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1
Introduction1
An estimated 2 billion people, one-third of the global population,
are infected with Mycobacterium tuberculosis (M.tb.), the bacterium that
causes tuberculosis (TB) (Keshavjee and Seung, 2008). Spread through the
air, this infectious disease killed 1.7 million people in 2009, or approxi-
mately 4,700 each day (WHO, 2010a). TB is the leading killer of people
with HIV, and it is also a disease of poverty—the vast majority of TB deaths
occur in the developing world (WHO, 2010a). Exacerbating the devastation
caused by TB is the growing threat of drug-resistant forms of the disease
in many parts of the world. Identifying and addressing barriers to effective
and timely diagnosis and treatment of drug-resistant TB will be critical to
preventing the further emergence of strains of TB with broad-spectrum
resistance (Keshavjee and Seung, 2008). The workshop summarized in this
volume, held in Moscow, Russian Federation, was the second international
1 The workshop was organized by an independent planning committee whose role was
limited to the identification of topics and speakers. While the Institute of Medicine’s (IOM’s)
Forum on Drug Discovery, Development, and Translation conceived the idea for this work-
shop, this summary was prepared by the rapporteurs as a factual summary of the presentations
and discussions that took place at the workshop. Statements, recommendations, and opinions
expressed are those of the individual presenters and participants, are not necessarily endorsed
or verified by the Drug Forum or the National Academies, and should not be construed as
reflecting any group consensus.
1
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2 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA
meeting in a series designed to gather information from experts around the
world on the nature of this threat and how it can be addressed.2
THE PROBLEM OF DRUG RESISTANCE
The development of drug resistance is a predictable, natural phenom-
enon that occurs when microbes adapt to survive in the presence of drug
therapy (Nugent et al., 2010). Although antibiotics developed in the 1950s
are effective against a large percentage of TB cases, resistance to these
first-line therapies has developed over the years, resulting in the growing
emergence of multidrug-resistant (MDR) and extensively drug-resistant
(XDR) TB (see Box 1-1 for definitions). Workshop participants noted that
the rapid spread of drug-resistant forms of TB poses new challenges to
effective control of this disease, as diagnosing and effectively treating MDR/
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 preserve the effectiveness
of current drugs and create new treatment regimens to combat resistant
strains as they emerge.
During the workshop, Paul Farmer, founding director of Partners In
Health, noted that although the advent of diseases such as drug-resistant
TB, methicillin-resistant Staphylococcus aureus (MRSA), and extensively
drug-resistant malaria was inevitable, it is possible to change the course of
these epidemics and the rate at which acquired and transmitted resistance
to the drugs used to treat those infected takes hold in a population.
THE BURDEN OF DRUG-RESISTANT TB
Based on global drug resistance surveillance data from the World
Health Organization (WHO), it is estimated that 3.6 percent of global
TB cases, or a total of 440,000 cases, were MDR TB in 2008 (95 percent
confidence interval, 390,000–510,000) (WHO, 2010b). However, a number
of TB experts at this and prior workshops explained that available data
on drug-resistant TB are inadequate and yield a gross underestimation
of the true global burden of disease (see Chapter 2). Surveillance systems
2 The
Drug Forum held a foundational workshop in Washington, DC, in 2008. The sum-
mary of that foundational workshop, Addressing the Threat of Drug-Resistant Tuberculosis:
A Realistic Assessment of the Challenge: Workshop Summary, and the accompanying white
paper (Keshavjee and Seung, 2008) provided background for and informed the development
of and proceedings at the Russian Federation workshop summarized in this volume.
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3
INTRODUCTION
BOX 1-1a
The Nature of the Threat
Definitions
Multidrug-resistant tuberculosis (MDR TB) is caused by bacteria
resistant to isoniazid and rifampicin, the two most effective first-line anti-
TB drugs, originally developed and introduced in the 1950s and 1960s.
Extensively drug-resistant tuberculosis (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 tuberculosis (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
created by providing an incorrect combination of drugs. For example,
a patient might display resistance to streptomycin and isoniazid at the
beginning of treatment and subsequently become resistant to streptomy-
cin, isoniazid, and rifampicin during the course of treatment. Even when
an empirically appropriate drug regimen is selected at the beginning of
treatment, by the time drug susceptibility information is available, resis-
tance may be amplified.
Treatment
MDR/XDR TB treatment requires 2 years or more of daily, directly
observed treatment 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 pro-
duced 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).
aThe information in this box was originally presented at the Forum’s 2008 workshop on
drug-resistant TB (IOM, 2009).
