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Factors related to previous tuberculosis treatment of Multidrug resistant Tuberculosis patients in Bangladesh

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008273

Article Type: Research

Date Submitted by the Author: 22-Mar-2015

Complete List of Authors: Rifat, Mahfuza; University of Newcastle, School of Medicine and Public Health; BRAC, Health Nutrition and Population Programme Hall, John; The University of Newcastle, School of Medicine and Public Health Oldmeadow, Christopher; The University of Newcastle, School of Medicine and Public Health Husain, Ashaque; National Tuberculosis Control Programme, Directorate General of Health Services

Hinderaker, Sven; University of Bergen, The Department of Global Public Health and Primary Care Milton, Abul; The University of Newcastle, School of Medicine and Public Health

<b>Primary Subject Heading</b>:

Infectious diseases

Secondary Subject Heading: Public health, Health services research

Keywords: Tuberculosis < INFECTIOUS DISEASES, Public health < INFECTIOUS DISEASES, Epidemiology < INFECTIOUS DISEASES

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Factors related to previous tuberculosis treatment of Multidrug resistant

Tuberculosis patients in Bangladesh

Authors and Institutions:

Mahfuza Rifat 1, 2 *

, John Hall 1, Christopher Oldmeadow

1, Ashaque Husain

3,

Sven Gudmund Hinderaker 4, Abul Hasnat

Milton

1

1. School of Medicine and Public Health, Faculty of Health and Medicine, the University of

Newcastle, Newcastle, Australia.

2. BRAC, Dhaka, Bangladesh.

3. National Tuberculosis Control Programme, Directorate General of Health Services,

Bangladesh

4. The Department of Global Public Health and Primary Care, the University of Bergen,

Bergen, Norway

Corresponding Author:

Dr. Mahfuza Rifat

HMRI Building

School of Medicine and Public Health; Faculty of Health and Medicine

The University of Newcastle,

Newcastle, NSW 2308, Australia

Phone: +612 404 20631

Fax Number: +61 2 40420044

Email: [email protected]

Abstract: 300 words

Word count of full article (excluding abstract, article summary, acknowledgement,

references and tables): 3906 words

4 tables, 29 References

Keywords: Tuberculosis, Public Health, Multidrug resistant tuberculosis, Health system,

Retreatment tuberculosis

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ABSTRACT 1

Objective: Previous tuberculosis treatment status is established risk factor for multidrug 2

resistant tuberculosis. This study explores which factors related to previous tuberculosis 3

treatment may lead to the development of multidrug resistance in Bangladesh. 4

Design: We previously conducted a case-control study to identify the risk factors for 5

developing multidrug resistant tuberculosis in Bangladesh. Patients, who had a history of 6

previous tuberculosis treatment, either multidrug resistant tuberculosis (MDR-TB) or non-7

multidrug resistant tuberculosis (non-MDR-TB), were interviewed about their previous 8

treatment episode. This study restricts analysis to the strata of patients that have previously 9

treated for tuberculosis. Information was collected through face-to-face interviews and record 10

reviews. Unadjusted and multivariable logistic regression was used to analyse the data. 11

Setting: Central, district and subdistrict level hospitals in rural and urban Bangladesh. 12

Results: The strata of previously treated patients includes a total of 293 patients (245 with 13

current MDR-TB; 48 non-MDR patients). Overall, 64.5% of patients received previous 14

tuberculosis treatment more than once, and all of these patients were multidrug resistant. 15

MDR-TB patients were more likely to have experienced the following factors: incomplete 16

treatment (4.2; 95% CI 1.7-9.7), adverse reactions due to TB treatment (OR 6.3; CI 2.8-14.2), 17

hospitalization for symptoms associated with tuberculosis (OR 8.9; CI 1.2-65.3), DOTS 18

center as treatment unit (OR 4.4; CI 1.3-14.3), supervised treatment (OR 3.7; CI 1.6-8.6); 19

time to treatment center (OR 0.986; CI 0.977-0.996). 20

Conclusion: Incomplete treatment, hospitalization for tuberculosis treatment and adverse 21

reaction are the factors related to previous tuberculosis treatment of MDR-TB patients. 22

Although the presence of supervised treatment (DOT), less time to treatment centers and 23

being treated in DOTS centers were relatively higher among the MDR-TB patients compared 24

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to the non-MDR-TB patients, these findings include information of their most recent TB 25

treatment episode only. Most (64.5%) of the MDR-TB patients had received tuberculosis 26

treatment more than once. 27

ARTICLE SUMMARY 28

Strengths and Limitations of the study 29

• Previous tuberculosis (TB) treatment is an important risk factor for Multidrug 30

resistant TB (MDR-TB) patients. Information regarding the previous tuberculosis 31

treatment of MDR-TB is not available in Bangladesh. 32

• Strata of previously treated patients have been taken from a previously conducted 33

large case control study with adequate sample size and power. 34

• We only extracted the information on recent episode of previous tuberculosis 35

treatment to minimize recall bias. Majority of the MDR-TB patients were treated 36

more than once and we do not have information on other treatment episodes. 37

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INTRODUCTION 38

Global tuberculosis (TB) control efforts are facing the additional challenge of Multidrug 39

Resistant tuberculosis (MDR-TB).1 MDR-TB cannot be treated with first line anti-40

tuberculosis medicines and needs a longer treatment period with stronger second-line 41

medicines.2 A total of 0.14 million cases of drug resistant TB were reported worldwide in 42

2013; however the estimate for MDR-TB incidence is at least five times higher.3 The number 43

of reported MDR-TB cases has been increasing in recent years.3 Globally, 20.5 % (13.6–44

27.5%) of previously treated cases and 3.5% (2.2-4.7%) of new cases are estimated to have 45

MDR-TB.3 Previous tuberculosis treatment is a known risk factor for MDR-TB.

4-10 Patients 46

with previous TB treatment are difficult to manage and might be infectious for a longer 47

period. ‘Previous treatment’ may mean a relapse after a successful treatment, a return after 48

treatment discontinuation, a treatment failure, or any other type.11

Previously treated recurrent 49

TB is no longer a neglected area; rather it is considered to be an important factor to be 50

considered for TB control.12,13

Programmatic factors such as poor management of the 51

patient, lack of directly observed treatment, limited or interrupted drug supplies, poor drug 52

quality, widespread availability of anti-tuberculosis drugs without prescription, lack of 53

uniformity between the public and private health sectors regarding the treatment regimens, 54

and poorly managed and supported National TB Control Programmes (NTP) were cited to be 55

the factors related to development of drug resistance.14,15

56

The World Health Organization (WHO) has identified 27 high burden countries for MDR-57

TB. Four of these countries, including Bangladesh, belong to the South-East Asian region.16

58

In Bangladesh, MDR-TB is an emerging public health problem.17

According to a recent 59

WHO estimate, 1.4% of new cases and 29% of the retreatment cases in Bangladesh have 60

MDR-TB.3 Although the rate of MDR-TB is still relatively low, due to the overall high TB 61

burden in Bangladesh the absolute number of MDR-TB cases is quite large, with 2100 among 62

new TB patients and 2600 among the previously treated TB patients. A recent study in 63

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Bangladesh suggests that previous tuberculosis treatment is an important risk factor for 64

MDR-TB.3 However, the detailed information regarding the previous tuberculosis treatment 65

has not yet been collected. Factors related to previous management of tuberculosis need to be 66

identified to develop control strategies. The main objective of this study is to explore the 67

factors related to the previous tuberculosis treatment of current MDR-TB patients compared 68

to the non-MDR-TB patients of Bangladesh. 69

METHODS 70

We previously conducted a case-control study to identify the risk factors of multidrug 71

resistant tuberculosis in Bangladesh.18

The study included 250 MDR-TB and 750 non-MDR-72

TB tuberculosis patients, and the sample size demonstrated sufficient power (80%) to detect 73

at least a 10% difference in the prevalence of any of the exposure variables at 5% 74

significance threshold.18

We found that 293 patients (29.3%) (245 MDR-TB and 48 non-75

MDR-TB) had previously received treatment for tuberculosis. All patients with a history of 76

previous tuberculosis treatment were interviewed about parameters related to their previous 77

treatment history. This study restricts analysis to the strata of patients that have previously 78

treated for tuberculosis. 79

The setting, definition and the inclusion and exclusion criteria of the study have been 80

described in detail previously.18

The setting was central, district and subdistrict level hospitals 81

in rural and urban Bangladesh. MDR-TB patients aged between 18 and 65 years who gave 82

their informed consent were included in the study. Patients, who received treatment for 83

MDR-TB following the criteria of the NTP guidelines, were classified as MDR-TB. The NTP 84

has adopted automated real time PCR (Xpert MTB/RIF) as the diagnostic tool of MDR-TB 85

patients. Culture and Drug Sensitivity Testing (DST) and Line probe assays were also used.19

86

Xpert MTB/RIF diagnoses only Rifampicin resistance. Patients who are resistant to 87

Rifampicin are generally also resistant to Isoniazid (another first-line drug). Mono-resistance 88

to Rifampicin is fairly uncommon (0.2% and 0.4% among new and previously treated 89

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patients, respectively), as shown by a recent drug resistance survey (DRS) conducted in 90

Bangladesh.20

Drug susceptible TB patients aged 18 to 65 years, were diagnosed through 91

sputum smear microscopy or other investigations (X-ray, FNAC or Biopsy) as per NTP 92

guidelines and expected to respond to the standard combination of drugs. In this paper we 93

will refer to those as non-MDR-TB patients. We excluded patients who were not within the 94

eligible age group or had any serious illness requiring admission to the Intensive Care Unit 95

(ICU), recent surgery, or any medical emergency that needed continuous observation. 96

As the patients might have had more than one previous treatment episode, we collected 97

detailed information based on their most recent episode, to aid the accuracy of the recalled 98

information. According to the national TB guidelines, the recommended duration of 99

tuberculosis treatment is six and eight months for new and retreatment types of drug-sensitive 100

patients, respectively 21

. Presence or absence of incomplete treatment during the previous TB 101

treatment was based on patient’s statement, which refer to any discontinuation of treatment 102

during the latest episode of previous TB treatment. Treatment discontinuation due to 103

treatment failure is also included under “Incomplete treatment”. 104

Data collection 105

MDR-TB and non-MDR-TB patients were identified as part of a previously conducted case 106

control study on risk factors of MDR-TB [18]. MDR-TB patients from all over Bangladesh 107

are referred to one of the three government hospitals, the national hospital in Dhaka or a 108

regional hospital in either Chittagong or Rajshahi. All eligible MDR-TB patients who were 109

admitted from September 2012 to mid- April 2013 were recruited from these hospitals under 110

the previously conducted study. The hospitals that were providing MDR-TB treatment were 111

receiving patients referred by the various treatment units from rural and urban Bangladesh. 112

