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Introduction and Overview of the Workshop1

Since 2008, the Forum on Drug Discovery, Development, and Translation (“the Forum”) of the Institute of Medicine (IOM) has hosted or cohosted six domestic and international workshops addressing the global crisis of drug-resistant (DR) tuberculosis (TB). The first, held in Washington, DC, on November 5, 2008, built on a white paper commissioned by the Forum and authored by Keshavjee and Seung (2008) to examine seven broad issues (IOM, 2009):

1.   Limitations of global TB estimates

2.   The role of HIV infection in the spread of multidrug-resistant tuberculosis (MDR TB)

3.   The importance of infection and transmission control

4.   Problems associated with limited diagnostic capacity

5.   Low rates of treatment

6.   Bottlenecks in the procurement and distribution of quality-assured drugs

7.   The need for new TB drugs

__________________

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, and they should not be construed as reflecting any group consensus.



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1 Introduction and Overview of the Workshop1 Since 2008, the Forum on Drug Discovery, Development, and Transla- tion (“the Forum”) of the Institute of Medicine (IOM) has hosted or co- hosted six domestic and international workshops addressing the global crisis of drug-resistant (DR) tuberculosis (TB). The first, held in Washington, DC, on November 5, 2008, built on a white paper commissioned by the Forum and authored by Keshavjee and Seung (2008) to examine seven broad issues (IOM, 2009): 1. Limitations of global TB estimates 2. The role of HIV infection in the spread of multidrug-resistant tuberculosis (MDR TB) 3. The importance of infection and transmission control 4. Problems associated with limited diagnostic capacity 5. Low rates of treatment 6. Bottlenecks in the procurement and distribution of quality-assured drugs 7. The need for new TB drugs 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, and they should not be construed as reflecting any group consensus. 1

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2 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS The next three workshops were held outside the United States, in South Africa on March 3–4, 2010 (IOM, 2011a); in Russia on May 26–27, 2010 (IOM, 2011b); and in India on April 18–19 and 21, 2011 (IOM, 2012). Each international meeting took the form of a collaboration between the IOM and national science academies in the respective host countries.2 The fifth work- shop was held July 31–August 1, 2012, in Washington, DC, and focused on the global supply chain for second-line anti-TB drugs (SLDs) (IOM, 2013). Box 1-1 presents the major messages that emerged from these previous gath- erings, while Box 1-2 describes the nature of the threat of DR TB. Workshop Chair’s Key Messages To underscore her remarks summarizing the themes of the workshop series, Gail Cassell, Visiting Professor, Harvard Medical School; and Vice President of TB Drug Discovery, Infectious Disease Research Institute, exhorted the workshop participants to consider how an accurate and com- prehensive understanding of the realities of DR TB could be translated into policies to address the issues that are commensurate with the magnitude and urgency of the challenges. Cassell argued that several common public perceptions about DR TB have been shown in recent years, through the workshop series and other research and international meetings, not to accord with the reality of the disease. These perceptions include that TB is always treatable with available therapies, that the burden of DR TB is small compared with other unmet medical needs, and that DR TB rarely spreads from person to person. Cassell remarked that a failure to acknowledge the realities and to act rapidly to address the challenges would be catastrophic for many countries, adding that the effects would not be contained, as global public health would be jeopardized by way of international travel and immigration. Cassell concluded that a “polio approach” is needed—a focus on prevention, as was achieved with polio when the emphasis shifted from building more iron lungs to developing a vaccine. The Beijing workshop The sixth workshop was held in Beijing, China, on January 16–18, 2013, co-sponsored by the IOM and the Institute of Microbiology, Chinese Academy of Sciences (IMCAS). Box 1-3 describes the statement of task for the workshop. 2  TheSouth Africa workshop was co-hosted by the Academy of Science of South Africa; the Russia workshop was co-hosted by the Russian Academy of Medical Sciences; and the India workshop was co-hosted by the Indian National Science Academy and the Indian Council of Medical Research.

