Drug Resistant Tuberculosis in the South-East Asia Region

Status Report

December 2011

Drug Resistant Tuberculosis in the South-East Asia Region Magnitude of Multidrug-resistant TB in the Region In 2010, there was an estimated prevalence of 650,000 cases of multidrug-resistant TB (MDR-TB), and in 2008 it was estimated there were 150,000 MDR-TB deaths annually. While more people are being treated for MDR-TB in 2010. Although the absolute numbers of TB cases tested for drug resistance, diagnosed with MDR-TB and started on appropriate treatment remain low, they are increasing. The reported number of patients enrolled on treatment for MDR-TB reached 45, 553 in 2010, equivalent to 16% of the estimated 290,000 cases of MDR-TB among TB patients notified in 2010 (Ref: Global TB Report 2011) In the South-East Asia Region, well-functioning national TB control programmes achieving high cure rates has resulted in maintaining the slow but steady decline in TB incidence rates during the past decade. It is estimated that 88,000 cases of MDR-TB among notified cases of pulmonary TB in 2010 (Range: 68,000- 110,000). The notified case of MDR-TB is 4.3 among all notified cases of pulmonary TB in 2010. The number of MDR-TB cases enrolled for treatment is 3,937 in 2010. However, given the large numbers of TB cases, nearly one third of the worlds MDR-TB cases are in the SEA Region, with India estimated to have the highest number globally. Extensively drug resistant TB (XDR-TB) has also been reported from 5 countries in the Region. MDR-TB could potentially replace drugsusceptible TB, and constitutes a threat to global public health security. In areas of high HIV prevalence, the potential for increased transmission of MDR-TB, is high. The estimated MDR-TB cases and rates in SEAR Member Countries, 2010 is shown below in Table 1.
Table 1: Estimated MDR-TB cases and rates in SEAR Member Countries, 2010 Country Source of estimates model model model DRS,a 2005 DRS,a 2004 model DRS, 2007 DRS, 2007 DRS, 2006 DRS, 2006 model % MDR among new TB cases (95% CI) 2.2 (0.05.6) 2.2 (0.05.6) 2.2 (0.05.6) 2.3 (1.82.8) 2.0 (0.56.9) 2.2 (0.05.6) 4.2 (3.25.6) 2.9 (1.94.3) 0.2 (0.01.0) 1.7 (1.12.6) 2.2 (0.05.6) % MDR among previously treated TB cases (95% CI) 14.7 (0.039.6) 14.7 (0.039.6) 14.7 (0.039.6) 17.2 (14.919.5) 14.7 (0.039.6) 14.7 (0.039.6) 10.0 (7.114.0) 11.7 (7.617.6) 0.0 (0.010.2) 34.5 (28.241.5) 14.7 (0.039.6) Number of MDR-TB among incident total TB cases (95% CI) 9 800 (1 00019 000) 33 (461) 3900 (6587 200) 99 000 (79 000120 000) 9 300 (021 000) 3 (06) 9 300 (6 40012 000) 1 700 (9902 300) 63 (0130) 2 900 (2 1003 800) 130 (6260)

Bangladesh Bhutan DPR Korea India Indonesia Maldives Myanmar Nepal Sri Lanka Thailand TimorLeste

a Estimates based on subnational drug resistance data. DRS = drug resistance surveillance or survey data; CI = confidence interval; MDR-TB = multidrug-resistant TB DRS Survey in Indonesia was completed for Mimika District (2004) and Central Java province (2006). Mimika district: MDR TB in newly diagnosis TB cases: 2.0 %. Central Java province: preliminary result; MDR TB in newly diagnosis TB cases was: 1.8 % and among previously treated TB cases was: 16.7 %. Source: 2010 Global Report on Surveillance and Response

