9

Addressing Diagnosis and Treatment Across the Spectrum of Drug Resistance

Key Messagesa

•   People who have MDR and XDR TB exhibit a wide variety of patterns of resistance.

•   Treatment decisions about these patients often are made in the absence of full susceptibility data, which can result in amplifying resistance.

•   Properly applied adjunct therapies can help shorten treatment time, control damage in the lungs, and help establish productive and non-damaging immune responses.

•   “Untreatable TB” is a function of both the resistance that exists in the organism and the drugs available to clinicians for the infected patient.

•   The term “untreatable” can garner attention among policy makers and the public, but it sends the wrong messages to patients, families, and caregivers.

__________________

a Identified by individual speakers.

MDR TB is defined as strains of TB that are resistant to at least isoniazid and rifampicin, while XDR TB denotes strains with additional resistance to fluoroquinolones and injectables. TDR TB has been defined as resistance to all available drugs or all drugs tested, although no official definition of the term exists. A session at the workshop focused on issues



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9 Addressing Diagnosis and Treatment Across the Spectrum of Drug Resistance Key Messagesa • People who have MDR and XDR TB exhibit a wide variety of patterns of resistance. • Treatment decisions about these patients often are made in the absence of full susceptibility data, which can result in amplifying resistance. • Properly applied adjunct therapies can help shorten treatment time, control damage in the lungs, and help establish productive and non­ damaging immune responses. • “Untreatable TB” is a function of both the resistance that exists in the organism and the drugs available to clinicians for the infected patient. • The term “untreatable” can garner attention among policy makers and the public, but it sends the wrong messages to patients, families, and caregivers. a Identified by individual speakers. MDR TB is defined as strains of TB that are resistant to at least isoniazid and rifampicin, while XDR TB denotes strains with additional resistance to fluoroquinolones and injectables. TDR TB has been defined as resistance to all available drugs or all drugs tested, although no official definition of the term exists. A session at the workshop focused on issues 91

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92 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS of diagnosis and treatment across this broad range of drug resistance, with eight speakers considering both the general topic and treatments directed at specific points along the spectrum of resistance. This session also featured an extended discussion, summarized at the end of this chapter, of the scien- tific validity and societal implications of using the term “untreatable” TB. The spectrum of MDR and XDR TB1 Patients with MDR and XDR TB exhibit a wide variety of resistance patterns, noted Richard E. Chaisson, Professor of Medicine, Epi­ emiology, d and International Health, Center for TB Research, Johns Hopkins Uni- versity. To illustrate, Chaisson cited recent data from China (Zhao et al., 2012). According to a national survey conducted by the China CDC, 5.7 percent of new cases and 25.6 percent of retreatment cases had MDR TB. Eleven percent of the new cases and 18 percent of the retreatment cases had what Chaisson called “simple MDR”—resistance to two drugs. At the other end of the spectrum, 8 percent had XDR TB. In the middle, 55 percent of MDR TB patients had ethambutol resistance, and 32 percent had resistance to kanamycin or ofloxacin. Similarly, in a study of more than 1,200 patients with MDR TB from eight countries, half had resistance to all FLDs tested, and a large pro- portion had resistance to SLDs as well (Dalton et al., 2012). More than 40 percent had resistance to at least one SLD, 20 percent to an injectable, and 13 percent to a fluoroquinolone, and 6.7 percent had XDR TB. Thus, resistance is highly heterogeneous in this sample, and studies of other popu- lations have found similar variety (Salvo et al., 2012). Clinicians frequently know nothing about this heterogeneity when they make treatment decisions. As pointed out earlier in the workshop, new technologies for detecting and characterizing MDR TB work very quickly. In real life, however, other problems can delay the results of drug susceptibility tests. In laboratories studied in South Africa, for example, the availability of Hain genotyping reduced the period from sputum col- lection to availability of drug susceptibility results in half, but 26 days still separated the two (Hanrahan et al., 2012). Furthermore, the median time to the initiation of treatment remained 62 days because of the challenges of implementing the test in a clinical setting. There is a large menu of drugs for the treatment of MDR TB, Chaisson pointed out (Table 9-1), some newly developed and others older and with unclear efficacy. But patients can be treated only with those drugs that are available in the settings where they are being treated. If a preferred drug 1  This section is based on the presentation by Richard E. Chaisson, Professor of Medicine, Epidemiology, and International Health, Center for TB Research, Johns Hopkins University.

