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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Summary 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 can be treated effectively with available antibiotics. But multidrug-resistant TB (MDR TB)—strains of TB that are resistant to the two principal first-line TB drugs—is a major and growing global problem. While MDR TB has been under control in the United States since it was first recognized, worldwide an estimated 4.8 percent of all new and previously treated TB cases diagnosed in 2006—nearly half a million cases—were MDR according to the World Health Organization (WHO, 2008b). These cases are considered by many to be a substantial underestimate. Moreover, some strains of TB—termed extensively drug-resistant TB (XDR TB)—are resistant even to second-line therapies, and strains of TB that are totally resistant to all drugs are now emerging. The combination of HIV and TB has proven to be especially deadly. At least one-third of the 33 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 identified as the cause of 11 percent of all AIDS-related deaths (Corbett et al., 2003).
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary The global health apparatus has been slow to respond to the transformation of TB into highly drug-resistant forms. Outmoded techniques for diagnosis and treatment are still common throughout the world, and only a small fraction of MDR TB worldwide is currently diagnosed and treated. The characterization and epidemiology of MDR TB have been slow to emerge. Only 11 of the 22 highest-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. Severe problems exist in the supply of drugs, and adequate health systems for delivering treatment to patients are lacking. When treatment is delivered, moreover, it is often inappropriate or incomplete. The failures of the system are themselves adding to the problem—when treatment is inadequate or interrupted, drug resistance accelerates. WORKSHOP OBJECTIVES To examine these issues and explore strategies for enhancing the global response to MDR TB, the Institute of Medicine’s (IOM’s) Forum on Drug Discovery, Development, and Translation held a workshop in Washington, DC, on November 5, 2008. The goals of this workshop were to understand the magnitude and nature of the drug resistance problem; to assess the adequacy of the current global response; and to examine key obstacles to effective diagnosis and treatment, including inadequate diagnostic capacity, a lack of new drugs, bottlenecks in the supply chain of existing drugs, drugs that are counterfeit or of poor quality, suboptimal treatment regimens and patient management practices, inadequate infection control, inadequate in-country health systems, and a lack of resources. The workshop brought together a wide range of experts and organizations engaged in the global effort to combat TB to share information, develop an understanding of the challenges, and consider opportunities and strategies for confronting the problem. 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. In addition, 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. The workshop presentations and discussions focused attention on seven key issues: Limitations of global TB estimates, The role of HIV in the spread of MDR TB, The importance of infection/transmission control, Limited diagnostic capacity, Low rates of treatment,
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Bottlenecks in the procurement and distribution of high-quality drugs, and The need for new TB drugs. ISSUES Limitations of Global TB Estimates WHO has estimated that of the more than 9 million cases of TB in 2006, approximately half a million (or 4.8 percent) were MDR TB, and about 40,000 (or 0.4 percent) were XDR TB (Nunn, 2008) (see Table S-1). Many consider these to be underestimates of the actual incidence of drug-resistant TB, however, for several reasons. First, drug resistance surveys have not been conducted in 25 of the 46 countries in Africa. Second, in many countries, the availability of diagnostic laboratories is limited; for example, 9 African countries lack even a single reference laboratory capable of culturing TB and making a diagnosis. Further, current drug resistance surveys include only smear-positive TB cases, yet not all MDR TB cases are smear positive. In particular, in many countries with a high TB burden, the incidence of HIV infection is also very high, and HIV-positive TB patients are more likely than other TB patients to be smear negative. It was pointed out during the workshop that underreporting of rates of infection may have serious consequences, since it may weaken the political will to take appropriate measures to combat the MDR TB threat. Role of HIV in the Spread of MDR TB As noted, individuals who are HIV positive have compromised immune systems and are thus more susceptible than the general population to TB TABLE S-1 Estimated Number of TB Cases and Number of Deaths, by Type, 2006 Form of TB Estimated Number of Cases Estimated Number of Deaths All forms 9,200,000 1,650,000 Multidrug-resistant (MDR TB) 489,000 120,000 Extensively drug-resistant (XDR TB) 40,000 20,000 HIV-associated 700,000 200,000 SOURCE: Nunn, 2008. (The data on total cases and deaths are from WHO, 2008a; the number of MDR TB cases is from WHO, 2008b; the deaths from MDR and XDR TB were estimated by Nunn’s team from published literature using the case numbers listed in the table; and the number of XDR TB cases [according to the revised October 2006 definition of XDR TB] was estimated from the MDR TB number listed in the table using the percentages from CDC, 2006.)
