3

The Global Burden of Drug-Resistant TB

Key Messages

  • Delays in establishing strong national and international commitments to treat MDR TB aggressively have allowed the disease to spread.
  • Several workshop participants noted that many high-burden countries could rapidly scale up their culture and DST laboratory capacity so that MDR TB patients can be diagnosed and placed on treatment quickly.
  • Patients need quality-assured, second-line drugs at affordable prices.
  • Community-based care can be preferable to hospital care if patients are being treated adequately, but care needs to be well managed in either setting.
  • Many countries with high levels of MDR TB could benefit from international assistance to bridge the gap between current and needed capabilities.
  • A gap between global notification of TB each year and estimated incidence indicates that many people, including people with MDR TB, are not being diagnosed and treated by current approaches.

The response to drug-resistant TB in India is occurring against the backdrop of a worldwide epidemic. An estimated 440,000 new cases of MDR TB occur annually around the world, causing an estimated 150,000



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3 The Global Burden of Drug-Resistant TB Key Messages • elays in establishing strong national and international commit- D ments to treat MDR TB aggressively have allowed the disease to spread. • everal workshop participants noted that many high-burden coun- S tries could rapidly scale up their culture and DST laboratory ca- pacity so that MDR TB patients can be diagnosed and placed on treatment quickly. • atients need quality-assured, second-line drugs at affordable P prices. • ommunity-based care can be preferable to hospital care if pa- C tients are being treated adequately, but care needs to be well managed in either setting. • any countries with high levels of MDR TB could benefit from inter- M national assistance to bridge the gap between current and needed capabilities. • gap between global notification of TB each year and estimated A incidence indicates that many people, including people with MDR TB, are not being diagnosed and treated by current approaches. The response to drug-resistant TB in India is occurring against the backdrop of a worldwide epidemic. An estimated 440,000 new cases of MDR TB occur annually around the world, causing an estimated 150,000 37

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38 DRUG-RESISTANT TUBERCULOSIS IN INDIA deaths (with a range of 53,000 to 170,000) (WHO, 2010b,c).1 Failure to treat these cases adequately increases the risk of the disease spreading to others. Salmaan Keshavjee, Harvard Medical School, presented an overview of the global profile of TB and drug-resistant TB using data provided by Matteo Zignol, STOP TB Partnership, WHO. Keshavjee also described the global challenges to effective treatment and control of drug-resistant TB, with a focus on the slow pace of treatment scale-up and the consequences of inaction. In addition, Gail Cassell, Harvard Medical School and Infec- tious Disease Research Institute, presented data from another high-burden country—China, which will host the fourth and last workshop in the Forum’s series. OVERVIEW OF THE GLOBAL BURDEN OF TB AND MDR TB2 According to official WHO data reported by countries in 2009, the esti- mated number of new cases of TB worldwide was 9.4 million, with a range of 8.9 to 9.9 million. The estimated number of deaths from TB, excluding those among HIV-positive people, was 1.3 million, with a range of 1.1 to 1.5 million (WHO, 2010b).3 About 1 in 8 cases of TB are associated with HIV—an estimated total of 1.1 million people (ranging from 1.0 to 1.2 million). Among these individuals, 380,000 deaths occur each year (ranging from 320,000 to 450,000). Overall, approximately 4,600 people die each day on average from TB, both with and without HIV coinfection. According to WHO, the incidence of TB peaked in 2004 and has declined slightly since then. The prevalence of TB has been declining and by 2015 will be approaching, although it will not achieve, the Millennium Development Goal of half the 1990 level. With respect to mortality, the Millennium Development Goal of half the 1990 level will be achieved if the current trend continues (WHO, 2010b). A substantial gap exists between global notifications of TB each year and estimated incidence, indicating that many people are not being reached by current approaches. The treatment success rate for regular TB has been improving—to 87 percent according to 2009 data (WHO, 2011a). How- 1 See footnote 4 in Chapter 1 and the updated WHO (2011a) report on TB control for more information on global estimates of MDR TB. 2 This section is based on slides prepared for the workshop by Matteo Zignol, STOP TB Partnership, WHO, and presented by Salmaan Keshavjee, Assistant Professor, Harvard Medical School. 3 An updated WHO (2011a) report, released after the workshop, estimates that in 2010, there were 8.8 million new cases of TB, 1.1 million deaths from TB in HIV-negative individuals, and an additional 0.35 million deaths from HIV-associated TB.

