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2
Drug-Resistant TB in India1
Key Messages
• ndia accounted for 24 percent of the 5.7 million new and relapse
I
TB cases notified globally in 2010 (WHO, 2011a).
• ndia had the second highest total number of estimated MDR
I
TB cases (99,000) in 2008, after China (100,000 cases) (WHO,
2010b).
• rug resistance surveys in several states have indicated that the
D
prevalence of MDR TB in India is 2–3 percent among new cases
and 12-17 percent among reinfection cases.
• ndia’s RNTCP has an overall goal of providing universal access
I
to quality diagnosis and treatment for all TB patients, with an inter-
mediate goal of successfully treating at least 90 percent of all new
and at least 85 percent of all previously treated patients.
continued
1 This chapter is based on the presentations of Ashok Kumar, Deputy Director General and
Head, Central TB Division, and Project Director, RNTCP; Kuldeep Singh Sachdeva, Chief
Medical Officer, Central TB Division; S. K. Sharma, Chair, Department of Medicine, All India
Institute of Medical Sciences (AIIMS); Rohit Sarin, Senior Consultant, Lala Ram Sarup (LRS)
Institute of Tuberculosis and Respiratory Diseases; and Aleyamma Thomas, Scientist G and
Director-in-Charge, National Institute for Research in Tuberculosis. (Since the workshop, the
Tuberculosis Research Centre [TRC] has been renamed the National Institute for Research in
Tuberculosis. For the remainder of this workshop summary report, the organization will be
referred to by its current name.)
17
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18 DRUG-RESISTANT TUBERCULOSIS IN INDIA
Key Messages Continued
• he RNTCP is scaling up the number of culture and DST lab-
T
oratories nationwide, along with treatment services, including
DOTS-Plus.
• espite these achievements, India’s efforts to control TB and MDR
D
TB still suffer from too few laboratories, slow diagnostic tools, inad-
equate management of treatment, insufficient supplies of second-
line drugs, and shortages of trained personnel.
• ommunity-based MDR TB treatment is being implemented as an
C
alternative model of treatment.
• ata from the RNTCP from 2007 to 2010 indicate that the majority
D
of MDR TB cases were undiagnosed in India.
Drug-resistant TB has existed in India virtually since anti-TB drugs
were introduced into the country. ICMR carried out state-of-the-art surveys
for drug-resistant TB more than 40 years ago (ICMR, 1968, 1969), and
surveys have continued since then (Paramasivan and Venkataraman, 2004).
Resistance to rifampicin, streptomycin, and other anti-TB drugs has been
detected for decades, and MDR TB also was seen in early surveys, although
at different levels depending on the place, time, and testing parameters.
However, the increasing burden of drug-resistant TB introduces new chal-
lenges to TB control and treatment. Ashok Kumar, Deputy Director General
and Head, Central TB Division, and Project Director, RNTCP; Kuldeep
Singh Sachdeva, Chief Medical Officer, Central TB Division; S. K. Sharma,
Chair, Department of Medicine, All India Institute of Medical Sciences
(AIIMS); Rohit Sarin, Senior Consultant, Lala Ram Sarup (LRS) Institute
of Tuberculosis and Respiratory Diseases; and Aleyamma Thomas, Scientist
G and Director-in-Charge, National Institute for Research in Tuberculosis,
described the current status of TB and MDR TB in India and the actions
taken by government at various levels to combat the disease.
THE BURDEN OF TB AND MDR TB IN INDIA2
India has the highest TB burden of any country in the world, account-
ing for an estimated one-fifth of global TB cases worldwide (Figure 2-1). It
has an estimated prevalence of 3 million TB cases, with 2 million new cases
2This section is based on the presentation of Kuldeep Singh Sachdeva, Chief Medical Officer,
Central TB Division.
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19
DRUG-RESISTANT TB IN INDIA
India
21%
Other countries
20%
Other 13 HBCs
16% China
14%
Philippines
Indonesia
3%
6%
Pakistan
3% Nigeria
Ethiopia 5%
South Africa
Bangladesh
3%
5%
4%
FIGURE 2-1 India has the highest TB burden of any country in the world. As of the
date of the workshop, annual incidence was 2 million cases, estimated prevalence
was 3 million, annual deaths due to TB totaled 280,000, and approximately 6.4
percent of incident TB cases were also HIV-positive.
NOTE: HBC, high-burden country.
SOURCE: Sachdeva, 2011. Based on data from Global Tuberculosis Control: WHO
Report 2010 (WHO, 2010b).
occurring each year. About 280,000 people die from TB in India annually.3
India has the second highest burden of MDR TB in the world after China,
with an estimated 99,000 new cases per year (WHO, 2010b).
Sachdeva noted that the RNTCP carried out a drug resistance surveil-
lance survey in accordance with global guidelines in the states of Gujarat
and Maharashtra in 2007 and in Andhra Pradesh in 2009 (Table 2-1). The
results of these selected surveys indicate an MDR TB prevalence of about
3 Since the workshop took place, an updated WHO report (2011a) cited new provisional
estimates of the TB burden in India in 2010. India has an estimated prevalence of 3.1 million
TB cases, with 2.3 million new cases occurring each year, and 320,000 deaths due to TB each
year.