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary infection. Coinfection with HIV and MDR TB has received particular attention in Africa, although it is also a growing problem in Eastern Europe. The progression of the TB epidemic in KwaZulu-Natal, South Africa, for example, has been closely intertwined with that of HIV. A large percentage of the province’s residents now have compromised immune systems that make them increasingly vulnerable to infection and the progression of disease. The coincidence of TB and HIV has both accelerated TB drug resistance and contributed to the rapid transmission of HIV. Limited infection control facilities and practices compound the problem. Health care facilities routinely house patients who are HIV positive with those who have drug-resistant TB, creating opportunities for nosocomial transmission. Recent efforts have been aimed at deinstitutionalizing and decentralizing care by focusing on community-based treatment in people’s homes, thereby reducing such opportunities. Importance of Infection/Transmission Control There are two pathways for infection with drug-resistant TB. Acquired, or amplified, resistance typically emerges in settings where TB treatment is inadequate, patients fail to adhere to proper treatment regimens, or incorrect or non-quality-assured drugs are used for treatment. Transmitted, or primary, resistance results from the direct transmission of drug-resistant strains from one person to another. Neel Gandhi of the Tugela Ferry Care and Research Collaboration stated that this latter mechanism has largely been neglected during the development of TB control programs. Drug-resistant strains of other diseases typically are not as resilient as drug-susceptible strains and therefore tend to die out. While acquired or amplified resistance due to inadequate treatment may explain how the cases of MDR and XDR TB first emerged in South Africa and other parts of the world, however, speakers presented substantial evidence of transmitted rather than acquired TB. In one study, for example, about half of those patients who died from highly resistant forms of TB had never before been treated for the disease, and 85 percent had a genetically similar strain, indicating that resistance was likely transmitted rather than acquired. Other studies using molecular fingerprinting have shown that patients who relapsed with MDR or XDR TB had different genotypes in their relapse isolate compared with their initial isolates, suggesting that their relapses occurred as a result of primary transmission rather than acquired resistance. Gandhi suggested several lessons from these studies: Efforts must focus on creating infection control programs to prevent the further transmission of drug-resistant strains.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Early diagnosis of MDR and XDR TB cases, which is currently hampered by a lack of laboratory capacity and rapid diagnostic tests (see below), will be critical to infection control. Further studies are needed to better characterize transmission patterns both in hospitals and in communities so that other means of curbing the epidemic can be devised. Implementing effective transmission control in resource-limited settings, however, presents major challenges. For example, establishing community-based treatment outside a hospital is not currently feasible in some settings because the tradition and infrastructure for community care do not exist. Transmission control can be very expensive, particularly when elaborate ventilation systems are required, and the necessary technical expertise is often lacking. Furthermore, the importance of undiagnosed and unsuspected cases in the spread of disease is often underappreciated. Edward Nardell of Brigham and Women’s Hospital described a number of potential strategies for reducing the transmission of drug-resistant TB, including hospital triage and separation; ventilation; and research on novel interventions, such as the use of germicidal ultraviolet (UV) air disinfection and the development of inhaled antibiotics. Limited Diagnostic Capacity WHO recommends that countries maintain at least one culture laboratory per 5 million people and one facility capable of conducting drug susceptibility testing per 10 million. Only a handful of high-burden countries meet these standards, and many countries lack even a national reference laboratory to perform some of the most basic surveillance. Furthermore, many experts consider the recommended numbers to be wholly inadequate. It is estimated that a mere 5 percent of all MDR TB cases are currently being detected. While current global capacity allows for the conduct of approximately 10 million culture tests, WHO has estimated that the actual need is at least 60 million (Weyer et al., 2007). According to John Ridderhof of the U.S. Centers for Disease Control and Prevention (CDC), to meet current needs, hundreds or even thousands of new laboratories would have to be developed worldwide, representing an investment in laboratory capacity of $1 billion or more. WHO and the Stop TB Partnership created the Global Laboratory Initiative (GLI) in 2007 to begin to address this gap, but the GLI’s modest goal is to diagnose 74,000 new MDR TB patients by 2011. Cost-effective point-of-care TB testing is also critically important. Ideally, such tests would be performed during a patient’s visit so that appropriate treatment could begin immediately. There have been recent breakthroughs
