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1
Introduction1
The workshop summarized in this volume was the third international
meeting in a series sponsored by the Forum on Drug Discovery, Devel-
opment, and Translation of the Institute of Medicine (IOM) to gather
information from experts around the world on the threat of drug-resistant
tuberculosis (TB) and how it can be addressed. The workshop was held
April 18–19 and 21, 2011, in New Delhi, India, in collaboration with the
Indian National Science Academy (INSA) and the Indian Council of Medi-
cal Research (ICMR).
The Forum held a foundational workshop in Washington, DC, in 2008.
The summary of that workshop, Addressing the Threat of Drug-Resistant
Tuberculosis: A Realistic Assessment of the Challenge: Workshop Summary
(IOM, 2009), and the accompanying white paper (Keshavjee and Seung,
2008) provided background for and informed the development of four
subsequent workshops in countries with a high burden of drug-resistant TB.
The first international workshop in the series was held in Pretoria, South
Africa, on March 3–4, 2010 (IOM, 2011a). The second international work-
shop was held in Moscow, Russia, on May 26–27, 2010 (IOM, 2011b). The
final workshop in the series is being planned for China. Box 1-1 summarizes
1 The planning committee’s role was limited to planning the workshop, and the workshop
summary has been prepared by the workshop rapporteurs as a factual summary of what
occurred at the workshop. Statements, recommendations, and opinions expressed are those
of individual presenters and participants, and are not necessarily endorsed or verified by the
Forum or the Institute of Medicine (IOM) and they should not be construed as reflecting any
group consensus.
1
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2 DRUG-RESISTANT TUBERCULOSIS IN INDIA
BOX 1-1a
Key Viewpoints from Previous Workshops
To set the stage for the workshop in India, Gail Cassell, Visiting
Professor, Harvard Medical School, and Vice President of TB Drug Dis-
covery, Infectious Disease Research Institute, provided an overview of
selected key messages from the first three workshops held by the Forum
in Washington, DC; Pretoria, South Africa; and Moscow, Russia (IOM,
2009, 2011a,b).
Global Surveillance of Drug-Resistant TB
According to Cassell, a clear message that emerged from these meet-
ings is that the actual number of multidrug-resistant (MDR) TB cases is
certain to exceed the 440,000 (range of 390,000 to 510,000) new cases
estimated by the World Health Organization (WHO) to have occurred in
2008 (WHO, 2010b). Quality data on the incidence and prevalence of
MDR TB are not always available for a country or region. Data from many
countries are based on statistical modeling results rather than laboratory-
based surveillance, often because the laboratories in countries with a
high burden of MDR TB lack the capacity to test for susceptibility to
second-line drugs.b
Pediatric Drug-Resistant TB
Existing MDR TB surveys rarely include children. Cassell noted that
even when children are included, they generally are lumped together into
broad age groups, a practice that obscures the profile of pediatric MDR
TB. If South Africa is an indication of the situation in other countries,
Cassell said, MDR TB in children is a significant problem. According to
a 2008 study of 148 children who underwent drug susceptibility testing
(DST) while being treated for TB at two hospitals in Johannesburg, 8.8
percent, or 13 children, had MDR TB (Fairlie et al., 2011). Of those 13
children, 53.9 percent were HIV-coinfected, and 10 children received
appropriate treatment. Four children with MDR TB died within 0.1 to 4.0
months after the date of TB investigation. In other studies presented at
the Moscow meeting, data for Argentina and Peru indicated that MDR TB
represented 15.4 percent of 136 previously treated TB cases in children
in Argentina and 23.6 percent of 360 previously treated TB cases in
children in Peru (IOM, 2011b; Llerena et al., 2010; Wright et al., 2009).
The microbiological diagnosis of drug-resistant TB in children is a
challenge as children often have paucibacillary disease (few bacilli in
sputum for testing), and specimens for DST are difficult to obtain. Cassell
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3
INTRODUCTION
suggested that to measure infection in the pediatric population accu-
rately, the presence of the organism in other types of specimens must
be detectable in a more sensitive way.