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20 DRUG-RESISTANT TUBERCULOSIS IN INDIA
TABLE 2-1 Drug Resistance Surveillance in Three Indian States
MDR TB Among
MDR TB Among Previously Treated
State (survey year) Population New Cases (%) Cases (%)
Gujarat (2007–2008) 56 million 2.4 17.4
Maharashtra (2008) 108 million 2.7 14.0
Andhra Pradesh (2009) 86 million 1.8 11.8
SOURCE: Sachdeva, 2011.
2–3 percent among new cases and 12–17 percent among previously treated
cases.
According to Sharma and colleagues (2011a), the prevalence of MDR
TB among 177 cases of newly diagnosed pulmonary TB patients in New
Delhi in 2008–2009 was lower—about 1.1 percent. Among 196 patients
with pulmonary TB diagnosed in New Delhi between 2005 and 2008 who
had failed previous TB treatment, relapsed after treatment, or defaulted
during treatment, 20.4 percent had MDR TB (Sharma et al., 2011b).
Population-based data are highly limited for second-line drug resistance
among MDR TB patients, according to Sachdeva. According to drug resis-
tance surveillance data from Gujarat, fluoroquinolone resistance occurred
in 24 percent and kanamycin resistance in 3 percent of 219 MDR TB cases
detected. XDR TB was observed in about 3 percent of MDR TB isolates,
and all 7 of these cases were in previously treated patients.
Accurate estimates of drug resistance require that results come from
well-qualified and accredited laboratories. The reliability of the data and
quality control issues are essential considerations both in estimating current
levels and in making historical comparisons, noted Sharma.
PLANS OF THE REVISED NATIONAL TB CONTROL PROGRAM4
Initiated in 1997, the RNTCP has been implementing all of the compo-
nents of the WHO STOP TB Partnership, including early diagnosis, quality
smear microscopy, and prompt treatment with DOTS using quality first-
line drugs, said A. Kumar. Sachdeva noted that the RNTCP’s overriding
goal is to provide universal access to quality diagnosis and treatment for
all patients. Intermediate goals (by 2015) are to achieve early detection of
at least 90 percent of all TB cases, including HIV-associated TB; perform
initial screening of all smear-positive patients for drug-resistant TB; provide
4 This section is based on the presentations of Kuldeep Singh Sachdeva, Chief Medical
Officer, Central TB Division; and Ashok Kumar, Deputy Director General and Head, Central
TB Division, and Project Director, RNTCP.
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21
DRUG-RESISTANT TB IN INDIA
HIV counseling and testing for all TB patients; and successfully treat at least
90 percent of all new and at least 85 percent of all previously treated TB
patients. A national strategy for the RNTCP for the next Five-Year Plan,
which extends from 2012 to 2017, is currently being developed. Since the
RNTCP’s inception, more than 12 million TB patients have been initiated
on DOTS, and approximately 2 million lives have been saved, A. Kumar
noted.
Preventing Drug-Resistant TB
To combat drug-resistant TB, the RNTCP has developed a multiphase
response plan, said A. Kumar. With regard to prevention, the plan calls
for improving and sustaining high-quality DOTS implementation, promot-
ing the rational use of anti-TB drugs, and implementing infection control
measures. The RNTCP is also seeking to improve laboratory capacity,
effectively treat MDR TB patients, initiate and rapidly scale up MDR
TB services, and evaluate the extent of second-line anti-TB management
strategies.
Airborne infection control is crucial for preventing the spread of TB
from person to person, as well as reducing the risk of TB among health
workers in institutional settings, said A. Kumar. The National Airborne
Infection Control Committee was established in 2008 with representatives
from the medical profession, the National Center for Disease Control,
the National Center for TB Resistance, WHO, architects, and engineers.
The committee has developed provisional guidelines on airborne infection
control in health care and other settings. These guidelines are expected to
augment the infection control measures undertaken by the RNTCP. Work-
shops on airborne infection control have been organized by the RNTCP
with the support of the U.S. Centers for Disease Control and Prevention
(CDC), WHO, and others, and pilot implementation programs have been
initiated. The RNTCP also has disseminated provisional airborne infection
control guidelines to all states in India.
A. Kumar noted that the national guidelines for infection control still
need to be operationalized, not just for TB but for the general health system
and at the community level. Chapter 4 of this report summarizes several
workshop presentations specifically addressing infection control.
Diagnosing Drug-Resistant TB
Sachdeva reported that a staggered approach is currently being used to
diagnose MDR TB in India. MDR TB is suspected in all patients who fail the
first-line drug regimen, all patients whose sputum is positive after 4 months
of treatment, and all smear-positive contacts of MDR TB patients. These
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22 DRUG-RESISTANT TUBERCULOSIS IN INDIA
criteria will be changed over the years as laboratory capacity expands. DST
is conducted at an accredited laboratory, with the line probe assay (LPA)
being the preferred testing method if available. Treatment is initiated on the
basis of results for rifampicin resistance, since resistance only to rifampicin
is rare.
Edward Nardell, Associate Professor of Medicine, Harvard Medical
School, pointed out that because previously untreated TB cases are much
more numerous than those previously treated,5 more than half of MDR TB
cases globally are new. However, more effort is required to detect such cas-
es.6 A strategy that focuses on smear-positive patients for MDR TB testing
will be more likely to miss these new cases. Sharma noted that sometimes
it is unclear whether patients were previously treated or not.