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary in the development of point-of-care systems, and two portable systems were presented and discussed at the workshop. But such technology is likely to remain unattainable for those in resource-poor settings. An example of the type of test envisioned by many is the dipstick test used in HIV diagnostics. That test, which costs US$1.00 and is 99 percent sensitive and specific, revolutionized HIV testing and was a key element in the scale-up of antiretrovirals worldwide. As Mark Harrington of the Treatment Action Group noted, “In some ways [point-of-care testing] is even more important than a new drug or a new vaccine. There is a cure for most cases of TB, and there is reasonable treatment for MDR. But if it can’t be diagnosed, millions of people will die of a treatable and curable disease.” To achieve the goal of a rapid, inexpensive, and effective point-of-care diagnostic test, support will be needed from large organizations such as the National Institutes of Health and the Bill and Melinda Gates Foundation, along with small-scale innovative efforts supported by smaller donors. Low Rates of Treatment Only a small proportion of newly diagnosed cases of MDR TB are being treated either through Green Light Committee (GLC)–approved or non-GLC-approved treatment programs (see Figure S-1). Even among the small proportion of patients who are being treated, many are not receiving drugs that are quality assured through the GLC program. For others, treatment may not address their drug resistance profile, making their treatment ineffective. Furthermore, the public health infrastructure needed to deliver TB care cost-effectively is inadequate in many resource-poor environments. Current programs are often fragmented and limited in scale, and it is frequently difficult to scale up successful programs to the regional or country level. Effective public health models, such as providing patients with housing as an alternative to hospitalization and training villagers to serve as community health workers, have yet to be widely adopted. Technical assistance, when available, often lacks coordination. It was noted that experience with the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) could be instructive for the fight against TB. Substantial funding for HIV/TB programs was an important factor in the success of PEPFAR—funding increased from $18.8 million in 2005 to $169 million in 2008, more than 700 percent. In addition, PEPFAR established a supply chain management system for both forecasting demand and delivering drugs, fast-tracked U.S. Food and Drug Administration (FDA) approval of new and generic antiretroviral drugs, fostered community-based delivery of care, invested in improved laboratory surveillance systems, built a tiered
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary FIGURE S-1 MDR TB burden and patients in treatment. NOTES: The bars represent the number of new MDR TB cases in each year. Data for 2007 and 2008 are WHO estimates. The lavender portions indicate the number of patients treated in non-GLC-approved projects; the purple portions indicate the number of patients treated in GLC-approved projects; and the yellow portions represent patients receiving no treatment. GLC = Green Light Committee. SOURCE: Zintl, 2008 (based on unpublished data from GLC Secretariat, Geneva 2008). public health laboratory network and transport system for samples, and set specific performance targets. Bottlenecks in the Procurement and Distribution of High-Quality Drugs Continuing problems constrain the procurement and distribution of high-quality TB drugs worldwide. Treatment and drug quality vary tremendously across programs and countries. The markets for second-line drugs in priority countries are large and growing rapidly, but they are fragmented, and regulation is inconsistent. The absence of accurate demand forecasting creates financial risks for both suppliers and programs and disrupts the flow of drug supplies. Ruth Levine of the Center for Global Development discussed the critical role of accurate demand forecasting, drawing on lessons learned from