Transmission of MDR TB
Cassell noted that another strong message from the South Africa
workshop was that human-to-human transmission of drug-resistant
strains of TB is much more common than previously appreciated. In the
past, infection control has been overlooked because there was a belief
that drug-resistant strains are not spread as easily from person to person
as susceptible strains. Whereas in the 1970s and 1980s, most MDR TB
appeared to result from a lack of patient compliance with treatment or se-
quential treatment regimens, transmission of MDR and extensively drug-
resistant (XDR) TB strains appears to dominate today, as evidenced by
experience in Shanghai, South Africa, Tomsk, and Lima (IOM, 2011a,b).
Transmission of drug-resistant strains among children also is occur-
ring in South Africa. In the 2008 South African study noted above, only
4 of the 13 children diagnosed with MDR TB had known exposure to an
adult with TB, and none of these adult contacts had MDR TB (Fairlie
et al., 2011). “Spread in the pediatric population is an important public
health issue,” said Cassell. Similarly, data presented at the Moscow
workshop described 128 culture-confirmed pediatric cases in Colombia,
South America. Almost all of these cases had never been treated, and
most had no history of adult MDR TB contacts.
Diagnosis and Treatment of MDR TB
As discussed in a white paper prepared for the Washington, DC,
workshop (Keshavjee and Seung, 2008), the number of patients receiv-
ing treatment for TB worldwide is small, and in many cases the treatment
they are receiving is ineffective because it is not based on DST. Rather,
patients have failed treatment with first-line drugs and therefore have
been put on second-line drugs without the susceptibility of their TB strain
to those drugs being known. In 2010, only 16 percent of global MDR TB
cases estimated to exist among reported TB cases were actually enrolled
in MDR TB treatment regimens (WHO, 2011a). It is also estimated that as
of 2010, fewer than 5 percent of TB patients were being tested for MDR
TB in most parts of the world (WHO, 2011a).
Cassell cited the views expressed by some speakers at previous
workshops that while enhancing laboratory capacity might improve
surveillance, it would be unlikely to affect individual patient treatment
and thus would fail to affect the spread of drug-resistant strains. It is
continued
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4 DRUG-RESISTANT TUBERCULOSIS IN INDIA
BOX 1-1 Continued
unrealistic to think that in countries that currently have fewer than 1 labo-
ratory per 10 million population, which is the case in most high-burden
countries, sufficient resources and time would be available to scale up
capacity quickly enough to have a major impact on rapid diagnosis and
treatment, especially given that most patients are in remote settings.
Countries need one laboratory per 5 million population to perform cul-
ture and DST, according to standards developed by WHO (2011a). Of
27 countries with a high burden of MDR TB, however, just 13 meet both
of these standards (Armenia, Azerbaijan, Bulgaria, Estonia, Georgia,
Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Republic of Moldova, Russian
Federation, South Africa, and Ukraine).
Recently introduced diagnostics and technologies in late-stage de-
velopment increase the speed and sensitivity of diagnosis. GeneXpert,
for example, is an impressive advance. But a diagnostic still is needed
that can determine antimicrobial susceptibility quickly at the point of care
so that patients can be managed appropriately. Also, new technologies
still require laboratory infrastructure and have limited capability to detect
MDR genes or to detect infection other than in sputum.
The three previous workshops also emphasized the importance of the
procurement and distribution of high-quality drugs. Critical issues include
the need for better data on drug quality, quality enforcement, quality
strategies, and accurate demand forecasting.
One of the most urgent needs is to obtain accurate data on the ex-
istence of totally drug-resistant (TDR) TB, said Cassell, because only
then will the rest of the world take notice of the problem and policy
makers increase funding for its control. Striking new data from KwaZulu-
Natal reveal the magnitude of the problem: in the studied population, 88
percent of cases identified as XDR TB were actually TDR.c Even under
the best of circumstances—as has been the case in Tomsk (Keshavjee
et al., 2008) and in Peru (Mitnick et al., 2008)—only 48 percent and 60
percent, respectively, of XDR TB cases are treatable, which means that
52 and 40 percent, respectively, are untreatable. Currently there are no
consistent policies for dealing with patients whose TB is untreatable.
Proof that the disease in these patients is untreatable may take months,
during which time they may spread their resistant organisms to family
members and others in the community, including health care workers.
