Original Article

[Received: May 11, 2006; accepted after revision: October 3, 2006]

Correspondence and reprint requests: Dr Rupak Singla, Senior Chest Physician and Head, Department of TB and
Respiratory Diseases, L.R.S. Institute of Tuberculosis and Respiratory Diseases, Sri Aurobindo Marg, New Delhi-110 030,
India; Tele.: 91-11-26854922/26517829; Telefax: 91-11-26517834; E-mail: drrupaksingla@yahoo.com.
DOTS-Plus for Patients with Multidrug-resistant
Tuberculosis in India: Early Results After Three Years
V.K. Arora, R. Sarin, R. Singla, U.K. Khalid, K. Mathuria, Neeta Singla and V.P. Myneedu
Department of Tuberculosis and Respiratory Diseases, L.R.S. Institute of Tuberculosis and Respiratory
Diseases, Sri Aurobido Marg, New Delhi, India
ABSTRACT
Setting. Tertiary referral hospital in Delhi, India with a well established directly observed treatment, short-course (DOTS)
infastructure.
Objective. The study aimed to evaluate pilot project of DOTS-Plus strategy in India using a standardised treatment regimen
(STR).
Methods. Retrospective analysis of the records of 66 patients with multidrug-resistant tuberculosis (MDR-TB) who failed
on short-course chemotherapy and were treated with a fully supervised STR containing kanamycin, pyrazinamide (both for
initial intensive phase of 6-9 months), ofloxacin, ethionamide and cycloserine was done. Continuation phase drugs were given
for at least 18 months after conversion to a negative culture. Thirteen patients required intensive phase of more than six
months (mean duration of 7.4 months). Clinical and bacteriological progress was monitored at regular intervals.
Results. Of the 66 patients included for analysis, 53 (80.9%) became culture-negative, 77.3% of these within three months.
Four (6.1%) failed to convert within nine months. Rest died or defaulted. Among 28 patients completing two years of
treatment, 67.9% were cured, 14.3% died, 17.9% defaulted, but none failed treatment. Cycloserine had to be stopped in five
patients, and kanamycin in three patients due to adverse effects. Other drugs were better tolerated.
Conclusions. In resource-poor settings, well-designed STR under DOTS-Plus programme may provide reasonable results.
However, this approach is associated with significant operational difficulties in the enrolment, diagnosis and management
of MDR-TB patients. [Indian J Chest Dis Allied Sci 2007; 49: 75-79]
Key words: Tuberculosis, Multidrug resistant, Treatment.
INTRODUCTION
Multidrug-resistant tuberculosis (MDR-TB) is defined
as resistance to at least isoniazid and rifampicin. The
third global report of anti-tuberculosis drug resistance
reported the prevalence of MDR-TB among new
tuberculosis (TB) cases from 75 settings ranging from
0 percent to 14.2 percent.
1
Directly observed treatment,
short-course (DOTS) strategy with standardised short-
course chemotherapy (SCC) using first-line drugs is
currently the mainstay of TB control globally. However,
in MDR-TB patients DOTS strategy does not provide
acceptable cure rates.
2,3
In India MDR-TB in new cases has generally been
reported to be less than or equal to 3% and MDR-TB in
treated patients has been reported to be 12% except in a
few settings.
4
It has been proposed that countries with
well-functioning DOTS programmes and having MDR-
TB endemic populations should provide additional
services, such as the DOTS-Plus programme, to
diagnose and treat MDR-TB patients.
5
Most MDR-TB
treatment programmes have used individualised
treatment regimens (ITRs) based on drug susceptibility
test (DST) results from each patient.
5,6
This
individualised treatment strategy requires resources
that are not available in most low-income countries.
The alternative strategy involves treating all MDR-
TB patients with a standardised treatment regimen
(STR) based on the common DST profile of the
