Addressing the Threat of Drug-Resistant Tuberculosis A Realistic Assessment of the Challenge: Workshop Summary (2009) / Chapter Skim
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Appendix C: Partners In Health White Paper - Stemming the Tide of Multidrug-Resistant Tuberculosis: Major Barriers to Addressing the Growing Epidemic
Appendix C: Partners In Health White Paper - Stemming the Tide of Multidrug-Resistant Tuberculosis: Major Barriers to Addressing the Growing Epidemic
Pages 139-236
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Appendix C Partners In Health White Paper -- Stemming the Tide of MultidrugResistant Tuberculosis: Major Barriers to Addressing the Growing Epidemic
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STEMMING THE TIDE OF MULTIDRUG-RESISTANT TUBERCULOSIS: MAJOR BARRIERS TO ADDRESSING THE GROWING EPIDEMIC A WHITE PAPER FOR THE INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES HARVARD MEDICAL SCHOOL PARTNERS IN HEALTH FRANÇOIS–XAVIER BAGNOUD CENTER FOR HEALTH AND HUMAN RIGHTS BRIGHAM AND WOMEN'S HOSPITAL November 2008 j 1
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THREAT OF DRug-RESISTANT TubERCulOSIS AUTHORS Lead Authors Salmaan Keshavjee Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital/ Partners In Health Kwonjune Seung Division of Global Health Equity, Brigham and Women's Hospital/ Partners In Health Contributing Authors Rajesh Gupta Stanford University School of Medicine Tom Nicholson Partners In Health Julie Rosenberg Talbot Division of Global Health Equity, Brigham and Women's Hospital Chris Vanderwarker University of Washington Paul Zintl Partners In Health/ Department of Global Health and Social Medicine, Harvard Medical School Other Contributors: Mercedes Becerra Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital Paul Farmer Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital/ Partners In Health Jennifer Furin Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital/ Partners In Health Stephen Hallisey Department of Global Health Equity, Brigham and Women's Hospital j i
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APPENDIx C Amy Judd Division of Global Health Equity, Brigham and Women's Hospital Kathryn Kempton Partners In Health David Kim Division of Global Health Equity, Brigham and Women's Hospital Jim Yong Kim Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital/ Harvard School of Public Health/ François–Xavier Bagnoud Center For Health And Human Rights/ Partners In Health Carole Mitnick Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital Joia Mukherjee Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital/ Partners In Health Edward Nardell Harvard School of Public Health/ Division of Global Health Equity, Brigham and Women's Hospital Catherine Oettinger Partners In Health Sonya Shin Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital Valerie Varco Division of Global Health Equity, Brigham and Women's Hospital Rebecca Weintraub Department of Global Health and Social Medicine, Harvard Medical School/ Division of Global Health Equity, Brigham and Women's Hospital In-depth Interviews Shalala Akhmedova Coordinator, International Committee of Red Cross (Azerbaijan) Peter Cegielski Unites States Centers for Disease Control and Prevention Agnes Gebhard KNCV Tuberculosis Foundation j ii
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Moses Joloba National Tuberculosis Program, Uganda Fabienne Jouberton Global Fund to fight AIDS, Tuberculosis and Malaria Robert Matiru Global Drug Facility, STOP TB Partnership Fuad Mirzayev World Health Organization Pierre-Yves Norval World Health Organization Madhukar Pai McGill University C
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APPENDIx C Tamara Russell Eli Lilly Global Manufacturing Nina Schwalbe Global Alliance for Vaccines and Immunization Alex Sloutsky Massachusetts State Laboratory Institute/University of Massachusetts Thelma Tupasi Tropical Disease Foundation, the Philippines Karin Weyer World Health Organization Abigail Wright World Health Organization Acknowledgement of Support Jaime Bayona Socios En Salud Ernesto Jaramillo World Health Organization Kitty Lambregts KNCV Tuberculosis Foundation Oksana Ponomarenko Partners In Health, Russia Mario Raviglione World Health Organization Peter Stephens IMS Health The authors would like to thank the many other colleagues who participated in numerous discussions on the topics covered in this document over the last year. The views expressed in this document are solely those of the authors and are not meant to represent the position of any individual who was interviewed or gave support to this project, nor the Institute of Medicine, Harvard Medical School, Partners In Health, the François-Xavier Bagnoud Center for Health Human Rights or Brigham and Women's Hospital.