Treating Drug-Resistant TB
To combat MDR and XDR TB, a national DOTS-Plus committee of
experts, established in 2005, developed national DOTS-Plus guidelines
for India aligned with the WHO guidelines for treatment of drug-resistant
TB. DOTS-Plus services for programmatic management of MDR TB were
introduced as a pilot in the states of Gujarat and Maharashtra in 2007 and
since then have gradually been expanded.
The model of DOTS-Plus care includes inpatient and community care.
Sachdeva explained that patients are identified at the community level
and then referred to the district TB officer, who collects a sample from
the patient and sends it to the culture and DST laboratory. The culture
and DST laboratory communicates the results to the district. The district
TB officer traces the patient and sends him or her to a DOTS-Plus site for
about a week for an initial workup. The patient then is placed on treatment
at the DOTS-Plus site. After a week of treatment, the patient is referred
back to the community, and the rest of the treatment is carried out on an
outpatient basis.
The DOTS-Plus program employs a decentralized and integrated model
of care. The DOTS provider at the community level sees the patient through
the course of treatment. At the health facility, the doctors and paramedics
5 Of the 6.2 million people diagnosed with TB in 2010, 5.4 million had TB for the first
time, and 0.3 million had a recurrent episode. In a small number of cases the treatment
history was not recorded, and 0.4 million had already been diagnosed with TB but had their
treatment changed to a retreatment regimen after treatment failure or interruption. In 2010,
an estimated 3.4 percent of new TB cases globally were MDR TB and an estimated 20 percent
of retreatment TB cases were MDR TB (WHO, 2011a).
6 Trends in global MDR TB rates remain largely unclear because of a lack of nationally
representative data in many large countries, including India and several African countries
(Zignol et al., 2012).
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23
DRUG-RESISTANT TB IN INDIA
are trained to supervise the DOTS provider, as well as to manage and moni-
tor minor side effects. At the district level, the district TB officer coordinates
case findings, follow-up examinations, and reporting.
The standardized treatment regimen for MDR TB in India is a 6-drug
regimen, with an intensive phase of 6–9 months and a continuation phase
of 18 months; the total duration of treatment is about 24–27 months. The
six drugs are kanamycin, levofloxacin, cycloserine, ethionamide, pyrazin-
amide, and ethambutol. P-aminosalicylic acid (PAS) is kept as a reserve drug
in the event of intolerance of or a reaction to any one of the other drugs.
The regimen involves daily DOT, with kanamycin given for 6 days in a
week. Patients are treated according to 3 weight bands: 16–25 kg, 26–45
kg, and more than 45 kg.
In the discussion period, Sachdeva noted that because many patients
were unwilling to be admitted to the hospital for a month, the period of
hospitalization was reduced to about a week. Also, many MDR TB patients
die in the time it takes for them to be traced, diagnosed, counseled, and put
on treatment. Therefore, the goal is to diagnose patients as early as pos-
sible, in part through scale-up of the country’s laboratory capacity. Another
problem is that transporting sputum from patients to the culture and DST
laboratories has been difficult, especially in remote areas. Accordingly,
greater involvement by private-sector laboratories is being sought.
Sachdeva also noted that reports of patients with XDR TB are surfac-
ing. Specifications for drugs for these patients are being analyzed, which
will generate guidance for DOTS facilities.7
Procuring Drugs
The RNTCP’s system of drug logistics and event-tree management
is integrated with first-line anti-TB management. There are two sources
of procurement: the GLC and the government of India. Quality-assured
second-line drugs are being procured by the government of India with
financial support from the World Bank, UNITAID,8 and the Global Fund,
7 In January 2012, following the workshop summarized herein, the emergence of TDR TB
in India was reported at Hinduja Hospital in Mumbai (Udwadia et al., 2012). The reporting
authors indicated that three of the four TDR TB patients had received erratic, unsupervised
second-line drugs, often in incorrect doses and from a variety of private practitioners, in an
effort to cure their MDR TB. The term “TDR TB” is not currently recognized by WHO or
the RNTCP, which instead refer to these cases as XDR TB. For more information on this
terminology, visit http://www.who.int/tb/challenges/mdr/tdrfaqs/en/index.html (accessed April
17, 2012).
8 UNITAID is an international purchase facility for medicines and diagnostics for HIV/AIDS,
malaria, and TB. Started in 2006 by Brazil, Chile, France, Norway, and the United Kingdom,
UNITAID generates program financing through a tax on airline tickets. Ninety-four countries
currently receive UNITAID funding. For more information, visit http://www.unitaid.eu/.
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24 DRUG-RESISTANT TUBERCULOSIS IN INDIA
with technical assistance from WHO and the GLC. The procurement of
23,000 drug doses for MDR TB for 2011-2012 has been initiated through
the GLC and the Global Drug Facility (GDF) mechanism. Loose drugs are
supplied to state drug stores and repackaged into three monthly boxes.
These boxes are supplied to the districts, with loose drugs being provided
to DOTS-Plus sites.
