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Predictors of treatment failure in

Drug Resistant Tuberculosis in Bangladesh Hill tracts

Student ID: 201063127

Module: Health System Research Methods

NUFF: 5710M

Public Health (I)

University of Leeds

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Contents: ________Page No:

1. Summary__________________________________________________________03
2. Introduction _______________________________________________________ 04
 Research question and Hypothesis
3. Objectives _________________________________________________________ 05
4. Methodology _______________________________________________________ 06
 Study setting

 Study population

 Study design

 Study period

 Inclusion and Exclusion criteria

 Case and control

 Variable definition

 Sample size

 Data collection

 Data analysis

4. Potential risk _________________________________________________________ 10

5. Ethical issue __________________________________________________________ 11
6. Plan for dissemination of result __________________________________________ 11
8. References ___________________________________________________________ 13
9. Timetable ____________________________________________________________ 14
10. Budget Sheet _________________________________________________________ 16
11. Appendix ____________________________________________________________ 17

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Summary:

Drug resistance in tuberculosis (TB) which is a severe public health problem has been increased
worldwide. Bangladesh is listed as among the top 27 high burden countries for tuberculosis drug
resistance by WHO (World health Organization). Delayed or inadequate treatment in drug
resistant TB allow progression of the disease and increases mortality and morbidity from drug
resistance. Despite success in TB control, drug resistant TB in Bangladesh is increasing due to
some specific and significant risk factors. Lack of knowledge of these predictors and failure to
identify the vulnerable areas of the country makes the control of the disease difficult.
The aim of this study is to determine the predictors of outcome of drug resistant TB in Hill tracts
of Bangladesh. This study will find out the associations between demographic, laboratory and
radio-graphical factors on one side and treatment outcome on the other side in the study
population of hill tracts. This study will also explain the relationship of specific factors to drug
resistant TB mortality which can be used to the predict during diagnosis and treatment.

This study will be a descriptive retrospective cohort study conducted among outdoor and indoor
patients in 8 Primary Health Center (PHC) and 12 DOTs corner of Rangamati Hill Tracts
Bangladesh for a duration of one year (from July 2017 to June 2018). Case and controls will be
matched by gender (male, female) and resident places (urban, rural). Sample size will be at least
549 of diagnosed drug resistant TB cases. Extra-pulmonary TB will not be included in this study.
Tests will be performed in PHC lab with expert technologists. Data will be collected in
questionnaire forms by trained physicians. Data analysis will be done in SPSS 23 software.
Frequency, tables, odds ratio (OR),chi square and T tests will be used to identify the statistical
association between dependent and independent variables. A result will be considered significant
at p value <0.05. Effects of exposure variables will also be assessed after adjusting for other
variables by binary logistic regression models. The estimated budget of this study is $ 60,000
(approx).
This information is important for physicians to come to a diagnostic conclusion and to predict
prognosis in drug resistant TB in Hill tracts Bangladesh. This study will help the policy makers
in making strategies for prevention, monitoring and control strategies against drug resistant TB.

Introduction:

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Tuberculosis (TB) remains a major public health problem in world despite of effective drug
therapy (WHO, 2007). More than a quarter of the preventable death in infectious diseases of the
world is caused by tuberculosis (WHO, 2007). Every year almost 400,000 new cases of drug
resistant TB emerge (WHO, 2007-08).. In South-East-Asia region the prevalence among new
cases is 2.8% (95% CI, 1.9 to 3.6) and for old treated cases it is 18.8% (95% CI, 13.3 to 24.3)
and it is estimated to be In India and Pakistan it is 1.6% - 5.2% and 0-21.6% respectively
(SAARC, 2009). Based on WHO report incidence of multi drug resistance in tuberculosis
(MDR-TB) is 5.4 per million population. In 2015, 5300 cases detected as MDR - TB. 1.6% of
new cases and 29 % previously treated patients were diagnosed as drug resistant. Among them
only 969 cases were initially diagnosed by Laboratory tests. Bangladesh is also counted as a
country with highest tuberculosis burden. In Bangladesh the estimated incidence of tuberculosis
is 225 per 100,000 populations each year (NTP, 2007). Five yearly DOTS plus pilot project
adopted by the Bangladesh government from year 2000 to tackle this emerging situation (NTP,
2009). With standard regimen a national tuberculosis guideline has also been developed for the
country. Drug resistant mutants become a dominant strain when an inadequate or poorly
administered treatment regimen continued in a patient infected with tuberculosis (Law WS et al.
2008).

