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Annex 7
Investigation of risk factors and transmission of multi-drug
resistant tuberculosis (MDRTB)
Final Report
Timeline: August 2002 - June 2003
Primary Investigator: Dr. J.N. Pande, Professor and Head
Co-Investigators:
Clinical and Microbiology:
Dr. S K Sharma, Professor
Clinical
Dr. R. Guleria, Additional Professor Clinical
Dr. GC Khilnani, Assoc. Professor Clinical
Dr. Urvashi Singh, Asst. Professor Microbiology
Dr. Rajendra Prasad, Professor and Head Clinical
Dr. Ramesh Ahuja, Professor
Clinical
Dr. Amita Jain, Professor
Microbiology
Dr. P P Joshi, Assoc. Professor
Clinical
Dr. Munje, Assoc. Professor
Microbiology
Dr. C S Ghosh, Professor and Head Clinical
Dr. Sarda Devi KL, Assoc. Professor Microbiology
Dr. Manjula Datta, Professor and Head Clinical
Dr. R J. Revarthy, Deputy Director Microbiology
Dr. K. Jagannath, Director
Clinical
Dr. Shantha
Microbiology
Dr. O C Abraham, Professor
Clinical
Dr. Mary V. Jesudasan, Professor and Head Microbiology
Dr. D. R. Joshi, Professor and Head Clinical
Dr. Anju Kagal, Assoc. Professor Microbiology
Coordinating Center: AIIMS: Dr. Sushama Singh, coordinator
AIIMS, New Delhi was the coordinating center and TRC, Chennai was the TB reference
laboratory.
Participating Centers: AIIMS, New Delhi; KGMC, Lucknow; GMC, Nagpur;
CMC, Vellore; MC, Trivandrum; BJMC, Pune; ITM, Chennai; andDr MGR, Chennai
Research Officers (AIIMS):
Dr. Ram C. Agrawal Clinical
Dr. Hema Pant Microbiology
Names of Technical Consultants:
Dr. Lee Riley, Professor, UCLA, USA

Dr. C. N. Paramasivan, Deputy Director, TRC, Chennai.
*Note that Professor Lee Riley was involved in the initial stages of the preparation of the
protocol only. He has not been involved in the study after the data collection started.
Background:
Tuberculosis continues to remain a major public health problem. The burden of disease
has increased with emergence of HIV, both in developed and developing countries. The
magnitude of primary and acquired drug resistance is not known in India. There is need
for continuous surveillance for drug resistant TB.
Primary infection with drug resistant organisms is uncommon in most parts of the world
including India, but this situation may change rapidly in regions with ineffective control
programs. Illiteracy, massive bacillary load, irregular supply of drugs with proven bioavailability
under the program, lack of supervision, poor patient compliance, free access
to drugs over the counter, interruption of chemotherapy, intestinal mal-absorption, and
use of anti-tuberculosis agents for indications other than tuberculosis (e.g. leprosy) may
be some of the factors responsible for the emergence of drug resistant organisms. These
factors may vary widely in different regions within the country. There is marked paucity
of information on the risk factors for drug resistant tuberculosis in different parts of India.
Drug resistance in India:
Limited data on prevalence of MDRTB in different parts of India
Reports of MDR bacilli in ~30% of patients with past history of SCC
Large pool of MDR patients in big cities
Frequent use of second line drugs in patients with poor clinical response
Limited facilities for testing and surveillance for drug susceptibility
Primary/initial resistance is ~15% for H and 2-3% for R
Acquired resistance to H is > 30% and to R >15%
RNTCP employing DOTs strategy implemented in ~300 districts in the
country
The following shows drug resistance studies in India:
Study Year No. of
Percentage of resistance
Patients
H S R Z E
ICMR 1968 1838 8.2 5.8 - - -
ICMR 1969 1183 9.1 7 - - -
Trivedi 1988 570 7.9 3.2 0 0 2.5
Jain 1992 324 18.5 0.6
North Arcot 1993 2779 13 4 2 - -
Pondicherry 1993 2127 6 4 0.9 - -
Mathur 2000 - 16.6 16.6 6.6 - 6.6
ICMR 2002 634 23.4 - 2.8 -

The primary resistance (as mentioned in the studies quoted) to rifampicin ranges from 0
to 6.6% while isoniazid the range is from 6 to 23.4.
Objectives:
Primary:
To investigate hypothesized risk factors for drug resistant tuberculosis amongst patients
with active sputum positive disease seen at designated locations: Delhi, Lucknow, Pune,
Vellore, Trivandrum, Chennai, Nagpur.
Secondary:
To define the magnitude of drug resistant pulmonary TB.
To investigate the transmission dynamics of TB using molecular techniques.
To assess the genetic determinants of rifampin resistance to M. tuberculosis by
DNA sequencing.
To establish and strengthen laboratory facilities at all participating centers for
culture and drug susceptibility testing for M. tuberculosis.
Implementation of the Study:
Subject recruitment:
A cross-sectional survey of all eligible patients was seen at the sites for enrollment at
each participating center. Subject recruitment commenced on August 1, 2000 for AIIMS
site and the dates for the other sites is as follows:
Site location: Date Commencement:
Lucknow 11-10-2000
Vellore 11-01-2000
Pune 9-11-2000
ITM-Chennai 5-11-2000
TN Dr.MGR 4-18-2001
Nagpur 10-12-2000
Trivandrum 10-25-2000
Recruitment of new patients was stopped by the end of August, 2002 to be able to have
enough time to obtain the culture and drug susceptibility results of the samples collected
by end December, 2002. However, some centers continued to recruit patients into the
study after this date.
Patients were recruited for the study from the following three sites (wherever
feasible): Medical college hospital, district tuberculosis center (DTC) and Primary health
center (PHC) attached to medical college. All patients enrolled in the study were
interviewed in detail using a structured proforma, and their medical history. Physical
findings, and results of investigations were recorded. History of previous treatment with
anti-tuberculosis agents was assessed using the WHO questionnaire. The following risk
factors were studied: socio-economic status, education; history of previous drug
treatment and duration; non-compliance; alcohol intake; tobacco smoking; co-morbidity;
HIV status; and bacillary load.