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11 1.2 Expanding Laboratory Capacity ................................................................................................ 12 2 The Anatomy of a Laboratory Network.........................................................................................
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49 4.2 Available drug supply through GLC initiative .......................................................................... 51 4.3 Incentives and disincentives for entry into the second-line anti-TB drug market .....................
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3. Ambiguous messaging about the importance of integration of MDR-TB into national tuberculosis control programs, perpetuated by a "pilot-program" mentality that has not been encouraging a push for universal access.
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This paper provides several recommendations to facilitate the expansion of global treatment and prevention of multidrug-resistant tuberculosis. These include: promoting universal access to treatment as part of national tuberculosis control programs; improving and expanding laboratory capacity, including rapid point-of-service testing; reforming the current procurement system to ensure an adequate and accessible supply of quality-assured second-line drugs; providing ongoing, on-site technical assistance; and expanding the delivery of ambulatory-based MDR-TB treatment.
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Increased TB clinical trial capacity needs to be created, and mechanisms developed to fast track new anti-TB drugs through the regulatory process. 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, non-governmental organizations, and within countries.
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TB that is resistant to at least two of the best anti-TB drugs, isoniazid and rifampicin. These drugs are considered first-line drugs and are used to treat all persons with TB disease.
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Developed by the British Medical Research Council (MRC) and the International Union Against Tuberculosis and Lung Disease (IUATLD)
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A recent nosocomial outbreak of XDR-TB among HIV-positive patients in South Africa resulted in a case fatality rate of almost 100 percent.51 According to the World Health Organization, there are an estimated 40,000 cases of XDR-TB each year, half of whom die in short-order.
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In 2000, to reassure those critics, the WHO and its partners established a multi-agency task force called the Green Light Committee (GLC) Housed at the WHO headquarters in Geneva, the GLC was assigned to improve access for programs to concessionary-priced second-line anti-TB drugs, while promoting the rational use of these drugs through appropriate programmatic management.57 The initial five projects approved by the GLC became known as DOTS-Plus pilot projects, and provided essential information for the development of the WHO's global drug-resistant TB guidelines (Guidelines For The Programmatic Management Of Drug-Resistant Tuberculosis)
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. Figure 2: GLC Projects and Patients as of August 2008 GLC Projects and Patients 42,000 patients approved; 45000 120 114 projects 40000 100 35000 30000 80 Number of Patients 25000 Cumulative Total 60 Cumulative Projects 20000 15000 40 10000 20 5000 0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year of Approval Alarmed over the surprising prevalence and growth of XDR-TB, policymakers from the WHO, key international partners, and affected countries met in the fall of 2006 to agree on a global strategy to combat MDR-TB and XDR-TB.
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Rather, we aim to highlight and analyze the common difficulties that confront healthcare policymakers in resource-poor settings as they attempt to integrate MDR-TB treatment into their own national TB-control strategies and as they seek to expand treatment to all afflicted patients 2 A GENERAL FRAMEWORK FOR UNDERSTANDING BARRIERS TO MDR-TB SCALE-UP Care delivery consists of myriad inter-connected activities. The care-delivery value chain (CDVC)
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The authors believe that by focusing on these three areas healthcare providers and policymakers stand the best chance of attaining universal access to drug-resistant TB treatment and care for patients with MDR-TB.
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Therefore, although sputum smear microscopy remains a vital service,77 it does not provide the information required to reliably diagnose TB, identify drug-resistant cases, or monitor resistance in settings with high tuberculosis drug-resistance. The success of the global response to drug-resistant tuberculosis hinges on the ability of the healthcare system to find and manage MDR- and XDR-TB cases.