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary dealing with malaria. WHO’s malaria drug demand forecasts have been off by orders of magnitude. For example, the original demand for Coartem was estimated to be 55 million doses; the actual orders turned out to total 14 million. The following year, WHO estimated that 100 million doses would be demanded and purchased; the actual number turned out to be 55 million. Likewise, the manufacturer had to discard 10million tablets of artesunate because of overforecasts. There are also serious problems with the quality of TB drugs, and countries are not sufficiently insistent that their MDR TB patients be treated with second-line drugs that are of high quality—meaning in most cases that they are potent enough. Anecdotal reports of quality issues are widespread, but actual data on the quality of many drugs being used are limited. Paul Nunn of WHO described current WHO efforts to collect data on drug quality by looking randomly at TB drugs from various sites in different countries and measuring their active ingredients—similar to what was done with AIDS and malaria. But results from those studies are months away. To ensure the quality of second-line drugs being supplied to high-burden countries and to improve the reliability of supply, the GLC was formed in 2000. Substantial growth has occurred in the number of GLC-approved projects and the numbers of patients treated. In 2006, just over 5,500 patients were enrolled in 32 approved projects; by 2007, 30,000 patients were enrolled in 104 projects. The latter figure includes a rapid ramp-up in the African region from 0 to 15 projects, as well as a large number of projects in Eastern Europe. Despite this recent growth, GLC projects represent only a tiny fraction of the more than 400,000 MDR TB cases estimated to occur each year. The vast majority of patients are being treated through non-GLC-approved projects under programmatic conditions that may not be ideal for treatment of MDR TB and with drugs that are not quality assured. But the requirements for GLC participation can be onerous and costly, and as a result, many countries and suppliers prefer to circumvent the GLC process. With one exception, only one quality-assured supplier exists for each of the second-line drugs for GLC projects. Workshop participants offered a number of suggestions for improving the procurement and distribution of TB drugs. These included improving forecasting, aligning the incentives for key stakeholders along the supply chain, and ensuring that the GLC procurement process is clear and straightforward. Need for New TB Drugs The global fight against TB has been impeded by the lack of new drugs and vaccines. The current classes of both first- and second-line TB drugs were all discovered between the 1940s and the 1960s. The last approval for
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary a newly developed drug to treat TB—rifampicin—occurred in the 1970s. The root of the drug resistance problem is the complexity and length of drug-sensitive regimens. Thus it is critically important to develop a pipeline of new drugs with shorter, simpler regimens for drug-sensitive TB, and ideally, novel mechanisms of action that are equally effective against MDR and XDR and drug-sensitive strains of TB. Ideal TB drugs would be taken once a day or less, and orally. They would have minimal drug–drug interactions for both HIV-positive and HIV-negative patients and would be obtainable at low cost. While some promising drug development efforts are under way—and far more drugs are in the pipeline than was the case even in 2000—both the time frames for such efforts and the probabilities of ultimate success for any given candidate are discouraging. A compound that has progressed to preclinical development from among the thousands of compounds that enter the discovery phase has about a 1 in 10 chance of making it to registration and therefore to patients. Only in Phase III development do the odds become fairly good. About two-thirds of drugs that make it all the way to pivotal clinical trials will ultimately be registered. Ann Ginsberg of the TB Alliance identified a number of strategies for addressing the challenges facing TB drug development: Focus on developing multidrug regimens rather than individual drug candidates. Improve biomarkers and validate surrogate end points to streamline clinical development. Validate animal models. Strengthen clinical trial capacity, including the development of sites, staff, and investigators who can work to current global registration standards. Harmonize regulatory guidance for TB drug development across the FDA, the European Medicines Agency (EMEA), and regulatory authorities in high-burden countries. Enter drug candidates with novel mechanism of action into simultaneous clinical development programs for both drug-sensitive and drug-resistant strains of TB, since they involve very different patient populations and study designs. Among the variety of candidates currently being pursued, the majority are cell wall active, which means they work well against the most rapidly replicating mycobacteria but are not likely to be effective against persistent organisms that are replicating slowly or not at all. These drugs are consequently unlikely to shorten therapy, an objective requiring drugs that act against other kinds of targets. A number of new discovery projects are focused on energy
