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PLOS ONE | https://doi.org/10.1371/journal.pone.0187223 December 20, 2017 1 / 18 

OPEN ACCESS 
Citation: Wai PP, Shewade HD, Kyaw NTT, Kyaw KWY, Thein S, Si Thu A, et al. (2017) Patients with MDR-TB on 
domiciliary care in programmatic settings in Myanmar: Effect of a support package on preventing early deaths. PLoS ONE 
12(12): e0187223. https://doi.org/10.1371/journal. pone.0187223 
Editor: Alejandro Escobar-Gutiérrez, Instituto de Diagnostico y Referencia Epidemiologicos, MEXICO 
Received: June 28, 2017 
Accepted: October 11, 2017 
Published: December 20, 2017 
Copyright: © 2017 Wai et al. This is an open access article distributed under the terms of the Creative Commons Attribution 
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source 
are credited. 
Data Availability Statement: The dataset and programme file in STATA format contain potentially identifying participant 
information. Therefore, they are available to all interested researchers upon request. Please contact the corresponding author to 
request these underlying data. 
Funding: The training programme within which this paper was developed were funded by the Department for International 
Development (DFID), 

RESEARCH ARTICLE Patients with MDR-TB on domiciliary 

care in programmatic settings in Myanmar: Effect of a support 
package on preventing early deaths 
Pyae Phyo Wai1*, Hemant Deepak Shewade2, Nang Thu Thu Kyaw1, Khine Wut Yee Kyaw1, Saw Thein3, 
Aung Si Thu1, Myo Minn Oo1, Pyae Sone Htwe1, Moe Myint Theingi Tun1, Htet Myet Win Maung3, Kyaw Thu 
Soe4, Si Thu Aung3 
1 International Union against Tuberculosis and Lung Disease (The Union), Mandalay, Myanmar, 2 International Union 
against Tuberculosis and Lung Disease (The Union), South-East Asia Office, New Delhi, India, 3 National 
Tuberculosis Programme, Ministry of Health and Sports, Myanmar, 4 Department of Medical Research (Pyin oo Lwin 
Branch), Ministry of Health and Sports, Myanmar 
4 [email protected] 

Abstract 
Background 
The community-based MDR-TB care (CBMDR-TBC) project was implemented in 2015 by The Union in collaboration 
with national TB programme (NTP) in 33 townships of upper Myanmar to improve treatment outcomes among 
patients with MDR-TB registered under NTP. They received community-based support through the project staff, in 
addition to the routine domiciliary care provided by NTP staff. Each project township had a project nurse exclusively 
for MDR-TB and a community volunteer who provided evening directly observed therapy (in addition to morning 
directly observed therapy by NTP). 

Objectives 
To determine the effect of CBMDR-TBC project on death and unfavourable outcomes dur- ing the intensive phase of 
MDR-TB treatment. 

Methods 
In this cohort study involving record review, all patients diagnosed with MDR-TB between January 2015 and June 
2016 in project townships and initiated on treatment till 31 Dec 2016 were included. CBMDR-TBC status was 
categorized as “receiving support” if project initia- tion in patient’s township was before treatment initiation, “receiving 
partial support” if project initiation was after treatment initiation, and “not receiving support” if project initiation was 
after intensive phase treatment outcome declaration. Time to event analysis (censored on 10 April 2017) and cox 
regression was done. 

Results 
Of 261 patients initiated on treatment, death and unfavourable outcomes were accounted for 13% and 21% among 
“receiving support (n = 163)”, 3% and 24% among “receiving 
 
CBMDR-TBC project and early deaths 
UK. The funder had no role in study design, data 
partial support (n = 75)” and 13% and 26% among “not receiving support (n 
= 23)” respec- collection and analysis, decision to publish, or preparation of the manuscript. 
tively. After adjusting for other potential confounders, the association between CBMDR- TBC and unfavourable 
outcomes was not statistically significant. However, when compared Competing interests: The authors have declared 
that no competing interests exist. 
to “not receiving support”, those “receiving support” and “receiving partial support” had 20% [aHR (0.95 CI: 0.8 
(0.2–3.1)] and 90% lower hazard [aHR (0.95 CI: 0.1 (0.02–0.9)] of death, respectively. This was intriguing. 
Implementation of CBMDR-TBC coincided with implemen- tation of decentralized MDR-TB centers at district level. 
Hence, patients that would have generally not accessed MDR-TB treatment before decentralization also started 
receiving treatment and were also included under CBMDR-TBC “received support” group. These patients could 
possibly be expected to sicker at treatment initiation than patients in other CBMDR-TBC groups. This could be the 
possible reason for nullifying the effect of CBMDR- TBC in “receiving support” group and therefore similar survival 
was found when compared to “not receiving support”. 

Conclusion 
CBMDR-TBC may prevent early deaths and has a scope for expansion to other townships of Myanmar and 
implications for NTPs globally. However, future studies should consider including data on extent of sickness at 
treatment initiation and patient level support received under CBMDR-TBC. 