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Observers have concluded that dramatic improvements in baseline capacity are necessary to meet anticipated surveillance and treatment targets.81,82,83,84,85 In 2005, the World Health Assembly passed a resolution requesting the Director General "to implement and strengthen strategies for the effective control of, and management of persons with, drug-resistant tuberculosis." The 2006 Global Plan to Stop TB stresses the importance of laboratory services, stating that "every country should have a well-resourced and fully functioning national reference laboratory."86 The MDR-TB working group identified culture and DST services as indispensable components of the TB control effort."87 The WHO Global Taskforce on XDR-TB echoed these recommendations in The Global MDR-TB and XDR-TB Response Plan. The plan called attention to three core priorities for TB laboratory infrastructure: accelerating access to laboratory services, improving infection control, and expanding surveillance.88,89 Smear microscopy is still the foundation for TB control, but a broad consensus among public health officials now supports increased use of culture and DST services.90,91 Page 12 of 88
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, are not yet widely available; the scale of the XDR-TB problem globally is not yet known." 92 To address this problem, the World Health Organization's Stop TB Department created the Global Laboratory Initiative (GLI) , whose mandate is laboratory capacity development and coordination.
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services Sputum smear Culture DST thousands number per 100000 number per 5 million number per 10 of labs pop of labs pop of labs million pop 0.03 0.07 1 India 1,151,751 Y 11,968 1.0 8 8 1.4 2.7 2 China 1,320,864 Y 3,010 0.2 360 90 0.9 1.8 3 Indonesia 228,864 N 4,855 2.1 41 11 4 South Africa 48,282 Y 143 0.3 13 1.3 8 2.7 0.0 0.0 5 Nigeria 144,720 N 694 0.5 0 0 0.1 0.2 6 Bangladesh 155,991 Y 687 0.4 3 0 7 Ethiopia 81,021 Y 713 0.9 1 0.1 1 0.1 0.1 0.2 8 Pakistan 160,943 N 982 0.6 3 1 0.2 0.3 9 Philippines 86,264 Y 2,374 2.8 3 3 10 DR Congo 60,644 Y 1,069 1.8 1 0.1 1 0.2 Russian 34 68 11 143,221 N 4,953 3.5 978 302 Federation 12 Viet Nam 86,206 Y 874 1.0 18 1.0 2 2.1 13 Kenya 36,553 Y 770 2.1 2 0.3 2 0.5 14 UR Tanzania 39,459 Y 690 1.7 3 0.4 1 0.8 15 Uganda 29,899 Y 726 2.4 3 0.5 2 1.0 5.1 10 16 Brazil 189,323 Y 4,044 2.1 193 38 17 Mozambique 20,971 Y 250 1.2 1 0.2 1 0.5 18 Thailand 63,444 Y 937 1.5 65 5.1 18 10 19 Myanmar 48,379 Y 391 0.8 2 0.2 1 0.4 20 Zimbabwe 13,228 Y 180 1.4 1 0.4 1 0.8 21 Cambodia 14,197 Y 186 1.3 3 1.1 1 2.1 22 Afghanistan 26,088 N 500 1.9 1 0.2 1 0.4 Source: Global Laboratory Initiative, Stop TB Department, World Health Organization 2 THE ANATOMY OF A LABORATORY NETWORK 2.1 TB laboratory networks A laboratory network coordinates the shipment of specimens from peripheral sites to central laboratories, and provides for the reporting of results. Though commonplace in the developed world, such networks are relatively new to developing nations, which in the past have relied on simpler, on-site testing.
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. Level III Labs: These national reference laboratories provide services, such as culture and DST, which are appropriate for a referral facility.
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Any program that seeks to accredit and utilize third-party laboratories -- as will soon be the case in the Philippines as the move toward universal access to MDR-TB treatment -- will need to ensure quality levels, equitable access, and close coordination with the public network established by the country's National TB Reference Laboratory. 2.3 Drug resistance surveillance (DRS)
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is a centrally coordinated laboratory system created to manage the diagnostic needs of the global eradication campaign. Seven supra-national reference laboratories, 15 regional laboratories, and 123 national laboratories operate the polio surveillance safety net.
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Nevertheless, the general systems developed to monitor polio -- including the establishment of laboratories as centers of excellence, the sharing of capacity and funding, and the coordination of activities -- can certainly inform the development of MDR-TB laboratory services at the local, regional and global levels. 2.4 Capacity gap One proxy for laboratory capacity is total laboratory volume reported compared against total estimated need.