Scaling Up Laboratory Capacity
As of March 2011, India had 25 accredited culture and DST labora-
tories, noted Sachdeva (Figure 2-2). As of December 2010, 12 states were
implementing basic DOTS-Plus services, and all planned to do so by the
end of 2011. At the end of 2010, the DOTS-Plus program covered about
24 percent of the population in the 141 of the country’s 658 districts that
at that point had MDR TB diagnostic and treatment services available.
Sachdeva reported that as of December 2010, more than 19,000
patients suspected of having MDR TB had been examined and about 3,600
had been initiated on treatment. The number of patients placed on treat-
ment has been increasing each year.
The RNTCP is currently scaling up the number of accredited culture
and DST laboratories nationwide to at least 43 by 2013, with the potential
for 65–70 laboratories, including private-sector and medical college labo-
ratories, to be accredited under the program, said Sachdeva. Capacity will
be increased at each laboratory through investments in sputum processing
capacity, the introduction of high-throughput molecular DST, automated
liquid culture systems, stronger specimen transport systems, and electronic
reporting of results. By 2013, access to laboratory-based, quality-assured
MDR TB diagnosis and treatment will be available to all smear-positive
retreatment TB cases and new cases that have failed an initial first-line drug
treatment, said Sachdeva. Also by 2013, the expected annual DST capacity
will grow from 35,000 in 2010–2011 to 220,000, and at least 30,000 MDR
TB patients are projected to enter treatment annually. By 2015, all smear-
positive TB cases, whether new or retreatment cases, will have access to
MDR TB diagnosis and treatment. UNITAID, the Global Fund, the World
Bank, and WHO have all supported the laboratory scale-up effort.
Sachdeva described several components of the strategy for scaling up
treatment services. Human resource capacity will be strengthened by hav-
ing a DOTS-Plus coordinator in every district and additional staff at labo-
ratories and DOTS-Plus sites. By 2012, the number of DOTS-Plus sites is
slated to increase from about 24 currently to 200 sites covering all states
across the country—the equivalent of 1 site per 10 million people (RNTCP
Status Report, 2011). All DOTS-Plus sites will be upgraded to national
airborne infection control standards. The RNTCP is advocating that drug
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JAMMU & KASHMIR
Srinagar
Jammu
HIMACHAL PRADESH
NDTC
Tanda MC
PUNJAB Dharampur AIIMS
CHD Dehradun LRS
Patiala
Karnal UTTARAKHAND
ARUNACHAL PRADESH
HARYANA
DELHI
Gurgaon SIKKIM Itanagar
Agra
Gangtok
Jaipur
RAJASTHAN UTTAR PRADESH
JALMA ASSAM
Guwahati FIGURE 2-2 Distribution of Re-
BIHAR NAGALAND
Lucknow
Ajmer
Jodhpur
MEGHALAYA
Patna vised National TB Control Program
Imphal
(RNTCP) culture and drug suscep-
MANIPUR
Jabalpur JHARKHAND TRIPURA
GUJARAT MADHYA PRADESH
Ahmedabad WEST BENGAL
Ranchi tibility testing (DST) laboratories
MIZORAM
MIZORAM
Kolkata
Indore across India as of March 2011. As
Jamnagar CHHATISGARH
of that date, there were 25 accred-
Nagpur Cuttack
Wardha Raipur ORISSA ited laboratories (4 national refer-
MAHARASHTRA
Mumbai JJMC ence laboratories, 12 intermediate
PDHH
Hyderabad
Pune reference laboratories, 9 other labo-
Vizag
BPRC, Hyd ratories) and 8 laboratories whose
Intermediate reference laboratory (IRL) (accredited)
accreditation was pending. The line
ANDHRA PRADESH IRL (under accreditation)
GOA
probe assay (LPA) was available in
IRL (equipment being procured)
KARNATAKA
4 laboratories. The RNTCP is also
Bangalore TRC Medical college/nongovernmental organization
Manipal
Chennai encouraging a number of private-sec-
NTI CMC Vellore (NGO)/private laboratory (accredited)
PONDICHERRY tor laboratories and medical college
Medical college/NGO/private laboratory
(under accreditation)
TAMIL NADU laboratories to obtain accreditation
KERALA
Medical college/NGO/private laboratory (preparatory) (i.e., “preparatory” status in the leg-
Thiruvananthapuram National reference laboratory end above).
25
SOURCE: Sachdeva, 2011.
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26 DRUG-RESISTANT TUBERCULOSIS IN INDIA
manufacturers adhere to WHO prequalification and GDF quality assurance
programs and develop second-line drug production plans that take account
of the nation’s demand for the drugs. The RNTCP also is advocating with
professional associations and physicians for rational use of the fluoroqui-
nolones, especially in respiratory diseases, so that resistance to this class of
drugs does not become a major challenge in the management of MDR TB.9
Finally, an integrated national online electronic recording and reporting
system will be instituted, based on the E-TB Manager model used in Brazil.
Outcomes for patients who received standardized treatment through
DOTS-Plus have been mixed, said Sharma. In a retrospective analysis of
66 patients, 53 (80.3 percent) became culture-negative, 77.3 percent of
these within 3 months (Arora et al., 2007); 4 failed to convert within 9
months; and the rest died or defaulted. Among 28 patients completing 2
years of treatment, 67.9 percent were cured, 14.3 percent died, 17.9 per-
cent defaulted, and none failed treatment. Cycloserine had to be stopped
in 5 patients and kanamycin was stopped in 3 patients because of adverse
effects. Other drugs were better tolerated.