Each TB patient is assigned a unique TB registration number as a routine practice. Treatment 113

registration numbers of tuberculosis patients, who were diagnosed during the specified period 114

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i.e. during the same month that MDR-TB was diagnosed, were listed. Three non-MDR-TB 115

patients per MDR-TB patient, from the local tuberculosis treatment unit from where the case 116

was referred, were recruited under the previous study. 117

All patients who had a history of previous tuberculosis treatment were subsequently 118

interviewed about parameters related to their previous treatment; these findings are reported 119

under this study. 120

Trained investigators collected information from the study participants by face-to-face 121

interview using a pre-tested questionnaire and by review of records. All the investigators 122

received training on data collection procedures for one week. Diagnosis of tuberculosis 123

through microscopy is under an external quality assessment (EQA) network at country level. 124

The NTP has its inbuilt quality control mechanism for diagnosis of MDR-TB patients 125

through a laboratory based in Antwerp, Belgium. 126

Statistical analysis 127

We compared participant characteristics between MDR-TB (245) and non-MDR-TB (48) 128

patients using Student t-tests for continuous measures, and Chi-square (χ2) tests for 129

categorical measures. Unadjusted and multivariable logistic regression models were used to 130

estimate odds ratios (and 95% confidence intervals) for MDR-TB status with the following 131

variables: site of previous tuberculosis, adverse reaction due to tuberculosis treatment, 132

hospitalization due to tuberculosis, type of center for treatment initiation and follow up, 133

presence of supervised treatment (DOT), time to treatment center, incomplete treatment. We 134

initially included all variables in the adjusted model, but later excluded variables that had 135

insufficient frequencies or may have collinear relationships with the variables included in the 136

model. The excluded variables from the multivariable model were: treatment regimen, 137

treatment outcome, treatment extension, type of provider and cost and distance to treatment 138

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center. Cost to treatment center and distance to treatment center were excluded from the 139

model for possible colinearity with the variable “time to treatment center”. 140

We assessed statistical significance of odds ratios using the likelihood ratio tests, and we had 141

sufficient patients to include the variables in the multivariable model without risk of over-142

fitting. The odds ratios derived from these models correspond to effects specific to the strata 143

of patients that have been previously treated for tuberculosis. Data analysis was carried out 144

using Stata statistical software version 12 (StataCorp LP, TX, USA). 145

Ethics considerations 146

The study was approved by the Human Research Ethics Committee (HREC) of the 147

University of Newcastle (UoN), Australia and the Bangladesh Medical Research Council 148

(BMRC), Dhaka, Bangladesh. An information sheet describing the purpose of the study and 149

the individuals’ rights as study participants was handed to the participants to read. For 150

individuals with inadequate literacy, the information sheet was read out by the interviewers. 151

Participants consented by signing the consent form, or if unable to do so, by adding their 152

thumb impression. All patients had been treated through the National TB Control Programme 153

(NTP), Bangladesh. 154

RESULTS 155

We included the previously treated TB patients from the case control study of 250 MDR-TB 156

and 750 non-MDR-TB patients 18

. History of previous tuberculosis treatment was present in 157

293 of those patients, and this patient group forms part of the study described here. Patients 158

included are 245 MDR-TB and 48 non-MDR-TB patients. Among the previously treated 159

MDR-TB patients, 64.5% had been treated more than once and all non-MDR-TB patients had 160

only one episode of treatment previously. 161

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Mean age of previously treated MDR-TB patients was lower than non-MDR-TB patients. 162

The majority of the patients were male and had pulmonary tuberculosis. Among the MDR-163

TB patients, 63.7% received a retreatment regimen commonly known as category-2, 164

consisting of five drugs including injectable Streptomycin. All non-MDR-TB patients were 165

treated with the regimen for new tuberculosis patients that consists of a combination of four 166

oral drugs. The most frequent category for duration of previous treatment was five months 167

(59.6%). The majority (64.6%) of drug-sensitive TB patients discontinued their treatment at 168

three months or less. Treatment failure was higher among the MDR-TB patients compared to 169

non-MDR-TB patients (68.4% and 28.6%, respectively) during their previous treatment. Of 170

the MDR-TB patients, 32.6% reported having an extended treatment period since their 171

sputum remained positive after the intended period of treatment. This treatment extension 172

was only reported by 5.4% of the non-MDR-TB patients. Hospitalization for TB related 173

problems during their previous TB treatment mostly occurred for MDR-TB patients (13.5%). 174

The three main causes of hospitalization during previous TB treatment were massive 175

haemoptysis (33.3%), severe weakness (33.3%) and pleural effusion (15.2%). 176

Detailed demographic and clinical characteristics are presented in Table 1. For some patients, 177

it was not possible to get information regarding the previous treatment outcome (19%), 178

treatment extension (9%) and previous treatment regimen (11%). 179

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Table 1: Demographic and Clinical Characteristics of Previously Treated Tuberculosis

Patients

a Treatment regimen, treatment outcome and treatment extension had total 261, 231 and 267 observations respectively.

* Probability of χ 2

** Probability of t-test

Variable Non-MDR-TB MDR-TB Total P

Age 0.0001**

Mean 41 33.8 35

Median 40 30 30

SD 15.8 12.3 13.2

Sex 0.027*

Male 28 (58.3%) 163 (66.5%) 191 (65.2%)

Female 20 (41.7%) 82 (33.5%) 102 (34.8%)

Site of Previous TB <0.0001*

Extrapulmonary 7 (14.6%) 5 (2.0%) 12 (4.1%)

Pulmonary 41 (85.4%) 240 (98.0%) 281 (95.9%)

Treatment regimen a <0.0001*

Category 1 16 (100%) 86 (35.1%) 102 (39.0%)

Category 2 0 (0%) 156 (63.7%) 156 (59.8%)

MDR-NTP 0 (0%) 2 (0.8%) 2 (0.8%)

Non-standardized 0 (0%) 1 (0.4%) 1 (0.0%)

Duration of treatment <0.0001*

6-8 months 3 (6.3%) 15(6.1%) 18 (6.1%)

4- 5 months 14 (29.1%) 146 (59.6%) 160 (54.6%)

3 months or less 31 (64.6%) 84 (34.3%) 115 (39.3%)

Treatment outcome a 0.001*

Cured 6 (42.8%) 20 (9.2%) 26 (11.2%)

Completed 4 (28.6%) 43 (19.7%) 47 (20.3%)

Default 0 (0%) 6 (2.8%) 6 (2.6%)

Failure 4 (28.6%) 149 (68.3%) 153 (65.9%)

Adverse reaction <0.0001*

Absent 34 (70.8%) 57 (23.3%) 91 (31.1%)

Present 14 (29.2%) 188 (76.7%) 202 (68.9%)

Treatment extension a 0.001*

Absent 35 (94.6%) 155 (67.4%) 190 (71.2%)

Present 2 (5.4%) 75 (32.6%) 77 (28.8%)

Hospitalization due to

TB 0.069*

Absent 46 (95.8%) 212 (86.5%) 258 (88.1%)

Present 2 (4.2%) 33 (13.5%) 35 (11.9%)

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Patients were asked if they had stopped their treatment at any point of their previous 180

tuberculosis treatment and in this paper we refer it as incomplete treatment. Incomplete 181

treatment during previous TB treatment was reported by 63.3% and 29.2% of MDR-TB and 182

non-MDR-TB patients, respectively. Reasons for incomplete treatment among the MDR-TB 183

and non-MDR-TB patients are presented in Table 2. 184

Table 2: Incomplete Treatment and the Reasons Reported by Previously Treated

Tuberculosis Patients

Variable Non-MDR-TB

n (%)

MDR-TB

n (%) P

Treatment completion <0.0001*

Completed treatment 34 (70.8) 90 (36.7)

Incomplete treatment 14 (29.2) 155 (63.3)

Reasons for incomplete treatment

Felt better 7 (50.0) 7 (4.5)

Remained positive in microscopy test 1 (7.1) 143 (92.3)

Change of address 4 (28.7) 0 (0)

Expense of treatment 1 (7.1) 1 (0.6)

Adverse effect 0 (0) 2 (1.3)

Lack of Family support 1 (7.1) 0 (0)

Others 0 (0) 2 (1.3)

* Probability of χ 2 test

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Patients who do not complete their treatment are supposed to be followed up by one of their 185

health care providers, according to the national TB guideline. 21

A high proportion (91.6%) of 186

MDR-TB patients reported that they had been followed up during previous TB treatment, 187

although among non-MDR-TB patients follow-up was quite low (14.3%). 188

Supervised intake of medicine by Directly Observed Treatment (DOT) during their previous 189

treatment was reported by 78.4% of MDR-TB patients and 41.7% of non MDR-TB patients, 190

respectively. We further explored who had supervised the medicine intake and found that 191

70.3% of MDR-TB and 80% of non-MDR-TB patients were given their medicine by trained 192

providers (community health volunteers, health worker at facility or field level, village 193

doctors). The rest of the patients were given their medicine by a family member, neighbours 194

or other providers. 195

Current MDR-TB patients had been treated for their previous tuberculosis mostly in 196

designated centers for TB (DOTS center) (95.9%); for non-MDR-TB patients the proportion 197

was 70.8%. Rate of treatment in private centers was 4.1% and 29.2% for MDR-TB and non 198

MDR-TB patients, respectively. 199

Median travel time to visit the previous treatment center, which was the designated unit for 200

treatment initiation and follow-up, was 20 minute for MDR-TB and 40 minutes for non-201

MDR-TB patients. 202

Details of health system factors are presented in Table 3. 203

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Table 3: Health System Related Characteristics of Previously Treated Tuberculosis

Patients

Variable Non-MDR-TB MDR-TB Total p

Supervised treatment (DOT) <0.0001*

Unsupervised treatment 28 (58.3%) 53(21.6%) 81 (27.6%)

Supervised treatment 20 (41.7%) 192 (78.4%) 212 (72.4%)

Type of DOT provider 0.36*

Trained provider a 16 (80%) 135 (70.3%) 151 (71.2%)

Family/other provider b 4 (20%) 57 (29.7%) 61 (28.8%)

Type of treatment unit <0.0001*

Private center 14 (29.2%) 10 (4.1%) 24 (8.2%)

Designated DOTS Center 34 (70.8%) 235 (95.9%) 269 (91.8%)

Follow up by the providers after

incomplete treatment <0.0001*

Follow up done 12 (85.7%) 13 (8.4%) 25 (14.8%)

No follow up 2 (14.3%) 142 (91.6%) 144 (85.2%)

Time to treatment center (minute) 0.0005**

Mean 49.8 29.7 32.9

Median 40 20 30

SD 34.7 35.5 36.1

Range 5-150 1 -420 1-420

Cost to treatment center (BDT) 0.46**

Mean 27.3 22.9 23.6

Median 20 15 20

SD 22 38.3 36.1

Range 0-100 0-500 0-500

Distance to treatment center

(miles) 0.91**

Mean 4.6 4.3 4.3

Median 3 2 2

SD 4 16.1 14.9

Range 0.2-15 0-175 0-175


**Probability of t-test

a Trained providers include providers trained on supervision on medicine intake (DOT) such as community health volunteers, health workers

at facility and field level and village doctors

b “Family and other providers” includes family members, neighbours and other volunteers supervising the treatment

BDT is Bangladesh taka (1 USD is 77 BDT approximately)

Time to treatment center, cost to treatment center and distance to treatment center had total 286, 283 and 285 observations, respectively.