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39 THE GLOBAL BURDEN OF DRUG-RESISTANT TB ever, this success rate varies by region and is, for example, relatively low in Europe because of the high levels of drug resistance in that region. The proportion of MDR TB among new TB cases varies by region, with a high of more than 18 percent in the Russian Federation and some neighboring countries. Levels are high as well in some of the countries of Southeast Asia and South Asia—between 3 and 6 percent. In India, which has only subnational data, surveys point to a proportion of MDR TB among new TB cases that is within the 1.8 to 2.8 percent range (WHO, 2011b). Estimates of the proportion of MDR TB in TB retreatment cases in India range from 15 to 20 percent (WHO, 2011b). Globally, only 11 percent of the estimated 440,000 new MDR TB cases annually are reported (Keshavjee, 2011b). As noted in Chapter 2, the largest total number of estimated MDR TB cases are found in China (100,000 cases) and India (99,000 cases), followed by Russia (38,000 cases) (WHO, 2010b). Most countries had reported at least one case of XDR TB by the end of March 2011. The global proportion of XDR TB among MDR TB cases was 9.4 percent (confidence interval: 7.4–11.6 percent) (Zignol et al., 2012). The proportion of reported versus estimated MDR TB cases varies widely by region (Table 3-1). Laboratory capacity to diagnose TB is insufficient in many of the 36 countries with a high burden of TB, MDR TB, or HIV. Twenty-seven high- burden countries have fewer than one smear microscopy laboratory per 100,000 population. Diagnosing drug-resistant TB requires culture and DST capacity, with a minimum standard set by WHO of at least one culture laboratory per 5 million population and one DST laboratory per 10 million population. Very few high-burden countries have this capacity. Finally, treatment outcomes vary from country to country. Kazakhstan has shown a treatment success rate for MDR TB of around 75 percent, while Brazil, South Africa, and Romania have success rates below 50 per- cent (WHO, 2010b). In some cases, low success rates are due to a failure TABLE 3-1 Estimated Versus Reported MDR TB Cases in 2009 WHO Region Estimated Reported Ratio (%) African 69,000 10,735 16 American 8,200 2,795 34 Eastern Mediterranean 24,000 480 2 European 81,000 28,240 35 Southeast Asian 130,000 2,549 2 Western Pacific 120,000 2,057 2 Global 440,000 46,856 11 SOURCE: Keshavjee, 2011b.

