International Journal of Infectious Diseases 113S (2021) S91–S95

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Culture conversion at six months in patients receiving

bedaquiline- and delamanid-containing regimens for the
treatment of multidrug-resistant tuberculosis
Shynar M. Maretbayevaa , Anar S. Rakishevab , Malik M. Adenovc, Lyazzat T. Yeraliyevac,
Yerkebulan Zh. Algozhina , Assel T. Stambekovaa , Elmira A. Berikovac, Askar Yedilbayevd ,
Michael L. Riche,f , Kwonjune J. Seunge,f , Assiya M. Issayevab,*
a
Partners In Health, Almaty, Kazakhstan
b
JSC “National Medical University” named after Asfendiyarov, Kazakhstan
c
National Scientific Center of Phthisiopulmonology of the Ministry of Health of the Republic of Kazakhstan, Kazakhstan
d
World Health Organization Regional Office for Europe, Kazakhstan
e
Partners In Health, Boston, USA
f
Harvard Medical School, Boston, USA

A R T I C L E I N F O A B S T R A C T

Article history: Rifampicin-resistant/multidrug-resistant (RR/MDR) and extensively drug-resistant (XDR) strains of M.

Received 22 February 2021 tuberculosis (TB) are serious public health problem in Kazakhstan. In 2012 and 2013, stringent regulatory
Received in revised form 24 March 2021 authorities approved the first new TB drugs in fifty years, bedaquiline and delamanid, offering hope for
Accepted 25 March 2021
more effective and less toxic MDR-TB treatment. The endTB Observational Study is a multi-country study
that enrolled patients receiving a bedaquiline- or delamanid-containing regimen for RR/MDR-TB
Keywords: between 01 April 2015 and 30 September 2018. In Kazakhstan, 675 patients participated in the study; all
tuberculosis
had at least 6-months or longer of follow-up after the start of treatment. The present analysis focuses on
multidrug-resistant
extensively drug-resistant tuberculosis
endTB Observational Study patients living in Kazakhstan who had a positive baseline sputum culture
antitubercular agents (220 patients) and initiated a bedaquiline- or delamanid-containing regimen between February 1, 2016
and March 31, 2018. Of them, 195 (89%) of patients experienced culture conversion within six months.
© 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).

Introduction notoriously toxic, and marked by unacceptably high rates of lost to

Rifampicin-resistant/multidrug-resistant (RR/MDR) and exten-
sively drug-resistant (XDR) strains of M. tuberculosis (TB) are
serious public health problem in Kazakhstan. According to WHO,
Kazakhstan is one of the 30 countries on the WHO's high MDR-TB
burden list, with an estimated 4800 new MDR-TB patients in
Kazakhstan each year. 27% of new TB cases, and 64% of previously
treated cases are estimated to have RR/MDR-TB. In comparison
with many other countries, Kazakhstan does a better job of
diagnosis and treatment of MDR-TB—treatment coverage is close to
100% and an estimated 80% of MDR-TB patients who start
treatment are cured (World Health Organization, 2019). Neverthe-
less, MDR-TB treatment in Kazakhstan continues to be long,
* Corresponding author.
E-mail address: issayeva17@mail.ru (A.M. Issayeva).
follow-up, failure and death.
In 2012 and 2013, stringent regulatory authorities approved the
first new TB drugs in fifty years, bedaquiline and delamanid,
offering hope for more effective and less toxic MDR-TB treatment.
Because bedaquiline and delamanid represent new classes anti-TB
drugs, they should be effective against even highly resistant MDR-
and XDR-TB strains. Since then, WHO has endorsed and gradually
broadened indications for their use. In 2019, WHO recommended
for the first time that bedaquiline should be used for treatment of
all patients with MDR-TB. Delamanid is also recommended for
treatment of MDR-TB, but is considered lower priority than drugs
like fluoroquinolones, bedaquiline, linezolid, clofazimine and
cycloserine.
Globally and in Kazakhstan, the uptake of bedaquiline and
delamanid has been slow. In 2015, endTB (http://www.endtb.org/)
began supporting the Kazakhstan Ministry of Health in the
treatment of MDR- and XDR-TB patients with bedaquiline and
delamanid under routine programmatic conditions. As part of the