The subclass of MDR-TB known as extensively drug resistant tuberculosis (XDR-TB), defined as Mycobacterium tuberculosis isolates resistant to at least isoniazid, rifampicin, any fluoroquinolone, and at least one of the three injectable drugs (amikacin, kanamycin, or capreomycin), has been isolated in samples from 5 countries in the Region. Considerable effort will be required to expand capacity for quality assured drug susceptibility testing in the
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Region in order to more accurately estimate the extent of MDR and XDR TB in the Region. Given the widespread availability and use of second-line drugs, and as laboratory capacity to conduct second-line drugs susceptibility testing increases, additional numbers of patients with XDR-TB are likely to be identified. Laboratory Capacity for the Detection of MDR and XDR-TB in the Region The national reference laboratories at the Tuberculosis Research Centre, Chennai, India, and at the Bureau of TB at Bangkok, Thailand, are the two designated supra-national TB reference laboratories in this Region. These two laboratories are part of a global network of 26 supra-national reference laboratories. National Reference Labs (NRLs) in all Member countries (with the exception of Maldives and Timor-Leste) have capacity for mycobacterial culture. However this capacity is quite limited even in these countries. In Nepal, culture and DST facilities are being provided through an NGO-run laboratory, quality-assured by the SNRL at Gauting, Germany. A national reference laboratory is in the process of being established. The national reference laboratories in Bangladesh, Indonesia, and Myanmar have recently been accredited for quality assurance for culture and drug susceptibility testing, while Sri Lanka is in the process of upgrading the national reference laboratory for TB. As a result, NRL in some countries are linked up to SRLs outside the region: Bangladesh to the SRL in Antwerp, Belgium; DPR Korea to the SRL in Hong Kong; Indonesia and Timor- Leste to the laboratory at Adelaide, Australia, and Nepal to the Gauting laboratory in Germany. The national reference laboratories in India and Thailand are currently undertaking DST for second-line anti-TB drugs to determine the extent of XDR-TB. Reference laboratories in Bangladesh, Indonesia, Myanmar and Nepal are also engaged in rapid surveys for XDR-TB among mycobacterial isolates from patients who have failed retreatment regimens, through linking with the SRNLs in the global network. Resource mobilization and cross-cutting issues The costs of containment of already existing multi-drug resistant TB, however, if not addressed at this stage, will be beyond the capacity of national health systems and worse; epidemic proportions of multi-drug resistance could emerge over a period of time. The priorities are to establish quality-assured culture and drug susceptibility testing facilities, expand drug resistance surveillance to monitor trends in MDR-TB and then to establish and rapidly scale-up services to treat TB patients with drug-resistant forms of TB. In this regard updated guidelines need to be implemented and treatment in line with international standards for TB care (ISTC) should be in place in all sectors, particularly the private sector. The guidelines should include control strategies, such as tracing and treatment of close contacts of MDR-TB patients, particularly for people at high risk, like children and HIV-infected people and cross-border TB control strategies. Strategies to prevent defaults before and during the treatment need to be carefully designed, including large scale integration of community-based treatment of MDR-TB into national programmes. Regardless the model of treatment delivery in place, infection control measures have to be adequately and urgently implemented. With the exception of Thailand, all countries identified laboratory capacity as a major constraint to scaling up diagnosis and treatment of MDR-TB cases. Considerable effort will be required to expand capacity for quality assured DST in the Region in order to more
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accurately estimate the extent of MDR and XDR TB in the Region. Given the widespread availability and use of second-line drugs, the majority of which are prescribed outside of national programmes, in the absence of treatment protocols for MDR-TB patients, additional numbers of patients with XDR-TB are likely to occur and need to be identified. Adequate quantities of quality assured first and second-line anti-TB drugs for uninterrupted treatment of the planned number of MDR-TB cases should be secured and legislative measures to ensure rational use of drugs need to be strengthened. The pharmaceutical sector should be encouraged to provide competitively priced high quality second-line drugs. Substantial amount of additional resources required to provide adequate trainings create a pool of skilled personnel and to provide quality infrastructures for diagnosis, patient management and surveillance. Sustainable financial support should be guaranteed through application to global initiatives and funds and establishing domestic funding mechanism. Technical assistance required for MDR-TB control should be provided through well coordinated partnership and in-country capacity building. Resolution WHA 62.15 The Sixty-Second World Health Assembly (WHA 62.15) in May 2009 urged Member States to develop and implement long-term plans for tuberculosis including M/XDR-TB prevention and control, in line with the Global Plan to Stop TB 20062015. The Beijing Call for Action on Tuberculosis Control and Patient Care earlier in April 2009, and the resolution on Prevention and Control of Multidrug-resistant Tuberculosis and Extensively Drug-resistant Tuberculosis endorsed at the sixty-second WHA reiterated the need for urgent action to address M/XDR-TB. Delays will result in greater numbers of TB including M/XDR-TB cases, deaths, reversing progress made so far towards achieving the TB targets. Managing drug resistant tuberculosis requires much stronger TB control. This in turn requires addressing key weaknesses of the health systems through which TB services are delivered. A number of interventions are proposed in this regard To achieve universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant TB as part of the transition to universal health coverage, thereby saving lives and protecting communities by- developing a comprehensive framework for management and care of multi drug resistant and extensively drug resistant TB; strengthening health information and surveillance systems; aiming to ensure the removal of financial barriers to allow all tuberculosis patients equitable access to tuberculosis care; making available sufficiently trained and motivated staff; strengthening laboratory systems; engaging all relevant public and private health care providers; ensuring that national air borne infection-control policies are developed; ensuring uninterrupted supply of first-and-second line drugs; ensuring that tuberculosis medicines are sold on prescription only; undertaking effective advocacy, communication and social mobilization and establishing national targets in order to accelerate access to treatment according to WHO guidelines for multi drug-resistant and extremely drug-resistant TB. To enhance quality and coverage of DOTS in achieving 70% detection rate and 85% success rate of tuberculosis treatment, thereby preventing secondarily multidrug resistant tuberculosis. To use all possible financing mechanisms to fulfill the commitments made in resolutions WHA 58.14 and WHA 60.19, including the commitment to ensure sustainable domestic and external financing, thereby filling the funding gaps identified in the Global Plan to Stop TB 2006-2015.