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Logistic regression analysis 204

In the multivariable adjusted analysis, MDR-TB patients were shown to be more likely to 205

have a history of incomplete tuberculosis treatment (4.1; 95% CI 1.7-9.7), adverse reactions 206

due to anti-tuberculosis medicines (OR 6.3; 95% CI 2.8-14.2), hospitalization due to 207

tuberculosis (OR 8.9; 95%; CI-1.2-65.3), have been treated in a designated DOTS center (OR 208

4.4; 95% CI 1.3-14.3) and time to treatment center (OR .986 CI 0.987- 0.996). 209

Directly observed treatment (OR 3.7; 95% CI 1.6-8.6) was high among MDR-TB patients 210

during their previous TB treatment compared to the non-MDR-TB patients. Site of previous 211

TB (pulmonary or extrapulmonary) was no longer associated in the adjusted model. Findings 212

of the logistic regression are shown in Table 4. 213

Table 4: Univariate and Multivariable Analyses on Multidrug Resistance Tuberculosis

Status and Previous Treatment Related Factors

Univariate analysis Multivariable analysis

Variable Odds

Ratio

Confidence

Interval a Odds Ratio

Confidence

Interval a

Site of Previous TB

Extrapulmonary 1

1

Pulmonary 8.2 2.5-27.1 3 0.6-15.2

Adverse effect

Absent 1

1

Present 8 4.0-16.0 6.3 2.8-14.2

Hospitalization due to TB

Absent 1

1

Present 3.6 0.8-15.5 8.9 1.2-65.3

Supervised treatment

(DOT)

Absent 1

1

Present 5.1 2.6-9.7 3.7 1.6-8.6

Type of treatment unit

Private 1

1

DOTS Center 9.7 4.0-23.5 4.4 1.3-14.3

Incomplete treatment

Completed treatment 1

1

Incomplete treatment 4.2 2.13-8.2 4.1 1.7-9.7

Time to Treatment center

(minutes) 0.988 0.979-0.997 0.986 0.977-0.996

* Confidence interval at 95% level

** P is the value of Wald test statistic

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DISCUSSION 214

Multidrug resistance is more commonly reported among previously treated tuberculosis 215

patients than in new tuberculosis patients, globally as well as in Bangladesh.3 According to 216

the recent drug resistance survey, 28% of previously treated TB patients in Bangladesh have 217

MDR-TB.20

Most of the MDR-TB patients (98%) had a history of previous tuberculosis 218

treatment.18

Re-treatment patients constitute approximately 3% of all tuberculosis patients in 219

the national data collection.17

This corresponded to 3906 patients in 2011.17

Our study 220

examines how these patients had been managed during their previous treatment. 221

MDR-TB patients were found to be four times more likely to have a history of incomplete 222

tuberculosis treatment than non-MDR-TB patients. Incomplete treatment refers to 223

discontinuation at any phase of the previous treatment reported by patients. This finding has 224

been supported by many studies.4,9,22-24

The majority of MDR-TB patients (92.3%) stated 225

that the reason for incomplete treatment was that they remained positive to tuberculosis 226

bacteria in microscopy test and had stopped their previous treatment to initiate diagnosis and 227

treatment for MDR-TB. Remaining positive for TB bacteria is an indication of treatment 228

failure and thus “incomplete treatment” in this study also includes the treatment failure. This 229

finding reflects the implementation of national guidelines that recommend that the patients 230

who do not respond to the retreatment regimen should be referred for diagnosis of MDR-231

TB.19

However, half of the non-MDR-TB patients did not complete their treatment as they 232

felt better after starting the treatment. The second major cause for treatment discontinuation 233

reported by non-MDR-TB patients was change of their address. Although the NTP has a 234

system in place to provide service to the patients transferred from one place to another, these 235

figures show that patient education regarding discontinuation of treatment needs to be further 236

strengthened through advocacy communication and social mobilization activities.21

Although 237

the MDR-TB patients reported that non-responsive previous treatment was the main cause of 238

their incomplete treatment, these findings are based on their most recent episode of previous 239

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treatment and most of the MDR-TB patients had more than one episode of earlier TB 240

treatment. The TB control programmes should address the reasons for incomplete treatment 241

for all types of tuberculosis patients. Incomplete treatment may lead to development of drug 242

resistance at any point of time irrespective of number of treatment episodes. 243

MDR-TB patients were more likely to have adverse reactions to anti-tuberculosis medication 244

during their previous TB treatment. Association of MDR-TB with adverse reaction during 245

their previous TB treatment was found in another study and this association was explained as 246

the use of second line drugs during their previous TB treatment, and these are commonly 247

more toxic than first line anti-tuberculosis drugs.25

In our study, we found most of the MDR-248

TB patients were treated previously with retreatment regimens that did not include any of the 249

second line drugs commonly used for MDR-TB treatment. The retreatment regimen included 250

injectable Streptomycin additional to the medicines used for new patients. Additionally, 251

adverse reaction as a cause of incomplete treatment was reported by only 1.3% of MDR-TB 252

patients. However, the patients with adverse reactions to anti-tuberculosis medicine can be 253

treated with special care. Patient education at the beginning of treatment can be strengthened 254

by advice on adverse reactions. 255

Hospitalization for more than fourteen days associated with MDR-TB and XDR-TB was 256

found in one study.26

In our previous study, we did not find any association of MDR-TB 257

status with hospitalization due to any other cause within the last seven months of current 258

treatment.18

Hospitalization due to TB-related causes during previous treatment was 259

associated with MDR-TB in our current study. This finding indicates that patients may have 260

experienced some difficulties and complicated TB disease. Another possibility is that these 261

patients were not diagnosed properly as drug resistant patients, and became sick enough for 262

hospitalization during their previous episode. The NTP may consider MDR-TB testing for 263

patients admitted to hospitals for TB specific problems. The recent national guideline 264

recommends that the following groups to be tested for MDR-TB: previously treated patients, 265

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current TB patients with treatment failure, patients with delayed response in treatment, or 266

with smear-negative or extrapulmonary TB that does not improve clinically, patients with 267

relapse or who receive treatment after default, patients who have HIV, and people in contact 268

with MDR-TB patients.19

269

Camerino classified the risk factors for the emergence of MDR-TB into two categories, the 270

first category includes some of the factors facilitating the selection of resistance in the 271

community and is closely linked to the health system; it includes non-compliance, absence of 272

supervised treatment and the influence of private providers during previous treatment.6 The 273

other category includes factors that are related to the individual patient’s vulnerability to 274

develop MDR-TB, such as clinical and demographic factors.6 275

In our study, more MDR-TB patients reported supervised treatment (DOT) during their most 276

recent TB treatment episode compared to the non-MDR-TB patients (78.4% vs. 41.7%). 277

Absence of supervised treatment may lead to irregular intake and cause drug resistance, 278

which is an established fact, but our finding looks contradictory.27

However this finding is 279

based on the most recent episode of previous TB treatment and we do not have information 280

on their other previous episodes, when they might have had irregular intake. Moreover, 281

during the latest episode MDR-TB patients they might have been treated with a retreatment 282

regimen which contains injectable Streptomycin which requires more supervised care as the 283

injection must be administered by a provider. This could also explain the comparatively 284

higher level of follow up among the MDR-TB patients by the providers after incomplete 285

treatment. We found that more MDR-TB patients than non-MDR-TB patients reported being 286

followed up by a provider after treatment discontinuation during their previous episode. 287

Another possible explanation of these findings could be that the health system approach is 288

targeted towards retreatment patients, as 63.7% of the MDR-TB patients were receiving a 289

retreatment regimen (category-2) during their latest episode. Retreatment regimens are 290

complicated as patients have a higher chance to develop MDR-TB and might have taken 291

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more care compared to the patients who had been treated on a new patient’s regimen 292

(category-1). However, new tuberculosis patients require the same effort as retreatment 293

patients to prevent further development of drug resistance. 294

The national TB control programmes of high burden TB countries where a private sector is 295

also present face difficulties to implement treatment guidelines, resulting in inadequate 296

treatment or non-compliance.15

In Bangladesh, designated DOTS centers are the centers 297

managed by public and non-government organizations that are linked with the NTP, which 298

offers free services and medicine for TB treatment. These DOTS centers are the point of 299

treatment initiation and follow up. Private centers are for-profit private practitioners, clinics 300

and hospitals where patients need to pay for TB treatment and these services are not 301

commonly linked with TB control programme. In our study, MDR-TB patients had been 302

enrolled mostly with the designated DOTS centers during their most recent episode of 303

previous TB, rather than private centers. The possible explanation could be that retreatment 304

patients are complicated cases that private practitioners prefer not to treat. This study is a 305

hospital based study and we assumed that most of the MDR-TB patients are treated under 306

these three Government hospitals. We do not have any information on MDR-TB patients 307

treated by private physicians who are beyond national TB control programme. However, we 308

were not able to collect information on other episodes to evaluate if patients had been treated 309

in the private sectors previously. Another study reported similar rate of MDR-TB among 310

patients treated by DOTS center and by private providers.28

Thorough review of medication 311

given during previous treatment, regardless of its setting, was recommended.28

312

The National Tuberculosis Control Programme (NTP) of Bangladesh provides services 313

integrated into the basic health services.17

Tuberculosis control through DOTS services has 314

been expanded throughout the country in all sub-districts and metropolitan cities with the 315

support of Non-Government Organizations such as BRAC, the Damien Foundation and other 316

organizations such as UPHCSDP, NHSDP and BGMEA, or through public private 317

partnerships.17

Accessing services from DOTS centers might reflect the expansion of DOTS 318

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services and their reach of more patients. Widespread deployment of community health 319

workers and their involvement in high priority health areas including TB has brought these 320

services to the household level.29

The community-based approach is adopted widely in 321

Bangladesh, so patients do not have to travel to health centers for every administration of 322

medicine; it can be given by community level providers and the patient only visits the center 323

for diagnosis, follow up and complications. Time to treatment center was relatively lower (20 324

vs. 40 minutes in MDR-TB and non-MDR-TB, respectively) among the MDR-TB patients 325

compared to non-MDR-TB patients. We did not find any significant difference in cost and 326

distance to treatment centers. Although access to treatment could be a factor for developing 327

drug resistance, we could not make conclusions about this factor from our findings. Patients 328

may be living in closer proximities, along with some other problems other than time, cost and 329

distance, to access the treatment. We also found that the second major reason for incomplete 330

treatment was change in address which might be due unstable living circumstances, such as 331

the eviction of slum in some areas or losing a job. A detail qualitative study needs to be 332

conducted in future regarding other treatment access factors of tuberculosis patients. 333

