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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary 8 Strategies for Confronting the Global MDR and XDR TB Crisis Throughout the workshop, problems with the current approaches to the diagnosis and treatment of MDR and XDR TB were highlighted and discussed. Participants suggested potential strategies for dealing with these problems, ranging from incremental adjustments to systemic changes in the global health system. RECOMMENDATIONS PRESENTED BY DR. KESHAVJEE Keshavjee summarized recommendations presented in a white paper commissioned for the workshop; the full text of the paper is presented in Appendix C. The paper offers 15 recommendations in three areas: diagnosis, drug supply, and treatment delivery (see the detailed listing in Box 8-1). Diagnosis Keshavjee discussed the urgent need for investment in in-country laboratory capacity and point-of-care testing. Smear microscopy, though useful, is increasingly inadequate. Keshavjee argued that it works just over half the time, it fails to detect extrapulmonary TB, it does not work well in patients with HIV, and it does not aid in diagnosing drug-resistant disease. Of the 22 high-burden countries, only 7 have one culture facility per 5 million population, and only 9 have one DST facility per 10 million population. Recent experience in Lesotho, discussed in Chapter 4, demonstrates how laboratory capacity can be expanded effectively in a resource-deprived area.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary BOX 8-1 Specific Recommendations from the Report Stemming the Tide of Multidrug-Resistant Tuberculosis: Major Barriers to Addressing the Growing Epidemic Diagnostics Sustainable funding from bilateral and multilateral donors must be increased to support construction of in-country drug-sensitivity testing/rapid-testing laboratories and ongoing external quality assessments by supranational reference laboratories. Creation of a system of long-term on-site technical assistance would help countries build and/or rapidly expand their capacity to perform mycobacterial culture, DST, and rapid molecular genetic tests for drug-resistant tuberculosis. In-country laboratory networks for specimen transport, data management, and certification and coordination of private laboratories need improvement. Use of excess laboratory capacity formycobacterial culture and drug-susceptibility testing in wealthy nations should be encouraged while laboratories are being built in poorer regions. Priority must be given to research on—and funding for—the immediate development and rapid deployment of point-of-care testing for drug-susceptible and drug-resistant tuberculosis. Drug Supply WHO and international partners should take immediate and rapid steps to increase the number of manufacturers of quality-assured second-line antituberculosis drugs. A mechanism needs to be developed to make these drugs available at pre-negotiated prices to programs purchasing via the GDF and through direct-purchase by countries. The GDF should create a tiered system of approval for manufacturers of second-line drugs—and purchase of product by the GLC mechanism—consistent with a manufacturer’s progress in WHO’s Essential Drugs Monitoring (EDM) prequalification process. Large countries operating within the GLC mechanism should be allowed to purchase second-line anti-tuberculosis drugs from domestic manufacturers who have entered the EDM prequalification process. The GLC mechanism should institute a transparent system for quantification of demand for second-line drugs. The GDF should maintain a second-line anti-tuberculosis drug buffer stock (at minimum, enough to treat 5,000 patients) in order to facilitate rapid delivery of drugs to programs (less than 1 month). There should be a global effort to increase the options available for treating MDR TB and XDR TB, by optimizing current regimens and by developing at least three new anti-TB drugs. Increased TB clinical trial capacity needs to be created, and mechanisms developed to fast-track new anti-TB drugs through the regulatory process.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Treatment Delivery Universal treatment for drug-resistant tuberculosis within national TB control strategies—side by side with drug-susceptible disease—has to be clearly and actively promoted by multilateral and bilateral agencies, nongovernmental organizations, and within countries. Universal TB treatment also must be well integrated with current HIV treatment initiatives. The system of international technical assistance provision is currently inadequate. It must be transformed in order to better draw on the experience of successful regional MDR TB treatment programs, to include the provision of on-site, long-term technical assistance, and where necessary, to involve onsite implementation teams. Community-ambulatory-based MDR TB treatment, and where appropriate, active collaboration with private-sector laboratories and tuberculosis treatment providers, should be actively promoted as a safe means of rapidly treating the largest number of patients. Delivery systems that support this will need to be strengthened and/or built. Infection control to prevent transmission of TB strains has to be integrated fully into national TB control strategies, with appropriate resources, training, implementation strategies, and monitoring. Large global health initiatives—such as PEPFAR—and bilateral and institutional donors for global health should make improving the capacity to deliver MDR TB treatment an important priority. The Global Fund and UNITAID have done so, and others should follow this lead with their influence and resources. SOURCE: Keshavjee and Seung, 2008, pp. 2–3. Several lessons were learned from this experience. For example, in addition to setting up the laboratory, it is essential to have ongoing quality assurance; long term on-site technical assistance; a laboratory system capable of interacting with the clinical system; systems for specimen transport, data management, and certification; and coordination of private laboratories. While laboratory capacity is being built in the high-burden countries, this process is lengthy, and officials in many countries are waiting until new laboratory capacity is available before treating MDR TB patients. At the same time, there is substantial untapped excess capacity for mycobacterial culture and DST in the developed world. One option would be to create a consortium of laboratories that could process samples from developing countries so that patients could begin receiving treatment while in-country laboratory capacity was being developed. Perhaps no other single step could radically improve treatment of MDR