To increase investment by countries and all partners substantially in operation research and development for new diagnostics, medicines and vaccines to prevent and manage tuberculosis including multidrug-resistant and extensively drug-resistant tuberculosis.

Action in Member countries to contain MDR-TB and XDR-TB The first priority in dealing with MDR-TB remains prevention of acquired drug resistance through continuing to ensure higher case detection and cure rates through high quality of DOTS services. Secondly, attention needs to be discussed on developing comprehensive national plans for the urgent scale-up of diagnostic and case management capacity for MDR-TB, conforming to internationally recommended protocols, including good infection control measures. In the context of both of the above, the priorities in the Region are: Securing adequate quantities of quality assured first and second-line anti-TB drugs for uninterrupted treatment of the planned number of MDR-TB cases; Ensuring treatment in line with international standards for TB care in all sectors, particularly the private sector, and strengthening legislative measures to ensure rational use of drugs; Urgent attention to building health systems capacity: skilled personnel and quality infrastructure, focusing on the weakest areas, i.e., laboratory capacity for diagnosis, and surveillance; Securing adequate external as well as domestic funds, (including from local governments under decentralized systems); Increasing the number of manufacturers in the Region meeting WHO prequalification or national drug regulatory standards, equivalent to international standards.

During the past two years, steady progress has been made in the Region in initiating MDR-TB cases on treatment. The Green Light Committee had approved the case management of patients with MDR-TB under national programmes in nine countries. Bangladesh, India, Indonesia and Myanmar are in the process of expanding these services, while Nepal has already established ambulatory case management services for MDR-TB throughout the country. Maldives continues to treat the few cases that occur on a case-bycase basis. Bhutan, Sri Lanka and Thailand began enrolling cases in 2011, while DPR Korea to establish MDR-TB case management under their respective national programmes in 2012. Until the end of 2010, a total of over 3000 patients with MDR-TB had been registered for treatment in the Region. Initial treatment success rates of above 55% have been reported. There are unique challenges to incorporating of the management of MDR-TB into national TB programmes. Developing comprehensive costed national plans for the urgent but feasible scale-up of diagnostic and case management capacity for MDR-TB, conforming to internationally recommended protocols, including good infection control measures, is a priority. The challenges facing countries in the Region may be summarized as below: a. Gaps in basic TB control : funding, drugs, supplies, and skilled personnel to ensure early diagnosis, treatment and care for all TB patients sub-optimal access to quality first-line drugs through all sectors and providers

ISTC not yet widely in use by all providers; links between hospitals/ medical schools and community-based providers for treatment follow-up not yet well established

b. In managing MDR-TB: In the absence of substantive evidence from national DRS in many countries, the understanding of the burden of MDR/XDR-TB is based on best estimates limited laboratory capacity for diagnosis of drug resistant cases and for DRS difficulties In procuring quality second-line drugs; long lead times for procurement of drugs limited capacity, experience in managing MDR-TB cases under programmes lack of infection control measures in most health facilities, including hospitals challenges to introducing new diagnostic tools/ technology substantial additional resources to manage relatively small number of patients (including training, drugs, service delivery, etc)