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 93 TABLE 9-1  Drugs Used to Treat MDR TB Group Drugs Group 1: First-Line Oral Drugs Ethambutol (E) Pyrazinamide (Z) High dose INH (H) Group 2: Injectable Drugs Kanamycin (Km) Amikacin (Am) Capreomycin (Cm) Group 3: Fluoroquinolones Moxifloxacin (Mfx) Levofloxacin (Lev) Ofloxacin (Ofx) Group 4: Oral Bacteriostatic Second-Line Drugs Ethionamide (Eto) Prothionamide (Pro) Cycloserine (Cs) OR Terizidone (Trd) Para-aminosalicylic acid (PAS) Group 5: Drugs of Unclear Efficacy Clofazimine (Clo) Clarithromycin (Cla) Amoxacillin-clavulanate (Aug) Linezolid (Lz) Thiocetazone (T) Group 6: New Products (approved or via Bedaquiline compassionate use) Delaminid PA824 SOURCE: Chaisson, 2013. Presentation at the IOM workshop on the Global Crisis of Drug-Resistant Tuberculosis and the Leadership of the BRICS Countries: Challenges and Opportunities. is not available, patients are treated with the drugs at hand, which can amplify resistance. Drugs may not be available for many reasons. Manufacturing prob- lems may force factories offline. Regulatory barriers may block drugs that are being manufactured, have yet to be manufactured, or have yet to be approved. Forces in the marketplace also can affect the availability of prod- ucts. Supply-chain management can pose major problems (see Chapter 10), as can cost. In India, for example, linezolid would be extremely useful, but it is unaffordable, said Chaisson. Similarly, during the past 2 years, India has experienced shortages of imipenem, linezolid, moxifloxacin, and rifampicin. Uganda has seen shortages of all FLDs because of management problems. Even in the United States, shortages of amikacin, capreomycin, clofazimine,

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94 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS cycloserine, ethambutol, kanamycin, and PAS have occurred in the past year. And isoniazid is in short supply worldwide because of the Fukushima earthquake and tsunami, which destroyed the plant that manufactured the bulk of the material used to produce the world’s supply of that drug. “Untreatable TB” is a function of both the resistance that exists in the organism and the drugs available to clinicians for treating the infected patient, Chaisson concluded. As described in the final section of this chap- ter, many problems surround the use of this term. The Need for a Paradigm Shift in the Treatment of the Spectrum of Drug-Resistant TB2 Adjunct treatment protocols are part of what Markus Maeurer, Profes- sor and Head, Division Therapeutic Immunology, Department of Labora- tory Medicine and Department of Microbiology, Tumor, and Cell Biology, K ­ arolinska Institutet, called the “entire picture” of TB treatment. A patient with sepsis is treated not just with antibiotics but also with individually t ­ ailored therapy, which may include anti-inflammatory treatments, to address the clinical situation. However, this does not happen with MDR TB. Maeurer reflected on what can be done to treat chronic inflammation and presented preliminary results of a small Phase I clinical trial conducted with colleagues in Belarus. First, patients with MDR TB tend to produce more gamma-interferon than those with drug-sensitive TB, although this is not true for gamma-interferon responses to cytomegalovirus or Epstein- Barr virus. Also, the lung tissue of patients with MDR TB is being destroyed through fibrosis of the alveoli and bronchioles even when the M.tb. infec- tion is controlled. Lung immune responses are poor or nonexistent, caus- ing major problems with oxygenation. This process is driven by TGF-beta production, with greatly increased collagen synthesis. One way to treat this problem may be to address long-term inflam- matory processes and provide access to drugs, particularly given the over- production of collagen in MDR TB patients, Maeurer said. Enhancing the immune response at the wrong time and in the wrong place can harm a patient. But properly applied adjunct therapies can help shorten treatment time, control damage in the lungs, and help establish productive and non- damaging immune responses. With sepsis, initial interferon delivery may endanger the patient, but interferon in the “contraction” phase of the immune response leads to significantly increased survival, counteracting interleukin 10 and TGF- 2  This section is based on the presentation by Markus Maeurer, Professor and Head, Divi­ ion Therapeutic Immunology, Department of Laboratory Medicine and Department of s M ­ icrobiology, Tumor, and Cell Biology, Karolinska Institutet.