Introduction 
Multidrug-resistant/rifampicin-resistant tuberculosis (MDR-TB/RR-TB) is a public health burden worldwide with an 
estimated 580,000 cases and 250,000 deaths in 2015 [1]. Globally, the MDR-TB treatment success rate was 52% for 
the 2013 cohort. The loss to follow-up and death contribute to the majority of unsuccessful treatment outcome [2]. 
Death during treat- ment is seen in 13% of all MDR-TB patients registered for treatment [3]. 
Myanmar is one of the 30 high MDR-TB burden countries in the world. Based on the recent drug resistant survey 
(2012–13), five percent of new patients and 27% of previously treated patients have MDR-TB[4]. In 2015, National 
Tuberculosis Programmer (NTP) reported that of the estimated 9000 cases, 2,793 MDR-TB cases were diagnosed 
and 2,207 were enrolled for treatment in the same year. [5,6]. 
The treatment and care of MDR-TB is provided according to World Health Organization (WHO) recommended 
programmatic management of DR-TB (PMDT) model since 2011 [7]. Baseline investigations and treatment 
initiation are done at DR-TB treatment centers followed by domiciliary care in the community by a directly 
observed treatment (DOT) provider (DOT at the patient’s residence) that extends to 20 months. The MDR-TB 
treatment success rate (TSR) of those initiated on MDR-TB treatment in 2012 and 2013 was 79% and 83% respec- 
tively. This was higher than WHO 2015 TSR target of at least 75% [8]. 
By 2020, Myanmar targets to enroll all MDR-TB patients on treatment within two weeks of their diagnosis and 
provide comprehensive patient support package to enable treatment suc- cess rates of >80% [5] To achieve this, the 
International Union against Tuberculosis and Lung Disease (The Union) in collaboration with NTP started the 
community-based MDR-TB care (CBMDR-TBC) project in upper Myanmar since 2015 with funding from Global 
Fund (GF) and Three Millennium Development Goal Fund (3 MDGF). 
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CBMDR-TBC project and early deaths 
Patients with MDR-TB diagnosed / registered under PMDT in project townships received support package under 
CBMDR-TBC through the project staff, in addition to the domiciliary care provided by PMDT staff. Trained 
community volunteers and project focal nurses (exclu- sively for MDR-TB) provided psychosocial and 
socio-economic support to patients and family members after MDR-TB diagnosis up to treatment initiation and 
completion under the guid- ance of NTP township TB team. 
Phase-wise implementation of project in Upper Myanmar between 2015 and 2016 provided us a unique 
opportunity to assess the impact of this project. There is no published literature on effect of a support package 
(CBMDR-TBC in our case) to reduce deaths and unfavourable out- comes in the context of domiciliary care through 
PMDT. Therefore, as a first ever study, we aimed to assess whether the Union’s CBMDR-TBC project prevented 
deaths and unfavourable outcomes during intensive phase of MDR-TB treatment. 

Methods Study sesign 

This is a retrospective cohort study involving record review. 

Setting 
General setting. Myanmar is a lower middle income country [9] in south-east Asia region with a population of 51 
million and predominantly mountainous in upper Myanmar, plain and delta region in middle and lower Myanmar 
[10]. It is administratively divided into states/ regions (n = 15) followed by districts (n = 67) and townships (n = 
330). Under the National Tuberculosis Program, there are TB centers at central level and systematically 
decentralized to state /region level, district level and township level[4]. 
PMDT in Myanmar. Patients with presumptive MDR-TB (Table 1) are referred from the township TB center to 
the nearest district TB center with Xpert MTB/Rif diagnostic facility. Each Xpert MTB/Rif facility has a laboratory 
register. A line list of presumptive MDR-TB reg- ister is maintained at the township level. 
All patients diagnosed as RR-TB by Xpert MTB/RIF are assumed as MDR-TB and started on second line 
treatment immediately. In selected cases (presumed to be having a low-risk of MDR-TB), an initial positive result is 
reconfirmed by a repeat Xpert MTB/Rif MTB/RIF. If needed, final confirmation is done with line probe assay 
(LPA) or culture and drug susceptibil- ity test (DST) using Mycobacteria growth indicator tube (MGIT) liquid 
system (7). 
After the patient is diagnosed with MDR-TB, the respective township TB team is informed. The township TB 
team includes township medical officer, township TB coordinator, basic health staff (BHS) and laboratory 
technician. The BHS (a nurse) provides care, including 
Table 1. Criteria to identify presumptive MDR-TB under programme setting who were referred to X- pert 
MTB/RIF testing facilities, Myanmar, 2015–16. 
1 All previously treated TB patients 2 All new smear positive TB patients 3 All non-convertor TB patients (whose 
sputum result is still positive at the end of intensive phase) 4 HIV (+) TB patients 5 TB patients with past history of 
close contact with an MDR-TB patient and 6 TB patient with diabetes mellitus 
DR-TB–multi drug-resistant tuberculosis, HIV–human immunodeficiency virus, TB—tuberculosis 
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CBMDR-TBC project and early deaths 
morning DOT, as per PMDT guidelines. The BHS is also responsible for implementation of other health programme 
related activities (in addition to coordinating TB related activities). After the patient principally agrees to undertake 
MDR-TB treatment through DOT for at least 20 months, the patient is referred to the nearest MDR-TB treatment 
center (at district level) for baseline measurements (body weight, height, blood pressure) and baseline inves- 
tigations followed by registration and treatment initiation. Baseline investigations include test for HIV, Hepatitis-B, 
Hepatitis-C, blood glucose, complete hemogram, liver function test, renal function test, ECG, thyroid function test, 
psychosocial assessment, hearing and oph- thalmic assessment. The total duration of treatment is 18–22 months and 
consists of 6–8 months of intensive phase with five drugs (Amikacin, Pyrazinamide, Levofloxacin, Ethion- amide, 
Cycloserine) followed by 12–14 months of continuation phase with four drugs (Pyrazi- namide, Levofloxacin, 
Ethionamide, Cycloserine). Patient treatment card and MDR-TB treatment register are maintained at the MDR-TB 
treatment center and patient has a treatment booklet. All services including baseline and follow-up laboratory tests 
are provided free of cost [5]. By April 2016, all townships were covered under PMDT with a MDR-TB center in 
each township. 
Community-based MDR-TB care (CBMDR-TBC) project. The Union’s CBMDR-TBC project supports PMDT 
in 33 townships (selected after consultation with NTP), across four states/regions in upper Myanmar since January 
2015 (Fig 1). The project was implemented phase wise across the 33 townships between January 2015 and June 
2016. Once the project implementation began in a particular township, all old and newly diagnosed patients received 
care under the project. 
Each project township has a project focal nurse under supervision of the township TB team who exclusively 
works for MDR-TB. The project focal nurse ensures the implementation of the care package under PMDT as 
mentioned in Table 2. The nurse also identifies and trains a volunteer who lives close to the patient and acts as 
evening DOT provider. These volunteers help the patients get access to treatment and follow-up specimen 
transportation. The BHS con- tinues to provide injection and morning DOT as per PMDT guidelines. The 
complementary support provided by the CBMDR-TBC project is summarized in Table 3. During 2015–16, of 49 
Xpert MTB/Rif machines in the country, 12 were in 33 CBMDR-TBC townships. 
Routine monitoring includes submission of monthly reports by volunteers to project focal nurse and then by the 
project focal nurses to project manager (one manager is assigned for every eleven townships) which are then 
forwarded to the monitoring and evaluation unit of The Union Office. 

