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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 kills 1.8 million people each year, or 4,500 each day (WHO, 2009a). 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, 2009a). Exacerbating the devastation caused by TB is the growing threat of drug-resistant strains of the disease in many parts of the world. The development of drug resistance is a predictable, natural phenomenon 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, and even totally drug-resistant (TDR) TB (see Box 1-1 for definitions).

In recognition of the grave threat posed worldwide by drug-resistant TB, in November 2008 the Institute of Medicine’s (IOM’s) Forum on Drug

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The workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. While the Forum on Drug Discovery, Development, and Translation conceived the idea for the workshop, this summary was prepared by the rapporteurs as a factual account 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 Forum or the National Academies, and should not be construed as reflecting any group consensus.



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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 kills 1.8 million people each year, or 4,500 each day (WHO, 2009a). 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 devel- oping world (WHO, 2009a). Exacerbating the devastation caused by TB is the growing threat of drug-resistant strains of the disease in many parts of the world. The development of drug resistance is a predictable, natural phenomenon 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, and even totally drug-resistant (TDR) TB (see Box 1-1 for definitions). In recognition of the grave threat posed worldwide by drug-resistant TB, in November 2008 the Institute of Medicine’s (IOM’s) Forum on Drug 1 The workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. While the Forum on Drug Discovery, Development, and Translation conceived the idea for the workshop, this summary was pre- pared by the rapporteurs as a factual account 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 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 SOUTHERN AFRICA 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 introduced in the 1950s. 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 drugs. Amplified resistance, or the enhance- ment of existing drug resistance as a result of initiating an inappropriate drug regimen at the beginning of care, is a significant challenge created by providing an incorrect combination of drugs. Even when an empirically appropriate drug regimen is selected at the beginning of treatment, by the time drug susceptibility information is available, resistance may be amplified. Treatment Treatment of MDR and XDR TB 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 produced successful outcomes in MDR and XDR TB patients. However, TDR TB is a growing threat. The spread of TDR TB is especially omi- nous as it would return the globe to the pre-antibiotic era with respect to this disease. Identifying and addressing barriers to effective and timely diagnosis and treatment of drug-resistant TB supports prevention of the further emergence of strains of TB with broad-spectrum resistance (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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3 INTRODUCTION Discovery, Development, and Translation held a workshop titled “Address- ing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge,” which brought together experts in drug-resistant TB and public health to speak frankly and openly about the problem.2 That work- shop led to plans for four additional workshops in countries with a high burden of drug-resistant TB. The first of these workshops, summarized in this volume, was held in Pretoria, South Africa, on March 3−4, 2010, with subsequent workshops being planned for Russia, China, and India. The workshop brought together about 65 disease experts, community leaders, policy makers, and patient advocates from South Africa, other countries in southern Africa, and the United States for 2 days of intensive discussions. The workshop was supported in part by the Doris Duke Foundation, by the Howard Hughes Medical Institute, and by the U.S. Department of State. THE BURDEN OF DRUG-RESISTANT TB Based on global drug resistance surveillance data, 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, 2010a). However, a number of TB experts at this and prior workshops, noted that the available data on drug-resistant TB are inadequate and yield a gross underestimation of the true global burden of disease. Surveillance systems 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, 2010a). According to the World Health Organization (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 reflective of a true decline in MDR TB cases (WHO, 2010a). 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 infecting organism to second-line drugs. (The relationship between the estimated incidence of drug-resistant TB and diagnostic tools is further discussed in Chapter 2.) Unfortunately, the drug susceptibility testing that many countries are ill- equipped to conduct is the basis for providing optimal patient care for 2 The summary of that workshop (IOM, 2009) and the accompanying white paper (Keshavjee and Seung, 2008) provided background for and informed the development of and proceedings at the workshop summarized in this volume.

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4 DRUG-RESISTANT TUBERCULOSIS IN SOUTHERN AFRICA 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. 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 effectively treat their drug resistance profile. WORKSHOP OBJECTIVES The objectives of the workshop were to learn from the experiences of the southern African public health community in its fight against drug-resistant TB, and to draw lessons regarding best practices and novel approaches that can be applied both within and beyond the region. The workshop was cohosted by the IOM and the Academy of Science of South Africa (ASSAf). As Roseanne Diab, executive officer of ASSAf, said in welcoming participants, the partnership between the IOM and ASSAf was particularly appropriate given ASSAf’s close association with the National Academies over the past 5 years through the African Science Academy Development Initiative (ASADI). Enriqueta Bond, chair of the ASADI board, also par- ticipated in the workshop. As moderator of the closing session, Bond facili- tated a discussion of the new scientific knowledge presented at the meeting and how this new evidence can inform future policy actions (see Chapter 8). Diab also assured the delegates that ASSAf would take the outcomes of the workshop forward for closer engagement with government.3 THE PROBLEM AND PRIORITIES In her opening remarks, Gail Cassell, Forum co-chair, Eli Lilly and Company (retired), provided a summary of the problem and themes arising from the 2008 workshop. She noted that strains of M.tb. that are resistant to the drugs conventionally used to treat TB have become well established in many countries. Accurate estimates of the prevalence of MDR, XDR, and TDR TB are not possible because of a lack of laboratory capacity in many 3 The National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), held a meeting focused on TB research March 1−2, 2010, the 2 days prior to the IOM workshop. This meeting was co-sponsored by the Medical Research Council (MRC) of South Africa and the Howard Hughes Medical Institute and focused on TB research in drug discovery and development, diagnostics, vaccines, and biomarkers as well as the identifica- tion of opportunities for TB research collaboration in Africa. Topics and meeting participants overlapped between the NIAID and IOM meetings in South Africa, 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.