By contrast, in another 2007 study of 172 MDR TB patients and
1 XDR TB patient described by Sharma, only 41.6 percent were cured,
38.7 percent failed, 15 percent defaulted, and 4.6 percent died, although
this study preceded the DOTS-Plus era. During the discussion period, in
response to a question about this cure rate, Sachdeva noted that many of
these patients had undergone second-line treatment multiple times, and the
risk of failure was greater because they were treatment experienced. Subse-
quent cohorts are showing better results, but they have not yet completed
the full course of treatment. Earlier diagnosis and treatment could boost
cure rates, said Sachdeva, but globally the treatment success rate for MDR
TB is only about 60–65 percent.
Salmaan Keshavjee, Harvard Medical School, observed that a high fail-
ure rate probably points to strains that are more resistant than is commonly
held. Moreover, default rates of 20 percent indicate that there is much work
9 At the 2010 IOM workshop in Moscow (IOM, 2011b), Peter Cegielski, CDC, shared
results from the Preserving Effective TB Treatment Study (PETTS), a prospective follow-up
study of MDR TB patients in nine countries aimed at determining the frequency of and risk
factors for acquired resistance to second-line drugs in a diverse group of MDR TB programs.
A large number of MDR TB patients already had resistance to second-line drugs at the start
of treatment: 11 percent for the fluoroquinolones, 11–18 percent for injectable agents, close
to 20 percent for ethionamide, and almost 10 percent for para-aminosalycylic acid. Cegielski
suggested that the high level and diversity of drug resistance found at baseline suggests that
standardized treatment approaches for MDR TB are not advisable. The 2010 IOM workshop
in South Africa (IOM, 2011a) also included a discussion of the sensitivity of the various strains
of M.tb. to the fluoroquinolones. Nesri Padayatchi, University of KwaZulu-Natal, shared that
moxifloxacin has been one of the most commonly used fluoroquinolones for treating patients
in South Africa.
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27
DRUG-RESISTANT TB IN INDIA
to be done in India and elsewhere to strengthen the health system’s capac-
ity to deliver care. High death rates mean that greater capacity is needed
to diagnose people quickly and place them on appropriate treatment. A 42
percent success rate is disturbing, he said, suggesting that the goal should be
60–80 percent. In the Tomsk prison system in Russia, for example, where
inmates are resistant to all first-line drugs plus some second-line drugs, the
cure rate approaches 80 percent under a collaborative DOTS-Plus pro-
gram that includes the penitentiary system and the civilian health service
and serves a combination of incarcerated and civilian patients, as well as
vulnerable populations such as the homeless, unemployed, and disabled
(Shin et al., 2006). Keshavjee explained that the reason for this success is
the presence of a health system within the prison that can deliver drugs to
patients each day and ensure that they take them.
Keshavjee also noted that MDR TB is a highly complex problem and
that India is attempting to incorporate a complex health intervention into
a health system that needs strengthening at multiple levels. Involvement of
the private sector is being sought to make these efforts more feasible (see
the next section and Chapter 7).
INVOLVEMENT OF THE PRIVATE SECTOR10
Indiscriminate use of anti-TB drugs, especially outside the RNTCP, has
contributed significantly to the emergence of drug-resistant TB in India, said
A. Kumar. In India, drugs available by prescription elsewhere are available
over the counter in any pharmacy, which complicates the management of
MDR TB. For example, fluoroquinolones are available over the counter
and are commonly used in households for fevers and infections. In 2006,
prior to the implementation of the DOTS-Plus program in India, based on
the total amount of money available for anti-TB drugs sold in India, 75
percent of first-line drugs and 100 percent of second-line drugs were being
used outside the RNTCP.
The National Center for Disease Control under the Indian Ministry
of Health has sought to restrict the sale of anti-TB drugs without a writ-
ten prescription. The Drug and Cosmetic Act of India also contains a
clause restricting the sale of anti-TB drugs. A. Kumar noted that meetings
organized by the GDF, WHO, and the RNTCP have brought Indian drug
manufacturers together to educate them and encourage them to adhere to
established standards.
An important component of the DOTS-Plus program has been the estab-
lishment of partnerships with the private sector, including nongovernmental
10This section is based on the presentation of Ashok Kumar, Deputy Director General and
Head, Central TB Division, and Project Director, RNTCP.
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28 DRUG-RESISTANT TUBERCULOSIS IN INDIA
organizations (NGOs), medical colleges, and other private institutions.
Such partnerships are critical, said A. Kumar, because it is not possible to
achieve control through the actions of a single agency. The partnerships
are designed to achieve community awareness, improve access to TB care,
reduce patient costs and inconvenience, detect cases early, promote the
rational use of anti-TB drugs, and ensure sustained funding. For example,
the Indian Medical Association and other private-sector professional societ-
ies, particularly those for chest physicians, have endorsed the application of
international standards of TB care.
Partners are also needed at the national and global levels. For exam-
ple, Sachdeva noted that the Foundation for Innovative New Diagnostics
(FIND) has aligned its work plans with India’s national scale-up plan, and
the Clinton Foundation has conducted an independent external validation
of the national plan.