The inclusion criteria were as follows:
Patients diagnosed to have smear positive pulmonary tuberculosis as per the
RNTCP guidelines, or
Patients strongly suspected to have pulmonary tuberculosis on clinical and
radiological grounds, but reported to be negative on smear examination
The exclusion criteria were as follows:
Patients who have already received treatment for >15 days after the diagnosis.
Patients who were unwilling to participate in the study after being given full
information.
Refusal to give consent for HIV test was not an exclusion criterion.
History of having been treated for tuberculosis on previous occasion(s) was not an
exclusion criterion.
Quality Assurance Measures:
Regular weekly meetings were conducted between the PI and members: clinical,
and microbiology research officers and the coordinator at AIIMS. This improved
the project implementation and monitoring.
Regular communication between the study PI and the Co-PI’s from all the sites
have provided critical inputs.
Newly recruited laboratory technical staff from each participating center
underwent an intensive hands-on training in mycobacteriology for three weeks at
TRC, Chennai in December, 1999 –January, 2000. A retraining program was
undertaken in July-August, 2001.
A standard laboratory manual was developed by TRC for use by all participating
centers.
The source for reagents was standardized for all participating centers.
Network Dynamics:
The study centers worked according to a fixed time line with weekly progress reports
being faxed or emailed to the coordinating center at AIIMS, New Delhi. Centers strictly
adhered to deadlines.
Quality Control:
TRC is a well recognized center for quality control in sputum microscopy and
drug susceptibility testing nationally and internationally. This served as the
reference laboratory.
TRC staff made several site visits to participating laboratories to oversee
testing procedures.
Quality of DST was assessed by exchanging coded material between TRC and
participating centers.
Repeat training was provided for technicians from centers whose performance was
sub-optimal.
Randomly selected cultures were re-tested at TRC for validation of DST results.

Four rounds of continuous quality improvement were undertaken. In Vellore and
ITM, Chennai, five rounds were undertaken. In Dr.MGR, Chennai only one round
was undertaken and in Trivandrum only three rounds were undertaken.
The reference laboratory accepted the results of the participating laboratories as
being highly satisfactory
Results:
For molecular typing, isolates along with the complete clinical information were received
from the following centers:
Center Total # of isolates Isolates in Viable Damaged in transit
received
condition
Lucknow 341 323 18
Pune 341 288 53
Nagpur 65 56 9
Vellore Nil Nil -
ITM 207 194 13
MGR Nil Nil -
Trivandrum 260 233 27
Total 1214 1094 120
Transportation of the isolates to the coordinating center was done by following the WHO
recommendations (Laboratory Biosafety Manual, 1993) on safe shipment of specimens
and infectious materials. All material used for continuous quality improvement (CQI)
was stored at –20C.
Data Storage:
The patients’ information sheets and the results of the drug susceptibility tests were
entered on a standard Fox Pro program at the coordinating center. This program was
developed with the help of Dr. Jeyseelan, Vellore. Data base back up was kept after each
data entry session by the data entry operator. The data forms were received monthly at
the coordinating center from the participating centers.
Data Analysis:
Multivariable logistic regression analysis was used to assess the significance of
hypothesized risk factors. The risk factors include: history of previous treatment, poor
compliance in previous treatment, adverse effects to drugs in previous treatment, low
educational level, low socio-economic status, positive family history, gender, lack of
medical facilities in the region, occupation, chronic diarrhea, extensive disease with high
bacillary load, poor nutritional status, and co-morbidity with other chronic and
debilitating diseases.
Laboratory Methods were as follows:
Culture on L-J medium - 8 weeks

Sensitivity to following drugs using the proportion method: Rifampicin, Isoniazid,
Ethambutol, Streptomycin
Table 1: Patient recruitment data from all the participating centers
S. No Center Patient. Recruited Updated Patients
until December 31, 2002 Recruited in the study
1. Delhi: AIIMS HOS 676 678
AIIMS PHC 346 346
AIIMS DTC 443 443
2. Pune HOS +
562 562
DTC
3. Vellore HOS 281 281
PHC 308 308
4. Nagpur HOS 415 415
5. Chennai (ITM)
HOS 46 46
DTC 175 175
PHC 191 191
6. Lucknow HOS 243 243
DTC 164 164
PCM 174 174
Trivandrum HOS 265 270
7
DTC 280 281
8. Chennai HOS
264
275
( Dr. MGR) DTC
181
181
Total 5014 5033
HOS-hospital; DTC –District Tuberculosis Center; PHC-Primary Health Center
All of the centers had recruited from the hospital. Only Pune, Nagpur and Vellore did not
recruit from the PHC. With Pune center, the DTC is within the hospital. Only AIIMS
has exceeded the target of approximately 315 patients per year per center.
Table II shows the drug susceptibility results from all the centers. A total of 3065 drug
susceptibility tests from all the centers are available.