This study is a stratified analysis of previously treated tuberculosis patients taken from a case 334

control study which recruited the MDR-TB and non-MDR-TB patients representing the 335

population. We do not have information of all previous treatment episodes for the patients as 336

we had extracted the information based on the most recent episode, to aid the accuracy of the 337

recalled information. It was not feasible to confirm drug susceptibility using Drug Sensitivity 338

Testing (DST) of the non-MDR-TB patients, as only high-risk patients are routinely tested, 339

and we did not have the funds for this. 340

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CONCLUSION 341

In conclusion, we found that incomplete treatment which includes treatment discontinuation 342

due to treatment failure, adverse reactions to anti tuberculosis medicine, and hospitalization 343

for TB complications during previous tuberculosis treatment are the main factors leading up 344

to MDR-TB. Although we found seemingly contradictory findings regarding supervised 345

treatment, less time required to visit treatment center and the designated DOTS center, it does 346

not necessarily mean that supervised treatment, accessibility or being treated in a designated 347

DOTS center contribute to MDR-TB. These findings are based on the most recent episode of 348

previous treatment of MDR-TB patients, as most patients have more than one episode of 349

previous tuberculosis treatment. In addition, the health system may be better prepared for the 350

retreatment of patients. Therefore basic DOTS services should be strengthened for new 351

patients to prevent development of drug resistance. Patients who are hospitalized for TB 352

related causes could be tested for MDR-TB. Patient education could be strengthened for all 353

TB patients regarding adverse effect and compliance related issues. 354

ACKNOWLEDGEMENT 355

We received cooperation from the National Tuberculosis Control Programme, Directorate 356

General of Health Services and Damien Foundation, Bangladesh and other partners including 357

UPHCSDP, NHSDP and BGMEA. We gratefully acknowledge the contribution of Md. 358

Akramul Islam, BRAC, for providing valuable inputs and extensive support to implement this 359

study. We are thankful to Bodrun Naher Siddiquea, Muhammad Amzad Hossen, Md. Zaidur 360

Rahman, Md. Momenul Islam, and all other BRAC colleagues who worked hard to collect 361

quality data. The authors thank Claudia Koller for assistance with editing this manuscript. 362

Finally, we are grateful to the study participants for their valuable time and assistance. 363

FUNDING STATEMENT 364

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This research was funded by the Australian Respiratory Council, BRAC Bangladesh and 365

University of Newcastle Australia. The funders had no role in study design, data collection 366

and analysis or decision to publish or preparation of manuscript. 367

COMPETING INTEREST 368

No competing interest declared. 369

AUTHOR’S CONTRIBUTION 370

MR, AHM and JH and all authors contributed in designing and planning the study. MR 371

collected, analysed the data and prepared the manuscript. CO provided input in data analysis 372

and writing. AH, SGH and all authors reviewed the document and provided their inputs. 373

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References

1. World Health Organization. Multidrug and extensively drug-resistant TB (M/XDR-TB),

2010 Global Report on Surveillance and Response. Geneva, 2010.

2. World Health Organization. Towards the universal access to diagnosis and treatment of

multidrug-resistant and extensively drug-resistant tuberculosis by 2015 ,WHO progress

report. Geneva, 2011.

3. World Health Organization. Global Tuberculosis Report 2014. Geneva, 2014.

4. Espinal MA, Laserson K, Camacho M, et al. Determinants of drug-resistant tuberculosis:

analysis of 11 countries. Int J Tuberc Lung Dis 2001;5(10):887-93.

5. Faustini A, Hall AJ, Perucci CA. Risk factors for multidrug resistant tuberculosis in

Europe: a systematic review. Thorax 2006;61(2):158-63.

6. Caminero JA. Multidrug-resistant tuberculosis: epidemiology, risk factors and case

finding. Int J Tuberc Lung Dis 2010;14(4):382-90.

7. Law WS, Yew WW, Chiu Leung C, et al. Risk factors for multidrug-resistant tuberculosis

in Hong Kong. Int J Tuberc Lung Dis 2008;12(9):1065-70.

8. Lomtadze N, Aspindzelashvili R, Janjgava M, et al. Prevalence and risk factors for

multidrug-resistant tuberculosis in the Republic of Georgia: a population-based study. Int J

Tuberc Lung Dis 2009;13(1):68-73.

9. Sharma SK, Turaga KK, Balamurugan A, et al. Clinical and genetic risk factors for the

development of multi-drug resistant tuberculosis in non-HIV infected patients at a tertiary

care center in India: a case-control study. Infect Genet Evol 2003;3(3):183-8.

10. Zaman K, Rahim Z, Yunus M, et al. Drug resistance of Mycobacterium tuberculosis in

selected urban and rural areas in Bangladesh. Scand J Infect Dis 2005;37(1):21-6.

11. World Health Organization. Treatment of tuberculosis Guidelines. Fourth ed. Geneva,

2009.

12. Zignol M, Wright A, Jaramillo E, et al. Patients with Previously treated tuberculosis No

longer neglected. Clinical Infectous Diseases 2007.

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13. World Health Organization. The Global Plan to Stop TB ,Transforming the Fight towards

Elimination of Tuberculosis. Geneva, 2011.

14. Lambregts-van Weezenbeek CS, Veen J. Control of drug-resistant tuberculosis. Tubercle

& Lung Disease 1995;76(5):455-9.

15. World Health Organization. Guidelines for the programmatic management of drug-

resistant tuberculosis. Geneva,, 2008.

16. World Health Organization. Anti-Tuberculosis Drug Resistance in the World, 4th Global

Report., 2008.

17. National TB Control Programme DGoHS, Bangladesh. Tuberculosis Control in

Bangladesh, Annual Report. Dhaka,, 2012.

18. Rifat M, Milton AH, Hall J, et al. Development of multidrug resistant tuberculosis in

Bangladesh: a case-control study on risk factors. PLoS One 2014;9(8):e105214.

19. National TB Control Programme DGoHS, Bangladesh. Operation manual for

management of Multidrug-resistant TB(MDR TB).2nd ed. Dhaka,, 2012.

20. National Tuberculosis Control Programme DGoHS, Dhaka ,Bangladesh Dhaka. First

Bangladesh National Tuberculosis Drug Resistance Survey 2010-2011. Dhaka, 2013.

21. National TB Control Programme DGoHS, Bangladesh. National Guidelines and

Operational Manual for Tuberculosis Control. Fourth ed. Dhaka, 2008.

22. Ejaz M, Siddiqui AR, Rafiq Y, et al. Prevalence of multi-drug resistant tuberculosis in

Karachi, Pakistan: identification of at risk groups. Trans R Soc Trop Med Hyg

2010;104(8):511-7.

23. Tanrikulu AC, Abakay A, Abakay O. Risk factors for multidrug-resistant tuberculosis in

Diyarbakir, Turkey. Med Sci Monit 2010;16(6):PH57-62.

24. Mendoza MT, Gonzaga AJ, Roa C, et al. Nature of drug resistance and predictors of

multidrug-resistant tuberculosis among patients seen at the Philippine General Hospital,

Manila, Philippines. Int J Tuberc Lung Dis 1997;1(1):59-63.

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25. Songhua C, Pengcheng H, Xiaomeng W, et al. Risk factors for multidrug resistance

among previously treated patients with tuberculosis in eastern China: a case–control

study. International Journal of Infectous Disease 2013.

26. Andrews JR, Shah NS, Weissman D, et al. Predictors of multidrug- and extensively drug-

resistant tuberculosis in a high HIV prevalence community. PLoS One

2010;5(12):e15735.

27. Ait-Khaled N, Fujiara PI, Armengol R, et al. Managment of Tuberculosis, A Guide to The

Essentials of Good Practice. Sixth ed: International Union Against Tuberculosis and

Lung Disease, 2010.

28. Gler MT, Macalintal LE, Raymond L, et al. Multidrug-resistant tuberculosis among

previously treated patients in the Philippines. Int J Tuberc Lung Dis 2011;15(5):652-56.

29. Chowdhury AM, Bhuiya A, Chowdhury ME, et al. The Bangladesh paradox: exceptional

health achievement despite economic poverty. Lancet 2013;382(9906):1734-45.

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STROBE Statement—checklist of items that should be included in reports of observational studies Item

No Recommendation

Title and abstract 1 √(a) Indicate the study’s design with a commonly used term in the title or the

abstract

√ (b) Provide in the abstract an informative and balanced summary of what was

done and what was found

Introduction

Background/rationale 2 √Explain the scientific background and rationale for the investigation being reported

Objectives 3 √State specific objectives, including any prespecified hypotheses

Methods

Study design 4 √Present key elements of study design early in the paper

Setting 5 √Describe the setting, locations, and relevant dates, including periods of

recruitment, exposure, follow-up, and data collection

Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of

selection of participants. Describe methods of follow-up

√Case-control study—Give the eligibility criteria, and the sources and methods of

case ascertainment and control selection. Give the rationale for the choice of cases

and controls

√Cross-sectional study—Give the eligibility criteria, and the sources and methods

of selection of participants

(b) Cohort study—For matched studies, give matching criteria and number of

exposed and unexposed

√Case-control study—For matched studies, give matching criteria and the number

of controls per case

Variables 7 √Clearly define all outcomes, exposures, predictors, potential confounders, and

effect modifiers. Give diagnostic criteria, if applicable

Data sources/

measurement

8* √For each variable of interest, give sources of data and details of methods of

assessment (measurement). Describe comparability of assessment methods if there

is more than one group

Bias 9 √Describe any efforts to address potential sources of bias

Study size 10 √Explain how the study size was arrived at

Quantitative variables 11 √Explain how quantitative variables were handled in the analyses. If applicable,

describe which groupings were chosen and why

Statistical methods 12 √ (a) Describe all statistical methods, including those used to control for

confounding

√ (b) Describe any methods used to examine subgroups and interactions

√ (c) Explain how missing data were addressed

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

√Case-control study—If applicable, explain how matching of cases and controls

was addressed

Cross-sectional study—If applicable, describe analytical methods taking account of

sampling strategy

(e) Describe any sensitivity analyses

Continued on next page

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Results

Participants 13* √ (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible,

examined for eligibility, confirmed eligible, included in the study, completing follow-up, and

analysed

√ (b) Give reasons for non-participation at each stage

(c) Consider use of a flow diagram

Descriptive

data

14* √ (a) Give characteristics of study participants (eg demographic, clinical, social) and

information on exposures and potential confounders

√ (b) Indicate number of participants with missing data for each variable of interest

(c) Cohort study—Summarise follow-up time (eg, average and total amount)

Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time

√Case-control study—Report numbers in each exposure category, or summary measures of

exposure

Cross-sectional study—Report numbers of outcome events or summary measures

Main results 16 √ (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their

precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and

why they were included

√ (b) Report category boundaries when continuous variables were categorized

√ (c) If relevant, consider translating estimates of relative risk into absolute risk for a

meaningful time period

Other analyses 17 √Report other analyses done—eg analyses of subgroups and interactions, and sensitivity

analyses

Discussion

Key results 18 √Summarise key results with reference to study objectives

Limitations 19 √Discuss limitations of the study, taking into account sources of potential bias or imprecision.