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40 DRUG-RESISTANT TUBERCULOSIS IN INDIA to perform sufficient evaluations rather than actual failure rates. In other cases, however, failure and death rates are in fact high. A striking feature of surveillance results for drug resistance is the high levels of resistance to the fluoroquinolones in some regions. In Belgium, a quarter of 31 patients tested showed fluoroquinolone resistance. In Latvia, 16 percent of 258 patients tested showed resistance. Rates were 14 percent in South Africa, 29 percent in Azerbaijan, 12.5 percent in Armenia, and 27.4 percent in China (WHO, 2011b). In India, recent statewide surveil- lance of drug-resistant TB in the state of Gujarat showed resistance to fluoroquinolones in 24 percent of TB cases (19 percent among new and 25 percent among previously treated cases) (Mohapatra, 2010; Ramachandran et al., 2009). These are troubling findings, since the fluoroquinolones are the backbone of second-line treatment regimens (see Chapter 2 for a descrip- tion of treatment regimens and anti-TB drug classifications). MDR TB PREVENTION AND CONTROL IN CHINA4 Depending on the 2007–2008 baseline survey of drug resistance used, it is estimated that China has 120,000 new MDR TB cases and 9,000 new XDR TB cases annually. Among new TB cases, 5.71 percent are MDR TB and 0.47 percent XDR TB. Among retreatment cases, the corresponding proportions are 25.6 and 2.06 percent, and for all cases, they are 8.32 percent and 0.68 percent. These rates vary greatly by province. The proportion can be as high as 10.8 percent for new cases and 41.9 percent for retreatment cases. The overall rate of MDR TB in China among all TB cases ranges from 3.5 to 23.3 percent, depending on the province. China has embarked on a Global Fund pilot project to control MDR TB that incorporates enhanced service system and management mecha- nisms. As of December 2010, this project had covered 41 prefectures in 12 provinces and had confirmed 1,978 MDR TB cases, with 1,049 patients enrolled in treatment. The sputum conversion rate was 75.6 percent at the end of 6 months, and the culture conversion rate was 65.2 percent. As part of a Gates Foundation initiative, China also is exploring rapid diagnosis; creating a standardized medical service package; establishing funding mechanisms that consist of multiple streams (including govern- ment funding and health insurance); and creating models for disburse- ment, supervision, and collaboration between hospitals and the country’s 4 This section is based on slides prepared for the workshop by Mingting Chen, National Center for Tuberculosis Control and Prevention of China, and presented by Gail Cassell, Visiting Professor, Harvard Medical School, and Vice President of TB Drug Discovery, Infectious Disease Research Institute.

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41 THE GLOBAL BURDEN OF DRUG-RESISTANT TB Center for Disease Control. Progress on MDR TB control constitutes a major national science and technology project and includes operational, biological, and epidemiological research. Technical preparation includes the development and issuance of guidelines for MDR TB chemotherapy and for infection control. The National Action Plan in China calls for reducing the number of MDR TB cases through both prevention and control. The prevention plan includes consolidation and enhancement of the strategy for DOTS imple- mentation, increased accessibility and equalization of general TB control services, the production of quality-assured anti-TB drugs, standardized use and management of the drugs, and reinforced infection control measures. The control plan includes guaranteeing complementary government funding of the Global Fund project and further exploring and expanding the Gates MDR TB project. Finally, China is strengthening its laboratory capacity to fulfill its National Development Plan, to implement accreditation, to establish regional reference laboratories, and to strengthen training and increase cadres of eligible staff. China also is expanding culture capacity at the county level and DST capacity at the prefecture level and introducing new diagnostics at multiple levels. HISTORICAL PERSPECTIVE ON TB AND MDR TB CONTROL EFFORTS The slow pace of treatment scale-up across the globe has affected MDR TB for decades, Keshavjee observed. However, the reversal of a TB epidemic in New York City in the late 1980s and early 1990s illustrates what can be done with resources, leadership, political will, and the implementation of well-designed public health programs. Fueled by poverty, homelessness, AIDS and other diseases, and the erosion of the city’s public health infra- structure, 4,000 cases of TB were reported in 1991—a 152 percent increase over 1980 (IOM, 2011b). The New York City Health Commissioner at the time, Margaret Hamburg, drew upon the strong political will of the mayor and others to gather resources and mobilize a comprehensive response to the resurgence of TB in the city. The city increased the number of patients receiving DOT and increased screening, monitoring, and isolation capacity in hospitals, shelters, and other congregate settings. These efforts effectively turned the epidemic around—TB cases in the city dropped by almost 46 percent and drug-resistant cases by 86 percent between 1992 and 1997 (IOM, 2011b). In 1995, a report called further attention to the TB epidemic in New York City and the steps completed to combat the problem success- fully (Frieden et al., 1995). On the global stage, however, a report from WHO (1996) stated that