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Measuring the strength of laboratory networks is a sufficiently complex task that different agencies have come up with widely divergent estimates of capacity. For example, FIND came up with a culture-laboratory density figure three times higher than the one arrived at by WHO's 2007 report (Global Tuberculosis Control 2008: Surveillance, Planning, Financing)
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They then formed teams of engineers and architects to improve individual laboratories. 1 The international team originally consisted of the Massachusetts State Laboratory Institute, Partners In Health, the Peruvian National Tuberculosis Program, the Peruvian National Reference Laboratory (NRL)
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standards established in 1993, which suggest that initial DST results be reported within 30 days. Thanks to a collaborative approach, external technical assistance and funding, from 1996 to 2007, the NRL expanded laboratory capacity and quality in culture, first-line DST (by BACTEC 460)
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This requires integration of laboratory services that goes beyond mycobacteriology, and in many settings, requires substantial strengthening of health systems. 3.2 Laboratory technical assistance Increasing laboratory capacity rapidly requires the input of experienced (senior)
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How such a system is orchestrated is critical to its success. Possible structures range from a centrally administered program at a multilateral institution to a completely decentralized system based at regional supra-national reference laboratories or at regional MDR-TB technical assistance centers.
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Discussions with the 10-year laboratory capacity building project in Peru noted that the greatest impediment to improving the speed of laboratory improvements was the lack of a dedicated, on-site, external (to the laboratory) , experienced, technical assistance provider that could work with laboratory management (e.g.
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Significant debate still exists about what level of accreditation and pre-service training is adequate for laboratory operations and how government hiring regulations should be adapted123 3.3.3 Biosafety personnel Another critical barrier to expanding laboratory capacity is the physical plant to support culture and DST services in the setting of an airborne infectious disease with high mortality. Rehabilitation or construction of new facilities demands scarce resources beyond mere financing, including advanced engineering and construction skills.
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To be successful, laboratory business plans focusing on maximizing network function need to be financed and encouraged. Laboratory services start at the point-of-care where a treatment team decides to request services, guided by indications for testing.
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As laboratories expand to networks and samples and data move geographically the complexity expands. Many commercial culture systems and DST allow for easy digital documentation, but getting electronic results to the local clinical information systems and central data repositories at the national reference lab is significantly challenged by highly variable resource levels.
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For instance, laboratories in Botswana had little trouble accessing talent from South Africa to build their reference laboratories but had more trouble maintaining the facility -- both getting the right people and ensuring the political support to fund the activities. As a result of these difficulties, it is no surprise that the availability of external quality assurance among high burden/high priority countries is still quite variable.
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SOP and quality assurance mechanisms were firmly embedded as staff training continued. The South African Medical Research Council (SAMRC)
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6. Local conditions create vastly different solutions – flexibility is paramount: In Lesotho centralized laboratory services was the preferred approach because of the geographic considerations and estimated volumes.
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This is not the only requirement -- others, as discussed above, include sufficient staffing, funding, and infrastructure -- but it is one that has repeatedly emerged from our discussions with sites that have undertaken capacity building. In order to facilitate long-term sustainability, any technical assistance has to involve laboratory management, training-of-trainers, and partnership with national TB programs.
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For patients with drug-resistant tuberculosis disease, the problem is exacerbated by the fact that simply diagnosing tuberculosis is not enough; the drug-resistant phenotype has to also be identified. It is toward addressing this problem that the GLI and FIND have been working to scale-up the ability for countries to rapidly test for drug resistance using rapid molecular tests (e.g.
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Ad hoc indications for testing, transport of specimens to central laboratories, and poor data management have been longstanding barriers to successful treatment programs. Country level resources and action plans targeting referral networks and data management, the processes of getting samples in and data out, are essential to expanding laboratory capacity.
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Current approaches to laboratory capacity-building are aimed at ensuring that existing diagnostics are available to countries. Efforts need to be expanded on the development of rapid point-of-care testing for TB as a means of ensuring timely and accurate diagnosis of TB and drug-resistant TB.