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 95 beta. Similarly, in influenza infection, death can result from the “cyto- kine storm” designed to protect from infection. Therefore, some influenza patients are treated with cyclophosphamide, which controls the immune response (Henter et al., 2010). Adjunct therapies also are being used suc- cessfully in cancer treatments. More evidence on the effects of adjunct therapies in TB is available than many realize, said Maeurer. Children with TBM are conventionally treated with glucosteroids. However, host-derived therapies that address excess inflammation are associated with better survival in these patients (Tobin et al., 2012). Likewise, studies have shown that both glucocortico- steroid treatment (Muthuswamy et al., 1995) and anti-tumor necrosis fac- tor treatment (Wallis, 2005) may accelerate M.tb. clearance in patients with pulmonary TB. In general, said Maeurer, key pathways in inflammation, tissue damage, and subsequent loss of immune control are as yet untapped. Robust markers are needed for adjunct therapies if they are to be incor- porated into clinical protocols. Experience shows that the state and extent of inflammation are critical. But many existing drugs target biologically and clinically relevant pathways. For example, some antimalaria drugs affect major histocompatibility complex (MHC) expression on macrophages. “Do not be afraid of cellular therapy,” Maeurer urged. Finally, Maeurer shared some results from a Phase I clinical trial con- ducted with colleagues in Belarus, where the number of MDR/XDR TB patients constitutes a crisis. The trial used stromal cells harvested from the bone marrow aspirate of XDR TB patients. The cells were grown for 2–3 weeks and reinjected initially into 9 and subsequently into 20 more patients. Six of the initial 9 patients responded well, as did a similar per- centage of the next 20 patients. Patients regained immune responses, as indicated by gamma-interferon production directed against TB antigens. In patients who responded, the treatment reduced unproductive inflamma- tion, rebuilt lung tissue, and refocused the anti-TB immune response. “It’s not dangerous,” said Maeurer, “and there may be beneficial effects, which is not so surprising, because you’re dampening the immune system in a productive way.” Maeurer concluded by calling for more scientifically and clinically rel- evant models and Phase I trials involving experts not just in TB but also in other diseases, including cancer. “We are not alone,” Maeurer said. “This is done in other fields, and it works perfectly well.” In particular, he noted in responding to a question from the audience, many drugs used in Chinese medicine have effects on inflammation.

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96 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS MDR, XDR, and Untreatable TB in africa3 Martie van der Walt, Interim Director, Tuberculosis Epidemiology and Intervention Research Unit, South African Medical Research Coun- cil; and Professor, Department of Internal Medicines, Faculty of Health Sciences, University of Pretoria, South Africa, highlighted the challenges of DR TB, including what has been termed “untreatable” TB, in the African context. The world has made great progress in reducing TB incidence, prevalence, and mortality, she said. However, progress in responding to DR TB remains low. During 2011, in the 27 HBCs, 60,000 MDR TB patients were diagnosed, and this number is a large underestimation, van der Walt said. Further­ ore, the average rate of XDR TB among these patients is m 9 percent. Although Africa has a small percentage of the world’s population, it has a high burden of both TB and DR TB, along with high HIV infection rates. According to WHO (2012), the success rate for MDR TB treatment for Africa in general is only about 45 percent, and the death rate is higher than in any other WHO region. The default rate also is relatively high, which is a concern because defaulted or intermittent therapy drives drug resistance. Of the 43 African countries covered in the WHO report, only 10 have culture capability, and only for FLDs. This limitation contributes to a marked lack of data for many African countries. Also, many countries do not treat TB with kanamycin and ofloxacin and therefore do not test for XDR TB. Only two laboratories in Africa, both in South Africa, perform second- line DST. Some other countries in the region can perform first-line DST, but they do not do so universally because the cost of both the testing and the drugs is prohibitive. In addition, clinicians have limited experience treating patients with SLDs, and many are concerned about overlapping toxicity with HIV drugs. The two laboratories in South Africa that perform second-line DST— the National Health Laboratory Service and van der Walt’s institution—are in Gauteng province in the north. Although the highest burden of TB is in the Eastern Cape and KwaZulu-Natal provinces, South Africa is fortunate to have a good specimen transportation system, such that specimens from even the most remote parts of the country can be delivered to one of these laboratories for DST within 3 days. One reason for the low coverage of DST in African countries is uncer- tainty about when and whom to test. For example, when should a sample be collected for second-line DST? Should universal screening be conducted 3  Thissection is based on the presentation by Martie van der Walt, Interim Director, Tuber- culosis Epidemiology and Intervention Research Unit, South African Medical Research Coun- cil; and Professor, Department of Internal Medicines, Faculty of Health Sciences, University of Pretoria, South Africa.

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 97 at case finding, at treatment initiation, or at regular intervals thereafter? Should attention be focused on particular populations, such as those who default, relapse, or do not culture convert? Should health care workers or other high-risk populations be tested? Should all patients with any r ­ ifampicin resistance undergo full DST? “I personally think this is the way to go,” said van der Walt. “The technology isn’t there, but we need to have a point-of-care microarray test that will give us, within a couple of minutes, results. Of course, then we also need the drugs.” In addition, organizing and running a laboratory network is expensive and requires trained staff. DST needs to be performed in a biosafety level 3 facility, which further raises costs. Even transportation of infectious mate- rial is an issue, because it requires accredited couriers. DST is slow and cumbersome, and contamination is a problem. Today, second-line DST is a culture-based method that takes 12 weeks, or probably longer, to confirm that a patient with suspected MDR TB has additional resistance. Should empirical treatment be started, or should the initiation of additional treatment be postponed? If treatment is postponed, should the patients be kept in the hospital or sent home? South Africa has an algorithm for the early detection of MDR TB that involves microscopy laboratories, the use of LPAs, and culture laboratories. Throughout this process, specimens need to be traced so patients need not be recalled to obtain new ones. Van der Walt also emphasized the quality control issue with second-line DST. Unless the quality of the diagnosis is high, defining such concepts as “untreatable TB” will be difficult. One mechanism for ensuring quality con- trol is the WHO’s Supranational Reference Laboratory Network, created in 1994 to support the Global Project on Anti-Tuberculosis Drug Resistance Surveillance. The objectives of the Global Project are to estimate the mag- nitude of drug resistance globally, determine trends, and provide data to inform WHO policy decisions. The Supranational Reference Laboratory Network monitors the proficiency of National Reference Laboratories in susceptibility testing of anti-TB drugs, thereby ensuring quality-assured diagnoses of drug resistance. In South Africa, van der Walt’s laboratory provides these services for many of the countries of sub-Saharan Africa as well as for the South African TB control program. Finally, van der Walt emphasized the importance of testing for drug resistance even in countries that do not treat XDR TB patients because they cannot afford the drugs. Migratory workers from many countries in Africa work in South Africa’s mines, and rates of TB among these mineworkers are some of the highest measured in the world—an estimated 3,000 to 7,000 per 100,000. Risk factors include the silica dust generated in the mines, reinfection caused by poor infection control and ongoing transmission, and high levels of HIV infection. When mineworkers contract DR TB in South