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INTRODUCTION
Development of New Antibiotics
Successfully treating these patients will require not just one new
antibiotic in the regimen but a combination of three to four new classes
of antibiotics simultaneously. This represents an enormous financial and
technical challenge requiring massive cooperation. Today the failure rate
from the time of target identification to regulatory approval of a new
drug is 90 percent. Half of drugs fail even in phase III clinical trials. The
average cost of developing a new drug is more than $1.5 billion, and the
average time for drug discovery and development from target identifica-
tion to approval is 10 to 14 years. Both of these figures would probably
be higher for TB drugs given the lack of infrastructure and point-of-care
diagnostics in high-burden countries. Yet in 2010, the world was invest-
ing only $226.8 million in TB drug research and development from all
sources (Treatment Action Group, 2011).
According to Cassell, the public perception is that TB remains a prob-
lem but that drugs are available to treat it. The reality is that MDR and
XDR TB are increasing at a rapid rate. As noted, current estimates are
that 440,000 new cases of MDR TB are occurring each year, which is not
a large number compared with other unmet medical needs. However, the
reality is that while the number of patients diagnosed with and treated
for MDR TB is increasing globally, the majority of MDR TB patients are
not diagnosed and not receiving treatment. Only 16 percent of the TB
patients estimated to have MDR TB in 2010 were diagnosed and given
appropriate treatment (WHO, 2011a,b; Zignol et al., 2012).
a This box is based on the presentation of Gail Cassell, Visiting Professor, Harvard Medi-
cal School, and Vice President of TB Drug Discovery, Infectious Disease Research Institute.
b A report from WHO (2011a) released after the workshop indicates that 60 percent of
countries currently have at least one direct and representative measurement of drug resis-
tance among their TB patients. Despite overall global increases in the coverage of data on
drug resistance, however, considerable uncertainty remains as to the actual levels of MDR
TB among TB patients.
c Data provided via personal communication, June 22, 2011, with Kristina Wallengren,
Acting Clinical Core Manager, KwaZulu-Natal Research Institute for Tuberculosis and HIV
(K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal.
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6 DRUG-RESISTANT TUBERCULOSIS IN INDIA
key viewpoints and findings from the workshops held previously in Wash-
ington, Pretoria, and Moscow.
The workshop in India brought together about 100 disease experts,
community leaders, policy makers, and patient advocates from India, the
United States, and other countries for 2 days of intensive discussions. While
the workshop was specifically designed to address the current status of
drug-resistant TB in India, the presentations and discussions were anchored
in a framework reflective of the global experience with MDR TB. The aim
of the workshop was to highlight key challenges to controlling the spread
of drug-resistant strains of TB and to discuss innovative strategies for
advancing and harmonizing local and international efforts to prevent and
treat drug-resistant TB.2
HISTORY AND DIMENSIONS OF THE PROBLEM3
Evidence indicates that TB has plagued mankind since ancient times,
said Prakash N. Tandon, Emeritus Professor, INSA, in his opening remarks
at the workshop. A human skeleton from a Neolithic cemetery near
Heidelberg, Germany, dating to 5000 BCE shows evidence of spinal TB. Of
interest, said Tandon, is evidence in this skeleton of healing in the absence
of any drugs. Egyptian skeletons dating back to 3500 BCE likewise show
evidence of TB. Hymns in the Rigveda and Yajurveda indicate that the early
Indo-Aryans were familiar with the disease in the second millennium BCE.
Today, an estimated 2 billion people, one-third of the global popula-
tion, are infected with Mycobacterium tuberculosis (M.tb.), the bacterium
that causes TB (Keshavjee and Seung, 2008). Spread through the air, this
infectious disease killed 1.7 million people in 2009, or approximately 4,700
people each day (WHO, 2010a).
Although antibiotics developed in the 1950s are effective against a large
2 The National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes
of Health (NIH), held a meeting focused on exploring opportunities for collaboration in TB
drug discovery research on April 20–21, 2011, the 2 days following the IOM workshop, also
in New Delhi. The NIAID meeting was cosponsored by the Department of Biotechnology,
Ministry of Science and Technology, Government of India, and ICMR. Meeting objectives
included sharing the latest scientific information on drug discovery research focused on
combating MDR and XDR TB, discussing TB drug development needs and the ways in which
biomedical research can contribute, and identifying partnership opportunities to advance and
accelerate new drug discovery efforts in order to simplify and improve therapeutic options for
drug-resistant TB. Topics and meeting participants overlapped between the NIAID and IOM
meetings in India, creating synergies and connections for future collaborations in the areas of
TB research and policy. Appendix B of this report includes a summary of the NIAID meeting.
