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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.