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98 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS Africa, they can take the disease back to their home countries, making it important for them to be tested to reduce the spread of the disease. Some thoughts on “untreatable” TB concluded van der Walt’s presen- tation. MDR and XDR TB are manmade problems, she said, exacerbated by high default rates, nonadherence, drug toxicity, and inappropriate use, and untreatable TB is following the same course. The reliability of DST will be critical to the design of individualized regimens for these patients. In addition, more needs to be learned about the connections among clini- cal failure, phenotypic resistance, and detection of mutations. Enhanced drug resistance also will require standardization of tests and expanded laboratory capacity. Finally, the idea of untreatable TB raises ethical issues involving health care and human rights. MDR, XDR, and Untreatable TB from a Laboratory Perspective4 Failure to treat MDR and XDR TB patients correctly will create prob- lems in the future, including the possibility of untreatable TB, said Sven Hoffner, Director, WHO Supranational Tuberculosis Reference Laboratory; and Department for Preparedness, Swedish Institute for Communicable Disease Control. He defined TDR TB as infection with a strain of TB that is resistant to all of the drugs available at a given time or place, as well as being more resistant than XDR TB. He then defined untreatable TB as a case of TB so severely drug resistant that a patient cannot be cured with any existing drug therapy. He acknowledged, however, that no official defi- nitions of these terms exist. They are useful for advocacy and fundraising purposes, but the signals they send to individual patients and health care workers need to be considered. Nevertheless, such strains do exist and are being transmitted, said Hoffner. They constitute an increasing public health threat and require modifying international guidelines accordingly. They also must be detected promptly if efforts to limit or stop the development of further resistance and the transmission of such strains are to be maximized. XDR TB cases have been detected in many countries, Hoffner said, and those countries that have not detected such cases generally lack the laboratory capacity to do so. In sub-Saharan Africa and South Asia, too few culture laboratories exist to meet the demand. Furthermore, creating laboratories that meet WHO’s biosafety standards is difficult, expensive, and time­ intensive. “I doubt that this is the way forward,” Hoffner said. Even in - 4  This section is based on the presentation by Sven Hoffner, Director, WHO Supranational Tuberculosis Reference Laboratory; and Department for Preparedness, Swedish Institute for Communicable Disease Control.

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 99 Europe, the proportion of laboratory-confirmed TB cases is low, so patients are treated without knowledge of whether they are drug resistant. Outside of Europe and the Americas, DST of both new and re-treated TB patients for rifampicin and isoniazid is well below 10 percent, and testing for SLD sus- ceptibility occurs worldwide for only about 20 percent of MDR TB patients. “Perhaps we need to rethink what we are doing,” Hoffner said. Hoffner discussed results on drug resistance from Belarus and Iran. In Belarus, surveillance for drug resistance performed in Minsk in 2010 and 2011 found the highest-ever reported figures from a quality-assured study (Skrahina et al., 2012). Among new TB cases, 29.2 percent and 35.3 per- cent, respectively, had MDR TB in the 2010 and 2011 surveys. Among previously treated cases in the 2011 survey, 76.5 percent had MDR TB and 19.4 percent XDR TB. Overall, 49 percent of the infectious cases of TB in Minsk city were MDR TB, and Hoffner cited unpublished data indicating similar levels in other regions. Furthermore, the clustering of cases points to ongoing transmission and the need for infection control. This information “must lead to some rethinking of how we are controlling the problem and what is needed also from the laboratory side,” Hoffner said. In Iran, based on specimens collected over 2 years in the national refer- ence center in Tehran, 5.4 percent of 146 MDR TB isolates proved to be XDR TB, and 10.2 percent were TDR TB, which Hoffner defined as resis- tance to all 13 of the drugs tested—amikacin, capreomycin, ciprofloxacin, ­ cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, ofloxacin, PAS, pyrazinamide, rifampicin, and streptomycin (Velayati et al., 2009). Among the latter 15 patients, 11 were men, and 7 were immigrants from the neighboring countries of Afghanistan and Azerbaijan. These patients all had different genotypic profiles, although primary MDR TB patients were not included in this group, which may have suggested transmission. Hoffner emphasized the importance of rapid detection of resistance to rifampicin and isoniazid for timely modification of drug regimens so that MDR TB patients can quickly become noninfectious and then cured. He also stressed the need for an early warning system for MDR TB. Prompt identification of patients with drug-resistant strains would enable more rapid initiation of treatment, better infection control measures, and thus reduced development and spread of MDR TB. In response to the observation that rapid testing is costly, Hoffner pointed out that, given the cost of the additional TB cases such testing can avoid, it is in fact extremely cost-effective. Furthermore, the cost of rapid testing is small compared with that of other kinds of tests. Hoffner concluded with a list of priorities for TB laboratory services: • A new algorithm is needed that takes new diagnostic possibilities into account. The roles of microscopy, culture, drug susceptibility