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary TB more than effective point-of-care testing. Because of the remoteness of many high-burden areas and the complexity of treatment, laboratory testing almost always leads to long delays in treatment, and delays represent one of the most critical factors in the development and spread of MDR TB. If a patient cannot be immediately diagnosed with TB, an antibiotic trial with first-line antibiotics needs to be conducted; this is a common cause of delay for patients beginning treatment. Data from Rwanda show that antibiotic trials delay treatment on average by 39 days. Other delays are due to routine health service and patient issues. In Rwanda, these issues result in an average 57-day delay in treatment. The problem is illustrated in Figure 8-1, which shows a patient being carried by a family member down a steep incline to get to a health clinic. It takes about 5–6 hours to walk to this village. When patients arrive, they are told to get an x-ray, then go home, and then return for the antibiotic regimen. The advantages of point-of-care testing are obvious—the delay in the start of treatment is only 1 day. Ideally point-of-care testing will detect disease during the patient’s initial visit, even if the patient has extrapulmonary TB, and will determine whether the TB is drug-resistant so the appropriate regimen can be initiated. FIGURE 8-1 A patient being carried by a family member to a clinic. SOURCE: Keshavjee, 2008. Copyright 2008 Open Society Institute/Pep Bonet, reprinted with permission.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Drug Supply Keshavjee next addressed the urgent need to increase the number of manufacturers of quality-assured second-line anti-TB drugs. Meeting this need will require addressing a number of bottlenecks in the supply chain, including poor demand forecasting, problems in obtaining GLC prequalification, poor-quality and counterfeit drugs, and the high risks and limited incentives facing suppliers. A number of different approaches can be used to address these issues. One is to shift the current focus from individual programs and to reduce barriers to countries’ direct purchase of drugs. Another is to enable manufacturers of second-line drugs to begin to sell the drugs conditionally early in the GLC prequalification process. Large countries operating within the GLC mechanism should be allowed to purchase second-line anti-TB drugs from domestic manufacturers that have entered the system. In addition, a more transparent system for forecasting demand and a larger buffer stock of second-line TB drugs are needed to smooth out demand and supply, reducing risk for both programs and manufacturers. Currently, programs wait up to 6 months for drugs, keeping patients waiting, transmitting disease, and potentially dying. Finally, there is a need for additional options for treating MDR and XDR TB by optimizing current regimens and by developing at least three new anti-TB drugs. Treatment Delivery As new drugs and diagnostic capabilities become available, the demands on the existing delivery system will increase dramatically. Meeting these demands will require substantial investment, as well as new approaches. Keshavjee described cost-effective approaches to improving the delivery of care in resource-poor environments. One program in South Africa, for example, provided patients with housing and found that it cost far less than hospitalization. In addition, ambulatory-based treatment can be more effective than hospitalization, which can lead to nosocomial transmission. Training villagers to be community health workers is another highly cost-effective approach. Technical assistance is an area that lacks coordination and needs improvement. The system for providing international technical assistance should draw on the experience of successful programs to include long-term on-site assistance and implementation teams. One of the limitations of current programs is that they tend to be fragmented and limited in scale. It is not always clear how to scale up successful programs to the regional or country level. Scaling up sometimes requires that stakeholders achieve a critical mass and share a belief in the future. Currently, effective strategies
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary for diagnosis and treatment are being deployed only for a small proportion of patients. It will be necessary to increase the number of patients being treated to create demand for increased supplies of drugs and diagnostics. Large bilateral and institutional donors for global health will have to make improving the capacity to deliver MDR TB treatment a priority. Perhaps this scale-up will require a PEPFAR-like initiative for TB. Michael Kimerling of the Bill and Melinda Gates Foundation reinforced the idea that scaling up requires a shift from project-level to country-level funding and planning. He cited Kazakhstan as an example of a government program that has transitioned from encompassing 300 MDR TB cases to covering 3,000 cases, based on the experiences of a model site in Almaty city that became GLC-approved recently. Scale-up is occurring at the national level, entirely within the government system and within a legislative framework, based on