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4 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA
do not exist or are not capable of valid and reliable reporting in many
developing countries where the MDR TB burden is likely to be substantial.
Even the most recent global surveillance data on MDR TB do not include
79 countries—41 percent of all countries in the world (WHO, 2010b, p. 6).
According to WHO, although the estimate of 440,000 MDR TB cases for
2008 indicates a decrease relative to 2006 (best estimate of 489,000 cases),
this change reflects the reporting of new data, changes in TB incidence, and
the use of updated diagnostic methods and should not be considered reflec-
tive of a true decline in MDR TB cases (WHO, 2010b, p. 18).
Data on the burden of XDR TB are even more limited 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. Unfortunately, moreover, the drug susceptibility testing that
many countries are ill equipped to conduct is the basis for providing opti-
mal patient care for MDR and XDR TB patients. It is through such testing
that physicians determine which drugs are likely to be effective against a
particular drug resistance profile (the relationship between drug suscepti-
bility testing and treatment is further discussed in Chapter 6). A number
of workshop participants noted that the vast majority of MDR and XDR
TB cases are undetected and thus untreated with appropriate second-line
drugs. Among the small proportion of patients who are being treated with
second-line drugs, many are not taking the right drugs to treat their drug
resistance profile effectively (see the section “Remaining Challenges” in
Chapter 2 for a discussion of the estimated proportion of MDR TB patients
receiving care and the challenges to providing quality-assured second-line
drugs for patients that need them).
Overall, Russia has experienced a high burden of MDR TB in recent
decades. Fluctuations in the level of disease in the population have mirrored
the social, political, and economic upheavals in the country. For instance,
the dissolution of the Soviet Union eliminated stringent federal control over
TB prevention and treatment programs across the vast country. This loss of
control over TB programs was accompanied by increased unemployment,
poverty, population displacement, crime rates, and military conflicts, all of
which exacerbated the spread of TB (see Chapter 3 for additional historical
background on TB control in Russia).
WORKSHOP OBJECTIVES
The workshop summarized in this volume is part of a series on drug-
resistant TB being conducted by the Forum on Drug Discovery, Develop-
ment, and Translation of the Institute of Medicine (IOM). The workshop
was held May 26−27, 2010, in collaboration with the Russian Academy of
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5
INTRODUCTION
Medical Sciences (RAMS) and held at the International Science and Tech-
nology Center (ISTC) in Moscow, Russian Federation.
The first workshop in this series took place in Washington, DC, on
November 5, 2008 (IOM, 2009) and led to plans for four additional
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, 2011). Future workshops are being planned for
China and India.
In a broader context, this workshop in Moscow was also the first
in a series that will occur over the next 5 years on biomedical research
and health issues of the highest priority between the United States and
Russia. This series grew out of a Memorandum of Understanding signed
between Presidents Barack Obama and Dmitry Medvedev at their summit
in July 2009, a date that also marked the 50th anniversary of collaboration
between the Russian Academy of Sciences and the U.S. National Academy
of Sciences. The workshop brought together about 100 disease experts,
community leaders, policy makers, and patient advocates from Russia, the
United States, South Africa, and China for 2 days of intensive discussions.
The workshop was supported in part by the U.S. Department of State.
The objectives of the workshop were to learn from the historical and
contemporary experiences of the Russian public health community in its
efforts to control and combat the spread of drug-resistant TB, and to draw
lessons regarding best practices and novel approaches that can be applied in
the region and across the globe. An important objective of the presentations
and discussions among workshop speakers and guests was to forge new
linkages and collaborations across multiple disciplines and countries and
facilitate the sharing of scientific knowledge to benefit TB control efforts.
Specifically, the workshop was designed to:
• i
ncrease awareness and create a renewed sense of urgency with
respect to the growing global burden of MDR and XDR TB and
its profile in Russia;
• c
onsider the magnitude of transmission of drug-resistant strains
and options for control of transmission and infection;
• a
ddress the MDR TB burden in vulnerable populations, including
children, those coinfected with HIV, and substance abusers;
• a
ssess current treatment options and approaches to patient care,
taking into account the unique needs of the population being
treated;
• d
iscuss the supply of quality-assured second-line TB drugs and the
pipeline for a new “cocktail” of TB drugs;
• a
ssess the current state of the art for rapid detection of drug resis-
tance and the implications for patient management; and
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6 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA
• s
uggest policies for accelerating improvements in treatment and
infection control for drug-resistant TB.