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100 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS tests, and rapid molecular tests should be optimized to allow sensi- tive, specific, and timely detection of MDR and XDR TB. • Necessary resources should be made available for implementing more rapid tests as soon and as widely as possible. • Unnecessary routine examinations should be discontinued to lower overall costs and make financial and physical space for improved techniques. • A plan for the future organization of national laboratory networks should be formulated that accounts for the implementation of new techniques. • A set of basic quality criteria and a licensing system should be established to ensure high-quality service. Standard operating pro- cedures should be developed and implemented, and laboratories failing to meet quality standards should be offered training and if necessary closed. • Methods for determining susceptibility to new drugs should be developed. These methods could include both phenotypic and geno- typic testing. • A human resources development plan should be established both to replace people leaving and to guarantee relevant knowledge in new techniques. • Infection control in TB laboratories needs to be improved, in part through a risk assessment of all diagnostic units and of the tests carried out. • Training needs should be analyzed and gaps filled. • Operational research should be strengthened. Complementing Hoffner’s presentation were remarks by two speakers from China who discussed the diagnosis and treatment of two different forms of TB—TBM and endobronchial TB. These presentations are sum- marized in Boxes 9-1 and 9-2, respectively. BOX 9-1 A New Approach to Diagnosis of TBMa TBM, an extrapulmonary disease in the central nervous system caused by M.tb., is associated with high mortality rates (up to 30 per­ cent). Infection may lead to brain damage that causes abnormal behav­ continued

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 101 BOX 9-1 Continued ior, mental impairment, motor paralysis, and seizures. As pointed out by Xiaoyou Chen, Director and Chief Physician, Tuberculosis Depart­ ment, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor R ­ esearch Institute, rapid diagnosis and early intervention are vital if patients are to have successful outcomes. The exact global incidence and prevalence of TBM are unknown. Data from 2010 indicate that 5.5 percent of extrapulmonary TB cases—­ equivalent to 1.2 percent of total TB cases—involve central nervous sys­ tem TB (Takahashi et al., 2012). In Beijing Chest Hospital, the number of TBM cases rose from about 30 in 2001 to about 150 in 2012, according to Xiaoyou Chen. Approximately 90 percent of patients are diagnosed in stage II or III, which means they are diagnosed late. Clinical response to anti-TB therapy in all forms of TB in the central nervous system is excellent if the diagnosis is made early, before irreversible neurological deficit is estab­ lished. Early diagnosis of TBM is therefore considered a key to effective treatment and a good prognosis. Diagnosis of TBM remains a major challenge because of inadequate diagnostic methods and the poor sensitivity and specificity of exist­ ing markers. Diagnosis is based on the clinical picture, neuroimaging abnormal­ties, changes in cerebrospinal fluid, and the response to anti- i TB drugs. But the clinical manifestation—including fever, headache, and vomiting—is broad and not specific to TBM patients, so early diagnosis is difficult. Bacteriological culture from cerebrospinal fluid is the gold standard for the diagnosis of TBM but is expensive, requires significant laboratory infra­ structure and expertise, and takes too long to guide patient management efficiently (Torok et al., 2008). In Xiaoyou Chen’s practice, no more than 10 percent of TBM patients are culture positive from cerebrospoinal fluid. Mass spectrometry-based quantitative proteomics has emerged as a powerful means of identifying and studying disease biomarkers that serve as indicators of disease progression, prognosis, and drug safety and can help elucidate the mechanism of drug treatment. In a recent study, Xiaoyou Chen and his colleagues used a quantitative proteomic approach to identify 338 differentially expressed peptides/proteins from the cerebrospinal fluid of TBM cases as compared with controls (non­ meningitis patients). They are now engaged in further work to confirm which of these markers will be useful for the diagnosis of TBM. a This box is based on the presentation by Xiaoyou Chen, Director and Chief Physician, Tuberculosis Department, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute.