Table II: Drug sensitivity results:
S.NO: Center: Total number recruited
December 31, 2002
1.
AIIMS HOS
PHC
DTC
678
346 1467
443
Number for which drug
susceptibility results available
219
204 648
225
2. NAGPUR 415 299
3. VELLORE
HOS
281 589
218
PHC
308
191 414
4. PUNE
562 338
HOS+DTC
5.
LUCKNOW
HOS
243
140
PCM
174 581
100 331
DTC
164
91
6. TRIVANDRUM
HOS
DTC
265 545
280
402
7. CHENNAI
ITM PHC
DTC
MC
8. CHENNAI
Dr.MGR
HOS
DTC
191
175 412
46
186
264
446
181 445
Total: 5033 3064

The data was analyzed for primary and acquired MDRTB after combining all the centers
and also individually for each center. The results are as follows: Primary (without history
of treatment) MDRTB (multi drug resistance) at the different centers are shown in tables
III - V:
Table III: Primary MDR at different centers
Center Patients MDR Percent
AIIMS 329 28 8.5
LKO 162 28 17.3
NAG 237 26 11.0
CHE 88 2 2.3
MGR 305 4 1.3
VEL 252 10 4.0
TRI 332 30 9.0
PUNE 187 18 9.6
Total 1892 146 7.8
Table IV: Primary MDR at different centers (Excluding Dr. MGR center)
Center Patients MDR Percent
AIIMS 329 28 8.5
LKO 162 28 17.3
NAG 237 26 11.0
CHE 88 2 2.3
VEL 252 10 4.0
TRI 332 30 9.0
PUNE 187 18 9.6
Total 1587 142 8.8
Table V: Primary MDR at different centers (Excluding Dr. MGR and Nagpur
Centers)
Center Patients MDR Percent
AIIMS 329 28 8.5
LKO 162 28 17.3
CHE 88 2 2.3
VEL 252 10 4.0
TRI 332 30 9.0
PUNE 187 18 9.6
Total 1350 116 8.5

The location of the participating centers as well as primary MDRTB is shown in the
following map:
Primary MDR at different centers
8.5%
Delhi –
Lucknow -
17.3%
11.0%
9.6%
2.5%
Vellore –
9.0%
Chennai
Analysis of acquired MDRTB (with past history of treatment) is shown in Tables VI –
VIII.
Table VI: Acquired MDRTB at Different Centers
Center Patients MDR Percent
AIIMS 319 95 29.8
LKO 169 49 29.0
NAG 29 7 24.1
CHE 98 34 34.7
MGR 108 1 0.9
VEL 159 58 36.5
TRI 60 22 36.7
PUNE 140 56 40.0
Total 1082 322 29.8

Table VII: Acquired MDRTB at Different Centers (Excluding Dr.MGR)
Center Patients MDR Percent
AIIMS 319 95 29.8
LKO 169 49 29.0
NAG 29 7 24.1
CHE 98 34 34.7
VEL 159 58 36.5
TRI 60 22 36.7
PUNE 140 56 40.0
Total 974 321 32.9
Table VIII: Acquired MDRTB at Different Centers (Excluding Dr.MGR
and Nagpur Center)
Center Patients MDR Percent
AIIMS 319 95 29.8
LKO 169 49 29.0
CHE 98 34 34.7
VEL 159 58 36.5
TRI 60 22 36.7
PUNE 140 56 40.0
Total 945 314 34.5
Acquired MDR at different centers
Delhi – 29.8
Lucknow - 29.0
Nagpur - 24.1
Pune - 40.0
ITM - 34.7
Chennai
MGR - 0.9
Vellore – 36.5
Thiruvananthapuram - 36.7
Primary MDRTB ranged from 2.5% in Chennai to 17.3% in

Primary MDRTB ranged from 2.3% in Chennai to 17.3% in Lucknow while acquired
MDRTB ranged from 24.1% in Nagpur to 40.0% in Pune. The results from TN Dr.MGR,
Chennai center were excluded as their performance was not optima. (Letter from Dr.CN
Paramasivan and Nagpur center, that results were excluded because of the molecular
typing results.)
Reports from participating centers:
Statistical significant testing for all the risk factors analyzed were calculated for each
center individually even though the numbers may be small. But it was analyzed
collectively from all the centers as well.
Trivandrum Center:
A total of 551 patients enrolled in the study which includes 270 from the hospital and 281
from the DTC. 779 sputum smears were tested and of these 576 were sputum positive.
Initial observations on 402 patients for whom drug susceptibility tests are available
indicated that 53 (13.2%) had MDRTB. Further, the risk for MDRTB was approximately
four times greater amongst those with a past history of ATT (OR 5.95). Except for past
history and compliance, the other factors analyzed were not significant. The analysis of
the quality control for this center is shown in Annexure I (vi).
Nagpur Center:
A total of 415 patients enrolled in the study until December 31, 2002. 787 sputum
smears were tested and 771 were found to be sputum smear positive. Drug susceptibility
results have been received from 299 patients and 415 proformas have been received at the
coordinating center. None of the risk factors analyzed were found to be significant.
The analysis of the quality control for this center is shown in Annexure I (v).
Pune Center:
This center recruited a total of 562 patients during the period of the study. Of these 562
patients, 1283 sputum samples have been collected and processed as follows: 562 spot,
500 overnight and 221 spot B. 923 sputum smears were found to be smear positive. The
number of cultures tested in this period is 209 and drug susceptibility results are available
in 338. Primary MDRTB was found to be 9.6% while acquired MDRTB was 40.0%. Of
all the risk factors studied, only past history of ATT was found to be significant (P value
10 - ³) and bacillary load the OR was 1.04. The analysis of the quality control for this
center is shown in Annexure I. (iii)
Lucknow Center:
A total of 581 patients enrolled in the study until December 31, 2002. 1130 sputum
smears were tested and 971 were found to be sputum smear positive. Drug susceptibility
patterns are available in 331 patients. Primary MDRTB was 17.3% and acquired
MDRTB at this center was found to be 29%. In bacillary load, the OR was found to be
0.9. None of the risk factors were found to be significant. The analysis of the quality
control for this center is shown in Annexure I(iv).