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary metabolism, and if these candidates are successfully developed, they will likely contribute to shortening therapy. Research Priorities at the National Institutes of Health Anthony Fauci of the National Institute of Allergy and Infectious Diseases discussed important lessons to be drawn from the experience with AIDS research. Solid funding and the resulting research efforts have led to a number of extraordinary advances over the 27 years since AIDS was first recognized in 1981. Today there are more antiretroviral drugs for HIV/AIDS than the total of all drugs available for all other viral diseases combined. This achievement was possible because of a serious investment in biomedical research, partnerships with industry, and the pharmaceutical industry’s realization that the development of antiretroviral drugs promised a large return on investment and would significantly impact the lives of patients in the United States and globally. Compared with the current National Institutes of Health (NIH) budget for HIV/AIDS, the budget for TB is modest. Fauci highlighted five priorities for expanded research: Development of rapid and reliable diagnostic methods that can be used at the point of care; Investment in the pipeline of new drugs, as well as proper use of existing first- and second-line therapies; Investment in research to understand the epidemiology that contributes to the spread of drug-resistant and drug-sensitive strains of TB; Understanding of the relationship between and comorbidities of HIV/AIDS and TB; and Development of effective vaccine and chemotherapy prevention strategies for all forms of TB. Fauci cited several critical success factors for accelerating the development of new TB drugs and vaccines: a commitment of substantial financial resources, enlistment of the best and brightest investigators, engagement of the affected communities, collaboration with industry and global organizations, and support from leaders and policy makers. He noted the importance of coordinating research efforts among government agencies such as NIH, CDC, and the U.S. Agency for International Development (USAID) and global partners such as other international government agencies, federal programs such as PEPFAR, philanthropic organizations such as the Gates Foundation, pharmaceutical and biotechnology companies, and public–private partnerships and research consortia. Fauci also emphasized the need to ensure the integration of scientific disciplines within infectious disease
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary research and immunology and state-of-the-art technological approaches, as well as the importance of balancing fundamental research and product development efforts. Economic Incentives Workshop participants discussed the types of economic incentives that are needed to accelerate the discovery and development of new therapies, including both push and pull mechanisms. Push mechanisms stimulate the supply or production side of the market, while pull mechanisms stimulate the demand side. The Orphan Drug Act of 1983 is an example of a push mechanism because it is aimed at making the development of an orphan product easier, less costly, or less risky for a company.1 BioShield2 represents another form of push mechanism that involves directly funding research and development for terrorism countermeasures. A third push approach is the development of a public–private partnership such as the TB Alliance. These partnerships are effective because they organize strategies within the field and facilitate the sharing of scientific knowledge and effort. Pull mechanisms include the use of advance market commitments, through which market demand—e.g., a price and a certain number of units to be purchased—is guaranteed in advance (typically by government or a philanthropic organization). Other pull incentives include extended patent life guarantees and priority review vouchers, which a company can use to receive priority review for another drug or can sell to another company. CONCLUDING REMARKS The workshop presentations and discussions highlighted a basic tension between the need to focus global health programs on drug-susceptible TB versus drug-resistant TB. While the current epidemic of TB is at risk of being replaced by an epidemic of drug-resistant strains, Nunn argued that 1 A therapy may be designated as an orphan product if one of the following conditions is met: (1) the disease or condition for which the drug is intended affects fewer than 200,000 people in the United States or, if the drug is a vaccine, diagnostic drug, or preventive drug, the persons to whom the drug will be administered in the United States are fewer than 200,000 per year as specified in 21 CFR Sec. 316.21(b); or (2)for a drug intended for diseases or conditions affecting 200,000 or more people, or for a vaccine, diagnostic drug, or preventive drug to be administered to 200,000 or more persons per year in the United States, there is no reasonable expectation that costs of research and development of the drug for the indication can be recovered by sales of the drug in the United States as specified in 21 CFR Sec. 316.21(c). 