Study participants 
All patients diagnosed with MDR-TB between January 2015 and June 2016 in 33 CBMDR-TBC project townships 
of upper Myanmar were identified. Records of all Xpert MTB/Rif, LPA and MGIT tested positive patients were 
extracted from the 12 Xpert MTB/Rif facility laboratory registers and upper Myanmar TB center located in 
Mandalay. After removal of duplicates each study participant was given a unique identifier which was a 
combination of Xpert MTB/Rif facility code, Xpert MTB/Rif laboratory number and year. Date of diagnosis was 
defined as the date of Xpert MTB/Rif, LPA or MGIT test results. Earlier date was used in case of more than one test 
results. 
Patients initiated on treatment until 31 December 2016 were included in the study. Entry of the patient into the 
cohort was based on the date of treatment initiation (01 January 2015 to 31 Dec 2016), while date of intensive phase 
treatment outcome or date of censoring (10 April 2017) whichever was earlier was the end date in the cohort. 
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CBMDR-TBC project and early deaths 

CBMDR-TBC exposure ascertainment and intensive phase treatment outcomes 

To study the effect of CBMDR-TBC project on unfavourable intensive phase treatment out- comes, we categorized 
patients as: “not receiving support”, “partially receiving support” and “receiving support”. Date of field level 
initiation of the project in a township was taken as proj- ect initiation date. The patients were categorized as “not 
receiving support” if the date of proj- ect initiation in patient’s township was after the outcome date; as “partially 
receiving support” if the date of project initiation in patient township’s was after treatment initiation date but 
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Fig 1. Map of Myanmar showing 33 community-based MDR-TB care project (CBMDR-TBC) supported 
townships across four states/regions of Upper Myanmar, 2015–16. 
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CBMDR-TBC project and early deaths 
Table 2. Package of support to all patients with MDR-TB under NTP’s PMDT in Myanmar, 2015–2016 [5]. 
Before treatment initiation 1 Initial home visit and pretreatment counselling including the nature of medicines to be 
taken, the 
treatment process and the necessity of directly observed treatment (DOT) to monitor the treatment and offer regular 
support by the township medical officer, township TB coordinator, Basic Health Staff (BHS). This includes a written 
informed consent signed by the patient 2 Base-line investigations at the MDR-TB treatment center 3 Transport of 
sputum to the MDR-TB treatment center (for confirmation, if required) 
After treatment initiation 1 Daily morning injections and morning DOT by basic health staff 2 Treatment adherence 
counseling to patient and family member 3 Household and close contact investigation 4 Management of minor side 
effects of treatment at township TB center and timely referral to MDR-TB 
center (district level) 5 Monthly sputum smear examination at township TB center, sputum culture examination (on 
3,5,8,12,14,16,18,20 months of treatment) and regular follow-up visits at DR-TB center 6 30 USD per month each 
to patient and DOT provider provided at township level 7 Nutritional support in the form of monthly ration of one 
nutrition powder package, rice (25 kg), beans 3.6 
kg, oil 1.8 kg and salt 0.375 kg provided during visit to MDR-TB center for monthly follow-up 
MDR-TB–multi drug resistant tuberculosis, NTP–national tuberculosis programme, PMDT–programmatic 
management of drug resistant tuberculosis, DOT–directly observed treatment 
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before outcome date; and as “receiving support” if the date of project initiation was before treatment initiation date. 
Operational definitions of intensive phase treatment outcomes are summarized in Table 4 and were in line with 
the prevalent WHO recommendations during the study period [11]. 

Data variables, sources of data and data collection 

Variables collected from the MDR-TB treatment registers were: age, sex, resident township/ region name, Xpert 
MTB/Rif facility name, Xpert MTB/Rif laboratory number, date of diagno- sis, date of treatment initiation, site of 
TB, past history of TB, HIV status, resistance pattern, 
Table 3. Support package by the community-based MDR-TB care (CBMDR-TBC) project in Myanmar, 2015–16. 
Focal point nurse exclusively for MDR-TB care at each project township to support 1 Existing PMDT package as 
summarized in Table 2 2 Recruit and train a volunteer for evening DOT once patient starts treatment 3 Community 
mobilization by providing health education to the patient and their family members and 
neighbours 4 Pre-treatment support: 30 USD /month (for a maximum of 4 months) for patients with intent to 
reduce, to some extent, their expenses in lodging during visit to nearest DR-TB center, some ancillary drugs not 
provided by PMDT 5 Volunteer support to access care and follow up investigations 6 30 USD per month treatment 
provision allowance to the community volunteer under CBMDR-TBC 7 Psychosocial support through reassuring the 
patient to finish the whole course of treatment and 
counselling to patient, family members and neighbour 
MDR-TB–multi drug resistant tuberculosis, PMDT–programmatic management of drug resistant tuberculosis, 
DOT–directly observed treatment, CBMDR-TBC–community-based MDR-TB care 
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CBMDR-TBC project and early deaths 
Table 4. Operational definition of MDR-TB treatment outcomes at end of intensive phase, Myanmar (2015–16) 
[11]. 
The standard duration of Intensive phase applied by the National program is 6 months. For treatment failed, 
lack of conversion by the end of the intensive phase implies that the patient does not convert within the 
maximum duration of intensive phase applied by the programme. If no maximum duration is defined, an 
8-month cut-off is proposed. For regimens without a clear distinction between intensive and continuation 
phase, a cut-off of 8 months after the start of treatment is suggested to determine when the criteria for 
Cured, Treatment completed and Treatment failed start to apply. Smear/Culture 
A patient who has completed intensive phase of MDR-TB treatment, and two conversion 
consecutive smear/culture is negative at the end of the intensive phase Smear/Culture non 
conversion 
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A patient who has completed intensive phase of MDR-TB treatment, and sputum culture is not converted at the end 
of the intensive phase Loss to follow up A patient whose treatment was interrupted for 2 consecutive months or more 
Died A patient who dies for any reason during the course of treatment Not evaluated A patient whose outcomes are 
not available at the end of eight months 
(includes transfer out patients whose outcomes are not available) Still on treatment A 
patient who is alive and taking treatment as on 10 April 2017, but has not 
completed 8 months of treatment and does not fit into any of the other outcome definitions Favourable outcomes 
includes smear/culture conversion and still on treatment Unfavourable outcomes includes smear/culture 
non-conversion, loss to follow-up, death and not 
evaluated 
MDR-TB–multi drug resistant tuberculosis, PMDT–programmatic management of drug resistant tuberculosis 
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diabetes status, hepatitis B and hepatitis C status, weight in kg, hemoglobin (g/dl), intensive phase treatment 
outcome and date. Distance between patient Township and MDR-TB treat- ment center was calculated using google 
maps (www.googlemaps.com). Date of project initia- tion in patient’s township was collected from CBMDR-TBC 
project records. 

