i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 8 4 e1 8 8

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Original article

Early efficacy and safety of Bedaquiline and

Delamanid given together in a “Salvage Regimen”
for treatment of drug-resistant tuberculosis

Rohit Sarin, Dr*, Vikram Vohra, Dr, Neeta Singla, Dr, Rupak Singla, Dr,
M.M. Puri, Dr, S.K. Munjal, Dr, U.K. Khalid, Dr, V.P. Myneedu, Dr,
Ajoy Verma, Dr, K.K. Mathuria, Dr
National Institute of Tuberculosis & Respiratory Disease, Sri Aurobindo Marg, Delhi 110030, India

article info abstract

Article history: Background: Drug-Resistant Tuberculosis (DR-TB) patients for whom a WHO recommended
Received 10 January 2019 regimen along with Bedaquiline (BDQ) cannot be prescribed, Delamanid (DLM) was added
Accepted 16 February 2019 along with other drugs to provide a “Salvage Regimen”. The experience of the Institute in
Available online 27 February 2019 respect of early efficacy and safety of both drugs given together is presented.
Objective: To ascertain the early efficacy, safety and tolerability of Bedaquline and Delam-
Keywords: anid given together as a part of salvage regimen.
Drug-resistant tuberculosis Methods: BDQ and DLM were used together to make regimens along with other drugs where
Bedaquline four effective anti TB drugs could not be prescribed as per WHO recommendations. Pa-
Delaminid tients were followed up for sputum smear and culture conversion and adverse events
QTc interval during the treatment.
Salvage regimen Results: In this cohort study, 53 DR-TB patients (Median age-24) were initiated on regimens
containing both BDQ and DLM. Sputum smear conversion was seen in 35% and 94% pa-
tients at the end of 1st week and 3rd month respectively. 84% patients had culture con-
version at the end of 4th month. 29 adverse events (AE) were reported among 17 patients
and there were 11 deaths. QTc prolongation more than 500 MS was seen in only 1 patient.
Conclusion: BDQ and DLM given together in a salvage regimen is efficacious with low rate of
adverse events. The combination provides hope to DR-TB patients with limited treatment
options and should be provided as a life saving option.
© 2019 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

toxicity, long duration and failure to the existing regimens. In

1. Introduction spite of best treatment efforts with the current recommended
regimens, treatment success is possible in about 50% of Multi
The treatment of drug resistant tuberculosis (DR-TB) is a drug resistant tuberculosis (MDR-TB) patients and 11e33% of
challenge due to poor outcomes as a consequence of drug the extensively Drug resistant tuberculosis (XDR-TB) patients1

* Corresponding author. National Institute of TB, and Respiratory Diseases, New Delhi 110030, India.
E-mail address: [email protected] (R. Sarin).
https://doi.org/10.1016/j.ijtb.2019.02.006
0019-5707/© 2019 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.
 i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 8 4 e1 8 8 185

The discovery of newer drugs Bedaquline (Bdq) and

Table 1 e Showing selection of drugs for OBR in
Delamanid (Dlm) have given some hope and limited reports of
decreasing order of preference.
effective results are available.2,3 However, both the drugs
History of exposure to drug Resistance pattern
exhibit cardio toxicity i.e. prolongation of the QT interval and
WHO has not recommended their combined use in the Nil Sensitive
absence of sufficient evidence.4 Nevertheless both the drugs Nil No documented resistance
present Sensitive
have been used in patients where a WHO recommended
present No documented resistance
regimen of four effective drugs could not be given without
using them and have been found to be both efficacious in
terms of sputum smear and culture conversion, safe in terms
of QTc prolongation and tolerability5,6 Clinical trials7 may
subsequently provide the evidence in coming years. Ophthalmological examination was done before starting the
Both Bdq and Dlm are available in India under the Revised treatment and repeated as per clinical status of the patients.
National Tuberculosis Control Programme (RNTCP) and are QTc values (as per Bazetts formula) were obtained directly
recommended individually for treatment of Pre-XDR and XDR from the calibrated 12 lead ECG machines. Four tablets
patients with an optimum background regimens (OBR) (100 mg each) of Bdq was given daily for 2 weeks, followed by
following the WHO principles of using at least four effective two tablets three times a week for 24 weeks whereas Delam-
drugs in addition. There are still no recommendations for the anid was given as two tablets (50 mg each) twice a day
use of both the drugs together. throughout the 24 weeks. All drugs were administered after a
NITRD is a Nodal DR-TB centre under the RNTCP and one of meal and under observation.
the six sites responsible for rolling out Bdq under the Condi- ECG was done twice daily during the period of hospitali-
tional Access Program. As a Nodal DRTB centre, it was zation and other investigations were done in accordance with
responsible for the treatment and monitoring of Pre eXDR and the RNTCP guidelines. Adverse drugs reactions (ADR) were
XDR cases. It was observed that some of the patients had been reported to DR-TB Review Committee for management and
treated with multiple courses of ATT (first and second line), any change in the ITR. The ADRs were also reported to the
had varied drug sensitivity pattern (DST) and could not be put National Pharmacovigilance Program through the causality
on Bdq with an effective OBR due to lack of effective drugs. In panel of the institute which was responsible for assessment of
such cases there was no option left other than putting them drug causality. Management of ADRs were done as per RNTCP
on a individualized treatment option of a “Salvage Regimen” guidelines.
(SR), containing both Bdq and Dlm along with other drugs. The Bacteriological monitoring, consisting of weekly smear and
selection of other drugs was based on the combination of culture (on liquid media) for first month and then subse-
resistance pattern of drugs consumed and the previous his- quently on a monthly basis for six months was done, addi-
tory of drug exposure. tional drug susceptibility testing (DST) for first-line and
Early experience of 53 such patients who were put on second-line drugs when positive cultures were obtained,
treatment with regimens containing both Bdq and Dlm is was done at the institute microbiology laboratory which is
shared. also, the National Reference Laboratory Service (NRL), under
the RNTCP.