https://doi.org/10.1016/j.ijid.2021.03.075
1201-9712/© 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
S.M. Maretbayeva, A.S. Rakisheva, M.M. Adenov et al.
endTB Observational Study, these patients were monitored closely
for treatment response. Sputum culture conversion—transition of
sputum culture results from positive to negative—is a standard
interim outcome used in clinical trials and observational studies of
MDR-TB treatment and endorsed by stringent regulatory authori-
ties. Here, we describe sputum culture conversion at six months
among patients receiving a bedaquiline- and delamanid-contain-
ing regimens, the largest such cohort to date in Kazakhstan.
Methods
Study population
The endTB Observational Study (NCT02754765) has been
described in detail elsewhere (Khan et al., 2019; Anon, 2021). In
brief, it is a study of patients receiving a bedaquiline- or delamanid-
containing regimen for RR/MDR-TB at sites in 17 countries. Patients
were eligible for inclusion if they received a regimen containing
either bedaquiline or delamanid at an endTB site and provided
informed consent to allow their clinical data to be analyzed. A study
protocol guided data collection, but not treatment, which was
according to national TB program guidelines; the treatment regimen
or duration of delamanid administration was not standardized
across sites. Sputum samples were collected monthly for smear and
culture as part of routine care. Data collection was standardized
across all sites and organized by the three endTB consortium
partners: Partners In Health (PIH), Médecins Sans Frontières (MSF)
and Interactive Research and Development (IRD). We restricted the
present analysis to endTB Observational Study patients living in
Kazakhstan who had a positive baseline sputum culture and initiated
a bedaquiline- or delamanid-containing regimen between February
1, 2016 and March 31, 2018.
Definitions
Positive baseline sputum culture was defined as a positive
culture in Lowenstein-Jensen medium from the sputum sample
collected closest (and less than 90 days prior) to the initiation of a
bedaquiline or delamanid-containing regimen. Culture conversion
within six months was defined as two consecutive negative
cultures collected at least 15 days apart. Patients who had no
culture results after baseline were classified as not having
converted.
Analysis
We estimated the proportion of patients who experienced
sputum culture conversion within six months of treatment. We
also calculated the frequency of sputum culture conversion in
various subgroups and examined whether these patient character-
istics were associated with conversion.
Ethics
The endTB Observational Study protocol was approved by
central ethics review committees for Partners In Health (PIH). Local
ethical review was obtained from the local ethics committee of the
National Scientific Center of Phthisiopulmonology of the Ministry
of Health of the Republic of Kazakhstan (NSCP MH RK). Participants
provided written informed consent to allow their clinical data to be
included in the analysis.
Results
Among 474 patients who started treatment with a bedaquiline-
or delamanid-containing regimen during the study period, 473
92
International Journal of Infectious Diseases 113S (2021) S91–S95
(99.8%) consented to participate in the endTB observational cohort
study. Of these, 220 had a positive sputum culture within the 90
days prior to the earliest initiation of bedaquiline or delamanid and
were included for analysis (Figure 1). There were high frequencies
of co-morbidities, including diabetes mellitus (9%), hepatitis B (5%)
and hepatitis C (20%). Self-reported alcohol use (12%) was high,
whereas substance use (0.6%) was low. 23% had bilateral and
cavitary disease on chest x-ray. 94% had a history of prior
treatment with second-line TB drugs. 86% had documented
resistance to second line drugs, and 60% had documented XDR-
TB (Table 1).
In this cohort, 85% received bedaquiline and 47% received
delamanid, meaning that a substantial proportion of patients (32%)
received both drugs. Almost all patients (99%) received linezolid.
Other commonly used drugs were clofazimine (84%), a fluoroquin-
olone (60%) and a carbapenem (39%).
Overall, 195 patients (89%) experienced culture conversion
within six months. The proportion of patients who experienced
culture conversion did not differ according to baseline co-
morbidities or resistance patterns in univariable or multivariable
analyses (Table 2).
However, it should be noted that 25 patients (11%) did not
achieve culture conversion at the sixth month of treatment. Their
baseline profile of resistance and lung lesions associated with
tuberculosis differed from the total cohort of 220 sputum culture
positive patients 90 days prior to treatment with bedaquiline or
delamanid. Thus, 11% of patients who did not achieve culture
conversion had confirmed XDR TB in 80% of cases compared to the
general cohort, where the proportion of XDR TB patients was 60%.
Also, the proportion of patients with bilateral (76%) and cavital
(100%) lung lesions among those who did not achieve conversion
was higher compared to the general cohort (Table 3).
Discussion
In this cohort from the endTB Observational Study, 89% of
patients who received treatment with bedaquiline or delamanid as
part of a multidrug regimen experienced sputum culture conver-
sion within six months. In the early years of endTB in Kazakhstan,
the patients who were treated with bedaquiline and delamanid
were often highly complex and difficult to treat. These included
chronic patients who had previously failed multiple treatment
courses with second-line TB drugs. Many of the isolates were XDR
or even more highly resistant. The conversion definition used in
the present analysis was relatively conservative, requiring culture
results that indicated conversion (rather than the absence of
positive results). Nevertheless, the culture conversion is not the
same as cure. Some patients who are negative at six months may
later revert back to positive, so long-term follow-up is necessary.
Nevertheless, considering the patient population, this is an
encouraging response rate. The endTB Observational Study
continues to follow these patients. Final outcomes and adverse
Figure 1. Overview of the study cohort.
S.M. Maretbayeva, A.S. Rakisheva, M.M. Adenov et al. International Journal of Infectious Diseases 113S (2021) S91–S95