Analysis and statistics 

Data collected in structured data collection forms were single entered into EpiData entry soft- ware (version 3.1, 
EpiData Association, Odense, Denmark) at each MDR-TB treatment centers by research assistants between March 
and April 2017. Descriptive analysis (frequency, propor- tion, means (SD), median (IQR)) and generation of derived 
variables was done using EpiData analysis software (version 2.2.2.183, EpiData Association, Odense, Denmark). 
STATA (version 12.1, copyright 1985–2011 StataCorp LP USA, serial number: 30120504773) was used for time to 
event analysis and to identify factors associated with death and unfavourable intensive phase treatment outcomes. 
Derived variables. Based on the dates of treatment initiation, project initiation and inten- sive phase treatment 
outcome, CBMDR-TBC status was categorized as “not receiving sup- port”, “partially receiving support” and 
“receiving support”. Sputum smear/culture conversion and ‘still on treatment’ were categorized as favourable and 
death, loss to follow-up, sputum smear/culture non-conversion and ‘not evaluated’ were categorized as unfavourable 
treatment outcome (Table 4).Time to initiate treatment (in days) was calculated from date of diagnosis and date of 
treatment initiation. Hemoglobin measurements were categorized into ‘anaemia status’ using the classification for 
Asian populations as per WHO recommendations [12]. Weight was categorized using the cut off 45 kilogram. 
 Under CBMDR-TBC status, “receiving support” and “receiving partial support” was the exposure of interest. 
Death and unfavourable outcomes during intensive phase was the 
 
CBMDR-TBC project and early deaths 
outcome of interest which was summarized as proportion and incidence rate (number of events per 1000 
person-days of follow-up) 
Unadjusted analysis was done to determine the association (Hazard Ratio, HR) between the exposure of interest, 
other potential confounders and outcome of interest. Unadjusted Kaplan Meier curves were used to describe the 
outcome free survival over time: overall and stratified by CBMDR-TBC status. Age, sex, CBMDR-TBC status and 
variables with p-value of <0.2 in the unadjusted analysis were included (after ruling out multi-collinearity) in the 
Cox regres- sion model (enter method). We assessed for proportional hazard assumption of the model by plotting the 
estimated survival curves using Cox model and Kaplan-Meier estimates (S1 and S2 Figs). Unadjusted and adjusted 
HRs were reported with 95% confidence intervals (CI). 

Ethics 
Ethics approval was received from Ethics Review Committee, Department of Medical Research, Ministry of Health 
and Sports, Myanmar (ERC No. 014216, dated 30th January 2017) and the Ethics Advisory Group of International 
Union against Tuberculosis and Lung Disease (The Union), Paris, France (EAG No. 81/16, dated 1st November 
2016). Permission to conduct the study was granted from National Tuberculosis Programme, Ministry of Health and 
Sports, Myanmar. As the study involved analysis of secondary data from programme rec- ords, waiver for informed 
consent was sought and approved by the ethics committees. 

