1
Introduction

Tuberculosis (TB) kills more than 4,500 people each day worldwide; approximately 1.7 million TB deaths occurred in 2006 alone (WHO, 2008a). TB is second only to AIDS as the leading infectious disease–related cause of adult deaths. Although antibiotic treatment for TB was discovered more than half a century ago, an estimated one-third of the world’s population is currently infected with Mycobacterium tuberculosis (Keshavjee and Seung, 2008), and 9.2 million new cases of active TB are estimated to occur around the world annually (WHO, 2008a).

A large percentage of TB cases are susceptible to available effective TB antibiotics. Nonetheless, multidrug-resistant TB (MDR TB) is a major and growing global threat.1 An estimated 4.8 percent of all new and previously treated TB cases diagnosed worldwide in 2006—a total of 489,139 cases (95 percent confidence level, 455,093–614,215)—were MDR TB (WHO, 2008b). However, many consider this global figure to be a significant under-estimate, and in many regions around the world the rates are much higher. Drug resistance is perpetuated for a number of reasons, including the failure to ensure regular treatment with high-quality existing drugs and the fact that only a few drugs to treat TB are available, and they are very old. The rifamycins, the last new treatments for TB, were developed in the 1960s. Because patients with MDR TB are resistant to treatment with first-line drugs, they must be treated with second-line drugs that are more expensive, have more side effects, often require injection, and involve longer treatment

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MDR TB is a form of TB that is resistant to the two principal first-line drugs used to treat TB—isoniazid and rifampicin.



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1 Introduction Tuberculosis (TB) kills more than 4,500 people each day worldwide; approximately 1.7 million TB deaths occurred in 2006 alone (WHO, 2008a). TB is second only to AIDS as the leading infectious disease–related cause of adult deaths. Although antibiotic treatment for TB was discovered more than half a century ago, an estimated one-third of the world’s population is currently infected with Mycobacterium tuberculosis (Keshavjee and Seung, 2008), and 9.2 million new cases of active TB are estimated to occur around the world annually (WHO, 2008a). A large percentage of TB cases are susceptible to available effective TB antibiotics. Nonetheless, multidrug-resistant TB (MDR TB) is a major and growing global threat.1 An estimated 4.8 percent of all new and previously treated TB cases diagnosed worldwide in 2006—a total of 489,139 cases (95 percent confidence level, 455,093–614,215)—were MDR TB (WHO, 2008b). However, many consider this global figure to be a significant under- estimate, and in many regions around the world the rates are much higher. Drug resistance is perpetuated for a number of reasons, including the failure to ensure regular treatment with high-quality existing drugs and the fact that only a few drugs to treat TB are available, and they are very old. The rifamycins, the last new treatments for TB, were developed in the 1960s. Because patients with MDR TB are resistant to treatment with first-line drugs, they must be treated with second-line drugs that are more expensive, have more side effects, often require injection, and involve longer treatment 1 MDR TB is a form of TB that is resistant to the two principal first-line drugs used to treat TB—isoniazid and rifampicin. 

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 THREAT OF DRug-RESISTANT TubERCulOSIS regimens. Moreover, some strains of TB—termed extensively drug-resistant TB (XDR TB)—are resistant even to these second-line therapies.2 According to estimations by the World Health Organization (WHO), the incidence of XDR TB worldwide is 0.4 percent (Nunn, 2008).3 While this is a rough global estimate, it is important to note that, as with MDR TB, in many regions of the world the rates are much higher. The combination of HIV and TB has proven to be especially deadly. At least one-third of the 33.2 million people living with HIV worldwide are coinfected with TB (WHO, 2008c). As a result of their weakened immune system, HIV-positive patients often develop active TB. In 2000, TB was iden- tified as the cause of 11 percent of all AIDS-related deaths, most of which occurred in Africa (Corbett et al., 2003); even higher percentages have also been reported (Mohar et al., 1992; Lucas et al., 1993; Nelson et al., 1993). ObSTACLES TO TREATMENT The fight against drug-resistant TB faces many obstacles. These include inadequate diagnostic capacity, a lack of new drugs, bottlenecks in the sup- ply chain of existing drugs, drugs that are counterfeit or of poor quality, suboptimal treatment regimens, suboptimal patient management practices, inadequate infection control, inadequate in-country health systems, and a dismal lack of resources. Until recently in most parts of the world, TB diagnosis was reliant on technologies dating back to the nineteenth century. Sputum smear micros- copy has played an important role in diagnosis, but drug-resistant TB requires faster and more specific diagnostic tools. To this end, the Global Laboratory Initiative (GLI), part of the Stop TB Partnership,4 has launched a program to scale up rapid mycobacterial culturing using liquid media and rapid molecu- lar testing for drug-resistant TB. While these developments have been sig- nificant, large gaps remain in the availability of appropriate TB diagnostics, primarily in the area of rapid point-of-care diagnostics—tests that can yield quick and accurate results on site without the need for a laboratory. After decades with no new TB drugs, there are now a handful of promising compounds in the pipeline. If clinical trials yield clear results demonstrating effectiveness, these new drugs may be developed within the next 10 years. However, even new drugs must be used only in combination, 2 XDR TB is MDR TB that is also resistant to any one of the fluoroquinolones and any one of the second-line injectable drugs. 3 Using MDR TB figures reported in WHO’s fourth report on anti-tuberculosis drug resis- tance (WHO, 2008b) and XDR TB percentages determined according to CDC (2006), WHO estimated that the global prevalence of XDR TB is 0.4 percent. 4 The Global Laboratory Initiative was launched to promote the detection of TB and drug- resistant TB.