Action taken at regional level Assistance to all countries (excepting Maldives given very few cases) to establish sound programmes and access to concessional priced second-line drugs; Support for the development of costed national plans and guidelines for the treatment of drug-resistant tuberculosis; Assistance with drug procurement and supply management of second-line anti-TB drugs in collaboration with GDF; Missions together with the GLC in countries undertaking MDR-TB case management (Bangladesh, Bhutan, DPR Korea, India, Indonesia, Myanmar, Sri Lanka, Thailand and Timor-Leste); Training of staff of national programmes and participating NGOs in the management of drug-resistant tuberculosis; Promoting the adoption and widespread dissemination of the International Standards of TB Care (ISTC) at country level, among private and un-linked public providers, to prevent further the emergence of drug-resistance; Establishment of a Regional expert group on M/XDR-TB to review and provide guidance on implementation of interventions for M/XDR-TB; Initiative to establish Regional GLC in the Regional Office.

Laboratory strengthening Supporting capacity of the two regional supra-national reference laboratories for trainings, external quality assurance of national reference laboratories; Organizing Regional training workshops and laboratory consultative meetings supporting in-country training for national reference laboratory staff on quality assurance, culture and drug susceptibility testing and laboratory network management; Supporting DRS protocol development for implementation of drug resistance surveys in selected countries;

Assisting in evaluating and deploying newer diagnostics (liquid culture, molecular tests for rapid diagnosis of MDR-TB, Gene Xpert MTB/RIF) together with FIND (Foundation for Innovative New Diagnostics) and UNITAID.

WHO Regional Office Activities for MDR-TB/XDR-TB for 2010-2011 A Regional response plan has been developed. The objectives of the Regional response plan for MDR and XDR-TB are to: (1) sustain and improve the quality of DOTS; (2) expand drug resistance surveillance; (3) strengthen laboratory capacity for diagnosis and follow-up of drug resistant cases and deploying new diagnostics at field level; (4) build capacity for programmatic management of MDR-TB and XDR-TB, including through other sectors (5) assist countries in establishing infection control measures in health facilities; (6) promote research, including field testing of new diagnostics, drugs and regimens. In order to fully achieve these objectives, considerable additional technical and financial resources will require to be mobilized. Activities have been planned for 2012-2013 Plans at regional level While the prevention of drug resistance through effective DOTS remains the key objective, several steps require to be taken to simultaneously engage in diagnosis, treatment and surveillance of MDR and XDR-TB. A rapid scale-up of laboratory capacity is crucial both to diagnose MDR-TB cases and conduct surveillance. Improved technical and managerial capacity within national programmes, additional funding, greater attention to effectively involving providers in other sectors, extending community-based care, and new tools to better diagnose and more effectively treat patients are required. a. In-country Technical assistance Assistance for assessment and evaluation missions for countries initiating and implementing MDR-TB case management; Support for updating national guidelines for the treatment of drug-resistant tuberculosis; Support for developing national plans and guidelines to introduce infection control measures at health facilities where MDR-TB and HIV-TB cases will be managed; Assistance with cross-border TB control in the context of MDR-TB (eg., MyanmarThai cross-border disease control project); Promoting the widespread dissemination and adoption of the International Standards of TB Care (ISTC) at country level, among private and un-linked public providers, to help prevent further emergence of drug-resistance to both first and second-line anti-TB drugs.

b. Scaling up Capacity for treatment Assist countries in monitoring progress and developing and/or revising expansion plans and targets for MDR-TB case management, based on the assessments of performance and outcomes from established treatment sites;
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Building capacity for drug procurement and supply management of second-line anti-TB drugs in collaboration with GDF; Ensure shorter lead times for procurements of increasingly larger requirements for second-line drugs in collaboration with GDF; Promote and facilitate technology transfer and pre-qualification of smaller manufacturers, particularly of generic drugs, in this Region who have capacity; Liase with the Global Drug Facility to organize a meeting of second-line drug manufacturers in the Region to pre-qualify suitable manufacturers to augment capacity for the manufacture of these drugs.