Results Baseline characteristics 

A total of 261 patients were initiated on treatment. Baseline demographic characteristics have been summarized in 
Table 5. Of the total, 118 (45%) were of the age group 15–34 years; 176 (67%) were males and 159 (61%) from 
Mandalay region. Sixty four (25%) patients had a 
Table 5. Demographic characteristics of patients with MDRTB registered for treatment between Janu- ary 
2015 and June 2016 in 33 community-based MDR-TB care (CBMDR-TBC) project supported town- ships in 
Myanmar. 
Characteristics N (%) Total 261 (100) Age (year) < 15 1 (0.4) 
15–34 118 (45) 35–54 103 (40) !55 39 (15) Sex Male 176 (67) Female 85 (33) Patient residence state/region 
Mandalay 159 (61) Magway 26 (10) Sagaing 33 (13) Northern Shan 26 (10) Southern Shan 17 (7) Distance from 
treatment facilities Same township 64 (25) <100 km 125 (48) ! 100 km 72 (27) 
MDR-TB-multidrug resistance tuberculosis, CBMDR-TBC- community based multidrug resistance tuberculosis care 
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Table 6. Clinical characteristics of patients with MDRTB registered for treatment between January 2015 and 
June 2016 in 33 community-based MDR-TB care (CBMDR-TBC) project supported townships in Myanmar. 
Characteristics N (%) Total 261 (100) Previously treated TB Yes 232 (89) No 29 (11) HIV status Non-reactive 156 
(60) Reactive 30 (12) Unknown 75 (29) Registration group Relapse 79 (30) Treatment after failure 121 (46) 
Treatment after default 11 (4) Treatment after second line 1 (0.4) New 28 (11) Other 20 (8) Not recorded 1 (0.4) 
Resistance pattern Resistance to first line 259 (99) 
Resistance to second line 1 (0.5) Not recorded 1 (0.5) Site of TB PTB 256 (98) 
EPTB 1 (0.5) Both 3 (1) Not recorded 1 (0.5) Diabetes mellitus No 35 (13) Yes 134 (51) Not recorded 92 (35) 
Hepatitis B infection status Positive 13 (5) 
Negative 246 (94) Not recorded 2 (1) Hepatitis C infection status Positive 10 (4) 
Negative 249 (95) Not recorded 2 (1) Anaemia No anaemia 87 (33) Anaemia 162 (62) Severe Anaemia 12 (5) Weight 
in kg <45 115 (44) !45 129 (49) Unknown 17 (7) Time in days from diagnosis to <14 36 (14) treatment initiation 14–49 
125 (48) 50–99 53 (20) !100 47 (18) 
MDR-TB-Multidrug resistance tuberculosis, TB–Tuberculosis; HIV–Human immunodeficiency virus 
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CBMDR-TBC project and early deaths 
MDR-TB center in their township. Baseline clinical characteristics have been summarized in Table 6. Of the total, 
30 (12%) were HIV positive, 256 (98%) had pulmonary TB and 115 (44%) had a weight of less than 45 kilogram. 
Days to treatment initiation was more than 14 days in 220 (86%) cases. 
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Table 7. Care under community-based MDR-TB (CBMDR-TBC) project and end intensive phase treatment 
outcomes among patient with MDR-TB registered for treatment between January 2015 and June 2016 in 33 
CBMDR-TBC project supported townships in Myanmar. 
Variable N (%) Total 261 (100) CbMDR-TBC status 
Receiving support Under care before treatment initiation 163 (62) Receiving partial support Under care after 
treatment initiation 75 (29) Not receiving support Not under care till declaration of outcomes 23 (9) Duration under 
CBMDR-TBC 
Under care !4months 178 (68) Under care 2–4 months 30 (12) Under care <2 months 53 (20) Treatment outcome 
Favorable 200 (77) Sputum/smear conversion 196 (75) End IP outcome not declared, not completed 8 months and 
still on treatment 4 (2) Unfavorable 61 (23) 
Sputum/culture non-conversion 4 (2) Death 26 (10) Loss to follow-up 4 (2) Not evaluated 27 (10) 
MDR-TB—Multi drug resistant tuberculosis 
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CBMDR-TBC project and early deaths 
Based on CBMDR-TBC status, 163 (62%) received support under CBMDR-TBC and 75 (29%) received partial 
support. We also looked at the duration in days for which the patient received CBMDR-TBC: 178 (68%), 30 (12%) 
and 53 (20%) received care for more than four months, two to four months and less than two months respectively. 
(Table 7) 

Intensive phase treatment outcomes 

Sixty one patients (23%) had unfavourable treatment outcome: death and not evaluated con- tributing to 26 (10%) 
and 27 (10%) outcomes respectively. (Table 7) 

CBMDR-TB and intensive phase treatment outcomes 

There were 47335 person-days of follow: it was 3702, 16037 and 27596 among “not receiving support”, “receiving 
partial support” and “receiving support” group. 
The number (% (0.95 CI)) of unfavourable outcome among those “not receiving support (n = 23)”, “receiving 
partial support (n = 75)” and “receiving support (n = 163)” was 6 (26.1 (11.1, 48.7)), 16 (21.3 (13.0, 32.6)) and 38 
(23.3 (17.2, 30.7)) respectively. Incidence rate (0.95 CI) for unfavourable outcomes was 1.3 (1.0, 1.6) per 1000 
person-days of follow-up. Based on CBMDR-TBC status, incidence rate (0.95 CI) among those “not receiving 
support”, “receiving partial support” and “receiving support” was 1.6 (0.7, 3.6), 1.0 (0.6, 1.6) and 1.4 (1.0, 1.9) 
respec- tively per 1000 person-days of follow-up. The survival curves for unfavourable outcome; overall and 
stratified by CBMDR-TBC status, are depicted in Fig 2. The outcome free survival was bet- ter for those “receiving 
partial support” when compared to those “not receiving support”. 
The number (% (0.95 CI)) of death among those “not receiving support (n = 23)”, “receiv- ing partial support (n 
= 75)” and “receiving support (n = 163)” was 3 (12.7 (3.4, 34.7)), 2 (3 (0.5, 10.2)) and 20 (12.3 (7.8, 18.5)) 
respectively. Incidence rate (0.95 CI) for death was 0.5 (0.4, 
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CBMDR-TBC project and early deaths 
0.8) per 1000 person-days of follow-up. Based on CBMDR-TBC status, incidence rate among those “not receiving 
support”, “receiving partial support” and “receiving support” was 0.8 (0.3, 2.5), 0.1 (0.0, 0.5) and 0.7 (0.5, 1.1) 
respectively per 1000 person-days of follow-up. The survival curves for death; overall and stratified by 
CBMDR-TBC status, are depicted in Fig 3. The death free survival was better for those “receiving partial support” 
when compared to those “not receiving support”. 
For the independent predictive effect of CBMDR-TBC project on intensive phase treatment outcomes, age, sex, 
HIV status, anaemia and CBMDR-TBC status were added in a cox regres- sion model. For the model predicting 
death, region was also included. Distance and duration of treatment were not included due to very high p value on 
unadjusted analysis. Diabetes was excluded because of high proportion of missing data. Unadjusted and adjusted 
HRs for unfa- vourable outcomes and death have been presented in Tables 8 and 9 respectively. 
After adjustment of potential confounders, when compared to “not receiving support”, those “receiving support” 
and “receiving partial support” had 50% [aHR (0.95 CI: 0.5(0.2– 1.3))] and 10% lower hazard [aHR (0.95 CI: 0.9 
(0.3–2.1)] of unfavourable outcome, respec- tively. However, this was not statistically significant. For death, 
“receiving support” and “receiving partial support” had 20% [aHR (0.95 CI: 0.8 (0.2–3.1)] and 90% lower hazard 
[aHR (0.95 CI: 0.1 (0.02–0.9)], respectively. The latter was statistically significant. (Tables 8 and 9) 
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Fig 2. Unfavourable outcomes (smear/culture non-conversion, loss to follow-up, death and not evaluated) in 
intensive phase among patients with MDR-TB registered for treatment between January 2015 and June 2016 
in 33 community-based MDR-TB care (CBMDR-TBC) project supported townships in Myanmar (all patients 
and by CBMDR-TBC status). 4under CBMDR-TBC after treatment initiation (“receiving partial support”); 
under CBMDR-TBC before treatment initiation (“receiving support”); Log rank test p value = 0.14 
(unadjusted). 
https://doi.org/10.1371/journal.pone.0187223.g002 
 