According to WHO, the main challenges to combat drug resistant TB is migration from border
area, good quality diagnostic services, Inadequate screening and funding (WHO, 2007).
Bangladesh Hill tract is a common border for transmission of drug resistant cases from
neighboring countries (India, Myanmar and Bhutan) (NTP, 2009). But, there is no data regarding
predictors of outcome of drug resistant cases in Hill tracts. People from Hill tracts frequently
travel to main land for job and business. So there is high chance of transmission of resistant cases
to other districts. Now the treatment success rate for TB is 93% but for drug resistant TB it
reduces to 73% (NTP, 2007). The current aim of Bangladesh government is to improve the
annual detection rate with 10% decrease of the prevalence by 2020 and 5% annually (NTP,
2009). But, without finding out the risk factors and predictors of outcome in hill tracts it is
almost impossible to achieve the target. The treatment success rate for new and relapse case is
93% and for MDR - TB the success rate is only 74% and XDR TB is 0% (NTP, 2009). This is
due to lack of detection and screening process in the community.

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This study has designed to determine the predictors of outcome of drug resistant TB in Hill tracts
of Bangladesh. This research will find out the associations between demographic, Laboratory
and radio-graphical factors on one side and drug resistant TB mortality on the other side in the
study population. This information is important for physicians to come to a diagnostic conclusion
and to predict prognosis in drug resistant TB in Hill tracts. This study will also help in making
strategies for treatment, prevention and control strategies against drug resistant TB.

Research question:

Is patient’s socio-demographic, laboratory and radio-logical factors are associated with high
treatment failure rate in drug resistant TB.

Hypothesis of the Research:

High rate of treatment failure in drug resistant TB is associated with patient’s socio-
demographic, laboratory and radio-logical factors.

Objectives:

1. To identify the risk factors which can predict the treatment failure in drug resistant TB.

2. To determine the association of socio-demographic, laboratory and radio-logical features with

treatment outcome of drug resistant TB.

3. To understand the relationship of specific factors with overall treatment outcome in drug
resistant TB.

Previously known facts of drug resistant TB:

1. Drug resistant TB incidence and prevalence is increasing and pointed out as an emerging
burden for the country.

2. Hill tracts in Bangladesh is a vulnerable border area for transmission of drug resistant TB.

This study will add:

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 Identification of risk factors (Socio- demographic like Gender, age, place, education and lab
radio-logical) for drug resistance.

 Relationship of factors for treatment failure in drug resistant tuberculosis.

Methodology:

Study setting:

This study will be conducted in PHC (Primary Heath Centre) and DOTs (Directly observed
Therapy) of Rangamati Hill tracts Bangladesh among tribal community. Total population of
Rangamati district is 1,25000. 54 % are male and 46 % are female. 9 % are under 5 children.

Number of PHC is 8 and number of DOTs corner is 12 (4 DOTs corners are placed in remote
community clinics). Total health care workers in the district are 125. Among those 25 physician,
5 consultants and 15 trained laboratory technician. Health care workers are trained with updated
knowledge and skills of drug resistant TB. 15 nurses are trained for sputum collection and TB
rehabilitation program.

Well established affiliated laboratory for sputum smear microscopy and culture is available in
each PHC and DOTs corner. Rapid drug susceptibility testing (DST) is available at only two
PHC. The radiology and pathology departments provide routine investigation services to drug
resistant TB patients in 8 PHC.

Study Population:

The entire Rangamati district constituted the study area. The district is divided into 8 regions
based on the 8 PHC locations. These also include 12 DOTs corners.

Sputum smear examination will be performed where tuberculosis suspected. Only smear positive
specimen will be sent to the PHC with DST facility.

Supervision:

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A trained doctor in each PHC will closely supervise all the investigations to ensure good co
ordination. He will be responsible for case selection, collection of sputum samples and referral
for DST.

Study Design:

This will be a health center based (PHC and DOTs) descriptive and retrospective cohort study
done among drug resistant TB patients of Hill tracts Bangladesh.

Study Period:

This study will be conducted for One year, between July 2018 and June 2019. During this period
patients will be monitored monthly.