2. Methods
3. Outcomes
This patient cohort consisted of those who received both Bdq
and Dlm in the regimen and included intake period 22 Efficacy is assessed in the cohort using sputum culture con-
months. Patients older than 18 years (one patient age 17 version i.e. two consecutive negative results taken at least 2
years), who consented for Bdq and Dlm combination were put weeks apart in a patient with a positive specimen at baseline8,
on treatment. After initial hospitalization of minimum two where the baseline was defined as the initiation of ITR. Cul-
weeks the patients were treated under routine programmatic ture status at 6 months was also assessed, as an efficacy
conditions at DOT centres. The combination of Bdq and Dlm outcome and included all people in the study who had a
was used as a part of an individualized, treatment regimen documented negative culture at 6 months regardless of
(ITR) along with 4e5 other drugs selected as per preference baseline culture status.
based on resistant pattern and previous exposure (Table-1). Safety was measured by occurrence of serious adverse
All the patients who had failed on Cat V regimen or had events and QTc prolongation of more than 500 Ms or increase
clinical failure or where a Bdq regimen as per RNTCP was not of more than 60 Ms from baseline during the period of treat-
possible, were reviewed by the institute DR-TB Review Com- ment. Serious adverse events were defined as deaths irre-
mittee to design an ITR. Written consent was taken from the spective of cause, hospital admissions, events leading to
patients, after informing the potential clinical benefits and disability or congenital malformation, and events considered
adverse effect before starting the treatment. life threatening or otherwise medically significant.
After admitting, pre-treatment evaluation consisting of Tolerability was defined as a person still on treatment for
base line. ECG, Serum Albumin, Thyroid functions, Heamo- drug-resistant tuberculosis 6 months after initiation of the
globin, Electrolytes, Renal and Liver function test, combination of Bdq and Dlm regimen.
186 i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 8 4 e1 8 8