CBMDR-TBC project and early deaths 
Other independent predictors (risk factors) for unfavourable outcomes as well as death were age more than 55 
years and anaemia. Weight less than 45 kilogram was also associated with unfavourable outcomes. (Tables 8 and 9) 

Discussion Summary of key findings 

In the context of high MDR-TB treatment success through domiciliary care under PMDT in Myanmar, patients who 
received support through CBMDR-TBC midway during their treat- ment had lower deaths in intensive phase of 
treatment. However, if support through CBMDR-TBC was received before treatment initiation, the deaths were 
comparable with patients who did not receive any support at all. CBMDR-TBC did not have an effect on unfa- 
vourable outcomes during intensive phase. Treatment delay and distance between patient’s township and DR-TB 
treatment center were not associated with unfavourable outcomes. 

Strengths and limitations 

This is first study from Myanmar and possibly worldwide, to determine the effect of a support package, 
complementing existing domiciliary care for MDR-TB under programme settings 
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Fig 3. Death in intensive phase among patients with MDRTB registered for treatment between January 2015 
and June 2016 in 33 community-based MDR-TB care (CBMDR-TBC) project supported townships in Myanmar 
(all patients and by CBMDR-TBC status). 4under CBMDR_TBC after treatment initiation (“receiving partial 
support”); under CBMDR-TBC before treatment initiation (“receiving support”); Log rank test p value = 0.03 
(unadjusted). 
https://doi.org/10.1371/journal.pone.0187223.g003 
 
Table 8. Risk factors for unfavorable treatment outcomes among patients with MDR-TB registered for 
treatment between January 2015 and June 2016 in 33 community-based MDR-TB care (CBMDR-TBC) project 
supported townships in Myanmar. 
Characteristics Total Unfavourable Outcome HR 
(0.95 CI) 
aHR* (0.95 CI) N n (%) Total 261 61 (23) Age (year) < 15 1 0 (0) - - 15–34 118 20 (17) Ref Ref 35–54 103 26 (25) 
1.6(0.9–3.0) 1.7(0.9–3.2) !55 39 15 (39) 2.0(1.1–4.1) 2.2(1.0–4.5)^ Sex Male 176 36 (20) Ref Ref Female 85 25 (29) 
1.2(0.7–2.1) 1.0(0.3–2.1) HIV status Reactive 30 12 (40) 1.9(0.9–3.9) 1.7(0.8,3.7) Unknown 75 21 (28) 1.6(0.9–2.9) 
0.6(0.2,2.3) Non-reactive 156 28 (18) Ref Ref Anaemia No anaemia 87 16 (18) Ref Ref Anaemia 162 39 (24) 
1.7(0.9–3.2) 1.9(1.0–3.6)^ Severe Anaemia 12 6 (50) 3.9(1.5–10.1) 2.7(1.0–7.1)^ Weight in kg <45 115 33 (29) 
1.8(1.1–3.1) 1.9(1.0–3.4)^ !45 129 22 (17) Ref Ref Unknown 17 6 (35) 2.4(1.0–6.0) 2.7(1.0–7.1)^ CbMDR-TBC 
Receiving support 163 39 (24) 0.9(0.4–2.3) 0.5(0.2–1.3) Receiving partial support 75 16 (21) 0.6(0.2–1.5) 
0.9(0.3–2.1) Not receiving support 23 6 (26) Ref Ref 
aHR: adjusted hazard ratio, CI: confidence interval 4aHR calculated using Cox regression (enter method): age, sex, 
CbMDR-TBC and variables with unadjusted p<0.2 were included in the regression model and shown in this table 
^p<0.05 Model AIC / BIC 591.3 / 598.4 
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CBMDR-TBC project and early deaths 
(PMDT), on early deaths and unfavourable outcomes in intensive phase. The study involved use of routine 
programmatic data; our findings reflect the ground reality. We followed the strengthening the reporting of 
observational studies in epidemiology (STROBE) guidelines to report our findings [13]. 
However, the study had some limitations as well. First, information on diabetes was missing for 35% of patients 
and height was not recorded. Therefore, we could not include diabetes sta- tus and body mass index variable in 
adjusted analysis. In addition to this, information on other patient level data (extent of exposure to CBMDR-TBC in 
the form of number of nurse /volunteer visits and extent of sickness at treatment initiation) and programmatic / 
health sys- tem level factors was not available as this was not collected routinely within the programme. This study 
was based on existing programmatic records; there might be some measurement and recording errors that are 
inherent to operational research and we do not have control over the numbers of participants in each group for 
comparison (there were 23 patients under ‘not receiving care’ group). Second, the date of project initiation was at 
the township level. We do not think that this will induce any clustering as all patients (including those already on 
treat- ment) were provided services once the project was implemented in a township. Third, if the township was 
large, there might be large margin of error depending where someone lived in that township. This error was possible 
as we did not consider the distance from actual patient 
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Table 9. Risk factors for death among patients with MDRTB registered for treatment initiation between 
January 2015 and June 2016 in 33 commu- nity-based MDR-TB care (CBMDR-TBC) project supported 
townships in Myanmar. 
Characteristics Total Death HR 
(0.95 CI) 
aHR* (0.95 CI) N n (%) Total 261 26 (10) Age (year) < 15 14 0 (0) - - 15–34 118 5 (4) Ref Ref 35–54 103 12 (12) 
2.6(0.9–7.6) 2.4(0.8–7.1) !55 39 9 (23) 5.9(2.0–17.7) 8.3(2.6–26.8)^ Sex Male 176 16 (9) Ref Ref Female 85 10 (12) 
1.2(0.5–2.6) 0.6(0.2–1.7) Patient Mandalay 159 18 (11) Ref Ref Residence Magway 26 4 (15) 1.4(0.4–4.2) 
1.1(0.3–3.6) Sagaing 33 2 (6) 0.5(0.1–2.2) 0.5(0.1–2.2) Northern Shan 26 1 (4) 0.3(0.4–2.4) 0.2(0.0–1.9) Southern 
Shan 17 1 (6) 0.5(0.7–4.0) 0.9(0.1–7.3) HIV status Reactive 30 7 (23) 3.4(1.2–9.4) 2.6(0.8–8.6) Unknown 75 9 (12) 
1.9(0.8–4.7) 2.2(0.8–5.8) Non-reactive 156 10 (6) Ref Ref Anaemia No anaemia 87 3 (3) Ref Ref Anaemia 162 19 
(12) 5.4(1.3–23.2) 5.7(1.2–26.7)^ Severe Anaemia 12 4 (33) 17.3(3.2–94.8) 8.3(1.2–56.8)^ Weight in kg <45 115 17 
(15) 2.7(1.1–6.5) 1.8(0.7–5.1) !45 129 7 (5) Ref Ref Unknown 17 2 (12) 2.3(0.5–11.0) 3.8(0.7–20.3) CbMDR-TBC 
Receiving support 163 21 (13) 1.0(0.3–1.1) 0.8(0.2–3.1) Receiving partial support 75 2 (3) 0.2(0.0–1.1) 0.1(0.0–0.9)^ 
Not receiving support 23 3 (13) Ref Ref 
aHR: adjusted hazard ratio, CI: confidence interval 4adjusted hazard ratio (aHR) calculated using Cox regression 
(enter method): age, sex, CbMDR-TBC and variables with unadjusted p<0.2 were included in the regression model 
and shown in this table AIC / BIC: 265.7 / 272.8 ^ p <0.05 
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CBMDR-TBC project and early deaths 
residence. However this error was not expected to vary differentially among the CBMDR-TBC groups (‘receiving 
support’, ‘receiving partial support’ and ‘not receiving support’). 