Inclusion criteria:

All the diagnosed TB patients will be tested for drug resistance. Diagnosed and registered drug
resistant cases will be considered eligible for this study. Main inclusion criteria will be

 At least resistance to Rifampicin or Isoniazide

 Mono, poly drug resistance, MDR and XDR TB.
 On treatment with 2nd line anti tubercular chemoprophylaxis.

Exclusion criteria:

 Extra pulmonary TB.

 Previous history of drug resistant TB.
 Diagnosis not confirmed as drug resistance.

Cases and controls:

All diagnosed TB patients new and old of the district will be considered as both case and control.
Cases are all tuberculosis patients resistant to both rifampicin and isoniazide (culture diagnosed
MDR TB). Controls (non-drug resistant TB patients) will be all tuberculosis patients not resistant
to any anti TB drugs (culture diagnosed non MDR TB). Both cases and controls are tested,
referred and reported in PHC and DOTs corner. After smear test positive, culture and drug

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sensitivity tests (DST) will be used to confirm drug resistant tuberculosis cases. For verification
clinical and radio-logical tests will be done.

Variables and definitions:

Variables will be searched for:

1. Socio demographic characters:

 Gender (Male, Female).
 Age group (<20, 20-40, >40),
 Occupation (Employed, Unemployed).
 Education (Primary, Secondary, Masters).
 Residence (Urban, Rural).
2. Laboratory results:
(Smear test-AFB, Culture and DST)
3. Radio logical results:
(Consolidation, Cavity diameter, Effusion, Hilar Lymphodenopathy)

Outcome variable:
1. Treatment success
2. 2. Treatment failure.
Treatment success includes total cure and Cure with completion, while treatment failure
includes no cure and death. The definitions are shown in Table 1.

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Table 1: Definition of tuberculosis types, drug resistance and outcome in treatment (WHO,
2007)

Drug resistant Tuberculosis: Resistance to at least one drug of Mycobacterium tuberculosis.

Mono-resistant tuberculosis: Resistant to one TB drug
Poly-resistant tuberculosis: Resistant to two or more TB drugs, but not at the same time, to
rifampicin and isoniazid
MDR-Tuberculosis: Resistance to at least two of the first-line drugs. (rifampicin and
isoniazid)
XDR-Tuberculosis: Resistance to rifampicin- isoniazid, and additional resistance to
fluoroquinolone drugs plus any injectable 2nd line drugs (kanamycin or amikacin)
Treatment completed: Treatment done without evidence of failure but with no record
indicating that after intensive-phase, 3 cultures (consecutive) taken 1month apart are test
negative.
Cured: At least three consecutive cultures taken at least 30 days apart are negative, without
evidence of treatment failure such that after intensive phase.
Death: Regardless of reason, the case documented as died during course of treatment.
Pulmonary Tuberculosis: Lung/pulmonary affected by Mycobacterium tuberculosis
Non-pulmonary Tuberculosis: Tuberculosis of body other than pulmonary TB.

Sample Size:

The estimated sample size to find out the predictors of drug resistance with 95% confidence
interval width and standard deviation 0.5 calculated using the following formula:

Sample size= (z score)2 X Std deviation X (1-Std Deviation)/ (Margin of error)2

True Sample= (Sample size X Population)/(Sample size + Population-1)

Where: 95% - Z score =1.96; Standard Deviation= 0.5

So, (1.96)2 X 0.5 X (1-0.5)/ (0.05) 2, Population= 1,25000

Sample Size= 384

As, detection rate of MDR TB is 70 % in Bangladesh

Invites needed = 549

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Data collection:

Socio-demographic characteristics:

Primary data collection by interview using structured questionnaires (case and controls).

Secondary data collection will be done by analysis of medical reports and logs (Case and
control). Physicians and nurses trained in drug resistant tuberculosis will conduct the interviews
and reviews. N-95 mask (respirator) will be used during data collection for preventive purpose.

Laboratory and Radio-logical characteristics:

Laboratory and Radio-logical tests will be done by trained lab technician and radiologist. Smear
test and culture will be performed by Z-N Stain ( for Acid Fast Bacillus) in the PHC laboratory.
BACTEC liquid culture and DST (Drug sensitivity test) will be conducted in specific TB lab
facility in two PHC labs. DST test is double checked by consultant physician. X ray will be done
in all PHC radiology room. Both posterior anterior view and lateral view will be analyzed by
trained radiologist for confirmation.

