Drug-resistant tuberculosis treatment

Section 3.5
and in a table 
note for 
Table 3.1
.
Additional data presented from the DELIBERATE trial highlighted that among the patients randomized 
to bedaquiline (n=28), delamanid (n=27) or both medicines (n=27), the on-treatment change in QTcF 
from baseline was 11.9 ms, 8.6 ms and 20.7 ms, respectively (Dooley K, unpublished data, Johns 
Hopkins Medicine, November 2019 – for this statement and the rest of this paragraph). Of the 27 
patients who received both medicines, 10 (37.0%) experienced a Grade 1
41
QT prolongation adverse 
event, and two (7.4%) experienced a Grade 2 QT adverse event. In the bedaquiline arm, 32.0% and 
3.6% of patients experienced Grade 1 and 2 QT adverse events; in the delamanid arm, these figures 
were 41.0% for a Grade 1 QT adverse event and 7.4% for a Grade 2 QT adverse event. No patients 
experienced Grade 3 or 4 QT adverse events. The study investigators concluded that the QTcF 
prolongation effects of concurrent delamanid and bedaquiline use were not greater than their additive 
effects. The GDG noted that the QT adverse events in the DELIBERATE trial were surrogate 
markers of sudden cardiac death. They also noted that 
levofloxacin was the fluoroquinolone of 
choice in regimens given to patients in the DELIBERATE trial, and that serum potassium was closely 
monitored. 
3.4 Subgroup considerations
MDR/RR-TB alone or with additional resistance. A longer regimen is more likely to be effective if 
its composition is guided by reliable information on drug susceptibility. The design of longer regimens 
for MDR/RR-TB patients with additional resistance follows a similar logic to that used for other 
MDR/RR-TB patients. All MDR/RR-TB patients should be tested for resistance to fluoroquinolones 
as a minimum before starting MDR-TB treatment. If the use of amikacin is being considered in the 
regimen, then rapid testing for second-line injectable agents should be performed. Other tests that 
may help to inform regimen choice and composition are those for resistance to agents such as 
bedaquiline, delamanid, linezolid and pyrazinamide, and for mutation patterns commonly associated 
41 
In the DELIBERATE trial, a Grade 1 QT adverse event was classified as an absolute QTcF in the following situations: >480 ms and ≤500 ms 
and QTcF change from baseline from >0 ms to ≤30 ms OR an absolute QTcF ≤480 ms and QTcF change from baseline from >30 ms 
to ≤60 ms. A Grade 2 QT adverse event was classified as an absolute QTcF in the following situations: >480 ms and ≤500 ms and QTcF 
change from baseline from >30 ms to ≤60 ms OR an absolute QTcF ≤480 ms and QTcF change from baseline >60 ms. A Grade 3 QT 
adverse event was classified as an absolute QTcF in the following situation: >500 ms OR an absolute QTcF >480 ms and QTcF change 
from baseline >60 ms. A Grade 4 QT adverse event was a life-threatening consequence; for example, torsade des pointes or other 
associated serious ventricular dysrhythmia (Dooley K, unpublished data, Johns Hopkins Medicine, November 2019). 

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WHO consolidated 
guidelines 
on
tuberculosis: 
drug-resistant tuberculosis treatment
35
with resistance to isoniazid and ethionamide or prothionamide. Currently, there is no approved rapid 
test for pyrazinamide resistance, and phenotypic DST may require several weeks to produce a reliable 
result, implying that a DST-based decision to include or replace pyrazinamide could delay the start 
of treatment by several weeks, which is not desirable. In many settings, DST for other medicines 
commonly used for MDR-TB treatment is not usually reliable enough to guide regimen composition. 
Because of this, other elements may be necessary to determine the likelihood of effectiveness (see 
Section 3.5
). NTPs should possess or rapidly build the capacity to undertake DST, and all efforts should 
be made to ensure access to approved, rapid molecular tests. Until the capacity for second-line 
DST – including for bedaquiline, linezolid and clofazimine – becomes available, treatment decisions 
may need to rely on the likelihood of resistance to medicines, based on an individual patient’s clinical 
history and surveillance data from the country or
region.
The analysis for the three PICO questions on the duration of treatment did not show any differences 
overall in treatment failure or relapse when comparing patients with MDR-TB with or without 
additional second-line drug resistance, including XDR-TB. In patients with resistance to amikacin 
and streptomycin, Recommendation 3.17 does not apply. The duration of treatment may need to be 
longer than 20 months overall in MDR/RR-TB cases with additional resistance, subject to the clinical 
response to
treatment.