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42 DRUG-RESISTANT TUBERCULOSIS IN INDIA “MDR TB is too expensive to treat in poor countries; it detracts atten- tion and resources from treating drug-susceptible cases.” Moreover, WHO indicated that DOTS alone would be able to bring drug resistance under control. This position was based on the mistaken notion that drug-resistant strains were less fit and would eventually disappear if short-course chemo- therapy was administered effectively, Keshavjee noted. In August 1996, Partners In Health and Harvard Medical School, together with the Peruvian National TB Program, initiated a large-scale, community-based program to combat drug-resistant TB in the Northern Cone of Lima—the first program of its kind in any poor country. At the time, Lima had a strong DOTS program, but treatment approaches over- all were weak. Physicians were prescribing drugs outside the system, and drug resistance was running at 2.5 to 3 percent, according to Keshavjee. Resistance was concentrated among poor people and in slums, where it was difficult to deliver care and where access to second-line drugs was limited. Working with the government, Partners In Health purchased the necessary drugs and mobilized community health workers (CHWs) to deliver care, demonstrating that community-based delivery of MDR TB treatment is feasible in resource-limited settings. It took another decade, until 2006, for WHO to adopt this model and incorporate it into the WHO TB guidelines. There was a lag of about 15 years or more between when it was known that MDR TB could be treated and when its treatment even in resource-limited areas became global policy. As a result, there was during that period very little investment in labora- tory infrastructure and in the comprehensive delivery systems required to treat patients. The good news, said Keshavjee, is that in 2009 the World Health Assembly approved a resolution urging all member states to “achieve uni- versal access to diagnosis and treatment of multidrug-resistant and exten- sively drug-resistant tuberculosis as part of the transition to universal health coverage, thereby saving lives and protecting communities” (WHA, 2009). The resolution also called for: a comprehensive framework for management and care of multidrug- resistant and extensively drug-resistant tuberculosis that includes DOT, community-based and patient-centered care, and which identifies and ad- dresses the needs of persons living with HIV, the poor and other vulnerable groups, such as prisoners, mineworkers, migrants, drug users, and alcohol dependants, as well as the underlying social determinants of tuberculosis and multidrug-resistant and extensively drug-resistant tuberculosis. Policies have finally changed, said Keshavjee, but for more than a decade, untreated patients were infecting other patients. “By leaving this

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43 THE GLOBAL BURDEN OF DRUG-RESISTANT TB disease untreated for that decade plus, untold amounts of damage have happened globally, and now we are in a real quagmire,” he said. GLOBAL CHALLENGES AND POTENTIAL SOLUTIONS5 Keshavjee discussed several global challenges faced in addressing drug- resistant TB: inadequate diagnostic capacity, an inadequate drug supply, inadequate capacity to deliver care, and inadequate international assistance. Inadequate Diagnostic Capacity To diagnose MDR TB, rapid culture testing and DST are essential, Keshavjee stressed. Today, liquid bacterial culture can provide results in about 2 weeks, while molecular tests can provide results in 2 hours to 2 days. Both types of tests have limitations: liquid and culture tests require extensive laboratory infrastructure, while molecular tests can be limited because they are designed to look only for the presence of specific genes. However, suggested Keshavjee, molecular tests are “a step in the right direc- tion.” One of the newest testing technologies, GeneXpert, may require less extensive infrastructure, but time will tell whether that is in fact the case. A major need, even with GeneXpert, is a test that works with children and people with HIV, said Keshavjee. Both represent large proportions of people with TB, but TB can be difficult to diagnose in these patients, and they are at the highest risk of death. There also has been little movement toward true rapid point-of-care diagnostics that would enable people to be diagnosed by their care provider and begin treatment immediately after testing. India and other countries are demonstrating how testing capacity can be built. Keshavjee cited the example of Lesotho in southern Africa, where the rate of TB is about 600 per 100,000 population, about 1,000 new MDR TB cases occur per year, and a quarter of the population is HIV-positive (Paramasivan et al., 2010). Between 2006 and 2008, with support from FIND, basic laboratories that performed only smear testing were converted at a cost of less than $500,000 into laboratories that could perform rapid liquid culture testing (Paramasivan et al., 2010). More recently, laboratories in Lesotho have been able to perform molecular testing, patients can receive results in less than 2 hours, and the general approach is being implemented in many other countries through the Expanding Access to New Diagnostics for TB (EXPAND-TB) program. “The Lesotho example demonstrates what 5 This section is based on the presentation of Salmaan Keshavjee, Assistant Professor, Harvard Medical School.