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to address the XDR-TB emergency and to foster effective communication with all relevant institutions and organizations. 2 THE GLC INITIATIVE: ACTORS AND RESPONSIBILITIES 2.1 The Green Light Committee (GLC)
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, International Union Against Tuberculosis and Lung Disease (Paris, France) , KNCV Tuberculosis Foundation (Den Haag, Netherlands)
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The GLC is responsible for ensuring that GLC-approved projects use only quality-assured drugs and deliver these drugs under optimal program conditions as described in WHO's Guidelines for the programmatic management of drug-resistant tuberculosis. The procurement of these drugs is the responsibility of the GDF and its contracted procurement agent -- currently the International Dispensary Association (IDA)
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The procurement agent is responsible for overseeing second-line drug purchases, identifying potential suppliers for each medication, and soliciting agreements with the manufacturers for reduced prices for GLC-approved projects. Such agreements may include the establishment of a maximum quantity or volume of reduced-price drugs.
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. Although the WHO Prequalification Program has approved a large number of drugs for HIV/AIDS, it has approved many fewer anti-TB medications and only two second-line anti-TB drugs (cycloserine and ethionamide, both from Macleods Pharmaceuticals Ltd of India)
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They found early on that they were unable to budget properly for medications because the prices offered through the GLC mechanism varied by year for each individual drug, especially ofloxacin, cycloserine, and capreomycin (see Figure 5 and Figure 6)
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In 2007, they began ordering second-line medications directly from the GDF's procurement agent, IDA. They calculated the average time between placing an order directly with IDA and receiving the drugs in the country (see Figure 8)
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It holds a monopoly on all GLC procurement, which interferes with legal requirements in some countries that all purchasing be open to transparent tender. As there are increasingly more GLC projects and patients, the GLC and the GDF are likely to find it increasingly difficult to maintain their insistence on a single procurement agent for projects around the world.
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With financial support from The Bill & Melinda Gates Foundation, the Prequalification Program has recently added professional staff, but it will be a challenge for this approval process to keep up with the rapidly increasing demand for second-line drugs in projects approved by the GLC. Second-line drugs are widely available in MDR-TB-priority countries and only a small proportion of these drugs are quality-assured.
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Although the authors stress the difficulty of accurately estimating second-line drug sales in Russia and China, the combined total for these two countries of more than $75 million represents roughly 8 to 10 times the value of quality-assured drugs sold to GLC projects in 2007. It will take a concerted effort by international partners and national regulatory authorities in large, high-MDR-TB-burden countries to facilitate and increasingly insist upon quality-assured products.
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700,000 650,000 600,000 550,000 500,000 450,000 MDR-TB number 400,000 350,000 300,000 250,000 200,000 150,000 100,000 50,000 0 To t a l C h in a + In d ia + C h in a In d ia R u s s ia n R u s s ia n F e d e ra t io n F e d e ra t io n Source: WHO 2003 Significant improvements in the economy of the Russian Federation in recent years have resulted in its reassignment as an upper-middle-income country by the World Bank. This designation preceded the announcement by World Bank president Robert Zoellick in October 2007 that Russia had changed its World Bank status from that of borrower to donor, effective immediately.
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GLC approval was required for the disbursement of both grants, as mandated by the GFATM grant agreements. In 2006, the Russian Federation changed the requirements for the importation of pharmaceutical products, primarily in the sphere of registration procedures.
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, as well as higher drug ceilings for importation as permitted by the Russian Federation's Humanitarian commission, could have allowed for projects to establish buffer stocks at their projects to prepare for potential cases of prolonged procedural or legal obstacles to the importation of GLC-approved second-line drugs. Because the government of the Russian Federation has not designated the MDR-TB crisis as an "emergency situation," fast-track importation of second-line medications has not been possible.
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4 DRUG SUPPLY AND ENGAGEMENT OF DRUG MANUFACTURERS IN MDR-TB RESPONSE 4.1 MDR-TB projects working outside the GLC initiative As described above, a large global proportion of patients receiving MDR-TB treatment do so outside of the GLC mechanism. Countries reported to the WHO that they treated an estimated 36.4 thousand patients outside of the GLC system in 2007 and that they will similarly treat 34.7 thousand patients in 2008.