Table 1
Baseline characteristics of patients initiating a bedaquiline or delamanid-containing regimen with a positive sputum culture (N = 220).

Characteristic n (%)a
Demographic
Median age at treatment initiation (interquartile range; range) 36 (35 - 42; 16 - 64)
Female 83 (38)
Comorbidities
Diabetes mellitus (N = 219)b 20 (9)
HIV infection (N = 220) 1 (0)
Hepatitis B infection (N = 220)c 11 (5)
Hepatitis C infection (N = 219)d 43 (20)
At least one comorbidity other than those above 27 (12)
Tuberculosis-related
Prior tuberculosis treatment with second line drugs (N = 220) 207 (94)
Bilateral disease (N = 220)e 151 (69)
Cavitary disease (N = 216)e 191 (88)
Smear positive sputum, if yes, grade (N = 217) 159 (73)
Scanty 2 (1)
1+ 68 (31)
2+ 37 (17)
3+ 52 (24)
Resistance profile (N = 215)
RR/MDR-TB without any injectable or fluoroquinolone resistance 30 (14)
RR/MDR-TB with any injectable resistance 26 (12)
RR/MDR-TB with any fluoroquinolone resistance 30 (14)
XDR-TB 129 (60)
Body mass index <18.5 (N = 219) 77 (35)
Indication for new TB drugs was toxicity or intolerance to other second-line TB drugs 11 (5)
Drugs comprising the baseline regimen
Bedaquiline 186 (85)
Delamanid 103 (47)
Moxifloxacin or levofloxacin 131 (60)
Amikacin 38 (17)
Capreomycin 41 (19)
Kanamycin 3 (1)
Linezolid 217 (99)
Clofazimine 185 (84)
Imipenem/cilastatin or meropenem/cilastatin 75 (39)
Prothionamide / ethionamide 15 (7)
Cycloserine 79 (36)
P-aminosalicylic acid 44 (20)
Median number of likely effective drugs included in baseline regimen (interquartile range; range)f 4 (4 – 5; 1 – 6)
a
Unless otherwise noted.
b
For the purposes of assessing diabetes mellitus disease control, we considered HbA1c results taken up to 90 days prior to initiation of the BDQ or DLM containing regimen
or up to 15 days after, with preference given to before.
c
Hepatitis B virus surface antigen positive.
d
Hepatitis C virus antibody positive.
e
Baseline chest radiograph was one that was taken before initiation of the BDQ- or DLM- containing regimen or up to 15 days after, with preference given to before.
f
A drug was considered likely effective if (1) all reported testing to that drug confirmed susceptibility, or (2) no resistance to the drug was reported and the patient had not
previously received the drug for one month or more. Otherwise, the drug was not considered likely effective.