3 This section and the two that follow are based on the welcoming remarks of Prakash N.
Tandon, Emeritus Professor, INSA; Krishan Lal, President, INSA; and Vishwa Mohan Katoch,
Director General, ICMR.
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7
INTRODUCTION
percentage of TB cases, resistance to these first-line therapies has developed
over the years, resulting in the growing emergence of MDR and XDR TB
(see Box 1-2 for definitions). Diagnosing and effectively treating MDR and
XDR TB patients requires increasingly complex public health interventions.
MDR TB, for example, is resistant to first-line drugs and must be treated
with second-line drugs that are more expensive and more toxic, often
require injection, and involve longer treatment regimens (2 years or more
to treat MDR TB compared with 6–9 months to treat drug-susceptible
TB). As drug resistance develops, the challenge is to stop the transmission
or spread of MDR TB and identify MDR TB cases early; treatment should
include efforts to preserve the effectiveness of current drugs and create new
treatment regimens to combat drug-resistant strains as they emerge.
THE BURDEN OF DRUG-RESISTANT TB
According to data from WHO on global drug resistance, an estimated
3.6 percent of global incident (new) TB cases, or a total of 440,000 cases,
were MDR TB in 2008 (95 percent confidence interval, 390,000-510,000)
(WHO, 2010c).4 The available data on drug-resistant TB are inadequate,
however, and lead to an underestimation of the true global burden of MDR
TB. In many developing countries where the MDR TB burden is likely to be
significant, surveillance systems do not exist or lack the capacity to gener-
ate reliable data. Even the most recent global surveillance data on MDR
TB do not include 79 countries—41 percent of all countries in the world
(WHO, 2010c, p. 6).
The burden of XDR TB is even less well known because many countries
lack the laboratory and infrastructure capacity necessary to test MDR TB
patients routinely for susceptibility of their infection to second-line drugs.
The provision of optimal patient care for MDR and XDR TB patients is
based on DST, and many countries are ill equipped to conduct such tests. It
is through such testing that physicians determine which drugs are likely to
be effective against a particular drug resistance profile. The vast majority of
MDR and XDR TB cases are undetected and thus untreated with appropri-
ate second-line drugs. Of those patients who are treated with second-line
drugs, many are not taking the right drugs to treat their drug resistance
profile effectively.
4 Instead of providing a global estimate of incident MDR TB cases each year, an updated
WHO (2011a) report on TB control, released after the workshop, estimates the prevalence of
MDR TB (number of cases) globally. According to that report, an estimated 650,000 MDR
TB cases existed among the world’s 12 million cases of TB in 2010. (Prevalence measures the
level of a disease in a population at a particular point in time, while incidence measures the
occurrence of new cases of a disease in a population.)
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8 DRUG-RESISTANT TUBERCULOSIS IN INDIA
BOX 1-2a
The Nature of the Threat
Definitions
Multidrug-resistant (MDR) TB is caused by bacteria resistant to iso-
niazid and rifampicin, the two most effective first-line anti-TB drugs,
originally developed and introduced in the 1950s and 1960s.
Extensively drug-resistant (XDR) TB is resistant to the same drugs
as MDR TB (isoniazid and rifampicin), as well as any fluoroquinolone
(levofloxacin, moxifloxacin, or ofloxacin) and at least one second-line
injectable drug (kanamycin, amikacin, or capreomycin).
Totally drug-resistant (TDR) TB is TB for which no effective treatments
are available.
Pathways for Infection
MDR/XDR TB results from either primary infection with a drug-
resistant strain of TB (i.e., transmitted by person-to-person contact) or
acquired infection with such a strain that occurs in the course of a
patient’s treatment, resulting, for example, from failure to ensure regular
treatment with high-quality existing drugs. Amplified resistance, or the
enhancement of existing drug resistance as a result of initiating an inap-
propriate drug regimen at the beginning of care, is a significant challenge
TREATING TB IN CONTEXT
The diagnosis of TB is no longer a death warrant, said Krishan Lal,
President, INSA, but the existence of treatments raises sociological and
psychological issues. Patients may take a treatment just until they feel well,
which can foster the development of resistance and lead to the spread of the
disease. In addition, many health problems other than TB, such as diabetes
and high blood pressure, occur in India, which can complicate treatment.