a smaller Almaty model project that was running for 5 years. Despite the success of this model, the Global Fund will not be able to sustain it over the long term since Kazakhstan exceeds the income index cutoff for further support. Hence, the concept of government ownership and commitment is key to both scaling up and sustainability. As for technical assistance, Kimerling noted that there are really two issues—the global capacity to provide technical assistance and the regional and in-country capacity to implement and sustain whatever assistance is given over the long haul. The critical need in this regard is human resource development planning at the global level that translates into regional and country-level capacity development that addresses both technical and managerial issues. Charles Wells of Otsuka Pharmaceutical Development and Commercialization suggested that the white paper expand on the need for the capacity of global programs to conduct clinical trials. Given the paucity of new drugs, that capacity is now limited, and it will be critical for scale-up once new drugs and new diagnostics become available. Research capacity, he argued, should be built along the way, and such that it can be harnessed for new drug development. LESSONS LEARNED FROM THE PRESIDENT’S EMERGENCY PLAN FOR AIDS RELIEF (PEPFAR) A theme throughout the workshop was the relationship between PEPFAR and efforts to combat MDR TB. Caroline Ryan of the U.S. Department of State presented some observations from the PEPFAR experience that could be useful in the fight against TB. She first noted that HIV/TB has been a priority area for PEPFAR from the beginning, and that funding for HIV/TB programs increased from $18.8 million in 2005 to $169 million in 2008—more than 700 percent. Ryan outlined some of the approaches
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary that have been effective and that could represent opportunities for further leveraging TB care at the community level: Establishing a supply chain management system, which is a central mechanism for forecasting both demand and delivery—similar in some ways to the GLC, Fast-tracking FDA approval of new and generic antiretroviral drugs, Investing in surveillance to ensure that information is readily available, Investing in improved laboratory surveillance systems in six countries to enable detection of outbreaks of MDR and XDR TB, Developing a strong tiered public health laboratory network, Developing effective transport systems to improve the utility of diagnostics at both regional and central laboratories, Establishing specific performance targets and metrics for assessing progress in antiretroviral treatment programs, and Expanding both testing and treatment at the community level through home-based delivery of care. Nacy observed that treatment strategies for MDR TB have become more systems oriented and less oriented toward individual patients. Farmer responded that while the focus has inevitably shifted to populations because of the scope of the crisis, programs remain patient-centric. Nacy added that there appear to be two different perspectives on diagnostics, one focused on epidemiologic tools and population metrics and the other on patient care—diagnosing and treating individuals. The current tests in development address the epidemiology of MDR TB (i.e., test for characteristic isoniazid and rifampin resistance), but little attention is currently being paid to identifying and developing clinical diagnostic tools that can identify to which drugs a particular patient is susceptible—a critical need in patient care. Friedland offered a number of suggestions for reducing the impact of the TB epidemic: A rapid and massive infusion of resources, Enhanced epidemiological characterization, Strengthened TB programs, Integration of TB and HIV efforts, Implementation of infection control strategies to reduce airborne transmission, Improved TB and drug resistance diagnosis, and Expansion of MDR and XDR TB treatment. Given the critical factor of immunosuppression due to HIV coinfection, Friedland suggested the need to continue to fast-track antiretroviral rollout
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary and provide improved access to current antiretroviral therapies. In addition, he argued for a shift in focus to the prevention of new infections. This would include earlier diagnosis with new rapid diagnostic tests, active intensive case finding, implementation of airborne infection control, and decreased reliance on hospital care. In the long term, the critical need is for new diagnostics, drugs, and vaccines. Kim reflected on the progress that has been made through PEPFAR, the largest public health program in history, and noted that the opportunity exists to extend its reach farther than ever before. He discussed the importance of consolidating the many efforts to build on one another and utilize resources effectively. This is already happening, he noted, in other areas of public health. For example, nine universities, civil society organizations, WHO, and the Italian government are leading an effort called Positive Synergies to examine how global health initiatives, such as PEPFAR, the Global Fund, and the Global Alliance for Vaccines and Immunization, can be harnessed to strengthen health systems. This kind of operational research is difficult and is rarely carried out, but is essential to determine how to capitalize on all these efforts within a functioning health system. One of the challenges going forward will be to link these vertical programs to health systems that serve the critical public health needs in these countries. POLICY FOCUS ON DRUG-RESISTANT VERSUS NON-DRUG-RESISTANT TB A major theme of the workshop was the need to shift focus from the control of drug-susceptible TB to MDR and XDR TB. The discussion elicited pros and cons on this view. Nunn acknowledged the possibility that the current epidemic of mainly susceptible disease is at risk of being replaced by