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Introduction AND OVERVIEW OF THE WORKSHOP 3 BOX 1-1 Themes of the Workshop Series­ Gail Cassell, chair of the planning committee for the workshop series; Visiting Professor, Harvard Medical School; and Vice President of TB Drug Discovery, Infectious Disease Research Institute, laid out the common themes from the preceding workshops in her opening address at the meet­ ing in Beijing: • According to Cassell, the magnitude of the problem is “grossly under­ estimated.” There were an estimated 310,000 (range of 220,000– 400,000) MDR TB patients among notified TB patients in 2011 (WHO, 2012). But, she argued, considering that MDR TB is an aerosol-borne infection that is treated in just a small fraction of patients, this estimate is unreasonably low. • Data from certain locations have demonstrated that most new cases of MDR TB result from person-to-person spread and are not caused by inadequate treatment, inappropriate drugs, or lack of patient compli­ ance. In addition, Cassell noted, many have held a mistaken belief that MDR TB is caused by organisms that have a lack of fitness; this misper­ ception has focused attention away from addressing transmission and has resulted in infection control receiving less attention than it should. • Problems with the supply chain of SLDs have created major barriers to access, and these barriers will persist even if drug developers are successful at launching new therapies. • Pediatric MDR TB remains a “silent epidemic” (Sentinel Project on Pediatric Drug-Resistant Tuberculosis, 2013). Children are often neglected by health care systems and the research communities (­ eddon et al., 2013). Although exact numbers are unknown, it has S been estimated that 100,000 children have MDR TB globally, but fewer than 500 children with MDR TB have been described in the medical literature to date (Ettehad et al., 2012). • The number of patients receiving treatment is small, and their treat­ ment often is ineffective. According to data from Salmaan Keshavjee, Director, Program in Infectious Disease and Social Change, Depart­ ment of Global Health and Social Medicine, Harvard Medical School, less than one-half of 1 percent of newly diagnosed patients have been treated since 2000. And even in the small proportion of patients who are being treated, many are not receiving high-quality drugs or drugs that specifically address their drug resistance profile, rendering treatment ineffective. As a result, millions of infected people are still in communities and likely to spread drug-resistant organisms. continued

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4 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS BOX 1-1 Continued • Enhancing laboratory capacity may improve surveillance techniques and output but is unlikely to influence the treatment of individual patients, according to Cassell. In countries with fewer than one labo­ ratory per 10 million population, including most high TB burden coun­ tries (HBCs), health care systems are not sufficient for scale-up at the speed needed to have a significant impact in making diagnosis and treatment more rapid, especially given that most patients are in remote settings. • New and developing diagnostics increase speed and sensitivity but still require laboratory infrastructure. Technology for detection of MDR TB and extensively drug-resistant tuberculosis (XDR TB) at the point of care is available but, Cassell noted, requires further development and evaluation. • When cases cannot be treated with available drugs, there is urgency to prevent transmission. Although the actual prevalence of TB that cannot be treated with any antibiotic therapies remains unknown, no consistent policies exist to deal with such patients. Proving that dis­ ease in these patients may be “untreatable” could take months, during which time they could spread the disease to others, noted Cassell. • Successful treatment of potentially “untreatable” patients requires us­ ing three to four new classes of antibiotics simultaneously. Developing the needed medicines presents a huge technical and financial chal­ lenge. Developing a single new drug has been found to cost more than a billion dollars and to take more than a decade. Notwithstanding these resource needs, the total global investment for research and development (R&D) on TB drugs was just $649 million in 2011 (Treat­ ment Action Group, 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. As Cassell noted in the opening session of the workshop, the BRICS countries (Brazil, Russia, India, China, and South Africa) represent 43 percent of the world’s population yet account for more than 80 percent of the world’s cases of MDR TB. As the economies of these countries have grown, they have demonstrated remarkable success in ameliorating poverty and making progress against other communicable and noncommunicable

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Introduction AND OVERVIEW OF THE WORKSHOP 5 BOX 1-2a The Nature of the Threat Definitions Multidrug-resistant (MDR) TB is caused by bacteria resistant to isoniazid ­ and rifampicin, the two most effective first-line anti-TB drugs (FLD), origi­ nally developed and introduced in the 1950 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-­ esistant r 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 treat­ ment, 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 inappropriate drug regi­ men 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 streptomycin, 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 suscep­ tibility information is available, resistance may be amplified. The World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (“The Union”) have urged re­ placement of the term “primary resistance” 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, continued

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6 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS BOX 1-2 Continued and much more expensive than those used to treat drug-susceptible TB. Despite the challenges, aggressive treatment with SLDs has produced positive outcomes in MDR/XDR TB patients. However, TDR TB is a grow­ ing 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 DR TB (IOM, 2009). BOX 1-3 Statement of Task for the Workshop This public workshop in Beijing addressed the current status of DR TB globally, and in China. The workshop objectives were to • consider lessons learned from the other three high burden countries; • highlight global challenges to controlling the spread of drug-­ esistant r strains; • discuss innovative strategies to advance and harmonize local and international efforts to prevent and treat DR TB; • consider urgent themes relating to the problem of MDR TB, XDR TB, and emergent TB strains that are potentially untreatable with drugs available; and • consider the critical leadership role of the BRICS countries in ad­ dressing the threats and opportunities in DR TB. diseases. These countries also have demonstrated their ability to achieve ambitious goals, such as hosting the World Cup and the Olympics. China’s political leadership has demonstrated a commitment to address- ing DR TB, said Cassell. The 2012 publication in the New England Journal of Medicine of epidemiological results from China examining the country’s burden of MDR TB represented a milestone in addressing the problem (Zhao et al., 2012). Shortly thereafter, the Minister of Health in China made treatment of MDR TB 70 percent reimbursable, making it only one