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5 INTRODUCTION of these countries, but current estimates are sure to be grossly understated (see Chapter 2). Not all of the countries with the highest burden of TB participate in surveys by the WHO, the existing data are 2 to 3 years old, and many of the data are derived from modeling rather than surveillance. Thus the total number of cases of drug-resistant TB is certainly higher than the official WHO estimate (for MDR TB, 440,000 new cases in 2008 [WHO, 2010a]). Furthermore, Cassell observed, the number of patients receiving appro- priate treatment for drug-resistant TB is distressingly small. WHO estimates that worldwide only 7 percent of MDR TB patients are diagnosed (WHO, 2010a), and only about 1 percent of estimated MDR TB cases globally are enrolled in MDR TB treatment programs that use quality-assured drugs (programs approved by the Green Light Committee [GLC]). Thus even among those patients who are being treated, many are not receiving the drugs that address their drug resistance profile, which reduces the effective- ness of treatment. Until recently, the perception was that resistant strains of TB were too weak to achieve high rates of transmission, and therefore that infection control was not the highest priority. However, new evidence indicates that human-to-human spread is more common than previously appreciated. Demonstrating infection in patients may take months, during which time they can spread the resistant organism within their households, to patients and health care workers, and to others in the community. Furthermore, the spread of TB has been greatly exacerbated by the HIV epidemic. The high prevalence of HIV threatens to make drug-resistant TB a more conta- gious, rapidly progressing, and highly lethal disease. Cassell suggested that, because the reality of drug-resistant TB is worse than the general percep- tion, the urgent need for action will not be recognized until it is too late unless the perception changes to reflect the reality of the threat. In Cassell’s view, the presentations and discussions at the 2008 work- shop yielded several themes: • To address the problem of drug-resistant TB head-on, it will be important to recognize that TB strains resistant to all approved drugs are growing rapidly in number, although the number is cur- rently unknown. • Revolutionary and rapid changes are warranted to redress the cur- rent absence or limited availability of effective infection control strategies in health care and community settings in order to reduce the transmission of drug-resistant TB. • The development and widespread deployment of accurate diag- nostics and treatment based on drug susceptibility testing will help support the maximal effectiveness of existing drugs.

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6 DRUG-RESISTANT TUBERCULOSIS IN SOUTHERN AFRICA Cassell also noted that the 2008 workshop highlighted the tremen- dous challenge drug-resistant TB poses for drug developers. If patients with TDR TB are to be successfully treated, three to four new classes of antibiotics will be needed simultaneously. The drug discovery process has a 90 percent failure rate from target identification to regulatory approval; it has a 50 percent failure rate even in phase III trials. The average time for drug discovery and development from target identification to approval is 10 to 14 years, and probably considerably longer for TB drugs when the follow-up period is taken into account. The average cost to develop a single new drug, from discovery to approval, is more than $1.5 billion, and this does not include postlaunch surveillance for adverse events, manufacturing compliance, drug delivery, and so on. The technical and financial obstacles to the development of new drugs are so great that no one government, institution, or company has enough resources or expertise to succeed on its own. Only through the collaboration of all sectors can such challenges be overcome. Cassell summed up by stating that the failure to acknowledge the new realities of drug-resistant TB and to act rapidly will be catastrophic for many countries. Furthermore, the volume of international travel and immigration, legal and otherwise, means that drug-resistant TB represents a grave threat to the public health of all countries, not just those in which TB is prevalent today. Members of the scientific and medical communities must communicate the realities of drug-resistant TB to the public and to policy makers, and they must translate data into policies commensurate with the magnitude of the problem. Cassell expressed the hope that this workshop summary, along with those of the three workshops to follow on this vitally important topic, will provide a base of information to help move such efforts forward. ORGANIZATION OF THIS 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 ASSAf; 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. Presen- tations at the workshop addressed the following topics: • the incidence of drug-resistant TB in southern Africa, including the relationship between TB and HIV infection (Chapter 2); • the molecular epidemiology of the epidemic and the challenges of monitoring and tracking the spread of drug-resistant TB (Chapter 3);

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7 INTRODUCTION • growing understanding of the modes of transmission of drug- resistant TB and experience with infection control programs (Chapter 4); • diagnosis of drug-resistant TB, as well as opportunities for the expansion of laboratory capacity and point-of-care diagnosis (Chapter 5); • treatment of drug-resistant TB, including the capacity of current health systems to address the needs of TB patients, the limited numbers of patients receiving appropriate treatment, and the devel- opment of new drugs (Chapter 6); • the devastating spread of drug-resistant TB among children and the unique challenges this group poses for prevention and treatment (Chapter 7); and • the major viewpoints expressed at the workshop and next steps suggested by workshop participants (Chapter 8). Each chapter of the report opens with a box listing the key messages emerging from the workshop presentations and discussions, as identified by the workshop rapporteurs.

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