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102 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS BOX 9-2 Surgical Treatment of Endobronchial TBa Endobronchial TB is defined as a TB infection of the tracheobronchial ­ tree with microbial and histopathological evidence. The clinical manifes­ tations may be acute, insidious, or delayed and include cough, expec­ toration, hemoptysis, shortage of breath, wheezing, and fever. Ten to 20 percent of patients may have a normal chest radiograph. The goals of therapy, said Xiao Ning, Thoracic Department, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Insti­ tute, are to eradicate M.tb. and to prevent tracheobronchial stenosis, a ­ lthough the course and prognosis of the disease vary widely. In the a ­ ctive stages of disease, anti-TB chemotherapy is generally a combina­ tion regimen comprising 4 kinds of anti-TB drugs, with treatment usually ­ lasting more than 9 months. Localized treatments include inhalation of nebulized anti-TB drugs and lavage or submucous injection of the dis­ eased region with anti-TB drugs. For patients in whom fibrostenosis has already developed or extensive granulation tissue appears, anti-TB chemotherapy is of limited efficacy. Surgical removal using a bronchoscope can be used to treat tracheo­ bronchial stenosis shaped by extensive granulation tissue. Available approaches include laser ablation, microwave ablation, electrocautery, and cryotherapy. Fibrostenosis also can be treated with balloon dilation and stent implantation. Severe tracheobronchial stenosis that cannot be relieved by medical treatment may require chest surgery. Most patients have a good prognosis, with the most frequent compli­ cation being anastomotic stenosis. Lobectomy or pneumonectomy with trachial or bronchial plasty is a useful technique in the latter cases. a This box is based on the presentation by Xiao Ning, Thoracic Department, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute. Totally Drug-Resistant TB in India: Lessons and Opportunities from a Clinical Perspective5 TB exists on an epic scale in India. The country sees fully 3 million cases of active TB and 300,000 fatalities every year (WHO, 2012). Zarir F. Udwadia, Consultant Chest Physician, Medical Research Council, Hinduja Hospital and Research Centre, Mumbai, personalized 5  This section is based on the presentation by Zarir F. Udwadia, Consultant Chest Physician, Medical Research Council, Hinduja Hospital and Research Centre, Mumbai.

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 103 the epidemic by recounting the history of a 37-year-old female who lived in India’s largest slum, Dharavi, Mumbai. She had a history of pulmonary TB for 5 years; had seen multiple physicians; and had taken almost every avail- able FLD and SLD, often in incorrect doses and with considerable toxicity. However, she had never undergone DST. She came to Udwadia after hearing about enrollment for an NIH-funded study of XDR TB. When this patient was tested for drug susceptibility, she proved to be resistant to 11 drugs—amikacin, capreomycin, ethambutol, ethionamide, ­ isoniazid, kanamycin, moxifloxacin, ofloxacin, PAS, rifampicin, and strepto­ ycin. A salvage regime that included isoniazid, capreomycin, m linezolid, clofazine, and cycloserine was initiated. After 2 months of treat- ­ ment, the patient underwent a right-sided pneumonectomy. She was doing well enough on the first day after the operation, but then went into a rapid decline and died on the fourth day from refractory hypoxemia. Udwadia listed the lessons he learned from this patient: • Untreatable forms of TB are increasingly being encountered. • Such patients have virtually no drug options. • New drugs are desperately needed. • The cost of DST is money well spent and is a fraction of the overall cost of treatment. • Surgery is often the sole option for such patients. • In no other disease is prevention more important than in TB. In the next few weeks, Udwadia saw three more cases from different parts of Mumbai with the same drug-resistance pattern, all in the free weekly clinic he has been running at Hinduja Hospital for the past two decades (where, he said, “I have witnessed firsthand the horrendous ampli- fication of resistance over the decades”). The hospital is a large private facility with an advanced mycobacterial laboratory that essentially acts as the reference laboratory for the city. A publication on these and other cases, entitled “Emergence of New Forms of Totally Drug-Resistant Tuberculosis Bacilli” (Udwadia et al., 2012), caught the attention of the Times of India, leading to a media flurry. The government seized the cultures from the hospital laboratory, and the authors were pressured to retract the paper. WHO’s responses were more measured, said Udwadia. Within a few weeks of the article’s publication, WHO’s website included frequently asked questions about TDR TB, and WHO held a meeting 2 months later in Geneva to discuss nomenclature. WHO’s Paul Nunn described the cases as “a wake-up call for countries to accelerate provision of proper care to MDR patients.” Participants in the March 2012 meeting in Geneva concluded that reports of TB patients with patterns worse than XDR are increasing and