4.3. Conversion status

4. Results
All the 53 patients initiated on treatment had positive smear
4.1. Patients profile and culture at baseline. Of them 42 patients have completed 6
months of intensive phase while 11 are still on intensive
Fifty three patients were initiated on regimens containing phase. Among the 42, 31 are on the OBR, 10 died and 1 was lost
both Bdq and Dlm from March 2017 to November 2018 to follow up (LTFU) (Table-3). Among the 31 patients on OBR,
(Table 2). The median age at initiation was 24 years (IQR sputum conversion was seen in 11 (35%) by the end of 1st week
21e33). 24 (45%) patients were men and had a median BMI of of treatment initiation, 29 (94%) had converted by the 3rd
20 (IQR 17.5e25). Of the 53 patients, 17 (32%) had XDR treat- month and remained negative at the end of 6th month.
ment failures, 02 (4%) had failed on a DST based drug regimen Sputum culture conversion was seen in 7 (23%) of these 31
and 34 (64%) had DST pattern in which an Bdq based regimen patients by end of 1st week and 26 (84%) had converted by end
could not be designed as per RNTCP guidelines. None of the of 4th month. Among these 26, culture re-conversion was seen
patients was HIV positive. in 1 patient only. Culture results were not available among 10
(32%) patients at the end of 6th month due to non production
4.2. Regimen
of sputum, contamination and results still pending (Table-4).
Two out of the 10 patients died during the 1st month of
The regimen used contained a median of 7 drugs IQR (6e8)
treatment and had positive smear and culture at the time of
including Bdq and Dlm. Twenty four (45%) of the patients had
death. The remaining 8 patients died at various points till
at least one more QTc prolonging drug i.e. either Clofazimine
completion of 13th months of treatment and had the last
or high dose Moxifloxacin while, in 27 (51%) patients both of
sputum smears and cultures negative at the time of death.
these drugs were used. A core regimen of Bedaquiline,
The LTFU patient also had a negative smear and culture at the
Delamanid, Imipenimen and Moxifloxacin was used along
time of outcome.
with other drugs in 42 (79%) patients. Both Bdq and Dlm were
planned for a minimum period of 6 months (taken as intensive 4.4. AE/SAE
phase of the regimen) and was extended beyond 6 months in 5
patients. Adverse Events (AE) and Serious Adverse Events (SAEs) were
reported during the initial hospitalization and during the
follow up period by the DOT providers. Seventeen patients
Table 2 e Profile of patients put on salvage regimen (32%) had reported at least 1 serious adverse event excluding
(n ¼ 53). death among the total of 29 adverse events reported. Among
Median age (years) 24 (21e33) these 29 adverse events 21 were serious. Bdq and Dlm were
suspected in 12 (41%) instances but could not be confirmed to
Sex
be the casual agent. More than 1 AE (maximum 5) were re-
Men 24 (45%)
Women 29 (55%)
ported in 5 patients who accounted for 14 AEs of which 08
Body-mass index, kg/m2 20 (17.5e25) were serious. Among the 53 patients both baseline and follow-
Drug resistant tuberculosis classification up ECGs were available for 50 (94%). Among them 07 (0.14%)
Multidrug-resistant 35 (67%) patients had increase of QTc >60Ms at any time. QTc prolon-
Pre-extensively drug-resistant 01 (2%) gation >480 Ms (requiring intervention as per RNTCP guide-
Extensively drug-resistant 17 (32%)
lines) was seen in 11(20%) patients but was resolved with
Type of patient
correction of electrolytes and interruption of the drugs within
Failed on Cat-V regimen 17 (32%)
Bdq based regimen not possible due to DST pattern 34 (64%) permissible limits. Seven (64%) out of these 11 patients were
Clinical failure while on DST based drug regimen 2 (4%) on 4 QTc prolonging drugs however did not require any
No. of drugs along with BDQ and DLM discontinuation of drugs. Only 01 of the patients had both QTc
5 1 (2%) >500Ms and increase of >60Ms. 01 patient with associated cor-
6 17 (32%) pulmonale presented with cardiac arrhythmia (Bigeminy) and
7 19 (36%)
the drug regimen had to be discontinued. Of the 11 deaths QTc
8 14 (26%)
prolongation had been reported in 05 patients (03 with >60Ms
9 1 (2%)
10 1 (2%) increase) at any one time but was resolved and could not be
Core-regimen used with OBR 21
BdqþDlm 53 (100%)
BdqþDlmþImp 21 (40%)
BdqþDlmþImpþMfx(H) 42 (79%) Table 3 e Current status of patients started on salvage
BdqþDlmþMfx(H) 31(58%) regimen.
BdqþDlmþImpþMfx(H)þLzdþCfz 22 (42%)
Outcome No.
Other QTc prolonging drugs along with BDQ & DLM
1 QTc prolonging drugs 24 (45%) Death 10
2 QTc prolonging drugs 27 (51%) LTFU 1
Adverse events reported On treatment with OBR after completion of 31
Adverse events 29 6 months of Bdq & Dlm
Serious adverse events including death 21 On IP with Bdq & Dlm regimen 11
 i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 8 4 e1 8 8 187

Table 4 e Smear and culture status of patients currently on treatment (n ¼ 31).