c. Human Resource Development Supporting country level workshops for the management of drug-resistant tuberculosis, in association with the introduction of national guidelines for the diagnosis and management of drug-resistant TB, and infection control; Training of national programme staff and participating NGOs in the management of drug- resistant tuberculosis and establishing measures for infection control; Developing and disseminating materials on standard clinical management to all health care providers; Supporting in-country training of laboratory staff to field test and deploy newer diagnostics that are now becoming available; Training of SNRL and NRL laboratory staff on second-line DST.

d. Laboratory strengthening Assist countries in assessing requirements and developing plans for the required laboratory infrastructure and technical capacity, as appropriate, for expanded quality-assured culture and DST for first- and second-line drug testing; Assist countries in identifying additional laboratories within medical teaching, established private facilities and research facilities and accredit these through inclusion within the quality assurance network coordinated by the SNRL network; Organizing Regional training workshops for NRL staff on quality assurance, culture and drug susceptibility testing and laboratory network management, including infection control; Building NRL capacity to respond to the needs of national TB control programmes, including through involvement of laboratories with capacity for MDR-TB diagnosis in the private sector and medical teaching institutions; Evaluating the operational use of liquid culture, molecular tests for rapid diagnosis of MDR-TB, as a means of speeding the detection and referral of patients eligible for MDR-TB treatment.

e. Supporting development of newer diagnostics/treatment modalities Provide NTPs with updated information on the feasibility and cost-effectiveness of newer diagnostics and drug regimens to guide programme decisions on adopting newer case management and diagnostic modalities; Facilitate the participation of institutions and national programmes in the Region in global operations research and field testing of newer diagnostics and treatment modalities to help generate the evidence base, and in the application of research findings to guide policy and strategy formulation for the management of MDR-TB.

f.

Establishing infection control measures Raise the issue of the need for greater attention to infection control within national health systems at the highest-level policy forums for greater attention to this neglected area; Mobilize a roster of experts and train additional staff at higher levels within ministries of public health trained to help disseminate internationally recommended guidelines and prepare sound infection control plans in countries.

g. Mobilizing resources Assist countries in developing detailed plans of action for MDR-TB surveillance, diagnosis and case management, including plans for human resource and infrastructure development and involvement of private sector and medical teaching and research facilities; Provide the necessary technical assistance to countries on a continuous basis, consistently undertaking technical support missions at least once a year so as to maintain continuity and consistency in the advice provided to effectively build the capacity of national programmes and reference laboratory networks; Assist countries in developing advocacy and media engagement strategies to augment the political and financial support required for wider implementation of MDR- and XDR-TB prevention, care and control.

h. Monitoring, evaluation, and operational research Assisting countries to evaluate MDR-TB case management, in collaboration with the Global Green Light Committee; Providing forums to review and propose steps to improve implementation, and disseminate best practices in countries; Supporting DRS protocol development for implementation of drug resistance surveys;

i.

Strengthening of Regional Office Capacity to provide technical assistance Developing and updating of a roster of laboratory experts and technical consultants to support laboratories and provide technical assistance to national programmes for the management of MDR-TB; Continued support to SNRLs and NRLs in the Region, through a full-time Regional TB laboratory and MDR-TB coordinator based at SEARO.

Country situation in SEA Region Bangladesh There are no representative data on drug resistance in the country. As per Global Tuberculosis Report -2011 of WHO estimates 5900 (CI: 4400-7400) MDR-TB cases (all forms) in 2010. MDR-TB estimated rate among new cases was 2.1% (CI:1.7- 2.5) and 28% ( CI: 25-32) among the previously treated in 2010. More realistic information on drug-resistant TB in the country is expected from the countrys first nationwide drug resistance survey which was started in September 2010 and expected to be published by 2nd Q of 2012. DRS is implemented by National TB Reference Laboratory with support from National TB Control Program and technical assistance from WHO. The exact extent of anti-TB drug resistance in Bangladesh is not known. Table 1 shows drug resistance data from limited surveys carried out in the past ten years. Table 1: Multidrug-resistant tuberculosis (MDR-TB) rate in new and resistant cases Retreatment cases 27.3% 15.4% 6.8% 3.0% 88%

Survey

New Cases

ICDDR,B/Shyamoli (n=647) ICDDR,B/Shyamoli (n=106)

CDC CDC

2001-03 2004-05

3.3% 3.0% 0.7% 0.4%

Damien Foundation 1995 (n=645) Damien Foundation 2001 (n=1041) NTP/NIDCH 2005-06 Cat.2 failures (n=96)