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104 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS present a formidable challenge. However, participants did not recommend a new definition of resistance beyond XDR TB because most laboratories already struggle to diagnose MDR TB, and the new designation would further stress their capacity. The meeting also called attention to concerns about the reliability, reproducibility, accuracy, and in vivo correlation of susceptibility testing for SLDs. In May 2012, the supranational reference laboratory to which the samples had been sent verified that the strains “are indeed resistant to all 12 drugs as reported” by the article. The article’s publication was respon- sible at least in part for a number of important changes: • Free drugs were offered to all the surviving patients, six of whom accepted. • Cluster investigations of their 43 contacts were initiated. • Notification of MDR TB was made compulsory in Mumbai, which resulted in a doubling of MDR TB notifications in 6 weeks com- pared with the previous 18 months. • The capacity of two state laboratories designated for closure was strengthened. • Staffing and funding for TB control were increased. • The health secretary wrote to each state directing the scale-up of DOTS-Plus. • The FDA commissioner spoke about reregulating the use of TB drugs. In January 2013, Hinduja Hospital and Research Centre received the “TB Champion of 2013” award from The Union. Since the article’s publication, 16 more cases of TDR TB have emerged. According to Udwadia, “they hold a mirror to the way that this disease has been mismanaged in India over the decades.” Cases have occurred among young people, male and female alike. These patients have seen an average of four doctors and received a mean of 10 drugs over an average of 26 months before receiving a diagnosis of TDR TB. The diagnosis of “untreatable” continues to generate controversy (Cegielski et al., 2012). As described in the final section of this chapter, some object to calling a disease untreatable if any treatments are possible. In that regard, Udwadia quoted Plato: “I have no objection to your giv- ing names any significance you please if you will only tell me what you mean by them.” (As Paul E. Farmer, Partners In Health, Harvard Medical School, and Brigham and Women’s Hospital, said in his opening remarks at the workshop, even MDR TB is “just a definition.”) Some forms of DR TB have a worse prognosis and outcomes based on the number of drugs to which a patient is resistant. Udwadia also said that each initial before

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 105 “DR” is “a reflection of our failure.” Meanwhile, “TDR TB” is being used by patients and is a familiar term online, with more than a million hits on Google. The term is not just a matter of semantics, said Udwadia. It means something to patients about their treatment and survival. TB patients in India face a Faustian choice, Udwadia said. Thirty per- cent go to the public system, which offers little choice of treatment and can have the effect of amplifying resistance. The other 70 percent go to the private health care system, but many see nonspecialists, including providers who offer low-quality alternatives to conventional care. “A tiny fraction of the MDR patients are going to end up cured,” said Udwadia. Udwadia characterized the dilemma of MDR and XDR TB in India, which he described as public health realpolitik: • The country has a large and expanding population. • MDR and XDR TB patients are accorded the status of untreatable and untouchable. • The national TB program has turned a blind eye to them. • WHO focuses on DOTS, which has been a tremendous public health success for the country but only for drug-sensitive patients. • Treatment of MDR TB is not considered cost-effective, because many drug-sensitive patients can be cured for the cost of treating a single patient with MDR TB. Udwadia quoted Farmer: “Our mission must be to treat the sick, not just the sick who can pay. Our mission must be to treat TB regardless of resis- tance pattern. . . . It is failure to treat, not treatment failure, that accounts for the vast majority of MDR TB deaths.” After a year of individualized regimens for each of the 20 TDR TB patients Udwadia has seen, 6 have died, and 3 have been lost to follow- up. But seven have shown radiological improvement, five have culture- converted, seven have smear-converted, and seven have shown clinical improvement. “So, TDR does not mean totally doomed, which is again something the press seized on,” said Udwadia. Udwadia listed several difficult questions that surround these patients: • How do we treat XDR TB patients who have failed treatment? • What do we do when we have run out of all drugs, and surgery is not possible? • Do we continue to treat with the aim of reducing infectiousness rather than curing? • Should we have a protocol for withdrawal of all drugs as we do in cancer patients? • What emotional support do we give these patients?