Interpretation of findings 
There were many programmatic relevant findings in our study. 
First, receiving support beginning from a period before treatment initiation did not prevent deaths while receiving 
support beginning from anytime between treatment initiation and outcome declaration prevented deaths. This was 
intriguing as we expected even more deaths from being prevented in those receiving support beginning from a 
period before treatment initiation. 
High attrition before treatment initiation among MDR-TB has been documented in Myan- mar [4,5]. 
Implementation of CBMDR-TBC coincided with implementation of decentralized MDR-TB centers at district level. 
Hence, patients that would have generally not accessed MDR-TB treatment before decentralization of MDR-TB 
centers started receiving treatment 
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CBMDR-TBC project and early deaths 
and were also included under CBMDR-TBC “received support” group. These patients could possibly be expected to 
be sicker at treatment initiation than patients in other CBMDR-TBC groups. This could be the possible reason for 
nullifying the effect of CBMDR-TBC in “receiv- ing support” group and therefore similar survival was found when 
compared to “not receiving support”. 
Overall, the effect of CBMDR-TBC on early deaths could be due to more effective imple- mentation of 
domiciliary care under PMDT through a focal nurse at township level who exclu- sively worked for MDR-TB. We 
are assuming that a patient after enrolment into CBMDR-TBC must have received all the benefits at all the time. 
Therefore, the estimates pro- vided in our study are conservative and the true effect could be higher. 
Second, the project did not have an effect on unfavourable treatment outcomes as a whole. One plausible reason 
for this may be the large proportion of “not evaluated” patients at the end of 8 months within the cohort (10%). 
These were the patients who completed 8 months of treatment without any unfavourable outcome, but the culture 
results were not available in time for declaring them as ‘culture converted’. Of these 27, eleven received partial 
CBMDR- TBC support and 14 received support throughout. Hence, the absence of effect of CBMDR- TBC on 
unfavourable outcomes in intensive phase could be a false negative result due to miss- ing culture results in records. 
Third, treatment delay was high as only 14% of the patients were initiated on treatment within 14 days of 
diagnosis. This delay was also not associated with early death or unfavourable intensive phase treatment outcomes. 
In 2016, a systematic review identified no published evi- dence linking delay in treatment initiation and MDR-TB 
outcomes[14]. Recently, a study from India has reported delayed treatment initiation (>30 days) as a risk factor for 
unfavour- able outcomes [15]. 
Fourth, among all patients, twelve percent died or were lost to follow-up at the end of eight months. Low loss to 
follow up may be attributable to nutritional support provided to the patient. Monetary support under PMDT in the 
form of 30 USD per month provided each to BHS and patient for DOT provision and support respectively may also 
have a role to play. In India, among a cohort of patient enrolled in 2011–12 for MDR-TB care, nineteen percent of 
patients documented unfavourable end treatment outcomes occurred within six months of treatment [16]. 
Fifth, high unfavourable outcomes including death among those aged more than 55 years may be due to existing 
co-morbidities in this age group. Diabetes is one of them: we could not include it in the risk factor analysis due to 
large number of missing values. Like in our study, other risk factors like anaemia and low weight or body mass 
index have also been linked to unfavourable outcomes. [17]. A systematic review identified HIV as a factor for early 
deaths: it was not the case in our study[18]. 