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APPENDIx C Strict purchasing regulations apply in Brazil, resulting in a TB system that only utilizes the international drug market as a last resort, after all public and private domestic options have been exhausted. In 2007, the Brazilian TB community commissioned quality screening for dozens of samples of state produced anti-MDR-TB medications.
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PASER 4 gram granules 30 $59.10 $1.97 Jacobus Pharma NO sachet Company Ltd. Prothionamide 250 mg tablet 100 $16.00 $0.16 Fatol Arzneimitel NO Moxifloxacin154 400 mg tablet 1 $5.93 $5.93 Bayer NO Pharmaceuticals Source: Stop TB155 3 Moxifloxacin, which has been recommended in the 2008 version of the WHO guidelines for the programmatic management of drug-resistant tuberculosis as a newer-generation fluoroquinolone for use in certain groups of patients, is still protected by patent in some countries until 2011.
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, which predicts stable, reliable forecasting for manufacturers through the GLC initiative, proves to be the least true of the four advantages over the past seven years; only now are more sophisticated forecasting systems being designed at the GDF to strengthen the existing ad hoc ordering system inherited from the early days of the GLC initiative.157 Many manufacturers of anti-MDR-TB drugs based outside of North America and Western Europe have not been overly eager to participate in the GLC Initiative, as they have existing, often lucrative contracts with their national TB programs. It is fair to assume that some of these manufacturers are not subject to quality control or quality assurance at the level required for prequalification by the WHO.
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For this reason, expansion of the number of patients treated under the aegis of the GLC initiative and expansion of the GDF buffer stock to 5000 patients are particularly important to convince manufacturers to stay in the market. As discussed earlier, another disincentive to participating in the GLC Imitative and WHO Prequalification is that some countries (e.g.
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. Very recently, demand was also bolstered by UNITAID financing for a buffer stock of second-line drugs for up to 5,000 patients, to be purchased by the GDF.
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points out, "for the first time in 30 years, several new drug classes that hold promise for MDR-TB treatment are under development," and "the expansion of MDR-TB treatment programs provides the settings in which trials can be implemented… Four elements are needed to make MDR-TB treatment trials a reality: money; additional work on the drug pipeline; rigorous, interdisciplinary preclinical work on individual agents and regimens; and an understanding that TB clinical trials need not be a zero–sum endeavor."164 Aside from the availability of sites for clinical trials, a debate is currently underway regarding the cost and likelihood of development of major new TB therapies. Glickman et al.
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The GLC initiative/GDF and WHO Prequalification could assure that its capacity to provide second-line anti-TB drugs to participating projects are increased by assisting manufacturers through the process early on in return for agreements of supply at a reduced price for some period of time after approval. 4.6 Manufacturers in high-burden countries There are reasons to expect that manufacturers of second-line drugs in high-burden countries may become more amenable to GLC involvement in the future.
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and is assuming Lilly's share of cycloserine production for the GLC initiative. Its production of cycloserine had been approved by South Africa's regulatory body, Medicines Control Council (MCC)
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The GFATM and UNITAID will certainly continue to insist that their grant funds be used only for the purchase of second-line drugs that are quality-assu red, but they are not likely to long maintain their requirement that recipients use a single procurement agent, especially if the procurement agent is unable to procure and deliver the second-line drugs in a timely and consistent manner over an extended period of time. Through some modification in the way it operates, the GDF could strive to become the most attractive supplier of second-line drugs in the market -- on pricing and supply logistics -- becoming the option that GLC projects want to use.
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The GDF will retain access to information on all purchases of second-line drugs for GLC projects, can assist regional procurement agents in pooling purchases, and can increase the size of orders for projects as it fills its own UNITAID-funded buffer stock.
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In order to remain competitive and address some of the shortfalls in the current system, the GDF should increase the number of procurement agents available to countries participating in the GLC initiative. This would allow the system to take advantage of regional competencies such as knowledge of local manufacturers and understanding of national customs/regulatory rules.
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. The GDF has recently received funding from UNITAID for a 5,000-patient buffer stock of second-line drugs.