Discuss both direction and magnitude of any potential bias

Interpretation 20 √Give a cautious overall interpretation of results considering objectives, limitations,

multiplicity of analyses, results from similar studies, and other relevant evidence

Generalisability 21 √Discuss the generalisability (external validity) of the study results

Other information

Funding 22 √Give the source of funding and the role of the funders for the present study and, if applicable,

for the original study on which the present article is based

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and

unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and

published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely

available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is

available at www.strobe-statement.org.

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Journal: BMJ Open

Manuscript ID: bmjopen-2015-008273.R1


Date Submitted by the Author: 16-Jun-2015




Infectious diseases




BMJ Open on A


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1, Ashaque Husain

3,


Milton

1





Bangladesh


Bergen, Norway


Dr. Mahfuza Rifat

HMRI Building




Phone: +612 404 20631

Fax Number: +61 2 40420044


Abstract: 300 words




Keywords: Previous tuberculosis, Multidrug resistant tuberculosis, MDR-TB, Health

system, Retreatment tuberculosis, Risk factors

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2

Email addresses:

MR: [email protected]

JH: [email protected]

CO: [email protected]

AH: [email protected]

SGH: [email protected]

AHM: [email protected]

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ABSTRACT 1



treatment may lead to the development of multidrug resistant in Bangladesh. 4

Design: We previously conducted a large case-control study to identify the risk factors for 5




treatment episode. This study restricts analysis to the strata of patients that have been 9

previously treated for tuberculosis. Information was collected through face-to-face interviews 10

and record reviews. Unadjusted and multivariable logistic regression was used for data 11

analysis. 12


Results: The strata of previously treated patients include a total of 293 patients (245 current 14

MDR-TB; 48 non-MDR-TB patients). Overall, 54% of patients received previous 15



treatment (4.3; 95% CI 1.7-10.6), adverse reactions due to TB treatment (OR 8.2; 95% CI 18

3.2-20.7), hospitalization for symptoms associated with tuberculosis (OR 16.9; CI 1.8-156.2), 19

DOTS centre as treatment unit (OR 6.4; CI 1.8-22.8), supervised treatment (OR 3.8; CI 1.6-20

9.5); time to treatment centre (OR 0.984; CI 0.974-0.993). 21



Although the presence of supervised treatment (DOT), less time to treatment centres and 24

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4

being treated in DOTS centres were relatively higher among the MDR-TB patients compared 25

to non-MDR-TB patients, these findings include information of their most recent TB 26



ARTICLE SUMMARY 29










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5

INTRODUCTION 39


Resistant tuberculosis (MDR-TB).1 MDR-TB is caused by bacteria that are resistant to at 41

least isoniazid and rifampicin, the most effective anti-TB drugs for treating TB. 2 MDR-TB 42

cannot be treated with first line anti-tuberculosis medicines and needs a longer treatment 43

period with stronger second-line medicines.3 A total of 0.14 million cases of drug resistant 44

TB were reported worldwide in 2013; however the estimate for MDR-TB incidence is at least 45

five times higher than the reported cases.4 The number of reported MDR-TB cases has been 46

increasing in recent years.4 Globally, 20.5 % (13.6-27.5%) of previously treated cases and 47

3.5% (2.2-4.7%) of new cases are estimated to have MDR-TB.4 Previous tuberculosis 48

treatment is a known risk factor for MDR-TB.5-11

Patients with previous TB treatment are 49

difficult to manage and might be infectious for a longer period. ‘Previous treatment’ may 50

mean a relapse after a successful treatment, a return after treatment discontinuation, a 51

treatment failure, or any other types (other types include patients with an unknown previous 52

history; with unknown outcome of that previous treatment ; and/or who have returned to 53

treatment with smear-negative pulmonary TB or bacteriologically negative extra-pulmonary 54

TB).12

Previously treated recurrent TB is no longer a neglected area; rather it is considered to 55

be an important factor to be considered for TB control.13,14

Programmatic factors such as 56

poor management of the patient, lack of directly observed treatment, limited or interrupted 57

drug supplies, poor drug quality, widespread availability of anti-tuberculosis drugs without 58

prescription, lack of uniformity between the public and private health sectors regarding the 59

treatment regimens, and poorly managed and supported National TB Control Programmes 60

(NTP) were cited to be the factors related to development of drug resistance.15,16

61



63


According to the recent 64

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drug resistant survey, 1.4% of new cases and 29% of the retreatment cases in Bangladesh 65

have MDR-TB.19

Although the rate of MDR-TB is still relatively low, due to the overall high 66

TB burden in Bangladesh the absolute number of MDR-TB cases was quite large, with 2100 67

among new TB patients and 2600 among the previously treated TB patients, in 2013.4 Recent 68

studies in Bangladesh suggest that previous tuberculosis treatment is an important risk factor 69

for MDR-TB.19,20

Re-treatment patients constitute approximately 3% of all tuberculosis 70

patients in the national data collection which corresponded to 3906 patients in 2011.18 71

However, the detailed information regarding the previous tuberculosis treatment has not yet 72

been collected. Factors related to previous management of tuberculosis need to be identified 73

to develop control strategies. The main objective of this study is to explore the factors related 74

to the previous tuberculosis treatment of current MDR-TB patients compared to the non-75

MDR-TB patients of Bangladesh. 76

METHODS 77
















their informed consent were included in the study. Patients, who received treatment for 90

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MDR-TB following the criteria of the NTP guidelines, were classified as MDR-TB. The NTP 91

has adopted automated real time PCR (Xpert MTB/RIF) as the diagnostic tool of MDR-TB 92

patients. Culture and Drug Sensitivity Testing (DST) and Line probe assays were also used.22

93

Xpert MTB/RIF diagnoses only Rifampicin resistance. Patients who are resistant to 94

Rifampicin are generally also resistant to Isoniazid (another first-line drug). Mono-resistance 95

to Rifampicin is fairly uncommon (0.2% and 0.4% among new and previously treated 96

patients, respectively), as shown by a recent drug resistance survey (DRS) conducted in 97

Bangladesh.19

Drug susceptible TB patients aged 18 to 65 years, who gave their informed 98

consent, were diagnosed through sputum smear microscopy or other investigations (X-ray, 99

FNAC or Biopsy) as per NTP guidelines and expected to respond to the standard combination 100

of drugs. In this paper we will refer to those as non-MDR-TB patients. We excluded patients 101

who were not within the eligible age group or had any serious illness requiring admission to 102

the Intensive Care Unit (ICU), recent surgery, or any medical emergency that needed 103

continuous observation. 104










Data collection 113


control study on risk factors of MDR-TB21

. MDR-TB patients from all over Bangladesh are 115

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referred to one of the three government hospitals, the national hospital in Dhaka or a regional 116

hospital in either Chittagong or Rajshahi. All eligible MDR-TB patients who were admitted 117

from September 2012 to mid- April 2013 were recruited from these hospitals under the 118

previously conducted study. The hospitals that were providing MDR-TB treatment were 119









in this study. Site of previous treatment, treatment regimen and treatment outcome related 128

information was collected from patient record review. 129












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hospitalization due to tuberculosis, type of centre for treatment initiation and follow up, 142

presence of supervised treatment (DOT), time to treatment centre, incomplete treatment. We 143





centre. Cost to treatment centre and distance to treatment centre were excluded from the 148

model for possible colinearity with the variable “time to treatment centre”. 149












All participants consented by signing the consent form, or if unable to do so, by adding their 161



RESULTS 164

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We included the previously treated TB patients from the case control study of 250 MDR-TB 165

and 750 non-MDR-TB patients 21

. History of previous tuberculosis treatment was present in 166

293 of those patients, and this patient group forms part of the study described here. Patients 167

included are 245 MDR-TB and 48 non-MDR-TB patients. Among the previously treated 168

MDR-TB patients, 64.5% had been treated more than once and all non-MDR-TB patients had 169

only one episode of treatment previously. 170

Mean age of previously treated MDR-TB patients was lower than non-MDR-TB patients. 171

The majority of the patients were male and had pulmonary tuberculosis. Among the MDR-172

TB patients, 63.7% received a retreatment regimen commonly known as category-2, 173

consisting of five drugs including injectable Streptomycin. All non-MDR-TB patients were 174

treated with the regimen for new tuberculosis patients that consists of a combination of four 175

oral drugs. The most frequent category for duration of previous treatment was five months 176

(59.6%). The majority (64.6%) of drug-sensitive TB patients discontinued their treatment at 177

three months or less. Treatment failure was higher among the MDR-TB patients compared to 178

non-MDR-TB patients (68.4% and 28.6%, respectively) during their previous treatment. Of 179

the MDR-TB patients, 32.6% reported having an extended treatment period since their 180

sputum remained positive after the intended period of treatment. This treatment extension 181

was only reported by 5.4% of the non-MDR-TB patients. Hospitalization for TB related 182

problems during their previous TB treatment mostly occurred for MDR-TB patients (13.5%). 183

The three main causes of hospitalization during previous TB treatment were massive 184

haemoptysis (33.3%), severe weakness (33.3%) and pleural effusion (15.2%) (These results 185

are not shown in table). 186

Detailed demographic and clinical characteristics are presented in Table 1. For some patients, 187

it was not possible to get information regarding the previous treatment outcome (19%), 188

treatment extension (9%) and previous treatment regimen (11%). 189

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Patients




Variable Non-MDR-TB

(n=48)

MDR-TB

(n=245) Total P

Age 0.0001**

Mean 41 33.8 35

Median 40 30 30

SD 15.8 12.3 13.2

Sex 0.027*

Male 28 (58.3%) 163 (66.5%) 191 (65.2%)

Female 20 (41.7%) 82 (33.5%) 102 (34.8%)