Policy implications 
First, we recommend qualitative systematic enquiry to study patient and health-system related enablers and barriers 
for successful / unsuccessful treatment while receiving CBMDR-TBC support. This may also provide more insights 
as to why patients receiving CBMDR-TBC sup- port before treatment initiation did not have the same effect on 
deaths as those receiving CBMDR-TBC midway during the treatment did. 
Second, we recommend the follow-up of the same cohort till the end of treatment outcomes to determine the 
effect of CBMDR-TBC on end treatment outcomes. We may not get this opportunity in cohorts after this as all 33 
townships in the CBMDR-TBC project have been covered under the project. 
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CBMDR-TBC project and early deaths 
Last, the NTP may consider expansion of CBMDR-TBC to all townships. This has implica- tions for preventing 
early deaths across Myanmar. Currently, The Union is one of the non- Government organizations supporting the 
PMDT in providing this support package. This also may have implications for other countries, especially those with 
poor MDR-TB outcomes. The same may be modified to suit each country’s setting and implemented with 
appropriate modifications. 

Conclusion 
The Union’s community-based MDR-TB care project supported the existing domiciliary care provided under NTP 
in Myanmar. Under the project, a focal nurse in a township and a com- munity volunteer (providing evening DOT) 
ensured timely initiation and adherence to MDR-TB treatment. Support through CBMDR-TBC after treatment 
initiation prevented early deaths during MDR-TB treatment. This may have scope for expansion to other the 
township of Myanmar and has implication for NTPs globally. In addition, age more than 55 years, anae- mia and 
weight less than 45 kg were identified as predictors for unfavourable intensive phase outcomes including deaths. 
Further follow-up of the same cohort till end of MDR-TB treat- ment should be done to determine the effect of 
CBMDR-TBC on end treatment outcomes. However, future studies should consider including data on extent of 
sickness at treatment ini- tiation and patient level support received under CBMDR-TBC. 

Supporting information 
S1 Fig. Assessment of proportional hazards assumption for CBMDR-TBC status for occur- rence of 
‘unfavourable intensive phase treatment outcome’ by plotting the estimated sur- vival curves obtained using 
Cox model and Kaplan-Meier estimatesà (Model presented in Table 8). Ãexp2 variable categorized as (Yes) 
under care before treatment initiation; (Partial care) under care after treatment initiation; and (No) Not 
under care till declaration of out- comes; Model AIC / BIC 591.3 / 598.4 (TIF) 
S2 Fig. Assessment of proportional hazards assumption for CBMDR-TBC status for occur- rence of ‘death 
during intensive phase’ by plotting the estimated survival curves obtained using Cox model and 
Kaplan-Meier estimates (Model presented in Table 9). Ãexp2 variable categorized as (Yes) under care before 
treatment initiation; (Partial care) under care after treat- ment initiation; and (No) Not under care till 
declaration of outcomes; AIC / BIC: 265.7 / 272.8 (TIF) 

Acknowledgments 
This research was conducted through the Structured Operational Research and Training Ini- tiative (SORT IT), a 
global partnership led by the Special Programme for Research and Train- ing in Tropical Diseases at the World 
Health Organization (WHO/TDR). The model is based on a course developed jointly by the International Union 
Against Tuberculosis and Lung Dis- ease (The Union) and Medécins sans Frontières (MSF/Doctors Without 
Borders). The specific SORT IT programme which resulted in this publication was jointly organised and imple- 
mented by: The Centre for Operational Research, The Union, Paris, France; The Department of Medical Research, 
Ministry of Health and Sports, Myanmar; The Department of Public Health, Ministry of Health and Sports, 
Myanmar; The Union Country Office, Mandalay, Myanmar; The Union South-East Asia Office, New Delhi, India; 
the Operational Research Unit (LUXOR), MSF Brussels Operational Center, Luxembourg; Burnet Institute, 
Australia. 
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CBMDR-TBC project and early deaths 

Author Contributions 
Conceptualization: Hemant Deepak Shewade, Nang Thu Thu Kyaw, Saw Thein, Aung Si 
Thu, Pyae Sone Htwe, Htet Myet Win Maung, Kyaw Thu Soe, Si Thu Aung. 
Data curation: Pyae Phyo Wai, Hemant Deepak Shewade, Nang Thu Thu Kyaw, Khine Wut 
Yee Kyaw, Myo Minn Oo, Moe Myint Theingi Tun. 
Formal analysis: Pyae Phyo Wai, Hemant Deepak Shewade, Nang Thu Thu Kyaw, Si Thu 
Aung. 
Funding acquisition: Pyae Phyo Wai. 
Investigation: Pyae Phyo Wai. 
Methodology: Pyae Phyo Wai, Hemant Deepak Shewade, Nang Thu Thu Kyaw, Saw Thein, 
Aung Si Thu, Htet Myet Win Maung, Si Thu Aung. 
Project administration: Pyae Phyo Wai. 
Resources: Pyae Phyo Wai, Saw Thein. 
Software: Pyae Phyo Wai, Hemant Deepak Shewade, Nang Thu Thu Kyaw. 
Supervision: Hemant Deepak Shewade, Nang Thu Thu Kyaw, Si Thu Aung. 
Validation: Pyae Phyo Wai, Hemant Deepak Shewade, Nang Thu Thu Kyaw. 
Visualization: Pyae Phyo Wai, Hemant Deepak Shewade, Nang Thu Thu Kyaw. 
Writing – original draft: Pyae Phyo Wai. 
Writing – review & editing: Pyae Phyo Wai, Hemant Deepak Shewade, Nang Thu Thu Kyaw, 
Khine Wut Yee Kyaw, Saw Thein, Aung Si Thu, Myo Minn Oo, Pyae Sone Htwe, Moe Myint Theingi Tun, Htet 
Myet Win Maung, Kyaw Thu Soe, Si Thu Aung. 

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