an epidemic of mainly resistant disease. But the question is how to change the approach to address this risk. Nunn argued that the first priority in addressing MDR TB is preventing its occurrence in the first place, which places the emphasis on basic control of TB. This, of course, is partly a resource issue: Does it make sense in resource-limited countries to emphasize laboratory strengthening just for drug-resistant disease? The capacity of laboratories needs to be increased in a number of ways, including the initial diagnosis for TB. Also, with respect to infection control, Nunn argued that such initiatives should be integrated with other efforts. PEPFAR, for example, was at first focused just on HIV, but now the TB–HIV connection is a central element of the program. Cassell countered that, with MDR and XDR TB being nearly out of control, simply focusing on the susceptible strains will not be sufficient. It is in fact because of some countries’ very limited resources that this issue is so important. Unless it is addressed directly, they will focus on TB control first, while MDR and XDR TB continue to spread.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Castro suggested that both Nunn and Cassell were correct and affirmed the need for both types of interventions. This combined focus is in fact part of a national action plan to combat MDR TB that resulted in new resources being appropriated by Congress. A multipronged approach is needed, which should include focusing on MDR TB infection control, laboratory capacity building, and rebuilding of the infrastructure for basic TB control. Congressman James McDermott (D-WA) suggested that the need for medical infrastructure is perhaps even greater than what had been discussed already by workshop participants—that in addition to laboratories and medication, more people doing the work are required. He suggested that any major proposal should include U.S. involvement in training. He addressed the potential for an increased federal response to the crisis and the prospects for additional legislation. He noted that before the election, President Obama had expressed strong interest in reauthorization of the PEPFAR bill, which calls for $4 billion over 5 years to address TB. The legislation includes the requirement that USAID craft a plan and start setting targets to treat 90,000 MDR TB patients and 4.5 million standard TB patients. But this bill has not yet been funded. McDermott concluded that what is needed is a clear message as to what the plan should be, and he believes that Congress, working with the new administration, can get the plan implemented. THE LEVEL OF RESPONSE A substantial portion of the discussion focused on the level and nature of the U.S. and global response to the TB crisis. Nacy observed that the range of options discussed tended to be more incremental than transformative in terms of approaching the problem in innovative and creative ways. Matthew Cavanaugh of RESULTS encouraged the group to take a cue from the HIV/AIDS world and act boldly: “Most recently, it seems really clear that we have got only about half the funding we need to be tackling TB care around the world. We are short about $2.5 billion a year. The vast majority of funding is coming from countries themselves, meaning that the gap is really about wealthy countries doing their fair share.” The level of funding requested must be adequate to respond in a degree commensurate with the magnitude of the crisis. Harrington discussed lessons learned from AIDS activism that could be applied to TB. He acknowledged that AIDS is very different from TB, and that there may never be a grassroots movement for TB like that for AIDS. The question then becomes how to fill that gap and create the political will. He discussed the elements missing in the fight against drug-resistant TB: data, diagnosis, drug resistance testing and DST, drugs, delivery, dollars, determination, demand, and demonstration.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary Data were essential in transforming the struggle against HIV. Data were used to support requests for money, services, and the nation’s attention. Certain data are critical to making these arguments for TB—for example, data on the full extent of MDR and XDR TB and the degree to which transmission is acquired. Another missing ingredient is dollars. Increases in spending on TB since the launch of the Stop TB global plan have actually decelerated since 2005–2006. Spending increased by only 6 percent, or $26 million, from fiscal years 2006 to 2007. Domestically, investment in TB research has been almost stagnant since the flat NIH budget in 2005, which declined by 20 percent in real dollars. NIH invested $2.9 billion in HIV research last year compared with only $157 million in TB research, despite the fact that TB kills almost as many people. Unlike HIV and malaria, TB has no U.S. presidential initiative. In contrast with the United Nations–endorsed goal of universal access to treatment for HIV, the Stop TB global plan fails to set universal access targets for any kind of TB. Even if its goals were achieved, it would not reverse the TB epidemics in Africa or Europe—the continents most affected by HIV, TB, and drug-resistant TB. Harrington attributed this to the lack of political will, urgency, leadership, vision, and determination to address the problem. Even WHO, he argued, is not providing the leadership needed to determine how to solve the problem, not just control it. As noted, there is little grassroots activism for TB, and consequently there is inadequate political pressure to demand results. Yet Harrington believes that activism is needed at all levels—increased scientific investment, strong political leadership, and greatly increased resources. He recommended a combination of top-down and bottom-up approaches. A key step would be to launch a Presidential initiative to stop TB, whether integrated into the Office of the U.S. Global AIDS Coordinator; the