The lack of quick, accurate, and inexpensive tests for drug-resistant TB
hampers treatment, said Tandon. Drug-resistant TB needs to be diagnosed
earlier and with greater specificity than is currently the case, especially given
the much greater costs of treating drug-resistant TB.
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9
INTRODUCTION
created by providing an incorrect combination of drugs. For example, a
patient might display resistance to streptomycin and isoniazid at the be-
ginning of treatment and subsequently become resistant to streptomycin,
isoniazid, and rifampicin during the course of treatment. Even when an
empirically appropriate drug regimen is selected at the beginning of treat-
ment, by the time drug susceptibility information is available, resistance
may be amplified.
WHO and the International Union Against Tuberculosis and Lung
Disease (IUATLD) have urged replacement of the term “primary resis-
tance” with “drug resistance among new cases” and the term “acquired
resistance” with “drug resistance among previously treated cases.”
Treatment
MDR/XDR TB treatment requires 2 years or more of daily, directly
observed treatment (DOT) with drugs that are less potent, more toxic,
and much more expensive than those used to treat drug-susceptible TB.
Despite the challenges, aggressive treatment with second-line drugs has
produced positive outcomes in MDR/XDR TB patients. However, TDR TB
is a growing threat. The spread of TDR TB is especially ominous as it
would return the globe to the pre-antibiotic era (Keshavjee and Seung,
2008).
a The information in this box was originally presented at the Forum’s 2008 workshop on
drug-resistant TB (IOM, 2009).
India has in the past had great success in tackling major health prob-
lems such as leprosy, observed Vishwa Mohan Katoch, Director General,
ICMR. The country has instituted a massive program to deliver drugs to
TB patients, but the disease also needs to be monitored and managed very
carefully. Comprehensive approaches, such as those reflected in the agenda
of this workshop, are essential, V. M. Katoch said.
Tandon, Lal, and V. M. Katoch praised the extent of international col-
laboration in responding to drug-resistant TB, especially the collaboration
between India and the United States. Both countries are members of the
Global Network of Academies, Lal observed, and this organization also has
worked with the InterAcademy Medical Panel. Such collaborations will be
essential, he said, for evolving strategies to fight TB.
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10 DRUG-RESISTANT TUBERCULOSIS IN INDIA
OVERVIEW OF TB AND MDR TB IN INDIA5
In his opening keynote address, K. Srinath Reddy, President, Public
Health Foundation of India, provided a broad overview of TB in India
and the nation’s response to the disease. (Chapter 2 covers these topics in
greater detail.)
India accounts for approximately one-fifth of the global incidence of TB
(RNTCP Status Report, 2011). Fully 40 percent of the country’s population
is infected with the tubercule bacillus. Each year the country sees 2 mil-
lion new cases (the global incidence is 9.4 million), which lead to 280,000
deaths annually, although the prevalence of HIV among new cases in India
is just 6.4 percent compared with a global average of 12 percent. TB is one
of the leading causes of death among adults in India, and it also takes a
large toll on the country’s younger generation, which makes up a significant
proportion of the total population.6 TB also takes a disproportionately
large toll among young females: more than 50 percent of TB cases among
females occur before age 34, and an estimated 100,000 women are rejected
by their families every year because they have the disease. Some workshop
participants noted that national-level, all-India studies evaluating the effect
of a TB diagnosis on family dynamics could provide more specific data
and have an impact on understanding and preventing the rejection of TB
patients by their families.
TB also disproportionately affects the poorest and most marginalized
populations in India, as well as people in their most productive ages—70
percent of TB patients are aged 15–54. People with TB incur an average
potential loss of 20–30 percent of their annual household income as a result
of 3–4 months of lost work time. In India, about 14 million people fall into
poverty each year because they experience unaffordable health care costs,
and TB is a major cause of health-related impoverishment.