Vellore Center:
The total number of 281 patients from the HOS and 308 from the PHC setting enrolled
until December 31, 2002. 981 sputum smears were tested and 867 were found to be
sputum smear positive. Drug susceptibility results are available from 414 patients.
Primary MDRTB was found to be 4% while acquired MDRTB was 36.5%. Only past
history of ATT was found to be significant (P value 10 - ³). In bacillary load the OR was
0.6. The fifth cycle of the quality control exercise was completed in this center. The
results of Round V from CMC, Vellore have shown 100% agreement for Streptomycin,
Ethambutol and rifampicin. The agreement was 80% for isoniazid. The results of the
quality control analysis are shown in Annexure I (ii).
Chennai – ITM – Center:
The total number of patients recruited until December 31, 2002 were 412 and of these
371 were sputum smear positive. 984 smears were tested and of these 923 were found to
be sputum smear positive. The number of culture specimens sent was 748. 186 drug
susceptibility results were available. Primary MDRTB was found to be 2.3% and
acquired MDRTB was found to be 34.7%. Of all the risk factors analyzed only past
history of ATT was found to be significant (P value 10 - ³). In bacillary load, the OR was
1.02.
A number of cultures got lost either due to non-viability or contamination. Quality
control testing by TRC for the drug susceptibility testing was started late. However, five
cycles of quality control exercise were completed. Round V has shown 100% agreement
for isoniazid, rifampicin and ethambutol. The agreement for streptomycin was 70%. The
analysis of the quality control is shown in annexure I. (vii)
Dr.MGR Medical University:
A total of 456 patients enrolled in the study. 275 patients enrolled from the hospital and
181 from the DTC. The intake of the study started in early May 2001. Processing started
in mid June. The delay affected the viability of the isolates. Hence, the center had to
restart collection of the samples. 785 sputum smears were tested of which 611 were
found to be sputum smear positive. Drug susceptibility results are available from 446
patients. Primary MDRTB was found to be 1.3% while acquired MDRTB was 0.9%.
None of the other risk factors were found to be significant. Only one round of quality
control exercise took place at this center. Analysis of the quality control is shown in
Annexure I (viii).
AIIMS Center:
Recruitment from all of the three centers progressed satisfactorily. During the period of
the study, a total of 1467 patients have been enrolled: 678 from the hospital, 346 from
the PHC and 443 from the DTC. Of these, 1467 patients 3867 smears have been done
and of these 3867 smears 3166 have been found to be positive and 701 are negative.
Seventeen of these patients are HIV positive. A total of 648 drug susceptibility results
have become available and Primary MDRTB was found to be 8.5% at the hospital and
7.2% at the DTC and 6.9% at the PHC giving primary MDRTB at the AIIMS center to be
8.5. Acquired MDRTB was found to be 45.5% at the hospital and 23.6% at the PHC and

20% at the DTC giving acquired MDRTB to be 29.8% at the AIIMS center. Past history
of ATT (P value 10 -3 ) socioeconomic status (P value 10 - ²) and bacillary load (P value 10 -
4 ) were found to be significant. The analysis of the quality control for this center is
shown in Annexure I (i).
Risk factors:
Multivariate analysis of the data combined from all of the participating centers indicated
that of the risk factors studied for MDRTB bacillary load (p value: 10 -3 ), previous
treatment (p value: 10 -7 ) , socio-economic status (low) (p value: 10 -3 ), and uneducated (p
value 0.01) were found to be significant. Smoking (p value 0.04) and alcohol intake (p
value 0.05) were found to be protective. HIV status and sex were not significant.
However, there was a preponderance of males pointing to a possible difference in the
attendance in these clinics.
As the performance of the Dr.MGR, Chennai center was not optimal, it was decided to
re-analyze the data for the risk factors excluding the data from this center. The results are
depicted in the following table.
Table IX: Risk factors for MDRTB (All centers combined)
Previous treat
1082/2975 5.03 (4.05-6.26) 10-7
HIV
High bacillary load
Smoking
Alcohol
Male sex
Uneducated
SED (low)
82/2279 0.69 (0.32-1.43) 0.29
1463/1941 1.53 (1.19-1.96) 10-3
1162/2876 0.81 (0.65-1.00) 0.04
1217/2882 0.81 (0.66-1.01) 0.05
2135/2975 1.01 (0.80-1.26) 0.95
1754/2490 1.37 (1.04-1.65) 0.01
1475/3065 1.37 (1.12-1.68) 10-3
Risk Factors for MDRTB (All centers combined excluding Dr.MGR):
Previous treat
1588/2562 4.97 (3.97-6.21) 10-7
HIV 70/1876 0.66 (0.30-1.39) 0.33
High bacillary load
1463/1941 1.53 (1.19-1.96) 10-3
Smoking 1007/2460 0.80 (0.64-0.99) 0.03
Alcohol 1028/2466 0.85 (0.69-0.99) 0.12
Male sex 1839/2559 0.99 (0.79-1.25) 0.94
Uneducated 1529/2213 1.22 (0.97-1.54) 0.08
SED (low) 1081/2619 1.03 (0.83-1.26) 0.80