Data accumulation:
Data along with the samples for DST will be sent to PHC from DOTs monthly after re checked
and signed by medical officer. The data will be screened out before compilation to monitor the
patient enrollment for the surveillance study, quality of clinical information collected by the
medical officer and quality of samples collected and transported to PHC. PHC will assign code
number for surveillance study.
Data analysis:

Independent and dependent variables were collected and entered into an Microsoft Excel sheet.
After analysis and omitting the data using exclusion criteria, SPSS (Statistical Package for Social
Sciences) version 23 for windows will be used for final analysis.
Simple frequency tables will be used for describing variable characters. Analytical procedure
will be used by performing logistic regression (both bi variate and multi variate), odds ratio (OR)
with a 95% confidence interval. This analysis will find the association between exposure and
outcome variables. P value <0.05 will be considered as significant level. In addition, Pearson´s
chi-square tests and odds ratio (OR) will be used to assess the relationship of MDR tuberculosis

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with qualitative data and t- tests for quantitative data

Potential risks:
1. Transmission of tuberculosis infection:
a. From patient to patient
b. From patient to health worker
c. From patient to vulnerable people (children, pregnant and immune-compromised
patients)
To prevent the transmission N 95 mask used by all health workers. Patients are
advised to use surgical masks and personal sputum pan during travel.
2. Drop out of patients:
Some factors plays role in drop out of patients in drug resistant TB patients. Travel
expenses, social anxiety, initial improvement and long course treatment makes them drop
out and missed doses.
3. Bias: by physician, health workers and lab technicians. Particular TB setting makes
health care worker biased to diagnose drug resistant TB cases.
Lab technicians may give false positive reports.
4. Corruption:
As Anti TB drugs, lab equipment are free of cost supplied by the government, there is a
high chance of corruption for selling the products in the market where there is less
number of cases.

Ethical issue:
 Ethical clearance will be collected from the research ethics committee of
researcher’s University or hospital.
 Written and verbal consent will be taken from each study subject. For children
consent will be taken from parents or guardians.
 Subjects were also informed about the purpose of the study.
 Confidentiality of the patient’s records will also be ensured.

Plan for dissemination of result:

1. To ensure that the the results of this study will be used to improve the treatment outcome in
drug resistant TB the following will be done:
 The district council and local political leaders will involved in developing this proposal. This
will ensure maximum participation of the local community for testing drug resistant TB.
 Local NGO like BRAC and PROSHIKA will be involved in this project to collect samples
from hard to reach area. This will ensure extension of coverage of the study. They can also
ensure equity during the study.
2. After completion of the study,the result will be disseminated by:
 Result summary will be typed in local language. Pictures, Bar chart and easily explainable
sheets will be used to give a clear idea about the risk factors to local community leaders.

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Summary will be distributed to local government office and Political leaders.

 Copies will be also sent to the newly established Rangamati medical college Community
Medicine department for acknowledgment of academic staffs.
 In local health training, seminars and workshops, this result will be discussed to increase
the awareness of the health workers and local community.
Implications of expected findings:
 The main risk factors causing drug resistance in tuberculosis will be identified with this
study. Therefore if the reasons are pointed out, it will be easy for physicians to make early
diagnosis and treatment of drug resistant TB.
 The policy makers will get the source where they should focus to tackle this emerging health
problem. Overall this study will contribute in the government’s national TB control
program.

References:

Law WS, Yew WW, Chiu LC, Kam KM, Chan CK, Leung CC (2008) “Risk factors for
multidrug- resistant tuberculosis in Hong Kong”. Int J Tuberc Lung Dis, 12, 1065-70.
NTP (2007) National Tuberculosis Control in Bangladesh. Annual Report. National
Tuberculosis Control Programme, DGHS, MOH&FW. Dhaka.
NTP (2009) National Guidelines and Operational Manual for Tuberculosis Control. 4th Edition.

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National Tuberculosis Control Programme, DGHS, MOH&FW. Dhaka.