CHALLENGES TO THE REVISED NATIONAL
TB CONTROL PROGRAM11
India’s efforts to control TB and MDR TB face a number of challenges
and roadblocks, which were described by A. Kumar and Thomas.
Laboratories
For a variety of reasons, the establishment and accreditation of labo-
ratories in some states have been delayed. The RNTCP plans to link these
states with an accredited laboratory elsewhere so that services will not be
affected, said A. Kumar.
Diagnosis
A. Kumar noted that conventional tests to detect drug-resistant TB
are slow, tedious, and difficult to perform under field conditions. Timely
availability of results is crucial for prompt patient management to reduce
morbidity and mortality. Newer tools are being introduced into the RNTCP
in a phased manner. The LPA, when available, is the preferred DST method
in India.12 These tools need to undergo rigorous field evaluation before they
are used in populations with a significant burden of drug-resistant TB, and
11 This section is based on the presentations of Ashok Kumar, Deputy Director General and
Head, Central TB Division, and Project Director, RNTCP; and Aleyamma Thomas, Scientist
G and Director-in-Charge, National Institute for Research in Tuberculosis.
12 Capacity for DST with the LPA in India was less than 0.1 laboratories per 10 million
population in 2010 (WHO, 2011b).
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29
DRUG-RESISTANT TB IN INDIA
technologies that provide rapid diagnosis require staff support and train-
ing. Operational research to reduce these delays is ongoing in the state of
Andhra Pradesh, supported by UNITAID.
Management
Successful management of TB patients is the responsibility of health sys-
tems, said Thomas. First-line DOTS regimens need to be followed strictly.
The default rate in retreatment cases, a major source of drug-resistant
TB, remains quite high. Management of drug-resistant TB is a therapeutic
challenge that needs to be undertaken by experienced clinicians at centers
equipped with quality-assured, accredited laboratories and inpatient and
surgical facilities. Improving the efficiency with which suspected MDR
TB cases are referred and tracing patients who are lost to follow-up are
both critical, since the best treatment for MDR TB is to prevent it from
developing. The irrational use of first- and second-line drugs needs to be
discouraged, including in education and training provided at medical col-
leges. Patients and their relatives need to receive standardized counseling
because of the long duration of treatment. And infection control measures
are essential to keep the disease from spreading.
Drug Access and Supply
Ensuring an uninterrupted supply of quality-assured second-line drugs
is a key issue. A. Kumar noted that the diagnostic capacity for MDR TB
exceeds the number of patients who can be placed on treatment because
of the limited availability of drugs. Rising costs reduce the use of these
drugs. Addressing this problem will require intervention from the GLC and
incentives for Indian drug manufacturers to build their capacity to produce
better-quality prequalified drugs.
Human Resources
Thomas noted that the dramatic demands on program staff for super-
vision and treatment are posing human resource challenges in India.
Staff need adequate training in management and supervision. Specifically,
Thomas suggested that training should also focus on problem solving,
management skills, and planning to facilitate program expansion and per-
formance, as well as specialized training for dealing with MDR TB among
vulnerable populations. Nonprogram providers and communities also need
to be involved in diagnosis and management.
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30 DRUG-RESISTANT TUBERCULOSIS IN INDIA
Data
A robust system is needed to monitor and evaluate multiple program
indicators, said Thomas. Better performance will require good data collec-
tion and analysis, as well as timely dissemination of findings to end users
for further improvement.
TREATMENT OF DRUG-RESISTANT TB13
Before 1998, most treatment of drug-resistant TB was still being pro-
vided by individual clinicians, said Sarin. These clinicians treated very few
patients, and not all clinicians provided effective treatments. In 1998, WHO
and international partners adopted a different strategy for dealing with the
burden of drug-resistant TB, which included shifting to a community-based
programmatic approach. This decision contributed to the genesis of the
DOTS-Plus program, as well as the GLC.
WHO’s Guidelines for the Programmatic Management of Drug-
Resistant Tuberculosis: Emergency Update includes a hierarchy of the five
groups of anti-TB drugs and instructions for building a treatment regimen
(WHO, 2008, Table 7.1 and Figure 7.2):
• Group 1—first-line oral anti-TB drugs (isoniazid [H], rifampicin
[R], ethambutol [E], pyrazinamide [Z]; rifabutin [Rfb]);
• Group 2—injectable anti-TB drugs (kanamycin [Km], amikacin
[Am], capreomycin [Cm], streptomycin [S]);
• Group 3—fluoroquinolones (moxifloxacin [Mfx], levofloxacin
[Lfx], ofloxacin [Ofx]);
• Group 4—oral bacteriostatic second-line anti-TB drugs (ethion-
amide [Eto], protionamide [Pto], cycloserine [Cs], terizidone [Trd],
p-aminosalicylic acid [PAS]); and
• Group 5—agents with unclear efficacy or an unclear role in MDR
TB treatment not recommended for routine use in MDR TB patients
(clofazimine [Cfx], linezolid [Lzd], amoxicillin/clavulanate [Amx/
Clv], thioacetazone [Thz], imipenem/cilastatin [Ipm/Cln], high-
dose isoniazid [high-dose H], clarithromycin [Clr]).
WHO (2008) also has established basic guiding principles for designing
a treatment regimen for drug-resistant TB:
13This section is based on the presentation of Rohit Sarin, Senior Consultant, LRS Institute
of Tuberculosis and Respiratory Diseases.