Multivariate analysis of the data excluding the data from Dr.MGR center indicated that of
the risk factors studied for MDRTB bacillary load (p value: 10 -3 ) and previous treatment
(p value: 10 -7 ) were found to be significant. Smoking (p value 0.04) was found to be
protective. HIV status, alcohol intake, socio-economic status (low), education and sex
were not significant. Once again there was a preponderance of males.
Quality Control Results:
TRC Chennai: The details in brief of the Quality Control (QC) and the External
Quality Assurance (EQA) exercise from all the participating centers are as follows:
AIIMS: 4 rounds of QC & EQA completed. There was 100% agreement for
isoniazid and rifampicin while for streptomycin and ethambutol there was one
discrepancy each.
CMC Vellore: 5 rounds of QC & EQA completed. There was a 100% agreement
in results for the rifampicin, ethambutol and streptomycin. For isoniazid, the
agreement was 80%.
BJ Medical College Pune: 4 rounds of QC & EQA completed. 100% agreement
for ethambutol, isoniazid and rifampicin. The agreement for streptomycin was
90%.
KG Medical College Lucknow: 4 rounds of QC completed. There was 100%
agreement for isoniazid while only 90% agreement for the other three drugs.
GMC Nagpur: 4 rounds of QC completed. There was 100% agreement for all the
four drugs.
Medical College, Trivandrum: 1 round QC & EQA completed. 2nd round QC
sensitivity results had shown gross discordance due to problems faced in drug
concentration in the medium. Mr. P Venkataraman visited the center, rectified the
problem and sent them pre-weighed drug vials as requested. Retesting results in
the third round showed 90% concordance with ethambutol and rifampicin and
80% with isoniazid.
ITM Chennai: Had five rounds of QC & EQA testing. In round 5, there was
100% agreement with isoniazid, rifampicin and ethambutol. There was 70%
agreement with streptomycin.
MGR University Chennai: Only had one round of QC and EQA testing. In this
round there was 90% agreement with streptomycin, isoniazid and rifampicin.
There was 80% agreement with ethambutol.
The first two rounds of quality control and external quality assurance results from the
eight centers are shown in Annexure I (i – viii).
Molecular Typing: This component is being sent as a separate report.
Study Findings:
Results of the study bring out marked geographical variation in prevalence of MDRTB.
Although the resistance is at a relatively low level in the state of Tamil Nadu, it seems to
be fairly high in other parts of the country. Lower levels of resistance were observed in
the settings of PHC or DTC as compared to patients attending tertiary care centers.
Presence of extensive cavitary disease is a risk factor for MDRTB. These findings have

een presented to officials in the ministry of health (Director General TB, New Delhi)
and representatives of the regional center of WHO and USAID.
This study presents original results on the prevalence and risk factors for MDRTB, some
of which may be contrary to the beliefs of many of the planners and policy makers of the
TB program in the country. These results are inconsistent with those results reported in
literature.
Study Significance:
From this study, it was found that the most important risk factor for drug resistant
tuberculosis is previous chemotherapy for tuberculosis, which was either inadequate or
taken irregularly. The prevalence of MDRTB in various clinical settings (primary health
centers, PHC, district tuberculosis centers (DTC) or tertiary care centers) in different
geographical locations in India had not been systematically studied. This study provides,
for the first time, authentic data on these sites. Also analyzed critically, were various risk
factors involved in the presence of multi drug resistance amongst patients who have
never received anti-tuberculosis treatment (ATT) in the past, as well as those who have
been treated for tuberculosis.
The findings of the present study have major implications for the TB program in India.
The revised National Tuberculosis program having the strategy of DOTS is currently
covering approximately 50% of the Districts. In view of the risk of emergence of
primary MDRTB of a greater magnitude it is important that the program is expanded to
cover the remaining districts at the earliest.
Laboratory staff in eight participating centers all over the country has been trained in
culture and the drug susceptibility testing. The capabilities of these laboratories were
upgraded so that in future some of them could take up the role of reference laboratories at
the state level. This will have a very important role in the future if the MDRTB problem
escalates necessitating drug testing for individualized treatment.
There has also been an establishment of efficient networking between the eight
participating centers. The findings of this study are of considerable importance as they
will have some implications for the TB program in India.
Impact and global perspective of this study:
This study highlights important differences in the prevalence of multi-drug resistant
tuberculosis (MDRTB) in different parts of India. The prevalence of primary MDR-TB
in the state of Tamil Nadu (Chennai, Vellore) appears to be around 3% where as it
appears to be significantly higher in the centers at Lucknow, Pune, Delhi and Nagpur. It
is noted however, that the prevalence as estimated by the present study is based on
hospital attendees and the group prevalence in the community may be significantly lower.
This is reflected in the finding of the prevalence of primary MDRTB being much lower at
the District tuberculosis center ( Faridabad) and Primary tuberculosis center
(Ballabhgarh) as compared to the AIIMS center.