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44 DRUG-RESISTANT TUBERCULOSIS IN INDIA can be done in resource-limited settings with a little bit of money and a good plan,” said Keshavjee. Inadequate Drug Supply The second major challenge after inadequate diagnostic capacity is an inadequate drug supply. The creation of the DOTS-Plus program raised the question of how patients would receive needed drugs, given their expense and unavailability in many countries. In response, Jim Kim and colleagues at Partners In Health and Harvard Medical School created the GLC, together with key stakeholders such as Médecins Sans Frontières, KNCV Tuberculosis Foundation, IUATLD, CDC, and WHO. The GLC has a threefold mandate: (1) ensure access to quality-assured second-line TB drugs at affordable prices, (2) monitor and evaluate the use of second-line drugs in approved projects, and (3) promote technical assistance for MDR TB programs in keeping with WHO guidelines. The work done by the GLC had “amazing” results, according to Keshavjee, in terms of reducing the prices of second-line TB drugs neces- sary to treat MDR TB. Between 1997 and 2000, prices for second-line drugs declined by 84 to 98 percent (Table 3-2) as a result of negotiations based on GLC plans for pooled procurement of drugs. Although drug prices remain high in some places, they were much higher before the GLC existed. Despite the success in reducing prices for some drugs, the number of manufacturers of quality-assured second-line drugs remains inadequate, Keshavjee noted. Procurement is not pooled, eliminating the downward pressure on prices that pooled procurement would produce. The market has been opaque, with insufficient forecasting to provide assurance about future markets. Prices remain very high for some drugs, and delivery delays can be severe. The system for providing drugs remains centralized, and countries prefer to do business with local manufacturers. TABLE 3-2 Reduced Prices of Second-Line TB Drugs (1997–2000) 1997 Price 2000 Price Drug Formulation (USD) (USD) % Decline Amikacin 1 gm vial 9.00 0.90 90 Cycloserine 250 mg tab 3.99 0.50 87 Ethionamide 250 mg tab 0.90 0.14 84 Kanamycin 1 gm vial 2.50 0.39 84 Capreomycin 1 gm vial 29.90 0.90 97 Ofloxacin 200 mg tab 2.00 0.05 98 SOURCE: Keshavjee, 2011a.