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• Regimens should be based on the history of drugs taken by the
patient.
• Drugs commonly used in the country and the prevalence of resis-
tance to first- and second-line drugs should be considered in devel-
oping a regimen.
• At least four anti-TB drugs that are certain, or almost certain,
to be effective should be used. When evidence of effectiveness is
unclear, a drug can be included in the regimen, but it should not
be depended upon for success.14
• Drugs with cross-resistance should not be used. (For example,
amikacin and kanamycin have high levels of cross-resistance, as do
capreomycin and viomycin.)
• Adverse drug effects should be treated immediately and adequately
so as to minimize the risk of treatment interruptions and prevent
increased morbidity and mortality due to serious adverse effects.
• Drugs that are not safe in the patient should be eliminated.
Each dose of a drug is provided as DOT throughout the treatment regimen
and recorded.
In addition to the above guidelines, WHO has established principles for
the selection of drugs. The first is to perform DST and use a drug consid-
ered to be effective on the basis of the results. The patient should have no
previous history of treatment failure with a drug and no known close con-
tact with resistance to a drug, and drug resistance patterns should indicate
that resistance to a drug is rare among the population. Finally, the regimen
should include at least one injectable and one fluoroquinolone.
Drugs usually are administered at least 6 days a week. Dosage should
be linked to body weight, with a preference for the higher dosage within
a weight range. Injectables need to be administered for a minimum of 6
months (intensive phase), with treatment for a minimum of 18 months
beyond sputum culture conversion.15
The entire regimen should be administered under DOTS, but different
treatment options are available. One is an empirical treatment strategy, in
which a DST report is not available, but a course of treatment is devised on
the basis of a patient’s history of drug intake and other factors. In an indi-
vidualized treatment strategy, a DST report is available for a patient for all
14 A recent WHO (2011c) report updates this guideline to state that MDR TB treatment
regimens should include at least four second-line anti-TB drugs likely to be effective, plus
pyrazinamide (Z), in the intensive phase of treatment.
15 An updated WHO report (2011c) changes the guideline for duration of treatment
for MDR TB patients to at least 8 months of intensive-phase treatment (an increase of 2
months relative to the 2008 guidelines). A total treatment duration of at least 20 months is
recommended for MDR TB patients with no previous MDR TB treatment.
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32 DRUG-RESISTANT TUBERCULOSIS IN INDIA
first- and second-line drugs, and the regimen is based on the susceptibility
pattern. In a standardized treatment strategy, drug resistance surveillance
data from representative patient populations are used to design a treatment
regimen in the absence of individual drug susceptibility results. Patients in
a defined group or category then receive the same standardized treatment
regimen.
The advantages of a standardized treatment strategy are that the cost
of the regimen is lower than that of the other two strategies, DST is not
required for all drugs, the technical capacity of the physician need not be
high, the regimen can be applied on a large scale, implementation is less
complicated, drug ordering and training are easier, and mismanagement is
less likely. The disadvantages of a standardized treatment strategy are that
it is not as effective as an individualized strategy in all cases; it can amplify
resistance; the drug susceptibility pattern within a community needs to be
well documented; and organisms may be resistant to some of the drugs in
the regimen, resulting in an avoidable increase in both cost and toxicity.
Countries can adopt MDR TB treatment strategies on the basis of the
laboratory method used to confirm MDR TB. If the method involves a long
time gap before results are obtained, patients can be placed on an empiri-
cal treatment regimen. If the results then demonstrate drug resistance, the
patient can be placed on an individualized or standardized treatment regi-
men. If rapid detection methods are available, such that results are available
within 1–2 days, the patient can be placed on an individualized or standard-
ized treatment regimen as soon as results are available.
Surgery can be an adjunct to chemotherapy, but it is not indicated when
the disease is extensive and bilateral. About 2 months of anti-TB therapy
must be administered before surgical resection is attempted. And even with
surgery, the duration of treatment still must be a minimum of 2 years.
In India, a particular treatment regimen followed as national pol-
icy is an intensive phase of 6–9 months and a continuation phase of 18
months. As specified in the DOTS-Plus guidelines, patients are monitored
through sputum smears, cultures, x-rays, and some blood and laboratory
investigations.
XDR TB treatment follows similar guidelines but is of longer duration
since it is more difficult. A later generation of fluoroquinolones needs to be
used, with greater reliance on category IV and V drugs rather than category
II and III drugs; surgical resection also needs to be considered. Underlying
HIV infection must be treated if present, and side effects demand compre-
hensive monitoring and treatment.
Predictors of success in the treatment of MDR TB are the use of pyra-
zinamide and ethambutol if the strain of TB is susceptible to these drugs,
the use of a fluoroquinolone, the use of more than 5 drugs, sputum con-
version within 2 months, and surgical resection. Predictors of failure are
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previous therapy, resistance to the fluoroquinolones, resistance to inject-
ables, the presence of cavitation, low body mass index, HIV infection, poor
adherence, and positive culture at 2–3 months.
WHO also has issued recommended strategies for different program-
matic situations. In India, for example, all category I failures are placed on
category II treatments, and the regimen is adjusted to category IV if DST
reveals drug resistance. In some countries, category I failures are started
immediately on category IV treatments. In India, treatment choices for
category II failures depend on results of DST and overall drug resistance
patterns.