President’s Malaria initiative; the new State Department–level Office of AIDS, TB, and malaria; or a new Office of Global Health. Most appropriate would be an integrated global scale-up for all forms of TB, including but not limited to MDR TB. Roy Widdus from the Global Forum for Health Research noted that while there are no activist groups involving patients in industrialized countries, there are groups that have dealt historically with TB and lung disease at the national level in Japan, the Netherlands, the United States, and Denmark. There is probably a role for the IUATLD in advocacy. In addition, Harrington argued that WHO must rewrite the global plan and cease its internal argument on whether health sector strengthening or priority diseases should receive the greatest attention. It is important to integrate universal access to treatment for HIV and TB and other priority diseases into a comprehensive and universal plan. Said Harrington, “We need political leadership at the national level in countries, and we need to
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary strengthen community-based science and policy literacy to enable affected communities to participate effectively in fighting TB. I think that is one of the key differences between AIDS and TB—in that in AIDS we have treatment and research and policy literate communities in many countries around the world, and as a result many of the AIDS activists are leading efforts against TB in their countries.” A combination of stronger grassroots efforts and stronger leadership from the scientific and political communities is needed. Peter Hartsock from the National Institute on Drug Abuse discussed the concept of a PEPFAR equivalent for TB, and noted that TB’s national security implications make this concept compelling. In Russia, HIV and XDR TB have already collided, especially in the prison and military populations. Hartsock asserted that the Russian military is concerned about the epidemic, and therefore it is a threat to the United States. As a result, it is in the United States’ national security interests to press for an international TB initiative that is either similar to or part of PEPFAR. Friedland added that there is substantial stigma associated with TB, HIV, and drug-resistant TB in most environments and cultures, and this has blunted the response both nationally and globally. Some of the populations that are at risk for and acquire drug-resistant TB by transmission or by treatment failure—particularly in the former Soviet Union and in parts of Asia—are themselves stigmatized because of issues of substance abuse or mental illness. That is part of the context in which TB and drug-resistant TB occur. Therefore, addressing stigma and resultant ethical issues must be an integral part of the response to the crisis. Kim reflected on a recent article by Michael Porter in Business Week arguing that the U.S. government should not scrimp on its investments in such areas as education, science, and health care that will enhance the nation’s future productivity (Porter, 2008). Although the national debt has almost doubled in the last decade, investments in TB are urgently needed. Unlike investments that are focused on meeting current needs created by the financial crisis at the end of 2008, investment in TB is an investment in the future. Policy makers should be bold about combating global health threats and about investing money for that purpose. SUMMARY OF KEY POINTS Castro provided a brief distillation of key points from the workshop presentations and discussions: There is collective ignorance about the true magnitude of the drug-resistant TB problem, as well as the numbers of persons undergoing treatment.
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Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge - Workshop Summary It is recognized that transmitted rather than acquired resistance is driving this epidemic. This recognition highlights the key role of infection control and possibly isolation precautions in the community. A dramatic investment is needed in research into new drugs for individuals who are now relatively untreatable with available drugs. A renewed sense of urgency is needed to combat the relative complacency and lack of activism with respect to TB. Castro mentioned two studies that he considered relevant to the discussion. First, he noted that the IOM issued a report in 2000, Ending Neglect: The Elimination of Tuberculosis in the United States, which recommends strategies for the elimination of TB. A number of those recommendations have never been addressed (IOM, 2000). Also relevant is an interagency plan to respond to XDR TB that was developed by the Federal TB Task Force and published in the Morbidity and Mortality Weekly Report in February 2009 (CDC, 2009). Ongoing work on TB is also being conducted by the National Security Council and Homeland Security Council. Cassell added that other activities within the National Academies address TB and other infectious agents in terms of both security and global public health. CLOSING REMARKS Cassell, the workshop chair, closed by reflecting on the proceedings of the day. She reminded the audience that two studies published in the last 2 months indicate that anywhere from 30 to 40percent of patients diagnosed with XDR TB are untreatable with existing drugs. Gao presented information indicating that drug-resistant TB has been acquired from other infected patients, in stark contrast to what has generally been believed in the past about the ability of these organisms to spread. Gandhi and Friedland demonstrated that XDR TB is not limited to KwaZulu-Natal, but has spread to most of its southern African neighbors. Despite these growing concerns, the diagnostic capabilities, resources, treatment and infection control policies, data collection mechanisms, and research capacity needed to understand and effectively manage this crisis 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 XDR TB and MDR.”