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45 THE GLOBAL BURDEN OF DRUG-RESISTANT TB TABLE 3-3 Prices for Green Light Committee-Approved Drugs Price in July 2001 Price in March 2011 % Difference Drug (USD) (USD) (lowest price) 2001–2011 Amikacin 500 mg 0.11 1.20 +991 Kanamycin 1 g 0.36 2.58 +617 Cycloserine 250 mg 0.14 0.59 +321 Capreomycin 1 g 1.02 4.00 +292 Ethionamide 250 mg 0.10 0.09 Stable Prothionamide 250 mg 0.10 0.10 Stable P-aminosalicylic acid 1.51 1.57 Stable (PAS) 4 g sachet SOURCE: Médecins Sans Frontières (MSF) and the International Union Against Tuberculosis and Lung Disease (The Union). 2011. DR-TB Drugs Under the Microscope: Sources and Prices for Drug-Resistant Tuberculosis Medicines. http://www.msfaccess.org/content/dr-tb- drugs-under-microscope (accessed November 16, 2011). This table has been adapted from the original table in the report. Furthermore, although competition would typically lower prices and allow affordable access to medical technologies, second-line anti-TB drugs have been an exception. “The more we have bought, the higher the price has gone,” Keshavjee said. The standard 18- to 24-month treatment course for MDR TB, using drugs procured through the GLC, costs between $4,400 and $9,000 per patient (MSF and IUATLD, 2011). Prices for some drugs rose substantially between 2001 and 2011 (Table 3-3), with little economic explanation for the rise, according to Keshavjee. New mechanisms for providing access to drugs need to be explored, and new drugs now being developed could help. At the same time, however, getting both old and new drugs to patients remains a major problem (see Chapter 8 for a discussion of the supply chain for second-line MDR TB drugs). Inadequate Capacity to Deliver Care Many countries lack the systems needed to deliver care to patients and to manage adverse events over the 2-year period of treatment. In addition, said Keshavjee, systems are needed to help countries rapidly scale up their care delivery capacity. Infection control also must be made a priority in all treatment settings, even in areas with a weak health care system. People working in health facilities need respirators, and the facilities need proper ventilation when they contain inpatients. Most countries with many TB patients lack sufficient hospital beds, so patients must be treated outside the hospital. This can be an advantage, said Keshavjee, in that ambulatory care costs less, freeing resources to treat

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46 DRUG-RESISTANT TUBERCULOSIS IN INDIA more patients. Moreover, it is safer if patients are not concentrated in small spaces (such as hospital wards) where drug-resistant TB can spread. Community-based treatment also is preferable for TB patients, includ- ing MDR TB patients, who live away from major cities. Such patients gen- erally cannot travel regularly to a distant facility for treatment, so trained CHWs must go to patients’ houses to treat them. Treating all patients wherever they are is the most effective way to change the dynamics of the epidemic, suggested Keshavjee. Inadequate International Assistance Many countries need help to bridge the gap between current capabili- ties and what is needed, yet international technical assistance is inadequate, Keshavjee emphasized. Successful regional MDR TB treatment programs have shown what can be done with on-site long-term technical assistance and, where necessary, on-site implementation teams. Such teams may be provided for countries, or countries may create their own teams. Most countries that face problems with drug-resistant TB are relatively poor, with a large proportion of their populations living on less than $2 a day. As K. Srinath Reddy, Public Health Foundation of India, observed in his keynote address (Chapter 1), it is difficult or impossible to institute a strong anti-TB program within a weak health system. Today, a growing number of sites and countries have had experience with helping others scale up anti-TB programs. These centers of excellence can act as hubs for implementation by providing in-country support teams and helping other countries scale up. The alternative to strong action is clear, said Keshavjee. For example, in parts of the former Soviet Union where he has worked, more than 25 percent of all TB patients have MDR TB, and XDR TB remains a grow- ing threat. The global approach being taken today remains hampered by constrained structures and a lack of innovative thinking. Engagement with key partners, such as PEPFAR, UNICEF (United Nations Children’s Fund), UNDP (United Nations Development Program), and others, has been lack- ing, and a focus on implementation, the involvement of the private sector, and advocacy in countries have been limited. POTENTIAL INNOVATIONS AND ACTION ITEMS Through the presentations provided in this session and the subsequent discussions, individual workshop speakers and participants noted key inno- vations and action items. They include the following:

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47 THE GLOBAL BURDEN OF DRUG-RESISTANT TB • Community-based treatment is often preferable to improve the efficiency and effectiveness of treatment, and it benefits TB patients who live away from major cities. • A comprehensive framework for management and care of MDR and XDR TB would improve the effectiveness and efficiency of treatment. A comprehensive framework would also include vulner- able populations. • On-site long-term technical assistance and on-site implementation teams from within a given country or drawn from regional and international expertise can improve MDR TB treatment programs.

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