prevalent MDR-TB strains.
7,8
This study provides first
experience of a DOTS-Plus programme in India
employing such a standardised treatment strategy.
PATIENTS AND METHODS
A pilot project using STR for MDR-TB patients was
76 DOTS-Plus Pilot Experience in India V.K. Arora et al
started under DOTS-Plus strategy in January 2002 in
the domiciliary treatment area of a 520-bedded tertiary
referral institute in Delhi, India. This institute has
national reference microbiology laboratory and is
implementing the DOTS strategy in a population of
around 1.6 million.
A DOTS-Plus committee, consisting of clinicians,
bacteriologists, epidemiologists, social worker and
health education officer, was constituted and
operational guidelines were formulated. The service
providers were given formal training to manage MDR-
TB patients under this strategy. All major decisions,
such as enrolment in study, change over from intensive
phase to continuation phase, and modification of
treatment regimen due to adverse drug reactions, etc.,
were taken by the DOTS-Plus committee. The present
study reports on the retrospective analysis of the first
cohort of 66 patients enrolled from January 2002 to
March 2005.
Based on the prevalent drug resistance profiles, and
the cost and availability of various drugs, a
standardised regimen was devised and prescribed for
all enrolled patients free of cost. The funds for drugs
were arranged from the institute funds. Intensive phase
consisted of daily supervised treatment with
kanamycin, cycloserine, ofloxacin, ethionamide and
pyrazinamide given for at least six months or till three
consecutive negative sputum cultures, whichever was
later. The intensive phase could be extended to
maximum nine months if culture conversion was
delayed. This was followed by continuation phase
consisting of cycloserine, ofloxacin and ethionamide for
18 months. Para-aminosalicylic acid (PAS) was to be
substituted in case of initial drug resistance to
pyrazinamide or in case of intolerance to any of the
drugs.
The daily dosages prescribed were: kanamycin (0.75
g); ethionamide and cycloserine (0.5 g each); ofloxacin
(600 mg); pyrazinamide (1.5 g). Ethionamide, ofloxacin
and cycloserine were given in two divided doses. In
elderly patients and patients weighing less than or
equal to 30 kg, the dose of kanamycin was reduced to
0.5 grams. In patients weighing more than 50 kg, the
daily dose of ethionamide and cycloserine was
increased to 750 mg and ofloxacin to 800 milligrams.
Category II regimen subjects, who failed after
receiving re-treatment regimen with first-line drugs
under DOTS strategy, were initially enrolled. Two
sputum specimens were collected for smear microscopy
for acid-fast bacilli (AFB), culure and drug sensitivity
studies by conventional and BACTEC methods. The
drug susceptibility studies were performed for
isoniazid, rifampicin, ethambutol, streptomycin and
pyrazinamide using the proportion method.
9
There is
no standardised method for testing for pyrazinamide
sensitivity on solid media. For pyrazinamide special
modification of BACTEC susceptibility test was used
which correlated well with pyrazinamide test results of
other alternative methods.
10,11
Patients only with laboratory confirmed MDR-TB
and residing in geographical area supported by the
Institute were included in the study. Patients who had
already taken second-line drugs, pregnant patients,
human immunodeficiency virus (HIV) positive, and
unmotivated patients were excluded from the study.
Each participant provided written informed consent.
All patients were hospitalised for at least one month.
On admission, a team consisting of medical specialists,
social workers and health education officers evaluated
the patients. Baseline chest radiograph, biochemical and
haematological investigations were performed.
Serological investigations for HIV infection were