2 The Project BioShield Act was passed in 2004. This bill gave the U.S. Department of Health and Human Services authority to support the development and acquisition of medical countermeasures as part of a national strategic effort to prepare for threats to public health from chemical, biological, radiological, or nuclear events.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary the first priority in addressing MDR TB is preventing its occurrence in the first place, which places the emphasis on basic control of TB. Gail Cassell of Eli Lilly and Company countered that, with MDR and XDR TB being nearly out of control, simply focusing on susceptible strains will not be sufficient. Kenneth Castro of CDC suggested that both Nunn and Cassell were correct and affirmed the need for both types of interventions. A multipronged approach is necessary, he argued, which should include focusing on MDR TB infection control, laboratory capacity building, and rebuilding of the infrastructure for basic TB control. Several participants noted that the U.S. and global response to the MDR TB crisis has been more incremental than transformative, and some advocated for bolder action. A possible presidential initiative to combat drug-resistant TB, similar to the PEPFAR initiative, was discussed. It was also suggested that the debate over WHO’s emphasis on health sector strengthening versus priority diseases should be resolved through a comprehensive plan. It was noted that the 2000 IOM report Ending Neglect: The Elimination of Tuberculosis in the United States recommended important strategies, a number of which have yet to be addressed (IOM, 2000). Cassell, the workshop chair, reflected on the proceedings of the day and reminded the audience that not only are MDR and XDR TB growing, but also between 30 and 40 percent of patients diagnosed with XDR TB are totally untreatable with existing drugs. She remarked on the workshop presentations indicating the high degree of primary transmission, in stark contrast to what has generally been believed in the past about the ability of these organisms to spread. Despite these growing concerns, she observed that the diagnostic capabilities, resources, treatment and infection control policies, data collection mechanisms, and research capacity needed to understand the MDR and TB crisis effectively still are not in place. Said Cassell, “What we have also heard is the great need to directly confront MDR TB and XDR TB, whereas emphasis in the past has been on strengthening TB control programs per se, believing we could [thereby] control the problem of MDR and XDR TB.” REFERENCES CDC (U.S. Centers for Disease Control and Prevention). 2006. Emergence of Mycobacterium tuberculosis with extensive resistance to second line drugs—worldwide, 2000–2004. Morbidity and Mortality Weekly Report 55(11):301–305. Corbett, E. L., C. J. Watt, N. Walker, D. Maher, B. G. Williams, M. C. Raviglione, and C. Dye. 2003. The growing burden of tuberculosis: Global trends and interactions with the HIV epidemic. Archives of Internal Medicine163:1009–1021. IOM (Institute of Medicine). 2000. Ending neglect: The elimination of tuberculosis in the United States. Washington, DC: National Academy Press.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Keshavjee, S., and K. Seung. 2008. Stemming the tide of multidrug-resistant tuberculosis: Major barriers to addressing the growing epidemic. http://www.iom.edu/Object.File/Master/60/204/IOM_MDRTB_whitepaper_2009_01_14_FINAL_Edited.pdf (accessed February 17, 2009). Nunn, P.2008. Global incidence of MDR and XDR-TB. Speaker presentation at the Institute of Medicine Workshop on Addressing the Threat of Drug-Resistant Tuberculosis, Washington, DC, November 5. Weyer, K., J. Ridderhof, and GLI Working Group. 2007. Symposium presentation at the World Congress on Lung Health in Capetown, South Africa, November 7–8. WHO (World Health Organization). 2008a. Global tuberculosis control 2008: Surveillance, planning, financing. Geneva, Switzerland: WHO. WHO. 2008b. Anti-tuberculosis drug resistance in the world, fourth global report by the WHO/IUATLD Global project on anti-tuberculosis drug resistance surveillance. Geneva, Switzerland: WHO. WHO. 2008c. TB/HIV facts. http://www.who.int/tb/challenges/hiv/tbhiv_facts08_en.pdf (accessed February 17, 2009). Zintl, P.2008. Speaker presentation at the Institute of Medicine Workshop on Addressing the Threat of Drug-Resistant Tuberculosis, Washington, DC, November 5.
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