Smear Culture
Period
Positive Negative N/A Positive Negative N/A
Week 1 17 11 3 19 7 5
Month 3 1 29 1 14 11 6
Month 4 1 29 1 1 26 4
Month 6 0 29 2 2 19 10

confirmed as cause of death in any patient. This was followed is 94% and 61% respectively. Sputum conversion rate of all
by reporting of symptoms of peripheral neuropathy in 5 (1%) the patients (n-53) is 52% and culture conversion is 27% at the
and Gastrointestinal symptoms in 3(0.6%) patients. The ADRs end of 1st month. This culture conversion is higher and
were more due to the accompanying drugs in the regimen faster than reported by Pietersen and colleagues who found
rather than the combination of Bdq and Dlm. conversion in 21% patients, with a median time to culture
conversion of 8.7 months (IQR 5$6e26$4)11 leading to a lower
5. Discussion transmission in the community. Further, the fact that ma-
jority of patients who died, were sputum smear and culture
This is first reported cohort of patients, who have been treated negative at the time of death indicates that transmission
with both Bdq and Dlm due to lack of at least 4 effective anti risks are reduced to a considerable extent even from seri-
tubercular drugs as per WHO recommendations under pro- ously ill patients. Culture conversion is closer to that ach-
grammatic conditions. Although not recommended by RNTCP ieved in patients reported by Gabriella and colleagues i.e. 74%
due to similar potential for QTc prolongation of both the against 61% at 6 months (with 32% still pending, and
drugs, they were used along with other drugs on compas- contaminated). Only 1 patient showed re-conversion with
sionate grounds as these patients did not have any other impending failure at 6th month culture.
effective regimen. The preliminary results show the combi- Tolerability of the regimens prescribed including Bdq and
nation is safe, has high culture conversation rates and toler- Dlm is evident as 42 (79%) of patients continue to take treat-
ated in these patients who otherwise have a low chance of ment while 31 (58%) have completed the Bdq and Dlm dura-
cure and survival. The findings are interim as the patients tion in spite of ADRs.
have yet to complete their full treatment; however the data
supports the safety and tolerability of the combination in spite 5.1. Limitation
of the theoretical risk of synergistic risk of QTc prolongation.9
There was no cardiac arrhythmias (except in one patient) This interim analysis reflects the treatment of an observa-
and only 01 patient had an absolute QTc interval greater than tional non-controlled cohort under programmatic conditions,
500 Ms. Eleven patients in the cohort had QTc prolongation of Tuberculosis patients with few treatment options and has
over 480 Ms requiring intervention. However, these events several limitations.
were managed without permanent discontinuation of either Adverse events, specifically QTc prolongation after initial
Bdq or Dlm when used in combination contrary to QTc pro- admission could have been missed as it was hardly reported
longation requiring permanent discontinuation of Bdq re- by the DOT providers or the absence, of such data could be
ported by Guglielmetti et al in 6% of their patients.10 Our that the QTc prolongation is transient and occurs in the initial
findings are similar to those of Gabriella and colleagues5 who treatment period only. This needs to be confirmed with a
could give the Bdq and Dlm combination in spite of transient larger cohort with more intensive ECG monitoring.
QTc prolongation. Of the11 deaths which occurred, none The small size of the cohort and absence of final outcomes
could be attributed to QTc prolongation. One patient who also needs to be kept in mind while interpreting the results.
presented with Bigeminy had associated cor-pulmonale and Since the patients had a varying resistance patterns, exposure
expired within 24 hours due to poor general condition and response to anti tubercular drugs, it was not possible to
resulting from her Tuberculosis condition. Of note is the conduct a controlled trial with a larger number. However the
higher ADRs which were reported attributing them to the LTFU is not as expected and may be due to the patients,
concomitant drugs, which were used along with Bdq and Dlm. continuing treatment in spite of ADRs due to the limited
The reporting of ADRs were done under the programmatic treatment options. Bdq and Dlm being new drugs for Tuber-
conditions and some may have been missed, but this also culosis, baseline sensitivity was not available/done so they
shows that it is feasible to provide the treatment under the were added considering that they would not yet be resistant
programme conditions. however this needs to be evaluated in further cohorts.
Our data though interim in nature, supports the efficacy
of Bdq and Dlm combination to treat complex resistant pat-
terns of Tuberculosis. We report 94% sputum conversion and 6. Conclusion
23% culture conversion at the end of 1st month among pa-
tients (n-31) who completed 6 months of Bdq and Dlm To conclude 53 patients, started on regimens containing both
combination and continue to take treatment, for these pa- Bdq and Dlm show a promising safety profile and culture
tients smear and culture conversion at the end of 4th month conversion results, at the end of 6 months. This is important
188 i n d i a n j o u r n a l o f t u b e r c u l o s i s 6 6 ( 2 0 1 9 ) 1 8 4 e1 8 8

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