Extrapulmonary 7 (14.6%) 5 (2.0%) 12 (4.1%)

Pulmonary 41 (85.4%) 240 (98.0%) 281 (95.9%)


Category 1 16 (100%) 86 (35.1%) 102 (39.0%)

Category 2 0 (0%) 156 (63.7%) 156 (59.8%)

MDR-NTP 0 (0%) 2 (0.8%) 2 (0.8%)



6-8 months 3 (6.3%) 15(6.1%) 18 (6.1%)

4- 5 months 14 (29.1%) 146 (59.6%) 160 (54.6%)

3 months or less 31 (64.6%) 84 (34.3%) 115 (39.3%)


Cured 6 (42.8%) 20 (9.2%) 26 (11.2%)

Completed 4 (28.6%) 43 (19.7%) 47 (20.3%)

Default 0 (0%) 6 (2.8%) 6 (2.6%)

Failure 4 (28.6%) 149 (68.3%) 153 (65.9%)


Absent 34 (70.8%) 57 (23.3%) 91 (31.1%)

Present 14 (29.2%) 188 (76.7%) 202 (68.9%)


Absent 35 (94.6%) 155 (67.4%) 190 (71.2%)

Present 2 (5.4%) 75 (32.6%) 77 (28.8%)


TB 0.069*

Absent 46 (95.8%) 212 (86.5%) 258 (88.1%)

Present 2 (4.2%) 33 (13.5%) 35 (11.9%)

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non-MDR-TB patients, respectively. Reasons for incomplete treatment among the MDR-TB 193

and non-MDR-TB patients are presented in Table 2. 194



Variable

Non-MDR-TB

(n=48)

n (%)

MDR-TB

(n=245)

n (%)

P





Felt better 7 (50.0) 7 (4.5)

Remained positive in microscopy

test 1 (7.1) 143 (92.3)





Others 0 (0) 2 (1.3)


195

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health care providers, according to the national TB guideline. 23




Supervised intake of medicine by Directly Observed Treatment (DOT) during their previous 200

treatment was reported by 78.4% of MDR-TB patients and 41.7% of non MDR-TB patients, 201

respectively. We further explored who had supervised the medicine intake and found that 202

70.3% of MDR-TB and 80% of non-MDR-TB patients were given their medicine by trained 203

providers (community health volunteers, health worker at facility or field level, village 204

doctors). The rest of the patients were given their medicine by a family member, neighbours 205

or other providers. 206


designated centres for TB (DOTS centre) (95.9%); for non-MDR-TB patients the proportion 208

was 70.8%. Rate of treatment in private centres was 4.1% and 29.2% for MDR-TB and non 209

MDR-TB patients, respectively. 210

Median travel time to visit the previous treatment centre, which was the designated unit for 211




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Patients

Variable Non-MDR-TB

n=48

MDR-TB

n=245 Total p








Private centre 14 (29.2%) 10 (4.1%) 24 (8.2%)

Designated DOTS Centre 34 (70.8%) 235 (95.9%) 269 (91.8%)



No follow up 12 (85.7%) 13 (8.4%) 25 (14.8%)

Follow up done 2 (14.3%) 142 (91.6%) 144 (85.2%)

Time to treatment centre (minute) 0.0005**

Mean 49.8 29.7 32.9

Median 40 20 30

SD 34.7 35.5 36.1

Range 5-150 1 -420 1-420

Cost to treatment centre (BDT) 0.46**

Mean 27.3 22.9 23.6

Median 20 15 20

SD 22 38.3 36.1

Range 0-100 0-500 0-500

Distance to treatment centre

(miles) 0.91**

Mean 4.6 4.3 4.3

Median 3 2 2

SD 4 16.1 14.9

Range 0.2-15 0-175 0-175




at facility and field level and village doctors b “Family and other providers” includes family members, neighbours and other volunteers supervising the treatment


Time to treatment centre, cost to treatment centre and distance to treatment centre had total 286, 283 and 285 observations, respectively.

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In the multivariable adjusted analysis, MDR-TB patients were shown to be more likely to be 216

male (OR 5.1; CI 1.8-14), have a history of incomplete tuberculosis treatment (4.3; 95% CI 217

1.7-10.6), adverse reactions due to anti-tuberculosis medicines (OR 8.2; 95% CI 3.2-20.7), 218

hospitalization due to tuberculosis (OR 16.9; CI 1.8-156.2), have been treated in a designated 219

DOTS centre (OR 6.4; CI 1.8-22.8) and time to treatment centre (OR 0.984; CI 0.974-0.993). 220





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Univariate analysis

Multivariable analysis

Variable Odds

Ratio

Confidence

Interval a P

Odds

Ratio

Confidence

Interval a P

Age

18-25 years 1

1

26 to 45 0.99 0.44-2.23 0.983 1.3 0.45-3.9 0.613

>45 0.31 0.14-0.71 0.006 0.33 0.10-1.12 0.075

Sex

Female 1

1

Male 1.4 2.5-6.7 0.277 5.1 1.8-14 0.002

Site of Previous TB

Extrapulmonary 1

1

Pulmonary 8.2 2.5-27.1 0.001 2.6 0.52-13.1 0.244

Adverse effect

Absent 1

1

Present 8 4.0-16.0 <0.0001 8.2 3.2-20.7 <0.0001


Absent 1

1

Present 3.6 0.8-15.5 0.087 16.9 1.8-156.2 0.013

Supervised treatment (DOT)

Absent 1

1

Present 5.1 2.6-9.7 <0.0001 3.8 1.6-9.5 0.004


Private 1

1

DOTS Centre 9.7 4.0-23.5 <0.0001 6.4 1.8-22.8 0.004



1

Incomplete treatment 4.2 2.1-8.2 <0.0001 4.3 1.7-10.6 0.002

Time to Treatment centre

(minutes) 0.988 0.979-0.997 0.007 0.984 0.974-0.993 0.001



DISCUSSION 225








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TB.22


felt better after starting the treatment. The second major cause for treatment discontinuation 237

reported by non-MDR-TB patients was change of their address. Although the NTP has a 238

system in place to provide service to the patients transferred from one place to another, these 239

figures show that patient education regarding discontinuation of treatment needs to be further 240

strengthened through advocacy communication and social mobilization activities.23

Although 241

the MDR-TB patients reported that non-responsive previous treatment was the main cause of 242

their incomplete treatment, these findings are based on their most recent episode of previous 243

treatment and most of the MDR-TB patients had more than one episode of earlier TB 244

treatment. The TB control programmes should address the reasons for incomplete treatment 245

for all types of tuberculosis patients. Incomplete treatment may lead to development of drug 246

resistance at any point of time irrespective of number of treatment episodes. 247












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treatment.21












273











However, this finding is 283

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In Bangladesh, designated DOTS centres are the centres 301


offers free services and medicine for TB treatment. These DOTS centres are the point of 303

treatment initiation and follow up. Private centres are for-profit private practitioners, clinics 304


commonly linked with TB control programme. Medicines for TB are also available in the 306

private market in Bangladesh and the unregulated private sector is likely to treat tuberculosis 307

patients using non-standardized regimen which may lead to development of drug resistance.30

308

In our study, MDR-TB patients had been enrolled mostly with the designated DOTS centres 309

during their most recent episode of previous TB, rather than private centres. The possible 310

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explanation could be that retreatment patients are complicated cases that private practitioners 311

prefer not to treat. This study is a hospital based study and we assumed that most of the 312

MDR-TB patients are treated under these three Government hospitals. We do not have any 313

information on MDR-TB patients treated by private physicians who are beyond national TB 314

control programme. However, we were not able to collect information on other episodes to 315

evaluate if patients had been treated in the private sectors previously. Another study reported 316

similar rate of MDR-TB among patients treated by DOTS centre and by private providers and 317

thorough review of medication given during previous treatment, regardless of its setting, was 318

recommended.31

319







partnerships.18

Accessing services from DOTS centres might reflect the expansion of DOTS 325





Bangladesh, so patients do not have to travel to health centres for every administration of 329

medicine; it can be given by community level providers and the patient only visits the centre 330

for diagnosis, follow up and complications. Time to treatment centre was relatively lower (20 331



distance to treatment centres. Although access to treatment could be a factor for developing 334




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This study is a stratified analysis of previously treated tuberculosis patients taken from a case 341

control study which recruited the MDR-TB and non-MDR-TB patients representing the 342

population. We do not have information of all previous treatment episodes for the patients as 343

we had extracted the information based on the most recent episode, to aid the accuracy of the 344

recalled information. It was not feasible to confirm drug susceptibility using Drug Sensitivity 345

Testing (DST) of the non-MDR-TB patients, as only high-risk patients are routinely tested, 346

and we did not have the funds for this. 347

CONCLUSION 348





treatment, less time required to visit treatment centre and the designated DOTS centre, it does 353


DOTS centre contribute to MDR-TB. These findings are based on the most recent episode of 355







ACKNOWLEDGEMENT 362

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CONTRIBUTERSHIP STATEMENT 371

MR, AHM and JH contributed in designing and planning the study. MR collected, analysed 372

the data and prepared the manuscript. CO provided input in data analysis and writing. AH, 373

SGH and all authors reviewed the document and provided their inputs. 374


The study was based in Bangladesh and partially supported by the Australian Respiratory 376

Council, BRAC Bangladesh and University of Newcastle Australia. The funders had no role 377

in study design, data collection and analysis or decision to publish or preparation of 378

manuscript. 379



DATA SHARING STATEMENT 382

The electronic version of the dataset is kept with University of Newcastle Australia, 383

following the original research protocol, which has also been approved by Human Research 384

Ethics Committee (HREC) of the University of Newcastle. It will be provided upon request 385

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to anyone who is interested in the research topic. Interested readers may contact the 386

corresponding author.387

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References



2. Caminero JA, ed. Guidelines for Clinical and Operational Management of Drug-

Resistant Tuberculosis. Paris, France: International Union Against Tuberculosis and Lung

Disease, 2013.



report. Geneva, Switzerland: WHO, 2011.












Tuberc Lung Dis 2009;13(1):68-73.






12. World Health Organization. Treatment of tuberculosis Guidelines.

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Fourth ed. Geneva, 2009.






& Lung Disease 1995;76(5):455-9.




Report. 2008.


Bangladesh, Annual Report. Dhaka, 2012.

19. Kamal SM, Hossain A, Sultana S, et al. Anti-tuberculosis drug resistance in Bangladesh:

reflections from the first nationwide survey. Int J Tuberc Lung Dis 2015;19(2):151-6.

20. Flora MS, Amin MN, Karim MR, et al. Risk factors of multi-drug-resistant tuberculosis

in Bangladeshi population: a case control study. Bangladesh Medical Research Council

Bulletin 2013;39(1):34-41.









2010;104(8):511-7.