The study has also confirmed the high risk of emergence of MDRTB amongst those who
received unsupervised daily short course regimens. The study will have a major impact
of the continuing practices of the private practitioners and other health practitioners
outside the RNTCP program of prescribing unsupervised daily regimens containing
rifampicin. The findings from the present study would also be relevant for other
developing nations where the DOTS strategy has not been fully implemented.
Study dissemination:
A workshop was held in Chennai on April 26, 2003, where all the clinical and
microbiology investigators from the participating centers were invited to present their
findings. This meeting was also attended by Professor C. N. Parmasivan and Mr.
Venkatraman who presented their data on the quality control exercises. Representatives
of WHO East Asia Region, Dr. Fraser Wares; Ministry of Health TB; Dr. Chauhan and
USAID, Dr. Dora Warren were special invitees. The meeting was chaired by Dr. P. R.
Narayanan, Director TRC. For the first time, data on MDRTB in India has been gathered
from eight geographical sites in the country using standard methodology with strict
quality control. The results indicated higher prevalence of MDRTB amongst individuals
who had not received anti-tuberculosis treatment in the past. Although the prevalence of
MDRTB in these groups of subjects was quite low in the centers in Tamil Nadu, it was
appreciably higher in the remaining centers in Lucknow, Delhi, Nagpur, Pune and
Trivandrum. It was recommended in the committee that continuation of this study would
help generate useful data that may impact on the current policy of the revised national TB
Control Program. It was also recommended that a portion of strains of mycobacteria
obtained from the other centers may be cross checked for drug susceptibility results and
molecular finger printing for RPOβ gene.
This data was presented by Dr. JN Pande on behalf of the IndiaCLEN MDRTB group at
the INCLEN Global meeting XIX, Kunming, PR China, in February, 2003. The title of
the presentation was “Investigations of Risk factors and transmission of drug resistant
TB. Abstract No: 28.
References:
1. Trivedi SS, Desai SG. Primary antituberculosis drug resistance and acquired
rifamicin resistance in Gujarat, India. Tubercle 1988; 69 (1):37-42
2. Paramasivan CN, Chandrasekaran V, Santha T, Sudarsanam NM, Prabhakar R.
Bacteriological investigations for short-course chemotherapy under the
tuberculosis programme in two districts of India. Tuber Lung Sis 1993; 74 (1):
23-7.
3. Mathur ML, Khatri PK, Base CS. Drug resistance in tuberculosis patients in
Jodhpur district. Indian J Med Sci 2000; 54(2): 55-8

4. Paramasivan CN, Venkataraman P, Chandrasekaran V, Bhat S, Narayanan PR.
Surveillance of drug resistance in tuberculosis in two districts of South India. Int.
J Tuberc Lung Dis 2002; 6(6): 479-84.
5. Paramasivan CN. Status of drug resistance in tuberculosis after the introduction of
rifampicin in India. J Indian Med Assoc 2003; 101(3): 154-6.

Annexure I (i)
Results of the Quality Control and External Quality Assurance Exercise: center
wise.
AIIMS, New Delhi Center:
QC Round I QC Round II
S H R E S H R E
Total No. tested 7 9
Resistant 4 2 3 3 4 7 4 5
Susceptible 3 5 4 4 5 2 5 4
True Resistant 3 2 3 2 4 7 4 3
False Resistant 1 0 0 1 0 0 0 2
True Susceptible 3 4 4 4 5 2 5 4
False Susceptible 0 1 0 0 0 0 0 0
Sensitivity (%) 75 100 100 67 100 100 100 60
Specificity (%) 100 80 100 100 100 100 100 100
Predictive Value for R (%) 100 67 100 100 100 100 100 100
Predictive Value for S(%) 75 100 100 80 100 100 100 67
Efficiency (%) 86 86 100 86 100 100 100 78
EQA Round I EQA Round II
S H R E S H R E
Total No. tested 7 10
Resistant 5 7 3 3 5 5 3 3
Susceptible 2 0 4 4 5 5 7 7
True Resistant 3 6 2 1 5 5 3 3
False Resistant 2 1 1 2 0 0 0 0
True Susceptible 2 0 4 4 4 5 7 6
False Susceptible 0 0 0 0 1 0 0 1
Sensitivity (%) 60 86 67 33 100 100 100 100
Specificity (%) 100 - 100 67 80 100 100 86
Predictive Value for R (%) 100 100 100 100 83 100 100 75
Predictive Value for S(%) 50 0 80 67 100 100 100 100
Efficiency (%) 71 86 86 71 90 100 100 90