Drug-Resistant TB in India
Reddy noted that, based on 2008 data, MDR TB represents an esti-
mated 2.3 percent of new TB cases in India (compared with 3.3 percent
5 This section is based on the presentation of K. Srinath Reddy, President, Public Health
Foundation of India.
6 According to the 2001 Indian census, the country has a large proportion of young
people—35 percent of the population is aged 14 and younger (Government of India, 2001).
Provisional population totals from the 2011 Indian census reveal a total population of 1.21
billion people, reflecting an additional 181 million people since 2001. The United Nations
has estimated that the world population grew at an annual rate of 1.23 percent from 2000 to
2010. Over this decade, China’s population grew at an annual rate of 0.53 percent and India’s
at an annual rate of 1.64 percent (Government of India, 2011).
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11
INTRODUCTION
worldwide) and 17 percent of retreatment cases. These figures represent
about 99,000 MDR TB cases in the country.
XDR TB has been reported in India. However, its magnitude remains
undetermined because of a lack of laboratories capable of conducting
quality-assured second-line DST.7
The Revised National TB Control Program
The United Nations’ Millennium Development Goals call for halt-
ing and beginning to reverse the incidence of TB by 2015. The STOP TB
Partnership has established the target of reducing the global burden of TB
(defined by per capita prevalence and death rates) by 50 percent relative to
1990 levels by 2015 and the long-term goal of reducing the global incidence
of active TB to less than 1 case per million population per year by 2050.
India’s strategy for working toward these goals is embodied in its
Revised National TB Control Program (RNTCP). This program is struc-
tured around five elements:
1. political and administrative commitment;
2. good-quality diagnosis, primarily by sputum smear microscopy;
3. an uninterrupted supply of quality drugs;
4. DOT; and
5. systematic monitoring and accountability.
A massive expansion of the program began in 1998, so that by 2006,
Directly Observed Treatment-Short course (DOTS) coverage had been
extended to 632 districts and more than 1.1 billion people.
In 2010, DOTS-Plus services were introduced in some states of India
to treat MDR TB. By 2012, these services will have been extended to all
smear-positive retreatment cases and to new cases that have failed an ini-
tial first-line drug treatment. By 2015, services are to be made available to
all smear-positive pulmonary TB cases registered under the program. By
2012–2013, the program’s goal is to treat at least 30,000 MDR TB cases
annually. Providing DOTS-Plus for MDR TB requires giving special atten-
tion to several key factors in program design and delivery:
7 The emergence of what has been described as TDR TB was reported in January 2012
(Udwadia et al., 2012) at Hinduja Hospital in Mumbai when four patients were found to be
resistant to all first- and second-line drugs tested. India’s Revised National TB Control Pro-
gram (RNTCP) has issued a response to the report and provided information on the program’s
approach to combating all forms of drug-resistant TB. For more information, visit http://
tbcindia.nic.in/pdfs/RNTCP%20Response%20DR%20TB%20in%20India%20-%20Jan%20
2012%20update.pdf (accessed April 17, 2012).
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12 DRUG-RESISTANT TUBERCULOSIS IN INDIA
• quality-assured laboratory capacity for smear, culture, and drug
sensitivity testing;
• treatment design;
• adherence to difficult-to-take regimens for long periods of time;
• management of side effects;
• drug procurement;
• recording and reporting; and
• human and financial resource constraints.
As of the end of 2010, MDR TB treatment had been scaled up to
cover 287 million people in 139 districts across 12 states of India. Since
the inception of services, more than 19,000 suspected MDR TB cases have
been examined for diagnosis, more than 5,000 cases have been confirmed,
and more than 3,500 cases have been initiated on category IV treatment
through 20 DOTS-Plus sites.
Reddy noted that in general, India has a strong national program for
basic TB control with a high treatment success rate. The country has made
provisions for the participation of all health care providers, including pri-
vate practitioners. Efforts also have been made to control the dual epidem-
ics of TB and HIV (see the discussion of this topic in Chapter 6). Extensive
laboratory expansion is planned in collaboration with the private sector,
which has to date been a largely untapped resource in the development of
laboratory capacity. (The expansion plans for the program are described in
Chapter 2 and public–private participation in Chapter 7.)