SAARC Tuberculosis Center (2009). Tuberculosis in the SAARC Region-an update. Kathmandu,
Nepal, SAARC Tuberculosis Center:
WHO (2009) Communicable Diseases, Tuberculosis. TB in South- East- Asia, Country profile-
Bangladesh.
WHO (2007) WHO Report 2007. Global Tuberculosis Control. Surveillance, Planning,
Financing. World Health Organization Switzerland.
WHO (2007-08). Stop TB Partnership. The global MDR-TB and XDR-TB response plan.
http://www.who.int [accessed on Feb 02, 2018]

Research Timetable:

Befor Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun
e
Literature X X
review
Research X X
protocol
Data X X
collection
instrument
Training X X
Specimen X X X X X X X X X X X X
collection
Primary X X X X X X X X X X X
Analysis
Data entry X X X X
Data X X X X X

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analysis
Periodic X X X
Reporting
Report X X X
Writing

Project Requirement: (8 PHC, 12 DOTs corner with 8 DOTs in PHC)

Items Amount (n)

A. Health Team
 Consultant 2
 Medical Officer 8
 Nurse 16
 Field worker 32
 Trainers 8
 Lab technician 12
8
 Office worker
2
 Computer operator
Total Manpower 88
B. Equipment
 Laboratory
Sputum collectors 700
Culture settings 700
DST settings 700
Microscope 16
Slides 100 box
Reagents 100 box
N 95 Mask 700
Surgical Mask 700
 Papers 10000
 Pen, pencils, rubber, eraser 100
550

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Files 8
 Computer 8
 Printer 8
 Bicycle
C. TB Training sessions:
 Projectors, slides 8
 Computer 8
 Training materials 32 set
 Hands on training materials 32

The Budget Sheet: Breakdown of Budget: All costs are in US Dollar $ ( 1 year)

Worker salary Cost /Unit/ year Unit (n) Total required

Consultant 1100 2 2200
Medical Officer 500 8 4000
Nurse 300 16 4800
Field Workers 150 32 4800
Trainers 120 8 960
Lab technician 150 12 1800
Office worker 120 8 960
Computer operator 120 2 240
Total Salary 88 19760

Equipment Budget Cost / Unit Unit Total

Laboratory
Sputum collectors 0.5 700 350
Culture settings 3 700 2100
DST settings 10 700 7000
Microscope 50 16 800
Slides 5 100 box 500
Reagents 10 100 box 1000
N 95 mask 2 700 1400
Surgical Mask 0.1 1000 100
Radio-logical
X ray Machine 1000 8 8000
X ray Film 10 50 set 500

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 Papers 50 50 box 2500

 Pen, pencils, 40 20 box 800
rubber, eraser
 Files 1 550 550
 Computer 300 8 2400
 Printer 100 8 800
 Bicycle 100 8 800

Total 29,600
D. TB Training sessions:
 Projectors, slides 100 8 800
 Computer 250 8 2000
 Training materials 25 32 set 800
 Hands on training
materials 50 32 1600
 Refreshment 5 32 160

Total 5360
Total: 19760 + 29600 + 5360 = $ 54720 ; Reservation (10%): $ 5000;

Grand Total Budget: $ 54720 + $ 5000 = $ 59720

Appendix: Sampling Technique:

Rangamati Hill tracts, Bangladesh (Population 120000)

8 Union

1 PHC + 1 DOTs corner for each Union

Total 8 PHC (8 DOTs) + 4 DOTs corner (in remote community clinics)

Both Outdoor and Indoor TB cases (Inclusion + Exclusion Criteria)

Initial Diagnosis: Pulmonary Tuberculosis

Confirmed by: Smear (PHC & DOTs) and Culture (only PHC)

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Samples sent for DST confirmation (specialized lab PHC)

Secondary Diagnosis: Drug resistant Tuberculosis (Mono, MDR, XDR)

Radio-logical (X ray) Confirmation (PHC)

46 samples /center estimated ( Total Estimated 549)

Appendix 2: The Questionnaire:

District Name:
Union No:
House No:
Gender: Male/ Female
Data collector’s name:
Date of interview:

Serial Question Answer Code

No:
1 Age/ Date of Birth
2 Occupation
Employed/ Unemployed
3 Education
Illiterate/ Below primary/ Primary/
Secondary/ Masters
4 Residence
Urban/ Rural
History of TB:
5 Past diagnosis of TB
Pulmonary/ Extra-pulmonary

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6 Previous contact with TB

7 Past treatment with anti TB drug

Student ID: 201063127 ; MPH (I)