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Although early intervention with appropriate and aggressive second-line drug regimens can result in cure rates over 75 percent, MDR-TB diagnosis and treatment programs have not even begun to keep pace with the epidemic.177,178,179,180 At the country level, the growing problem of drug-resistance is unwelcome by most NTPs, many of which are still struggling to control drug-sensitive TB. Spurred by the rapid increase in MDR-TB and XDR-TB observed globally, programs are trying to come to terms with their drug-resistant TB epidemics.
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Initial pilot projects in Estonia, Latvia, Peru, the Philippines, and Tomsk (Russian Federation) were quite successful and yielded cure rates of 77 percent among new cases of MDR-TB and 69 percent among previously treated cases of MDR-TB patients.195,196,197,198 Recent data suggest that the MDR-TB epidemics in Estonia and Latvia -- both of whose pilot projects offered universal access to MDR-TB treatment -- might in fact be leveling off.199 The WHO's Global Plan to Stop TB: 2006-2015 established a set of treatment targets for 2015, including the treatment of 800,000 patients with MDR-TB.200 With the XDR-TB outbreak in the Republic of South Africa in 2006, a two-year emergency plan called for an aggressive revision of the 2015 targets to include "universal access" by 2015 (equating to nearly 1.6 million patients)
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Because many countries lack the necessary infrastructure for MDR-TB treatment, nearly all projects are approved as part of a limited effort in a country -- a "GLC pilot project." The justification for pilot projects is that they allow clinical and programmatic experience to be gained and epidemiological data to be collected in preparation for scale-up of a larger, national program. While the reason for the pilot project approach is obvious -- to prevent the emergence of broad-spectrum anti-TB drug resistance resulting from poorly delivered MDR-TB care -- its most serious flaw is that it does not address the epidemiological reality of a rapidly spreading, airborne illness.
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This will require both a concerted effort on the part of the entire GLC initiative, the WHO, and international partners, innovative approaches to the provision of technical and material assistance, and in some cases, long-term on-site teams that can aid ministries of health with actual program implementation. 3 ADDRESSING THE MDR-TB TREATMENT IMPLEMENTATION GAP Countries as diverse as Azerbaijan, Peru, Latvia, and Lesotho all emphasize the important role that technical assistance played in the initial stages of their MDR-TB programs.
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While the GLC initiative has done its utmost to provide technical assistance to projects before and during MDR-TB treatment implementation, there is limited capacity to engage with projects with the depth of commitment required to fuel rapid scale-up. The GLC's mandate is to approve projects based on their applications and to provide guidance as to how they may improve their projects if needed.
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THREAT OF DRug-RESISTANT TubERCulOSIS Figure 12: MDR-TB patients scheduled to receive treatment in WHO/GLC-approved projects and non-GLC projects compared to the estimated number of patients who require treatment (1000s of patients; 2004 to 2006; Source: WHO 2008) 500 450 400 350 300 Estimated # of new cases 443.8 non-GLC 250 403.5 426.6 GLC 406.5 407.5 200 150 100 50 36.4 34.7 21.3 16.4 16.3 11.6 0 10.1 1.2 2.1 2.0 2004 2005 2006 2007 2008 Estimate Figure 13: The number of individuals receiving antiretroviral treatment in PEPFAR's 15 focus-countries202 Countries included: Botswana, Cote d'Ivoire, Ethiopia, Guyana, Haiti, Kenya, Mozambique, Namibia, Nigeria, Rwanda, South Africa, Tanzania, Uganda, Vietnam (added in 2004)
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the participation of global health initiatives, such as PEPFAR, in MDR-TB treatment expansion; and (4) the prioritization of MDR-TB treatment delivery (program implementation)
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Ambulatory care allows patients to integrate themselves into community and family life and rejoin the workforce. Many GLC-approved MDR-TB treatment programs have a strong ambulatory care component using trained community-based workers, and some of the most successful have initiated MDR-TB treatment on an outpatient basis in all but the most severely ill patients.
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At the time, the country also faced a shortage of TB medications, did not have a national reference laboratory, had limited managerial capacity, and no longer offered tuberculosis-treatment training previously mandated by the former Soviet Union. In 1994 TB prevalence in the prisons was almost 50 times the national rate and 24 percent of cases died.