A REALISTIC ASSESSMENT OF THE
CHALLENGES OF DRUG-RESISTANT TB
Gail Cassell, Forum co-chair, Eli Lilly and Company (retired), pro-
vided opening remarks to set the stage for the workshop. She summarized
major themes from the Drug Forum’s foundational 2008 workshop and the
March 2010 workshop in Pretoria, South Africa, both of which focused on
understanding and addressing the realistic challenges of drug-resistant TB
globally and in country.
Drug-resistant TB is a global challenge, but (as noted above) global esti-
mates of the burden of disease grossly underestimate the magnitude of the
MDR and XDR TB problem. Given the limitations of surveillance systems
in many developing countries, statistical models are often used to derive the
estimated burden of TB in a community or country. Moreover, the number
of patients receiving treatment is small compared with the number of new
and existing MDR TB cases. It is estimated that only 10 percent of new
MDR TB cases are treated each year, and fewer than 2 percent of patients
are receiving verifiable, quality-assured second-line anti-TB drugs. Cassell
stressed that, among the small population of patients receiving treatment,
many are not receiving drugs that actually address their drug resistance
profile, and therefore their treatment is ineffective.
Cassell cited several themes that emerged from the presentations and
discussions at the 2008 and 2010 workshops in Washington, DC, and Pre-
toria, South Africa, respectively:
• P
rimary infection, or human-to-human transmission, is more com-
mon than many experts previously thought.
• T
he development and implementation of a point-of-care diagnostic
test would speed the effective diagnosis of patients and permit ini-
tiation of treatment as soon as possible. Such an innovation could
reduce the period of a patient’s infectivity, protecting others in the
community, and speed delivery of the appropriate care regimen.
• B
ottlenecks in the procurement and distribution of high-quality
drugs are a major barrier to effective treatment of patients.
• D
evelopment of a “cocktail” of three to four new TB drugs is
warranted to treat the variety of drug-resistant strains that are
emerging, as well as cases that are considered to be untreatable
with existing drugs.
• T
echnical, regulatory, and financial challenges to the successful
development of multiple new TB drugs include
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7
INTRODUCTION
—A high failure rate in the drug development process—There is
a 90 percent failure rate from the time a drug target is identi-
fied to the time a drug achieves regulatory approval.
—Lengthy time line—The average time from discovery of a new
drug to its approval is 10–14 years.
—High financial cost—The average cost of bringing a single
drug to market is $1 billion, whereas the total global invest-
billion, invest-
ment in TB drug development was $179 million in 2009.
Cassell closed by emphasizing her view that failure to acknowledge the
new realities of drug-resistant TB and to act rapidly will be catastrophic
for many countries and will greatly jeopardize the public health globally.
She urged the scientific and medical communities to communicate the new
realities of drug-resistant TB to the public and to policy makers, who must
translate the data into policies that appropriately reflect the magnitude and
urgency of the problem.
ORGANIZATION OF THE REPORT
This report summarizes the main points made at the workshop dur-
ing both the formal presentations and the discussions among participants.
Observations and recommendations made at the workshop do not represent
the formal positions of the IOM or RAMS; however, they have provided
valuable input to the Forum on Drug Discovery, Development, and Transla-
tion and to the IOM as both bodies deliberate on future initiatives.
Presentations at the workshop addressed the following topics:
• a
global overview of TB and its growing drug resistance, as well
as epidemiological data on drug-resistant TB from two other high-
burden countries, South Africa and China (Chapter 2);
• t
he history of TB control and management in Russia and the epi-
demiology of drug-resistant TB in the country today (Chapter 3);
• T
B transmission and infection control, both in particular countries
and in specific settings, such as hospitals (Chapter 4);
• t
he development of new methods for diagnosing drug-resistant TB
in patients, as well as the need for improved laboratory capacity
(Chapter 5);
• t
reatment of drug-resistant TB, including TB and HIV coinfection
and innovative research on MDR TB treatment (Chapter 6);
• t
he incidence and treatment of MDR TB in vulnerable populations,
including children, substance abusers, and the incarcerated (Chap-
ter 7);
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8 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA
• t
he second-line drug supply chain for treatment of MDR TB (Chap-
ter 8); and
• t
he development of new TB diagnostics and drugs (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. Finally, Chapter 10 looks back at the major view-
points expressed at the workshop and looks forward to next steps suggested
by workshop participants.