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106 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS Finally, Udwadia offered some suggestions based on his experiences: • Laboratory capacity needs to increase. India has one supranational reference laboratory, yet the country bears a large burden of MDR TB. Fewer than 1 percent of MDR TB patients in the country receive DST. • All patients who fail to respond to DOTS need to receive DST early on rather than being subjected to 8 months of demanding treatment. • GeneXpert needs to be rolled out across the country. “South Africa is an inspiration in that regard,” said Udwadia. • DOTS-Plus needs to be expanded countrywide. • Additional funds are needed. Funds should not be diverted from drug-sensitive patients to cure MDR TB patients. That would be inappropriate. • New drugs are needed, and until they are available, existing drugs should not be squandered. The development of new drugs will require that pharmaceutical companies work together. • Not just new drugs but new regimens of existing or novel drugs are needed. • The dysfunctional relationship between the private and public health care sectors needs to be improved through public–private partnerships. • Legislation is needed to ensure that only designated specialists can treat MDR TB. Udwadia concluded by quoting Yale lecturer Jonathan Smith: “It’s not that we can’t cure TB, it’s that we can’t cure TB for poor people. TDR TB has been present for decades, but instead of pathological resistance the culprits are apathetic governments, broken promises, and non-functioning infrastructures that elude accountability. . . . TDR TB reinforces my claim that TB management should be deemed the largest violation of human rights the global health community has ever seen”—a sentiment with which Udwadia heartily agreed. TB terminology and advocacy needs Following the presentations on diagnosing and treating across the spectrum of drug resistance, an extended discussion took place regarding the use of the term “untreatable” TB. Chaisson began by pointing out that people with untreatable TB are not really untreatable. The patients with so-called TDR TB in India were and continue to be treated. As new drugs are developed, moreover, new treatments will become available, as has

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ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM 107 occurred with HIV infection. Thus, using the term “untreatable” sends the wrong message, Chaisson said. A term should not convey that a patient is doomed. Rather, drug resistance occurs along a spectrum from none to a great deal, and recognizing the existence of that spectrum is more important than calling a particular point on the spectrum untreatable. Farmer also took issue with the term “untreatable.” Before ­ treptomycin s was introduced, an effective set of interventions for TB did not exist. As antibiotics were developed, TB changed from an untreatable to a treatable disease. Similarly, leukemia in children used to be almost 100 percent fatal, but new treatments have resulted in good survival rates. Thus if new treat- ments can be developed and integrated into enabling platforms, untreatable diseases can become treatable. In fact, Farmer prefers the term “drug-­ resistant” TB to “MDR TB” so as not to dwell on the exact definition of MDR TB, XDR TB, or other forms of resistance. The term “untreatable” is not accurate clinically, sociologically, or historically, said Farmer. Families will always try to get treatment for sick members, and professionals will seek to treat them. The important thing is to ensure that treatments are effective and do not risk amplifying resistance. Neel R. Gandhi, Rollins School of Public Health, Emory University, pointed to the value of a term that would acknowledge the diversity of resistance beyond MDR and XDR TB. Patients who are resistant to 12 or 15 drugs are much more difficult to cure than those who are resistant to just 2 or 3 drugs. Anne E. Goldfeld, Harvard Medical School and GHC, emphasized the need to call attention to the problems entailed in procuring the drugs that can cure people on the far end of the resistance spectrum. In that respect, the situation with TB is different from that with forms of cancer that are untreatable. “Why don’t we have in our hands the ability to treat our fellow humans with what is available?” asked Goldfeld. Gail Cassell, Harvard Medical School and Infectious Disease Research Institute, said she is sympathetic to the argument that in reality, TB occurs on a spectrum, and the term “untreatable” may not always be clinically accurate. But she also spends a great deal of time trying to generate fund- ing for the treatment of DR TB, and the TB advocacy community needs powerful terminology to convey the urgency of the situation to the public and policy makers. Cassell suggested that discussion of the spectrum of resistance does not adequately communicate the severity of the problem. “If we hadn’t come up with the term MDR, I don’t think we would be treating nearly as many patients as we are today,” she said. Participants discussed several possible terms as alternatives to untreat- able, such as SXDR (for super XDR), XXDR (for extremely drug resistant), or CXDR (for completely drug resistant). Another possibility suggested was to assign resistance a number corresponding to the number of drugs to which a patient is resistant—thus, for example, 6DR, 10DR, or 15DR. ­

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108 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS Rifat Atun, Imperial College London, argued that a new term is unlikely to capture the attention of the policy makers who determine how much funding will be available for TB treatment. What will inspire them to action, he said, is the message that DR TB is a security risk that can affect any nation. Edward A. Nardell, Brigham and Women’s Hospital, Harvard Medi- cal School, observed that even today some drugs are available that are not being used to treat TB but may have an effect on the disease, even if they are not strong drugs. An alternative delivery system, such as the airway, may be needed for these drugs, but their existence and potential to treat DR TB demonstrates further that the disease is not untreatable. Chaisson questioned whether intensifying the rhetoric surrounding DR TB will be effective. In HIV advocacy, this tactic has not been the solution to the problem. Rather, advocates have emphasized that millions of people are dying and that it is unacceptable not to treat them. In response, the world has reacted much more strongly than it has to TB. “The fundamental problem is not how do we scare them into it, but how do we make people care. I think scaring them hasn’t been working,” said Chaisson. Farmer, too, emphasized the ability of optimistic messages to inspire action. Some data suggest that a positive message of doing something to save lives has a greater chance of generating a response than a negative mes- sage, he said. The TB community has hampered itself by dwelling on the limited amount of funding that is available. The agenda needs to emphasize saving lives, not the idea that a disease is untreatable.