performed in all the patients after obtaining consent.
The DOTS-Plus committee evaluated and started
treatment in eligible patients. During hospitalisation
period linkages were set up with peripheral directly
observed treatment (DOT) centers where patients were
to receive treatment after discharge.
After discharge patients received daily, supervised
treatment in the peripheral DOT centers. A household
member supervised the evening dose and patients
brought the empty blister packages the next day. House
visit was done for default retrieval within a day of
patient missing the visit to the DOT centre.
During follow-up, two sputum specimens for smear
microscopy and culture were collected at the end of the
each month of treatment in the intial intensive phase.
Clinical and bacteriological follow-up was then
conducted once in two months until treatment
completion. In order to define treatment outcomes, a
minimum of five-cultures must have been performed in
the last 12 months of treatment. Chest radiographs were
done at a six-month interval.
Treatment outcome definitions were as follows: a
patient who has completed MDR-TB treatment, is
culture-negative in the last month of treatment, and has
been culture-negative during the preceding 11 months
of treatment was defined as having been cured. A
patient who completed MDR-TB treatment but did not
meet the definition for cure or failure due to lack of
bacteriologic results was categorised as treatment
completed . Treatment failure was defined as more
than one positive culture in the last 12 months of
treatment, with a minimum of five cultures performed
during the last 12 months, or if patient is persistently
culture-positive and a clinical decision has been made to
terminate treatment early. Death was defined as
patient who dies for any reason during the course of
MDR-TB treatment. Treatment default was defined as
patient whose MDR-TB treatment was interrupted for
two or more consecutive months.
Culture conversion was defined as three negative
consecutive cultures taken at least one month apart after
treatment initiation. Time to culture/smear conversion
2007; Vol. 49 The Indian Journal of Chest Diseases & Allied Sciences 77
was defined as the time interval between the date of
MDR-TB treatment initiation and the date of the first of
three negative consecutive cultures/smears, taken at
least one month apart.
Data handling and statistical analyses were
performed using Epi Info (version 6.02, Centers for
Disease Control and Prevention, Atlanta, GA, USA).
The Ethical Committee of the Institute approved the
study.
RESULTS
Sixty-six patients were enrolled and were treated with
the standardised treatment regimen. The demographic
characteristics and drug resistance patterns of the final
cohort of 66 patients are given in table 1. The median
age of patients was 28 years (range 14-69 years). There
were 36 males. Drug-susceptibility testing results
showed 34.8% had RH resistance, 34.8% had RH plus
one more drug resistance, 25.8% had RH plus two more
drug resistance, and 4.5% had resistance to RH plus
three more drugs; 18.2% of the isolates were resistant to
pyrazinamide.
Out of the 66 patients included for analysis, 53
(80.9%) patients achieved sputum culture conversion
within nine months (Table 2). Notably, among these 53
patients, 77.4% patients became culture-negative within
three months and 92.5% became culture-negative within
six months of treatment. Another four (6.1%) patients
remained culture-positive even after receiving
treatment for more than nine months.
Table 1. Demographic profile and anti-tuberculosis drug
resistance pattern in 66 patients with MDR-TB
Age (years)* 28 (14-69)
Gender (Male : Female) 36 : 30
Duration of symptoms (months)* 30 (1-119)
Duration of past ATT (months)* 14 (6-57)
Chest radiograph severity
Bilateral