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Introduction AND OVERVIEW OF THE WORKSHOP 7 of five diseases in China for which this is the case. The Minister also has worked with manufacturers of SLDs to ensure that supplies are available and of high quality. The magnitude and urgency of the problem demand that the best and brightest young investigators be fully engaged and passionate about achieving success, said Cassell. She cited the return of Lixin Zhang from the United States to China to serve as Deputy Director, Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology; and Inaugural Director, Drug Discovery Center for Tuberculosis, IMCAS, as evidence of the engagement of investigators in China. Cassell also called attention to an important meeting of the health ministers from the BRICS countries that occurred the week before the workshop (Box 1-4). The communiqué that emerged from that meeting represents a recognition by the BRICS countries of the need to take strong action. Organization of the Report This report summarizes the presentations and discussions that occurred during the 3-day workshop in Beijing. Chapter 2 draws on the initial and final sessions of the Beijing meet- ing to outline the challenges facing the BRICS countries and their unique capabilities to lead the fight against DR TB. Chapter 3 summarizes the opening keynote address, delivered by Paul E. Farmer, Co-Founder, Partners In Health; Chair, Department of Global Health and Social Medicine, Harvard Medical School; and Chief, Division of Global Health Equity, Brigham and Women’s Hospital, who examined the history of TB and pointed to a strategy—community-based care—that has changed the course of the epidemic in the past and could do so in the future. Chapter 4 looks specifically at China. It describes the burden of DR TB in China, the health care delivery system in the country, and several factors that affect DR TB cases, including HIV infection and diabetes. Chapter 5 examines programs addressing MDR and XDR TB in ­ Russia, South Africa, Cambodia, and Ethiopia, which provide points of both contrast and similarity with programs in China and in the other BRICS countries. Chapter 6 turns to DR TB in children, reviewing the global burden and transmission of pediatric DR TB and the challenges of diagnosis and treatment. Chapter 7 explores issues of transmission and infection control, with a focus on the epidemiological, phenotypic, and genotypic evidence for primary transmission of DR TB. The chapter examines the role of infection

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8 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS Box 1-4 The Delhi Ministerial Communiqué On January 10–11, 2013—the week before the IOM and IMCAS workshop in Beijing—the ministers of health from the five BRICS coun­ tries met in Delhi, India, at the Second BRICS Health Ministers Meeting. The communiqué issued at that meeting called for “the implementation of affordable, equitable and sustainable solutions for common health challenges.” In particular, the 7th of 21 items in the communiqué stated: The Ministers recognized that multi-drug resistant tuberculosis is a major public health problem for the BRICS countries due to its high prevalence and incidence mostly on the marginalized and vulnerable sections of society. They resolved to collaborate and cooperate for development of capacity and infrastructure to reduce the prevalence and incidence of tuberculosis through innovation for new drugs/vaccines, diagnostics and promotion of consortia of tuberculosis researchers to collaborate on clinical trials of drugs and vaccines, strengthening access to affordable medicines and delivery of ­ quality care. The Ministers also recognized the need to cooperate for adopt­ ­ ing and improving systems for notification of tuberculosis patients, availabil­ ity of anti-tuberculosis drugs at facilities by improving supplier performance, procurement systems and logistics and management of HIV-associated tuberculosis in the primary health care system.a Other aspects of the communiqué related to DR TB include calls to face the continuing challenge of HIV, share existing resources, con­ duct effective health surveillance, enhance technology transfer, and pro­ vide universal health insurance. The Ministers also agreed to establish platforms for collaboration within the BRICS framework and with other countries with a view to realizing the goals and objectives outlined in the communiqué. a The text of the communiqué is available at http://www.brics.utoronto.ca/docs/130111- health.html (accessed October 4, 2013). control in China and considers infection control policies and practices in other countries with a high prevalence of DR TB. Chapter 8 looks at the current status and limitations of rapid diag­ nostic technologies. It describes the current use of diagnostic tests for drug-­ susceptible and DR TB in China and other countries, provides a laboratory and hospital-based perspective on drug susceptibility testing (DST), and reviews work on implementing programs for rapid diagnosis of DR TB.

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Introduction AND OVERVIEW OF THE WORKSHOP 9 Chapter 9 addresses diagnosis and treatment across the spectrum of drug resistance. It describes the prevalence of MDR, XDR, and potentially untreatable TB in key countries and considers the diagnosis and treatment challenges associated with defining and treating each. Chapter 10 investigates ways of developing and strengthening the drug supply chain for DR TB. It considers to what extent and in what ways cur- rent supply chain mechanisms are or are not effectively accomplishing what is needed, in China and beyond. It also considers the current allocation of responsibilities and roles of the private and public sectors and examines opportunities for enhancing and optimizing collaboration. Chapter 11 reviews the state of the art in TB research and identifies opportunities to apply new research tools to the problem of DR TB. Chapter 12 summarizes a talk by Salmaan Keshavjee, Director, Program in Infectious Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, that examined what, in his view, will be required to achieve zero deaths from DR TB. Finally, Chapter 13 records discussions and presentations from the penultimate session of the workshop, which considered steps that could be taken to create an evidence-based blueprint for action.

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