Table 2
Sputum culture conversion within 6-months of initiating a bedaquiline or delamanid-containing regimen, among high-risk subpopulations (N = 220a ).

n(%) Univariable odds ratio p-value Multivariable model 1a p-value

[95% Confidence interval] Odds ratio [95%
Confidence interval]
Hepatitis C status (N = 219)
Negative 160/176 (90) Reference
Positive 35/43 (81) 2.3 [0.9, 5.8] 0.08 2.0 [0.70 – 5.9] 0.19
Diabetes (N = 219)
No 178/199 (89) Reference
Yes 16/20 (80) 2.1 [0.65, 6.9] 0.21 2.1 [0.6 – 7.7] 0.25
Baseline resistance (N = 215)
MDR without additional resistance 27/30 (90) Reference
Pre-XDR with injectable resistance 23/26 (88) 1.2 [0.22, 6.4] 0.84 1.3 [0.1 – 10.7] 0.67
Pre-XDR with fluoroquinolone resistance 26/30 (87) 1.4 [0.28, 6.8] 0.93 2.1 [0.3 – 13.9] 0.12
XDR 115/129 (89) 1.1 [0.29, 4.1] 0.62 1.9 [0.4 – 9.9] 0.77
Cavitary and bilateral disease (N = 216)
No 150/167 (90) Reference
Yes 42/49 (86) 1.47 [0.57, 3.8] 0.42 1.3 [0.4 – 3.7] 0.19
a
Unless otherwise noted.

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S.M. Maretbayeva, A.S. Rakisheva, M.M. Adenov et al. International Journal of Infectious Diseases 113S (2021) S91–S95

Table 3
Baseline characteristics of patients starting bedaquiline or delamanid with culture-positive who have not achieved sputum conversion after 6 months of treatment (N = 25).

Characteristic n (%)a
Demographic
Median age at treatment initiation (interquartile range; range) 41 (27 - 45; 25 - 62)
Female 10 (40)
Comorbidities
Diabetes mellitus (N = 25)b 3 (12)
HIV infection (N = 25) 0 (0)
Hepatitis B infection (N = 25)c 1 (4)
Hepatitis C infection (N = 25)d 5 (20)
At least one comorbidity other than those above 7 (28)
Tuberculosis-related
Prior tuberculosis treatment with second line drugs (N = 25) 23 (92)
Bilateral disease (N = 25)e 19 (76)
Cavitary disease (N = 25)e 25 (100)
Smear positive sputum, if yes, grade (N = 19) 19 (76)
Scanty 1 (6)
1+ 8 (32)
2+ 4 (16)
3+ 7 (28)
Resistance profile (N = 25)
RR/MDR-TB without any injectable or fluoroquinolone resistance 3 (12)
RR/MDR-TB with any injectable resistance 0 (0)
RR/MDR-TB with any fluoroquinolone resistance 2 (8)
XDR-TB 20 (80)
Body mass index <18.5 (N = 25) 10 (40)
Indication for new TB drugs was toxicity or intolerance to other second-line TB drugs 4 (16)
Drugs comprising the baseline regimen
Bedaquiline 20 (80)
Delamanid 13 (52)
Moxifloxacin or levofloxacin 13 (52)
Amikacin 0 (0)
Capreomycin 4 (16)
Kanamycin 1 (4)
Linezolid 25 (100)
Clofazimine 23 (92)
Imipenem/cilastatin or meropenem/cilastatin 11 (44)
Prothionamide / ethionamide 5 (20)
Cycloserine 10 (40)
P-aminosalicylic acid 4 (16)
Median number of likely effective drugs included in baseline regimen (interquartile range; range)f 4 (4 – 5; 1 – 6)
a
Unless otherwise noted.
b
For the purposes of assessing diabetes mellitus disease control, we considered HbA1c results taken up to 90 days prior to initiation of the BDQ or DLM containing regimen
or up to 15 days after, with preference given to before.
c
Hepatitis B virus surface antigen positive.
d
Hepatitis C virus antibody positive.
e
Baseline chest radiograph was one that was taken before initiation of the BDQ- or DLM- containing regimen or up to 15 days after, with preference given to before.
f
A drug was considered likely effective if (1) all reported testing to that drug confirmed susceptibility, or (2) no resistance to the drug was reported and the patient had not
previously received the drug for one month or more. Otherwise, the drug was not considered likely effective.