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study. International Journal of Infectous Disease 2013;17(12):e1116–e1120.



2010;5(12):e15735.



Lung Disease, 2010.

30. Hossain S, Zaman K, Quaiyum A, et al. Care seeking in tuberculosis: results from a

countrywide cluster randomised survey in Bangladesh. BMJ Open 2014;4(5):e004766.





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No Recommendation


abstract



Introduction



Methods








and controls









Data sources/

measurement









confounding





was addressed


sampling strategy



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Results



analysed



Descriptive

data







exposure









analyses

Discussion







Other information










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Journal: BMJ Open

Manuscript ID: bmjopen-2015-008273.R2


Date Submitted by the Author: 23-Jul-2015




Infectious diseases




BMJ Open on A


http://bmjopen.bm

j.com/

BM



ber 2015. Dow

nloaded from



1






1, Ashaque Husain

3,


Milton

1





Bangladesh


Bergen, Norway


Dr. Mahfuza Rifat

HMRI Building




Phone: +612 404 20631

Fax Number: +61 2 40420044


Abstract: 300 words




Keywords: Previous tuberculosis, Multidrug resistant tuberculosis, MDR-TB, Health

system, Retreatment tuberculosis, Risk factors

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Email addresses:

MR: [email protected]

JH: [email protected]

CO: [email protected]

AH: [email protected]

SGH: [email protected]

AHM: [email protected]

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ABSTRACT 1



treatment may lead to the development of multidrug resistant in Bangladesh. 4

Design: We previously conducted a large case-control study to identify the risk factors for 5




treatment episode. This study restricts analysis to the strata of patients that have been 9

previously treated for tuberculosis. Information was collected through face-to-face interviews 10

and record reviews. Unadjusted and multivariable logistic regression was used for data 11

analysis. 12


Results: The strata of previously treated patients include a total of 293 patients (245 current 14

MDR-TB; 48 non-MDR-TB patients). Overall, 54% of patients received previous 15



treatment (4.3; 95% CI 1.7-10.6), adverse reactions due to TB treatment (OR 8.2; 95% CI 18

3.2-20.7), hospitalization for symptoms associated with tuberculosis (OR 16.9; CI 1.8-156.2), 19

DOTS centre as treatment unit (OR 6.4; CI 1.8-22.8), supervised treatment (OR 3.8; CI 1.6-20

9.5); time to treatment centre (OR 0.984; CI 0.974-0.993). 21



Although the presence of supervised treatment (DOT), less time to treatment centres and 24

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being treated in DOTS centres were relatively higher among the MDR-TB patients compared 25

to non-MDR-TB patients, these findings include information of their most recent TB 26



ARTICLE SUMMARY 29










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5

INTRODUCTION 39


Resistant tuberculosis (MDR-TB).1 MDR-TB is caused by bacteria that are resistant to at 41

least isoniazid and rifampicin, the most effective anti-TB drugs for treating TB.2 MDR-TB 42

cannot be treated with first line anti-tuberculosis medicines and needs a longer treatment 43

period with stronger second-line medicines.3 A total of 0.14 million cases of drug resistant 44

TB were reported worldwide in 2013; however the estimate for MDR-TB incidence is at least 45

five times higher than the reported cases.4 The number of reported MDR-TB cases has been 46

increasing in recent years.4 Globally, 20.5 % (13.6-27.5%) of previously treated cases and 47

3.5% (2.2-4.7%) of new cases are estimated to have MDR-TB.4 Previous tuberculosis 48

treatment is a known risk factor for MDR-TB.5-11

Patients with previous TB treatment are 49

difficult to manage and might be infectious for a longer period. ‘Previous treatment’ may 50

mean a relapse after a successful treatment, a return after treatment discontinuation, a 51

treatment failure, or any other types (other types include patients with an unknown previous 52

history; with unknown outcome of that previous treatment; and/or who have returned to 53

treatment with smear-negative pulmonary TB or bacteriologically negative extra-pulmonary 54

TB).12

Previously treated recurrent TB is no longer a neglected area; rather it is considered to 55

be an important factor to be considered for TB control.13,14

Programmatic factors such as 56

poor management of the patient, lack of directly observed treatment, limited or interrupted 57

drug supplies, poor drug quality, widespread availability of anti-tuberculosis drugs without 58

prescription, lack of uniformity between the public and private health sectors regarding the 59

treatment regimens, and poorly managed and supported National TB Control Programmes 60

(NTP) were cited to be the factors related to development of drug resistance.15,16

61



63


According to the recent 64

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drug resistant survey, 1.4% of new cases and 29% of the retreatment cases in Bangladesh 65

have MDR-TB.19

Although the rate of MDR-TB is still relatively low, due to the overall high 66

TB burden in Bangladesh the absolute number of MDR-TB cases was quite large, with 2100 67

among new TB patients and 2600 among the previously treated TB patients, in 2013.4 Recent 68

studies in Bangladesh suggest that previous tuberculosis treatment is an important risk factor 69

for MDR-TB.19,20

Re-treatment patients constitute approximately 3% of all tuberculosis 70

patients in the national data collection which corresponded to 6385 patients in 2013.4 71

However, the detailed information regarding the previous tuberculosis treatment has not yet 72

been collected. Factors related to previous management of tuberculosis need to be identified 73

to develop control strategies. The main objective of this study is to explore the factors related 74

to the previous tuberculosis treatment of current MDR-TB patients compared to the non-75

MDR-TB patients of Bangladesh. 76

METHODS 77
















their informed consent were included in the study. Previous history of TB treatment and 90

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number of episodes of previous TB treatment were based on patient’s statement. Patients, 91

who received treatment for MDR-TB following the criteria of the NTP guidelines, were 92

classified as MDR-TB. The NTP has adopted automated real time PCR (Xpert MTB/RIF) as 93

the diagnostic tool of MDR-TB patients. Culture and Drug Sensitivity Testing (DST) and 94

Line probe assays were also used.22

Xpert MTB/RIF diagnoses only Rifampicin resistance. 95

Patients who are resistant to Rifampicin are generally also resistant to Isoniazid (another first-96

line drug). Mono-resistance to Rifampicin is fairly uncommon (0.2% and 0.4% among new 97

and previously treated patients, respectively), as shown by a recent drug resistance survey 98

(DRS) conducted in Bangladesh.19

Drug susceptible TB patients aged 18 to 65 years, who 99

gave their informed consent, were diagnosed through sputum smear microscopy or other 100

investigations (X-ray, FNAC or Biopsy) as per NTP guidelines and expected to respond to 101

the standard combination of drugs. In this paper we will refer to those as non-MDR-TB 102

patients. We excluded patients who were not within the eligible age group or had any serious 103

illness requiring admission to the Intensive Care Unit (ICU), recent surgery, or any medical 104

emergency that needed continuous observation. 105










Data collection 114

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control study on risk factors of MDR-TB21

. MDR-TB patients from all over Bangladesh are 116

referred to one of the three government hospitals, the national hospital in Dhaka or a regional 117

hospital in either Chittagong or Rajshahi. All eligible MDR-TB patients who were admitted 118

from September 2012 to mid- April 2013 were recruited from these hospitals under the 119

previously conducted study. The hospitals that were providing MDR-TB treatment were 120









in this study. Site of previous treatment, treatment regimen and treatment outcome related 129

information was collected from patient record review. 130










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hospitalization due to tuberculosis, type of centre for treatment initiation and follow up, 143

presence of supervised treatment (DOT), time to treatment centre, incomplete treatment. We 144





centre. Cost to treatment centre and distance to treatment centre were excluded from the 149

model for possible colinearity with the variable “time to treatment centre”. 150












All participants consented by signing the consent form, or if unable to do so, by adding their 162



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RESULTS 165

Among the previously treated MDR-TB patients, 64.5% had been treated more than once and 166

all non-MDR-TB patients had only one episode of treatment previously. Mean age of 167

previously treated MDR-TB patients was lower than non-MDR-TB patients. The majority of 168

the patients were male and had pulmonary tuberculosis. Detailed demographic and clinical 169

characteristics are presented in Table 1. 170

For some patients, it was not possible to get information regarding the previous treatment 171

outcome (19%), treatment extension (9%) and previous treatment regimen (11%), from the 172

records. Among the MDR-TB patients, 63.7% received a retreatment regimen commonly 173

known as category-2, consisting of five drugs including injectable Streptomycin. Based on 174

the available records, all non-MDR-TB patients were treated with the regimen for new 175

tuberculosis patients that consist of a combination of four oral drugs. The most frequent 176

category for duration of previous treatment was five months (59.6%). The majority (64.6%) 177

of drug-sensitive TB patients discontinued their treatment at three months or less. Treatment 178

failure was higher among the MDR-TB patients compared to non-MDR-TB patients (68.4% 179

and 28.6%, respectively) during their previous treatment. Of the MDR-TB patients, 32.6% 180

reported having an extended treatment period since their sputum remained positive after the 181

intended period of treatment. This treatment extension was only reported by 5.4% of the non-182

MDR-TB patients. Hospitalization for TB related problems during their previous TB 183

treatment mostly occurred for MDR-TB patients (13.5%). The three main causes of 184

hospitalization during previous TB treatment were massive haemoptysis (33.3%), severe 185

weakness (33.3%) and pleural effusion (15.2%) (These results are not shown in table). 186

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Patients




Variable Non-MDR-TB

(n=48)

MDR-TB

(n=245) Total P

Age 0.0001**

Mean 41 33.8 35

SD 15.8 12.3 13.2

Age group (years) 0.002*

18-25 11 (22.9 %) 79 (32.2%) 90 (30.7 %)

26 to 45 years 17 (35.4 %) 121 (49.4 %) 138 (47.1%)

>45 20 (41.7 %) 45 (18.4%) 65 (22.2 %)

Sex 0.027*

Male 28 (58.3%) 163 (66.5%) 191 (65.2%)

Female 20 (41.7%) 82 (33.5%) 102 (34.8%)


Extrapulmonary 7 (14.6%) 5 (2.0%) 12 (4.1%)

Pulmonary 41 (85.4%) 240 (98.0%) 281 (95.9%)


Category 1 16 (100%) 86 (35.1%) 102 (39.0%)

Category 2 0 (0%) 156 (63.7%) 156 (59.8%)

MDR-NTP 0 (0%) 2 (0.8%) 2 (0.8%)



6-8 months 3 (6.3%) 15(6.1%) 18 (6.1%)

4- 5 months 14 (29.1%) 146 (59.6%) 160 (54.6%)

3 months or less 31 (64.6%) 84 (34.3%) 115 (39.3%)


Cured 6 (42.8%) 20 (9.2%) 26 (11.2%)

Completed 4 (28.6%) 43 (19.7%) 47 (20.3%)

Default 0 (0%) 6 (2.8%) 6 (2.6%)