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 INTRODuCTION or they, too, will quickly become ineffective because of the development of resistance. Thus a minimum of three to four new drugs are needed imme- diately to avert the escalation of drug-resistant TB. The delivery of drugs to the populations that need them is impeded by several factors, including burdensome procurement mechanisms, inad- equate demand forecasting, bottlenecks in country-level distribution, and inadequate public health infrastructure. Without accurate forecasting, manufacturers may have to dispose of unsold drugs; donors face uncertain supplies and prices; and shortages of quality-assured drugs may occur, resulting in incomplete treatments and increased drug resistance. Significant care-delivery problems exist as well, ranging from difficulties with infection control in congregate settings to inadequate capacity to deliver care over the 2-year course of treatment. WORkSHOP ObJECTIvES To address the issues outlined above, the Institute of Medicine’s (IOM’s) Forum on Drug Discovery, Development, and Translation held a workshop in Washington, DC, on November 5, 2008. This was the first in a series of anticipated workshops to be held in the United States and in countries with the highest TB burden—South Africa, China, Russia, and India. Those future workshops will be organized by and represent a broad range of stakeholders. The goals of the workshop summarized in this report were to understand the magnitude and nature of the drug resistance problem; to assess the adequacy of the current global response; and to examine in depth three primary areas of concern—diagnosis, drug supply, and treatment delivery. The workshop brought together a wide range of experts and organizations engaged in the global effort to combat TB so they could share information, develop an understanding of the challenges, and consider opportunities and strategies for confronting the problem. Key organizations and stakeholders in the global fight against TB were represented, including WHO, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), the TB Alliance, the Bill and Melinda Gates Foundation, the U.S. Centers for Disease Control and Prevention (CDC), the U.S. President’s Emer- gency Plan for AIDS Relief (PEPFAR), and many others (see Appendix A for a full listing of organizations represented at the workshop). Speakers from around the world presented data and described firsthand their experiences with MDR and XDR TB in multiple countries, including China, Cambodia, Ethiopia, Russia, and South Africa. To provide baseline information on MDR TB and outline the issues for discussion during the workshop, the IOM commissioned a white paper from Partners In Health (see Appendix C). This paper provides updated information on the epide- miology and treatment of MDR TB and describes the barriers to effective

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 THREAT OF DRug-RESISTANT TubERCulOSIS global response.5 The original intent of the workshop was primarily to release the white paper and to discuss its conclusions and recommendations with an expert audience. As the workshop agenda was being developed, however, the scope expanded significantly. Gail Cassell of Eli Lilly and Company, who served as chair of the workshop, said that the reporting of MDR TB (approximately 500,000 new cases annually) is a gross underestimate of the true burden. Only 11 of 22 high-burden TB countries provide data on drug-resistant TB, and even fewer have the capability to assess patients’ susceptibility to the second-line drugs used to treat MDR TB. To exploit the opportunity offered by having multiple major stakeholders present at the workshop, she encouraged all participants to engage in a frank discussion of the emerging crisis. Paul Farmer of Partners In Health discussed the lack of urgency and attention that has characterized the response to TB in the past three decades. Since the 1980s, public health officials have wrongly assumed that the tools necessary to combat TB were already available, that current drugs were safe and effective, and that the proper strategies for eliminating TB were at hand. In 1992, an editorial published in Science attempted to dispel these incorrect assumptions. The editorial argued that the world lacked proper drugs, diagnostics, and strategies for combating the disease (Bloom and Murray, 1992). Today the world stands on the precipice of a TB pandemic, the full extent of which is not known, and Farmer argued that the tools needed to combat the problem are still lacking. ORGANIZATION OF THIS REPORT This report is intended to provide a faithful summary of the presentations and discussions that took place during the workshop, although remarks have been substantially abbreviated and reorganized to improve the report’s read- ability and usefulness. It should be noted that, while a number of presenters and participants expressed opinions and recommendations, these should in no way be interpreted as attributable to the Forum or the IOM. Chapter 2 provides an overview of the global spread of MDR TB. The ensuing chapters address in turn MDR TB transmission, HIV coinfection, and transmission control (Chapter 3); diagnosis (Chapter 4); infrastruc- ture and health care delivery systems (Chapter 5); global systems for the purchase and delivery of TB drugs (Chapter 6); and research on the global control of TB and the role of drugs, vaccines, and funding (Chapter 7). The final chapter summarizes strategies put forth by workshop participants for confronting the global crisis of drug-resistant TB. 5 It should be noted that this paper represents the views of its authors and not those of the IOM.