event data will be eventually available for these and additional
patients enrolled in the study.
The endTB Observational Study population in Kazakhstan is
different from that included in previous clinical trials of bedaqui-
line and delamanid (Diacon et al., 2014; Gler et al., 2012). For
example, XDR-TB patients were generally excluded from clinical
trials, but they made up the majority of patients in this cohort. It is
encouraging to see that culture conversion rates were no different
in highly resistant forms of TB such as XDR-TB compared to simple
MDR-TB without second-line drug resistance. This indicates that
the introduction of new TB drugs has made the diagnosis of
fluoroquinolone or injectable resistance less serious. Patients with
pre-XDR or XDR-TB can expect similar treatment outcomes as
patients with simple MDR-TB, assuming a multidrug regimen
including new TB drugs is designed correctly by the responsible
doctor.
In previous clinical trials, serious concomitant illness and lab
abnormalities were often excluded (von Groote-Bidlingmaier et al.,
2019). In the endTB cohort, there was no such selectivity. Large
numbers of patients with diabetes mellitus, hepatitis B and C were
included. Furthermore, there was a non-statistically significant
trend towards lower culture conversion in patients with diabetes
and hepatitis C. While the relatively high rate of culture conversion
in both subgroups is encouraging, this suggests that it is critical in
improve the management of both of these co-morbidities in
patients with MDR-TB. Hepatitis clinics, for example, routinely
refuse to accept MDR-TB patients until they are culture negative.
But waiting to treat hepatitis C with directly active antivirals until
culture conversion is not justifiable from a clinical point of view,
and indeed can be considered medical malpractice.
One important caveat to this analysis is that bedaquiline and
delamanid was almost always used as part of a multidrug regimen
including other new and repurposed drugs such as linezolid and
clofazimine. In fact, linezolid was the most commonly used drug in
this cohort. This makes it difficult to isolate the contribution of any
single drug. Nevertheless, the findings suggest that bedaquiline
and delamanid can play an important role in the treatment of
MDR- and XDR-TB, if used as part of a well-designed regimen that
includes other drugs such as linezolid and clofazimine. In order to
maximize the benefits of these drugs, the Ministry of Health will

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S.M. Maretbayeva, A.S. Rakisheva, M.M. Adenov et al.
need ensure that physicians in TB and other services are well-
trained and supported with the necessary pharmacy and
laboratory services to care for these difficult patients.
Funding
This work was supported by Unitaid.
Potential Conflicts of Interest
The endTB Consortium coordinated donations of delamanid
(Otsuka Pharmaceutical) and bedaquiline (Janssen) to be used for
treatment by some of the patients included in the endTB
Observational Study. All authors report no additional potential
conflicts of interest. All authors have submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Conflicts that the
editors consider relevant to the content of the manuscript have
been disclosed.
Transparency Declaration
This article is part of a supplement entitled Commemorating
World Tuberculosis Day March 24th, 2021: “The Clock is Ticking”
95
International Journal of Infectious Diseases 113S (2021) S91–S95
published with support from an unrestricted educational grant
from QIAGEN Sciences Inc.
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