Failure 4 (28.6%) 149 (68.3%) 153 (65.9%)


Absent 34 (70.8%) 57 (23.3%) 91 (31.1%)

Present 14 (29.2%) 188 (76.7%) 202 (68.9%)


Absent 35 (94.6%) 155 (67.4%) 190 (71.2%)

Present 2 (5.4%) 75 (32.6%) 77 (28.8%)


TB 0.069*

Absent 46 (95.8%) 212 (86.5%) 258 (88.1%)

Present 2 (4.2%) 33 (13.5%) 35 (11.9%)

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non-MDR-TB patients, respectively, as stated by the patients. Reasons for incomplete 190

treatment among the MDR-TB and non-MDR-TB patients are presented in Table 2 191



Variable

Non-MDR-TB

(n=48)

n (%)

MDR-TB

(n=245)

n (%)

P





Felt better 7 (50.0) 7 (4.5)

Remained positive in microscopy

test 1 (7.1) 143 (92.3)





Others 0 (0) 2 (1.3)


192

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health care providers, according to the national TB guideline.23





designated centres for TB (DOTS centre) (95.9%); for non-MDR-TB patients the proportion 198

was 70.8%. Rate of treatment in private centres was 4.1% and 29.2% for MDR-TB and non 199

MDR-TB patients, respectively. Although majority of MDR-TB patients were treated in 200

DOTS centre, supervised intake of medicine by Directly Observed Treatment (DOT) during 201

their previous treatment was reported by 78.4% of MDR-TB patients and 41.7% of non 202

MDR-TB patients, respectively, as reported by the patients. 203

We further explored who had supervised the medicine intake and found that 70.3% of MDR-204

TB and 80% of non-MDR-TB patients were given their medicine by trained providers 205

(community health volunteers, health worker at facility or field level, village doctors). The 206

rest of the patients were given their medicine by a family member, neighbours or other 207

providers. 208

Median travel time to visit the previous treatment centre, which was the designated unit for 209




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Patients

Variable Non-MDR-TB

n=48

MDR-TB

n=245 Total p








Private centre 14 (29.2%) 10 (4.1%) 24 (8.2%)

Designated DOTS Centre 34 (70.8%) 235 (95.9%) 269 (91.8%)



No follow up 12 (85.7%) 13 (8.4%) 25 (14.8%)

Follow up done 2 (14.3%) 142 (91.6%) 144 (85.2%)

Time to treatment centre (minute) 0.0005**

Mean 49.8 29.7 32.9

Median 40 20 30

SD 34.7 35.5 36.1

Range 5-150 1 -420 1-420

Cost to treatment centre (BDT) 0.46**

Mean 27.3 22.9 23.6

Median 20 15 20

SD 22 38.3 36.1

Range 0-100 0-500 0-500

Distance to treatment centre

(miles) 0.91**

Mean 4.6 4.3 4.3

Median 3 2 2

SD 4 16.1 14.9

Range 0.2-15 0-175 0-175




at facility and field level and village doctors b “Family and other providers” includes family members, neighbours and other volunteers supervising the treatment


Time to treatment centre, cost to treatment centre and distance to treatment centre had total 286, 283 and 285 observations, respectively.

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In the multivariable adjusted analysis, MDR-TB patients were shown to be more likely to be 214

male (OR 5.1; CI 1.8-14), have a history of incomplete tuberculosis treatment (4.3; 95% CI 215

1.7-10.6), adverse reactions due to anti-tuberculosis medicines (OR 8.2; 95% CI 3.2-20.7), 216

hospitalization due to tuberculosis (OR 16.9; CI 1.8-156.2), have been treated in a designated 217

DOTS centre (OR 6.4; CI 1.8-22.8) and time to treatment centre (OR 0.984; CI 0.974-0.993). 218





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Univariate analysis

Multivariable analysis

Variable Odds

Ratio

Confidence

Interval a P

Odds

Ratio

Confidence

Interval a P

Age

18-25 years 1

1

26 to 45 0.99 0.44-2.23 0.983 1.3 0.45-3.9 0.613

>45 0.31 0.14-0.71 0.006 0.33 0.10-1.12 0.075

Sex

Female 1

1

Male 1.4 2.5-6.7 0.277 5.1 1.8-14 0.002

Site of Previous TB

Extrapulmonary 1

1

Pulmonary 8.2 2.5-27.1 0.001 2.6 0.52-13.1 0.244

Adverse effect

Absent 1

1

Present 8 4.0-16.0 <0.0001 8.2 3.2-20.7 <0.0001


Absent 1

1

Present 3.6 0.8-15.5 0.087 16.9 1.8-156.2 0.013

Supervised treatment (DOT)

Absent 1

1

Present 5.1 2.6-9.7 <0.0001 3.8 1.6-9.5 0.004


Private 1

1

DOTS Centre 9.7 4.0-23.5 <0.0001 6.4 1.8-22.8 0.004



1

Incomplete treatment 4.2 2.1-8.2 <0.0001 4.3 1.7-10.6 0.002

Time to Treatment centre

(minutes) 0.988 0.979-0.997 0.007 0.984 0.974-0.993 0.001



DISCUSSION 223








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TB.22


felt better after starting the treatment. The next cause after “feeling better” for treatment 235

discontinuation reported by non-MDR-TB patients was change of their address. Although the 236

NTP has a system in place to provide service to the patients transferred from one place to 237

another, these figures show that patient education regarding discontinuation of treatment 238

needs to be further strengthened through advocacy communication and social mobilization 239

activities.23

Although the MDR-TB patients reported that non-responsive previous treatment 240

was the main cause of their incomplete treatment, these findings are based on their most 241

recent episode of previous treatment and most of the MDR-TB patients had more than one 242

episode of earlier TB treatment. The TB control programmes should address the reasons for 243

incomplete treatment for all types of tuberculosis patients. Incomplete treatment may lead to 244

development of drug resistance at any point of time irrespective of number of treatment 245

episodes. 246











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treatment.21












272










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However, this finding is 282



















In Bangladesh, designated DOTS centres are the centres 300


offers free services and medicine for TB treatment. These DOTS centres are the point of 302

treatment initiation and follow up. Private centres are for-profit private practitioners, clinics 303


commonly linked with TB control programme. Medicines for TB are also available in the 305

private market in Bangladesh and the unregulated private sector is likely to treat tuberculosis 306

patients using non-standardized regimen which may lead to development of drug resistance.30

307

In our study, MDR-TB patients had been enrolled mostly with the designated DOTS centres 308

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during their most recent episode of previous TB, rather than private centres. The possible 309

explanation could be that retreatment patients are complicated cases that private practitioners 310

prefer not to treat. This study is a hospital based study and we assumed that most of the 311

MDR-TB patients are treated under these three Government hospitals. We do not have any 312

information on MDR-TB patients treated by private physicians who are beyond national TB 313

control programme. However, we were not able to collect information on other episodes to 314

evaluate if patients had been treated in the private sectors previously. Another study reported 315

similar rate of MDR-TB among patients treated by DOTS centre and by private providers and 316

thorough review of medication given during previous treatment, regardless of its setting, was 317

recommended.31

318







partnerships.18

Accessing services from DOTS centres might reflect the expansion of DOTS 324





Bangladesh, so patients do not have to travel to health centres for every administration of 328

medicine; it can be given by community level providers and the patient only visits the centre 329

for diagnosis, follow up and complications. Time to treatment centre was relatively lower (20 330



distance to treatment centres. Although access to treatment could be a factor for developing 333



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This study is a stratified analysis of all previously treated tuberculosis patients taken from a 340

case control study which recruited the MDR-TB and non-MDR-TB patients representing the 341

population. The sample size and power were calculated based on the initial risk factor study, 342

and as such our analysis of the subset has less power than the full study, but the results still 343

present important exploratory findings. We do not have information of all previous treatment 344

episodes for the patients as we had extracted the information based on the most recent 345

episode, to aid the accuracy of the recalled information. It was not feasible to confirm drug 346

susceptibility using Drug Sensitivity Testing (DST) of the non-MDR-TB patients, as only 347

high-risk patients are routinely tested, and we did not have the funds for this. 348

CONCLUSION 349





treatment, less time required to visit treatment centre and the designated DOTS centre, it does 354


DOTS centre contribute to MDR-TB. These findings are based on the most recent episode of 356





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ACKNOWLEDGEMENT 363









CONTRIBUTERSHIP STATEMENT 372

MR, AHM and JH contributed in designing and planning the study. MR collected, analysed 373

the data and prepared the manuscript. CO provided input in data analysis and writing. AH, 374

SGH and all authors reviewed the document and provided their inputs. 375


The study was based in Bangladesh and partially supported by the Australian Respiratory 377

Council, BRAC Bangladesh and University of Newcastle Australia. The funders had no role 378

in study design, data collection and analysis or decision to publish or preparation of 379

manuscript. 380



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DATA SHARING STATEMENT 383

The electronic version of the dataset is kept with University of Newcastle Australia, 384

following the original research protocol, which has also been approved by Human Research 385

Ethics Committee (HREC) of the University of Newcastle. It will be provided upon request 386

to anyone who is interested in the research topic. Interested readers may contact the 387

corresponding author.388

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References



2. Caminero JA, ed. Guidelines for Clinical and Operational Management of Drug-

Resistant Tuberculosis. Paris, France: International Union Against Tuberculosis and Lung

Disease, 2013.



report. Geneva, Switzerland: WHO, 2011.












Tuberc Lung Dis 2009;13(1):68-73.






12. World Health Organization. Treatment of tuberculosis Guidelines.

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Fourth ed. Geneva, 2009.






& Lung Disease 1995;76(5):455-9.




Report. 2008.


Bangladesh, Annual Report. Dhaka, 2014.

19. Kamal SM, Hossain A, Sultana S, et al. Anti-tuberculosis drug resistance in Bangladesh:

reflections from the first nationwide survey. Int J Tuberc Lung Dis 2015;19(2):151-6.

20. Flora MS, Amin MN, Karim MR, et al. Risk factors of multi-drug-resistant tuberculosis

in Bangladeshi population: a case control study. Bangladesh Medical Research Council

Bulletin 2013;39(1):34-41.









2010;104(8):511-7.

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study. International Journal of Infectous Disease 2013;17(12):e1116–e1120.



2010;5(12):e15735.



Lung Disease, 2010.

30. Hossain S, Zaman K, Quaiyum A, et al. Care seeking in tuberculosis: results from a

countrywide cluster randomised survey in Bangladesh. BMJ Open 2014;4(5):e004766.





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No Recommendation


abstract



Introduction



Methods








and controls









Data sources/

measurement









confounding





was addressed


sampling strategy



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2

Results



analysed



Descriptive

data







exposure









analyses

Discussion







Other information










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