Challenges in the Management of MDR TB in India
Several challenges are faced in the management of MDR TB in India,
said Reddy. First is the limited supply of human resources to carry out train-
ing and assessments. Indeed, India is a country where in general, human
resources in health care are limited and not well distributed. According to
Reddy, the country’s public health workforce needs to be expanded, and
those who are currently employed need training to augment their knowl-
edge and skills.
Second, there is a lack of funding for the management of MDR TB,
especially given the high cost of second-line drugs as treatment is scaled up.
A high-level expert group recently recommended that a larger portion of
the country’s health budget be allocated to providing drugs free of cost and
that the national capacity to produce and supply low-cost drugs, including
public procurement, be enhanced (Planning Commission of India, 2011).
Other workshop participants noted that policy implementation delays will
negatively affect MDR TB cases—diagnosed and undiagnosed.
Third, laboratory capacity for diagnosis and follow-up of MDR TB
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13
INTRODUCTION
patients and quality assurance is limited. Although expansion currently
is taking place, India now has only 23 functional laboratories across the
country, and according to Reddy, many more are needed. The availability of
second-line drugs and DST also is limited. High-throughput diagnostics and
a specimen transportation infrastructure are particular needs. An MDR TB
surveillance or survey program still does not exist, and an infection control
plan is lacking. Reddy stressed that all of these issues need to be addressed
and that managerial capacity must be improved as well. India needs a
strong vertical program that integrates all aspects of MDR TB control
and care, including infection control, diagnosis, treatment, and follow-up.
However, Reddy added, it is difficult to impose a strong vertical program
on a weak national health system.
The Need for Action
The prevalence of MDR and XDR TB in India and globally raises the
possibility that the current epidemic of mainly drug-susceptible TB will be
replaced by a form of TB with severely restricted treatment options, Reddy
observed. If so, plans to move toward a world where TB is no longer a
public health problem will be derailed.
Reddy stressed that the basic TB program in India needs to be strength-
ened to reach out to unnotified and missed cases and to poor and highly
vulnerable populations. More broadly, the social determinants of TB need
to be addressed. The Public Health Foundation of India is currently work-
ing with the RNTCP to assess the barriers experienced by vulnerable groups
in accessing services and determine how those barriers can be overcome.
In terms of surveillance, India’s Department of Health Research needs
to supplement efforts currently in place, particularly for MDR and XDR TB,
said Reddy. Laboratory networks need to be strengthened and expanded,
human resources and financial management need to be enhanced, and the
drug supply chain needs to be strengthened. Reddy also noted that the
National Board of Examinations is currently connected to more than 700
hospitals that are distributed across the country and have postgraduate
trainees who are expected to conduct research. According to Reddy, “If at
least 100 of these hospitals can be linked up and their surveillance changed
to regularly report on issues related to MDR TB and XDR TB—in terms of
detection as well as management and outcomes—we can develop a central-
ized surveillance system across the country extending to medical colleges.”
In this way, India could quickly build a cost-effective surveillance system
that would be nationally representative.
Policies should ensure that all TB patients have equitable access to care
and that their interests and rights are protected, said Reddy. Policies also
should ensure that all relevant public and private health care providers are
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14 DRUG-RESISTANT TUBERCULOSIS IN INDIA
engaged in managing TB according to national priorities. And the primary
health care system should be strengthened to ensure early detection, effec-
tive treatment, and support for patients.
Reddy emphasized that TB medicines should be sold by prescription
only and should be prescribed and dispensed by accredited public and
private providers. He noted that in India today, drugs often are sold over
the counter instead of through appropriate prescriptions, a situation that
can foster misuse. Infection control policies are needed, and investments
should be made to promote research, surveillance, molecular diagnostics,
and drug development.
Reddy concluded by lauding the collective commitment to combating
drug-resistant TB, “which now transcends geographical barriers and also
brings scientific coalescence from multiple disciplines.” In this context,
he suggested, “this workshop should be a landmark for initiating action
against MDR TB and XDR TB.”