47 (71.2)
Extensive

49 (74.2)
Cavitary

29 (43.9)
Not reported

10 (15.2)
Resistance to
RH only

23 (34.8)
RH + one more drug

23 (34.8)
RH+ two more drugs

17 (25.8)
RH + three more drugs

3 (4.5)
Any drug resistance
Isoniazid

66 (100)
Rifampicin

66 (100)
Streptomycin

30 (45.4)
Ethambutol

24 (36.4)
Pyrazinamide

12 (18.2)
*=data expressed as median (range); =data expressed as
number (%);

=extensive disease was defined as radiological evidence of

cavities and/or moderately dense infiltrates involving more
than one lobe;
ATT=anti-tuberculosis treatment; R=rifampicin; H=isoniazid
The patients under study were symptomatic for a
median of 30 months (range 1-119 months) at
presentation. They had taken treatment for TB for a
median of 14 months (range 6-57 months). Radiological
evidence of extensive disease affecting more than one
lobe; was observed in 74.2% patients 71.2% had bilateral
disease, and 43.9% had cavitary disease.
Table 3. Treatment outcome in MDR-TB patients treated with
standardised treatment regimen under DOTS-Plus strategy
Outcome Patients Enrolled Patients Enrolled
upto December upto December
2003 (n=28) 2004 (n=52)*
Cured 19 (67.9%) 36 (69.2%)
Treatment completed Nil Nil
Failure Nil 4 (7.7%)
Defaulted 5 (17.9%) 6 (11.5%)
Died 4 (14.3%) 6 (11.5%)
*=likely treatment outcome based on 12 months treatment;
MDR-TB=multidrug-resistant tuberculosis;
DOTS-Plus=directly observed treatment, short course-Plus
Table 2. Time taken for sputum smear and culture conversion of
53 patients
Sputum Months for conversion
AFB 1 2 3 4 5 6 7 8 >8
Smear 6 12 7 10 7 3 5 2 1
Culture 16 9 16 1 5 2 3 1 0
AFB=acid-fast bacilli
Twenty-eight patients enrolled upto December 2003
had completed full treatment and were analysed for
treatment outcome (Table 3). Nineteen (67.9%) were
cured, four (14.3%) died, five (17.9%) defaulted, and
none failed treatment.
Fifty-two patients enrolled upto December 2004 who
had completed more than one-year treatment, were also
analysed for interim treatment outcome (Table 3).
Thirteen patients required intensive phase of more than
six months (mean duration of 7.4 months). Thirty-six
(69.2%) were likely to have been cured (clinically
improving and sputum culture continued to be negative
at one year), six (11.5%) died, six (11.5%) defaulted, and
four (7.7%) were likely to have failed treatment (sputum
culture positive even after 12 months).
Six patients (9.1%) of the 66 died; four of them within
one month of enrolment in the study. The remaining
two patients did not achieve sputum culture conversion
despite more than nine months of treatment. Seven
patients under study defaulted, six due to migration to
another area, and one patient due to intolerance to
drugs.
Twenty-three (34.8%) patients had minor side-effects.
Loss of taste, nausea and occasional vomiting were
common mild adverse effects seen in 19 (28.8%)
78
patients. These were effectively managed in hospital by
dietary modifications and symptomatic treatment, but
after discharge these interventions proved more
difficult to implement. Mild depression, responding to
symptomatic treatment, was noticed in 11 (16.7%)
patients; three (4.5%) had mild skin reactions; seven
(10.6%) had minor joints pain.
However, 10 (15.1%) patients had major adverse
reactions requiring treatment modification. In five
(7.6%) patients cycloserine had to be stopped due to
major psychotic reactions varying from major
depression, psychosis to violent behaviour. Kanamycin
was stopped in three (4.5%) patients due to hearing
loss/giddiness. Ofloxacin and pyrazinamide were
stopped in one patient due to severe arthralgias.
Pyrazinamide was stopped in another patient due to
hepatotoxicity. Para-aminosalicylic acid was used in 12
patients, but did not produce major adverse reaction
requiring stoppage of drug.
DISCUSSION
In affluent countries, individualised treatment regimens
(ITR) based on the patients drug susceptibility profile
remain the standard of care. The original evaluation of
ITRs conducted at Denver, Colorado and subsequent
studies in Korea, Turkey, Peru and the US have
achieved clinical response rates as high as 96% among
HIV-negative patients.
12-14
A recent meta-analysis on MDR-TB treatment
outcome in 13 different studies across the globe
observed cure rates ranging from 38 percent to 100
percent.
6
All studies had used ITR except one.
Individualised treatment has several theoretical
advantages compared with a standardised approach
7
but is operationally demanding in terms of
infrastructure. Also, ITR applied in absence of properly
functioning DOTS-Plus programme may show poor
results. Reports from Bolivia, Uganda using ITR
observed successful outcome in only 28% patients; 48%
patients defaulted, and 13% died.
15
Poor results were
attributed to poor capacity for performing DST, lack of
regular availability of several second-line anti-
tuberculosis drugs and lack of administration of DOT.
The present pilot study has evaluated a DOTS-Plus
programme in a resource-poor setting employing a
carefully designed fully STR with well-established
DOTS infrastructure under the Revised National
Tuberculosis Control Programme (RNTCP). It achieved
good results with a sputum culture conversion rate of