Annexure I (ii)
Results of the Quality Control and External Quality Assurance Exercise: center
wise.
CMC, Vellore Center:
QC Round I QC Round II QC Round
III
S H R E S H R E
Total No. tested 9 7
Resistant 3 5 4 2 2 5 4 1
Susceptible 6 4 5 7 5 2 3 6
True Resistant 2 4 4 2 2 5 4 1
False Resistant 1 1 0 0 0 0 0 0
True Susceptible 5 3 4 6 5 2 3 6
False Susceptible 1 1 1 1 0 0 0 0
Sensitivity (%) 67 80 100 100 100 100 100 100
Specificity (%) 83 75 80 86 100 100 100 100
Predictive Value for R 67 80 80 67 100 100 100 100
(%)
Predictive Value for 83 75 100 100 100 100 100 100
S(%)
Efficiency (%) 78 78 89 89 100 100 100 100
EQA Round I EQA Round II EQA Round III
S H R E S H R E S H R E
Total No. tested 10 10 10
Resistant 2 6 4 3 5 7 5 4 5 5 6 6
Susceptible 8 4 6 7 5 3 5 6 5 4 5 8
True Resistant 2 6 4 3 5 7 5 4 5 5 5 2
False Resistant 0 0 0 0 0 0 0 0 5 3 5 8
True Susceptible 8 2 6 7 4 3 5 5 0 1 0 0
False Susceptible 0 2 0 0 1 0 0 1 0 1 0 0
Sensitivity (%) 100 100 100 100 100 100 100 100 100 83 100 100
Specificity (%) 100 50 100 100 80 100 100 83 100 75 100 100
Predictive Value for R 100 75 100 100 83 100 100 80 100 83 100 100
(%)
Predictive Value for 100 100 100 100 100 100 100 100 100 75 100 100
S(%)
Efficiency (%) 100 80 100 100 90 100 100 90 100 80 100 100

Annexure I (iii)
Results of the Quality Control and External Quality Assurance Exercise: center
wise.
BJ Medical College, Pune Center:
QC Round I QC Round II QC Round
III
S H R E S H R E
Total No. tested 9 5
Resistant 3 7 5 4 3 4 3 1
Susceptible 6 2 4 5 2 1 2 4
True Resistant 3 6 5 4 2 4 3 1
False Resistant 0 1 0 0 1 0 0 0
True Susceptible 6 2 4 5 2 1 2 3
False Susceptible 0 0 0 0 0 0 0 1
Sensitivity (%) 100 86 100 100 67 100 100 100
Specificity (%) 100 100 100 100 100 100 100 75
Predictive Value for R 100 100 100 100 100 100 100 50
(%)
Predictive Value for 100 67 100 100 67 100 100 100
S(%)
Efficiency (%) 100 89 100 100 80 100 100 80
EQA Round I EQA Round II EQA Round
III
S H R E S H R E
Total No. tested 18 9
Resistant 8 9 10 5 4 4 4 1
Susceptible 10 9 8 13 5 5 5 8
True Resistant 8 9 8 5 4 4 4 1
False Resistant 0 0 2 0 0 0 0 0
True Susceptible 9 9 8 13 4 5 5 8
False Susceptible 1 0 0 0 1 0 0 0
Sensitivity (%) 100 100 80 100 100 100 100 100
Specificity (%) 90 100 100 100 80 100 100 100
Predictive Value for R 89 100 100 100 80 100 100 100
(%)
Predictive Value for 100 100 80 100 100 100 100 100
S(%)
Efficiency (%) 94 100 89 100 89 100 100 100

Annexure I (iv)
Results of the Quality Control and External Quality Assurance Exercise
King George Medical College, Lucknow Center:
QC Round I QC Round II QC Round
III
S H R E S H R E
Total No. tested 7 10
Resistant 2 3 4 2 4 8 5 1
Susceptible 5 4 3 5 6 2 5 9
True Resistant 2 3 4 2 3 7 5 1
False Resistant 0 0 0 0 1 1 0 0
True Susceptible 5 3 3 5 5 2 5 7
False Susceptible 0 1 0 0 1 0 0 2
Sensitivity (%) 100 100 100 100 75 88 100 100
Specificity (%) 100 75 100 100 83 100 100 78
Predictive Value for R 100 75 100 100 75 100 100 33
(%)
Predictive Value for 100 100 100 100 83 67 100 100
S(%)
Efficiency (%) 100 86 100 100 80 90 100 80
EQA Round I EQA Round II EQA Round
III
S H R E S H R E
Total No. tested 7 10
Resistant 3 5 3 2 5 8 5 3
Susceptible 4 2 4 5 5 2 5 7
True Resistant 2 5 3 2 5 8 5 3
False Resistant 1 0 0 0 4 2 4 6
True Susceptible 4 2 4 4 0 0 0 0
False Susceptible 0 0 0 1 1 0 1 1
Sensitivity (%) 67 100 100 100 100 100 100 100
Specificity (%) 100 100 100 80 100 100 80 86
Predictive Value for R 100 100 100 67 83 100 83 75
(%)
Predictive Value for 80 100 100 100 100 100 100 100
S(%)
Efficiency (%) 86 100 100 86 90 100 90 90