SETTING THE STAGE8
To set the stage for the remainder of the workshop, Salmaan Keshavjee,
Assistant Professor, Harvard Medical School, provided a global overview of
the challenges and potential solutions in confronting drug-resistant TB (dis-
cussed in detail in Chapter 3), with an emphasis on the slow pace of treat-
ment scale-up and the consequences of inaction. He urged the participants
“to be blunt with each other, because we are TB experts, and if we can’t
be honest with each other, we are going to have big trouble as we move
forward.” To this end, throughout the workshop, there was discussion of
existing bottlenecks and challenges, as well as examples of incentives and
disincentives from other locations or experiences. Experiences with both
success and failure were shared.
In 2006, the STOP TB Partnership established a plan for combating
the epidemic of drug-resistant TB. At that time, WHO was estimating that
about 500,000 new cases of drug-resistant TB occurred each year, meaning
that between 2006 and 2015 there would be 5 million cases. The goal of
the 2006 plan was to treat 1.6 million cases, said Keshavjee, leaving the
other 3.4 million without treatment; he referred to this target as “dismal.”
Since that plan was established, official efforts to treat MDR TB
have failed to achieve even this target, Keshavjee stated. Of the 5 mil-
lion cases estimated to have occurred between 2000 and 2009, only
approximately 22,000 patients received treatment through programs
approved by the Green Light Committee (GLC)—a multilateral coali-
8 This section is based on the presentation of Salmaan Keshavjee, Assistant Professor,
Harvard Medical School.
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15
INTRODUCTION
~3.5 million patients
No treatment reported
Some treatment probably
obtained, quality unknown
Continued transmission
~5 million
Many are dead
cases
Treated through programs approved
0.5%
by Green Light Committee
~1.5 million patients dead
FIGURE 1-1 Of the estimated 5 million MDR TB cases that occurred between 2000
and 2009, only 0.5 percent were treated in programs approved by the Green Light
Committee.
SOURCE: Keshavjee, 2011a.
Figure 1-1
tion created in 2000 (Figure 1-1). About 3.5 million of the 5 million
patients received no reported treatment, although an unknown fraction
undoubtedly received some treatment of unknown quality from private
physicians, pharmacies, or other sources. Meanwhile, many continued
to transmit the disease while alive. According to global statistics, 1.5
million of these 5 million people died. Keshavjee emphasized that this is
an epidemic of profound proportions.
Scaling up treatment for drug-resistant TB is complex, Keshavjee
acknowledged. But treating HIV in poor countries is also complex, and
the global community has done a much better job of that. Between 2004
and 2008, the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR)
provided antiretroviral therapy to more than 1.6 million people, includ-
ing 367,000 patients who were coinfected with HIV and TB. The contrast
between the responses to TB and HIV, said Keshavjee, calls for a rethinking
of the global approach to TB.
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16 DRUG-RESISTANT TUBERCULOSIS IN INDIA
ORGANIZATION OF THE REPORT
This report summarizes the main points made at the workshop in
India during both the formal presentations and the discussions among
participants. In accordance with IOM and National Research Council
policies, this report provides an accurate summary of the presentations and
discussions held at the workshop; it does not contain any commentaries
or views that were not presented at the workshop, and any supplementary
viewpoints shared outside of the workshop context are not included in this
summary. Observations and recommendations made by individual speakers
and participants do not represent the formal positions of the planning com-
mittee, the Forum, the IOM, INSA, or ICMR; however, they have provided
valuable input to the Forum and to the IOM and the workshop contribu-
tors as they deliberate on future initiatives. Presentations at the workshop
addressed the following topics:
• TB and MDR TB in India, including local and national responses
to the epidemic (Chapter 2);
• the global burden of TB and drug-resistant TB, including data from
another high-burden country, China (Chapter 3);
• prevention of the transmission of drug-resistant TB in India (Chap-
ter 4);
• rapid methods of detecting drug resistance and strengthening labo-
ratory capacity (Chapter 5);
• approaches to reaching vulnerable populations affected by drug-
resistant TB (Chapter 6);
• public–private engagement and innovative methods in combating
drug-resistant TB (Chapter 7);
• the drug supply chain for second-line drugs (Chapter 8); and
• the major viewpoints expressed at the workshop and next steps
suggested by workshop participants (Chapter 9).
Each of these chapters opens with a box listing the key messages emerg-
ing from the workshop presentations and discussions, as identified by the
workshop rapporteurs.