Designing treatment regimens for MDR TB is highly challenging, said
Sarin. In resource-limited settings, standardized treatment regimens may
be necessary instead of individualized regimens. Different options for stan-
dardized regimens are available, depending on drug resistance patterns in
the country. Decisions on regimens also are linked to the availability of
resources, quality-assured DST, and drugs.
IMPROVING HEALTH SYSTEM PERFORMANCE TO
ADDRESS THE CHALLENGE OF DRUG-RESISTANT TB16
From 2007 to 2010, the staff of DOTS-Plus sites in India examined
19,178 MDR TB suspects, diagnosed 5,365 cases of MDR TB, and initi-
ated treatment for 3,610 MDR TB patients (RNTCP Status Report, 2011).
There is an estimated annual incidence of 99,000 cases of MDR TB in the
country (RNTCP Status Report, 2011); thus, the majority of MDR TB
patients are undiagnosed. Scale-up of the DOTS-Plus program is essen-
tial to increase the number of MDR TB patients receiving treatment, but
strengthening of the health care system also is necessary, said Thomas.
Health system strengthening is defined as an array of initiatives and strate-
gies that improves one or more functions of the system. It leads to better
health through improvements in access, coverage, quality, or efficiency. TB
remains a high priority for health system strengthening, especially in view
of the threat of drug-resistant forms of the disease.
With regard to human resources, Thomas continued, the goal is to
have the right number of people with the right skills in the right place at
the right time, who are motivated and supported to provide the right ser-
vices to the right people. Health workers at all levels—from physicians and
administrators to grassroots-level workers—need to be trained. Academic
institutions, including medical colleges, schools of nursing, and other allied
health institutions, need greater capacity. Beyond initial training, there
16This section is based on the presentation of Aleyamma Thomas, Scientist G and Director-
in-Charge, National Institute for Research in Tuberculosis.
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34 DRUG-RESISTANT TUBERCULOSIS IN INDIA
is a need for retraining, on-the-job training, continuing education, and
advanced training in management. Training in problem solving, supervi-
sion, management, and planning is needed to supplement core training in
TB management. Specialized training should focus on operations research,
drug management, treatment of drug-resistant TB, TB and HIV coinfection,
and infection control, said Thomas.
Training should be followed by in-service monitoring and supervision
to detect performance deficiencies, identify new staff in need of training,
and identify additional staff needed for current and new interventions.
Innovative strategies, some of which were described during the workshop
(see the next section), are needed to develop the appropriate competencies
to deliver services for drug-resistant TB effectively. Strategies for optimal
use of shared resources and coordination of different sectors, both govern-
mental and nongovernmental, also are needed.
Advocacy, communication, and social mobilization are important
aspects of TB control, said Thomas. Policy makers and administrators
should be sensitized to the need for
• adequate and sustained funding for TB control;
• sharing of resources with other public health programs;
• training of staff at different levels and retention of trained staff;
• periodic reviews to identify gaps and take corrective steps;
• communication with patients to improve adherence;
• communication with people to encourage them to demand free
diagnosis and care so that TB control becomes a people’s move-
ment; and
• dissemination of the national plan for advocacy, communication,
and social mobilization to field staff.
Finally, the scope for research on drug-resistant TB is broad. To improve
the performance of the health system, Thomas said, research is particularly
needed in the areas of
• epidemiology;
• newer tools for diagnosis and newer drugs for treatment;
• clinical trials to find ways to shorten the duration of treatment; and
• health system structure and operations, to identify constraints on
the effective use of resources and quality services.
More and better research can inform evidence-based decision making at
the policy level.
In conclusion, A. Kumar emphasized that antimicrobial resistance is
a major threat to humanity and the fight against communicable diseases.
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This vital issue requires an integrated and practical response guided by
principles adopted by all countries. Without action today, there will be no
cures tomorrow.
POTENTIAL INNOVATIONS AND ACTION ITEMS
Through the presentations provided in this session and the subsequent
discussions, individual workshop speakers and participants noted key inno-
vations and action items. They include the following:
• Based on lessons learned from recent Indian experience, inpatient
care was reduced from 1 month to 1 week where possible.
• Because diagnoses were taking such a long time, in part because of
a lack of laboratory capacity, private laboratories are now being
accredited and utilized for more rapid diagnoses.
• All types of health care providers, including private-sector labora-
tories, NGOs, medical colleges, other private institutions, and pro-
fessional societies, are now being incorporated into TB treatment.
• More and better managerial capacity in training programs for all
types of health care workers is needed.
• Greater attention needs to be focused on vulnerable populations,
especially pediatric populations, for whom there is currently a lack
of adequate research data and information.
• Community-based care is a key strategy to reach patients early,
initiate treatment, and help them stay on treatment.
• Decentralized and integrated models of care should be considered
to reduce the time from diagnosis to treatment, bring treatment
closer to patients, and increase the numbers of patients who com-
plete treatment.
• An integrated national online electronic recording and reporting
system will be instituted in India, based on the e-TB Manager
model in Brazil.
• Advocacy, communication, and social mobilization are important
aspects of TB control, and policy makers should be sensitized about
the multiple needs for TB treatment.
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