 
outcomes among women treated for RR-TB with second-line TB drugs during
pregnancy.
When reviewing evidence and formulating the recommendations, the GDG considered the need for the 
guidelines to cater also to key subgroups that were not well represented in the 2018 IPD meta-analysis 
– notably, children. Where data on children were unavailable, evidence from adults was extrapolated 

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WHO consolidated 
guidelines 
on
tuberculosis: 
drug-resistant tuberculosis treatment
27
to children. The best available evidence was used to construct recommendations for a regimen that 
has high relapse-free cure rates, and reduces the likelihood of death and the emergence of additional 
resistance while minimizing harms. The GDG was aware of the paediatric MDR-TB IPD meta-analysis 
on 975 clinically diagnosed or bacteriologically confirmed pulmonary or extrapulmonary TB cases 
that was used for the 2016 treatment recommendations (62). Children with XDR-TB were excluded 
from that analysis (n=36) because their treatment regimens were not considered to be comparable 
with those of other MDR-TB patients, and their numbers were too low to be analysed independently. 
No RCTs were included (or known to exist) at the time this dataset was compiled, and the overall 
certainty in the estimates of effect based on this evidence was judged to be very low. However, in July 
2019, preliminary data from the DELIBERATE trial were made available to the GDG to partly address 
PICO question 9; the overall certainty in the estimates of effect for this study was judged to be
low.