80.9% and cure rate of 67.9% with no failures. These
results are significantly superior to standardised
protocol used by the Peru National Tuberculosis
Programme (NTP) (32% failure rate and unknown
relapses among 298 proven MDR-TB cases).
8
Absence of data on prevalence of drug resistance
against second-line drugs in India is a limiting factor in
deciding about an effective STR regimen. Our treatment
regimen was meant to be a optimal combination
pretreatment, with possibility of replacing/adding PAS
wherever required thereby maintaining the
bacteriological effectiveness.
In the present study, full and daily DOT was
instituted in the intensive phase as well as continuation
phase of MDR-TB treatment, as recommended by
WHO.
8
The evening dose was supervised by a family
member and empty medicine strip was brought next
day and verified. However, daily DOT for two years
puts significant strain on programme as well as
patients. Many future MDR-TB treatment programmes
is resource-poor countries are likely to encounter
difficulties in attaining such high levels of supervision.
Almost one-third of the patients (34.8%) developed
minor side effects, that were manageable. Cycloserine
produced major psychotic reactions in five patients
requiring discontinuation of drug and modification of
treatment regime. Kanamycin was the second
commonest drug requiring discontinuation and
modification of treatment regime in three patients.
Other drugs such as ethionamide, pyrazinamide, PAS
and ofloxacin were better tolerated. No deaths due to
drug toxicity have been recorded in the present cohort.
Out of seven patients who defaulted, six had
migrated out of area and one developed drug
intolerance. Holding patients to a defined geographical
area for two years was difficult. At times patients
migrate into the domiciliary DOTS-Plus area to avail to
costly reserve drugs free of cost and this is an issue for
subsequent non-compliance.
Six of the 66 patients died; four of them within a
month of enrolment in the study. History of these
patients revealed that all these four patients had failed
to category I treatment and were receiving retreatment
regimens with first-line drugs under DOTS strategy.
Early recognition of their MDR-TB status and timely
institution of second-line drugs could have saved their
lives. This again adds to the ongoing debate that even in
developing countries whether category II treatment is
justified for category I treatment failure patients likely
to be having MDR-TB.
16
Multidrug-resistant tuberculosis is increasingly being
noticed in the last two decades. National programmes
in resource-poor endemic countries may feel pressured
into instituting DOTS-Plus programmes for their MDR-
TB patients.
5
This study demonstrates that the strategy
of using a standardised regimen provides acceptable
results. However, it also highlights the practical
difficulties in establishing MDR-TB treatment
programmes in resource-poor settings that may have
been understated to some extent by other authors.
6,13
Operational constraints to establish MDR-TB
treatment programmes include setting up proper
linkages of peripheral DOT centers with central
hospitals for referral/admission; problems in enrolling
patients due to work compulsions and inability to
DOTS-Plus Pilot Experience in India V.K. Arora et al
2007; Vol. 49 The Indian Journal of Chest Diseases & Allied Sciences 79
comply with daily DOT for two years; lack of ready
access to specialised laboratory facilities; arranging
daily DOT therapy for two long years, especially on
sundays and other holidays; managing severe adverse
drug reactions in field conditions. An MDR-TB
treatment trial in Rwanda found that nearly 50% of
eligible patients died or were lost to follow-up while
awaiting DST results from a distant reference
laboratory.
17
Arranging proper training to medical,
laboratory and non-medical workers for DOTS-Plus
programmes is another operational constraint.
Involvement of non-governmental organisation (NGOs)
or local private practitioners proved to be of great help
for some of these issues.
Though conducted in a resource-poor community in
India, this study was aided by several favourable
factors; an excellent laboratory services for DST was
easily available near to peripheral DOT centers; linkages
were already established between peripheral DOT
centers and referral hospital for admission; second-line
drugs (apart from the quinolones) had not been
commonly used for TB; and there was a well-
established RNTCP supported by a highly motivated
personnel. Therefore, the results of this study may not
be applicable to some other MDR-TB endemic
populations.
Although the number of patients in cohort are small,
the early results have shown that use of carefully
designed standardised treatment regimens with daily
DOT for full duration, well-established NTP supported
by highly motivated personnel and good linkage of
peripheral and referral central hospital, can provide
satisfactory results and can be implemented as part of a
successful DOTS programme. This study has also
highlighted the problems in enrolling, diagnosing and
managing MDR-TB patients in resource-poor countries.
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