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for funding to provide MDR-TB treatment nationally, building on the DOTS program. The first patients started the twoyear course of MDR-TB treatment in the prison system in April of 2007, close to the time a national reference laboratory was created.
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In Manila, Philippines, the Tropical Disease Foundation and the Philippines National Tuberculosis Program are working to provide private practitioners with training about MDR-TB and current treatment guidelines, are providing assistance with the provision of DOT and patient supports, and are registering and following patients who initiate therapy outside of the national system. They have also begun to enlist private laboratories in MDR-TB-treatment expansion through training and supervision and the provision of external quality assurance.
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Prisons have served as an "epidemiological pump" for transmitting resistant strains of TB.214 A similar phenomenon may be taking place in hospitals and clinics throughout the world, which are commonly crowded, poorly ventilated, and filled with highly-infectious TB patients. In one study performed at a large public hospital in Lima, Peru, 13 percent of the 250 patients admitted to the general medical ward had TB and 20 percent of those with TB had multi-drug resistance; 75 percent of MDR-TB patients had not been suspected of having TB at all when they entered the hospital.215 In a study of DOTS patients in Tomsk, Russia, hospitalization was found to be the greatest risk factor for the acquisition of MDR-TB.216 Similar findings have been noted elsewhere.217 The situation is exacerbated by the HIV epidemic in many countries and the increased risk of nosocomial transmission in health facilities.218 The XDR-TB epidemic in KwaZulu Natal, South Africa took place largely among HIV-infected patients who had been in congregate settings.219 Transmission control is possible in poor settings: an example from Lesotho 220 Lesotho is a mountainous country located entirely within the borders of South Africa, with a population of approximately two million people.
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. Guidance for renovation was obtained from an international infection control and engineering consultant working in South Africa.
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This is not an ideal transmission control program, since smear-negative TB patients are known to transmit and undiagnosed TB cases may be on the general medical ward, but it is a vast improvement over the chaotic conditions of hospitalization commonplace in many parts of the world. Implementation of such a program is not resource intensive and should be considered a minimum standard for transmission control in hospitals without the resources or expertise to do what Lesotho was able to do.
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Because of the high risk of TB infection in patients with HIV, TB control strategies have to be integrated with HIV treatment initiatives. 5.2 The system of international technical assistance provision is currently inadequate.
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The WHO, other multi-lateral and bilateral agencies, and international partners must increase the provision of technical assistance to strengthen transmission control, and ensure that it is a part of all funded projects. 5.5 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.
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Global surveillance for antituberculosis-drug resistance, 1994-1997. World Health Organization -- International Union against Tuberculosis and Lung Disease Working Group on antituberculosis drug resistance surveillane.
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The Russian equation: an evolving paradigm in tuberculosis control. Int J Tuberc Lung Dis 2000; 4 (Suppl 2)
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50 World Health Organization/International Union Against Tuberculosis and Lung Disease. Global Project on AntiTuberculosis Drug Resistance Surveillance.
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Tuberculosis Programs: Review, Planning, Technical Support. International Union Against Tuberculosis and Lung Disease: Paris, 1998.
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From page 229... ...
Barriers to reaching the targets for tuberculosis control: multidrug-resistant tuberculosis. Bull World Health Organ, 2007; 85(5)
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103 World Health Organization/International Union Against Tuberculosis and Lung Disease. Global Project on AntiTuberculosis Drug Resistance Surveillance.
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:392396. 135 World Health Organization/International Union Against Tuberculosis and Lung Disease.
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It was sponsored and organized by: Boston University School of Public Health, International Union Against TB & Lung Disease, KNCV Tuberculosis Foundation, MDR-TB Working Group of the Stop-TB Partnership, Médecins Sans Frontières, Partners In Health/Harvard Medical School, Potts Memorial Foundation, Treatment Action Group, World Health Organization. 168 Sun Q, Santoro MA, Meng Q, et al.
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Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampicin. Int J Tuberc Lung Dis 1998.
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Private doctors and tuberculosis control in India. Tubercle and Lung Disease.
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Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modeling study. Lancet, 2007.
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