Annexure I (v)
Results of the Quality Control and External Quality Assurance Exercise: center
wise.
Government Medical College, Nagpur Center:
QC Round I QC Round II QC Round
III
S H R E S H R E
Total No. tested 9 9
Resistant 5 1 5 0 1 7 6 3
Susceptible 4 8 4 9 8 2 3 6
True Resistant 3 1 4 0 1 5 5 3
False Resistant 2 0 1 0 0 2 1 0
True Susceptible 4 3 4 7 7 2 3 6
False Susceptible 0 5 0 2 1 0 0 0
Sensitivity (%) 60 100 80 0 100 71 83 100
Specificity (%) 100 38 100 78 88 100 100 100
Predictive Value for R 100 17 100 0 50 100 100 100
(%)
Predictive Value for 67 100 80 100 100 50 75 100
S(%)
Efficiency (%) 78 44 89 78 89 78 89 100
EQA Round I EQA Round II EQA Round
III
S H R E S H R E
Total No. tested 8 3
Resistant 0 1 1 0 0 1 1 0
Susceptible 8 7 7 8 3 2 2 3
True Resistant 0 0 0 0 0 1 1 0
False Resistant 0 1 1 0 0 0 0 0
True Susceptible 6 6 7 8 3 3 2 3
False Susceptible 2 1 0 0 0 0 0 0
Sensitivity (%) - - - - - 100 100 -
Specificity (%) - - - - 100 100 100 100
Predictive Value for R 0 0 0 - - 100 100 -
(%)
Predictive Value for 100 86 88 100 100 - - 100
S(%)
Efficiency (%) 75 75 88 100 100 100 100 100

Annexure I (vi)
Results of the Quality Control and External Quality Assurance Exercise: center
wise.
Medical College, Trivandrum Center:
QC Round I QC Round II QC Round
III
S H R E S H R E
Total No. tested 8 9
Resistant 6 7 7 8 - 7 4 2
Susceptible 2 1 1 0 - 2 5 7
True Resistant 2 5 5 4 - 6 4 2
False Resistant 4 2 2 4 - 1 0 0
True Susceptible 2 1 1 0 - 1 4 6
False Susceptible 0 0 0 0 - 1 1 1
Sensitivity (%) 33 71 71 50 - 86 100 100
Specificity (%) 100 100 100 - - 50 80 86
Predictive Value for R 100 100 100 100 - 86 100 66
(%)
Predictive Value for S(%) 33 33 33 0 - 50 100 100
Efficiency (%) 50 75 75 50 - 78 89 89
EQA Round I EQA Round II EQA Round III
S H R E S H R E
Total No. tested 12
Resistant 12 12 12 12
Susceptible 0 0 0 0
True Resistant 2 5 4 2
False Resistant 10 7 8 10
True Susceptible 0 0 0 0
False Susceptible 0 0 0 0
Sensitivity (%) 17 42 33 17
Specificity (%) 0 0 0 0
Predictive Value for R (%) 100 100 100 100
Predictive Value for S(%) 0 0 0 0
Efficiency (%) 17 42 33 17

Annexure I (vii)
Results of the Quality Control and External Quality Assurance Exercise: center
wise.
Institute of Thoracic Medicine, Chennai:
QC Round I QC Round II QC Round
III
S H R E S H R E
Total No. tested 8 8
Resistant 3 7 6 3 3 5 3 3
Susceptible 5 1 2 5 4 2 5 4
True Resistant 3 7 6 3 3 5 3 3
False Resistant 0 0 0 0 0 0 0 0
True Susceptible 5 1 2 5 4 1 3 4
False Susceptible 0 0 0 0 0 1 2 0
Sensitivity (%) 100 100 100 100 100 100 100 100
Specificity (%) 100 100 100 100 100 100 60 100
Predictive Value for R 100 100 100 100 100 83 75 100
(%)
Predictive Value for 100 100 100 100 100 100 75 100
S(%)
Efficiency (%) 100 100 100 100 100 86 75 100
EQA Round I EQA Round II EQA Round
III
S H R E S H R E S H R E
Total No. tested 10 10 10
Resistant 6 6 4 2 3 6 4 2 2 7 4 3
Susceptible 4 4 6 8 7 4 6 8 8 3 6 7
True Resistant 4 6 4 1 3 6 4 0 1 7 4 3
False Resistant 2 0 0 1 0 0 0 2 1 0 0 0
True Susceptible 4 4 6 8 7 4 6 7 6 3 6 7
False Susceptible 0 0 0 0 0 0 0 1 2 0 0 0
Sensitivity (%) 67 100 100 50 100 100 100 0 50 100 100
100
Specificity (%) 100 100 100 100 100 100 100 88 75 100 100
100
Predictive Value for R 100 100 100 100 100 100 100 0 33 100 100
(%)
100
Predictive Value for 67 100 100 89 100 100 100 78 86 100 100
S(%)
100
Efficiency (%) 80 100 100 90 100 100 100 70 70 100 100
100

Annexure I (viii)
Results of the Quality Control and External Quality Assurance Exercise: center
wise.
MGR University, Chennai:
QC Round I QC Round II QC Round III
S H R E S H R E
Total No. tested 10
Resistant 3 6 4 3
Susceptible 7 4 6 7
True Resistant 3 6 4 2
False Resistant 0 0 0 1
True Susceptible 6 3 5 6
False Susceptible 1 1 1 1
Sensitivity (%) 100 100 100 67
Specificity (%) 86 75 83 86
Predictive Value for R (%) 75 86 80 67
Predictive Value for S(%) 100 100 100 86
Efficiency (%) 90 90 90 80
EQA Round I EQA Round II EQA Round III
S H R E S H R E
Total No. tested 20
Resistant 13 6 11 3
Susceptible 7 14 9 17
True Resistant 4 0 0 0
False Resistant 9 6 11 3
True Susceptible 6 14 9 17
False Susceptible 1 0 0 0
Sensitivity (%) 31 0 0 0
Specificity (%) 86 100 100 100
Predictive Value for R (%) 80 0 0 0
Predictive Value for S (%) 40 70 45 85
Efficiency (%) 50 70 45 85