MDR-TB guidelines have been developed in 2007. A standardized regimen of 6ZKmOfxEtoCs/18ZOfxEtoCs (Z=pyrazinamide, Km=kanamycin, Ofx=ofloxacin, Eto=ethionamide, Cs=cycloserine) has been adopted for management of MDR-TB patients as per WHO recommendations. Intensive phase is at least 6 months provided 4 months of consecutive culture and smear negativity were reached within the period of time. The continuation phase will continue at least for 13 months. The total treatment duration will be at least 18 months after first culture conversion (not followed by any positive culture). Intensive phase is hospital-based and continuation phase is community based Treatment is given under daily DOT. In 2006, the National TB Program (NTP) of Bangladesh was approved by the Green Light Committee to implement programmatic management of drug-resistant TB (PMDT) for 700 patients as a pilot project over 5 years (2006-2011) in collaboration with the National Institute for Diseases of the Chest and Hospital (NIDCH) as a pilot site. Patient enrollment was started in August, 2008. GLC approved management of additional 1000 MDR-TB patients. In addition to NIDCH; Chittagong Chest Diseases Hospital is also initiated enrollment of MDR-TB patients as second treatment site since March 2011. A DOTS-Plus Coordination Committee has been providing direction in the overall implementation. Observing the current country capacity (eg: Human , facility resource), the country has adopted the target to enroll 270 cases within June 2011 to July 2012 and 360 cases in June 2013 to July 2014 under PMDT with support from GFATM.

The National TB Reference Laboratory, quality assured by the Antwerp (Belgium) Supranational Reference Laboratory, has been providing support for diagnosis and follow-up since its establishment in 2007. The NTRL is performing mycobacterial cultures on Lwenstein-Jensen media. DST is performed at NTRL by the proportion method. The NTRL provides primary culture; identification of M. tuberculosis complex and non-tuberculous mycobacteria (NTM), and testing for susceptibility to Isoniazid, Rifampicin, Ethambutol and Streptomycin. Clinical laboratory services including basic haematology, biochemistry, serology and urine analysis are also performed by NTRL. Two Regional Reference laboratories (RTRL) are functioning in the two cities, Chittagong and Rajshahi .One additional RTRL is in the process of operation in Khulna. Capacity building and drug management are jointly managed by the NTP and NIDCH. Several orientations were done for field level GO and NGO managers and community health workers. A clinical management and social support committees were established in 2007 for programmatic management of MDR-TB patients. Training of trainers from National Institute for Diseases of the Chest and Hospital (NIDCH) and other implementing partners were organized in 2008 and 2010. Social support for patients such as transportation costs, vocational training, etc has been established. A mechanism for continuation of treatment after discharge from hospital has been developed through providing training for the community health providers for provision of DOT and referral. Total 674 MDR TB patients were registered till the end of October 2011. In 2008 and 2009 (As of end of Sept), confirmed MDR-TB patients were 104 and 120 respectively among which Treatment Success rate were 63% and 60 % respectively. Damien Foundation (a NTP NGO partner) is providing MDR-TB services as an operational research project in designated geographical areas following a 9 months regimen: 4KPthCGHZE/5CGZE. The Damien Foundation has its own reference laboratory capable of performing cultures and DST for first-line drugs. The first regional reference laboratory was established by NTP in May 2008 in Rajshahi in collaboration with the Damien Foundation (DF). This laboratory performs slide cultures and DST. DF enrolled 181 and 147 MDR-TB cases in 2009 and 2010 respectively and success rate of 2009 cohort was 79%. Bangladesh developed an expansion plan for the programmatic management of Drug resistant Tuberculosis (2010-2015) in 2010.This expansion plan aims at achieving universal access which the Global plan to Stop TB defines as diagnosis and treatment of 80% of the estimated number of smear+ and/or culture+ cases of MDR-TB by 2015, in programs following the international guidelines for the management of drug-resistant TB. Bangladesh has been selected by EXPAND-TB project for introduction of new rapid diagnostic tools; e.g: Liquid culture, Line probe Assay . The MoU between NTP and EXPAND TB Project is under process of signing. Bangladesh also planned to procure four XPERT MTB/RIF (Gene Xpert) machine for rapid diagnosis of TB and DR-TB.

Bhutan Culture and DST facilities have been established at the National TB Reference Laboratory (NTRL) of the Public Health Laboratory Thimphu. There is a plan to upgrade the existing Culture and DST facilities by introducing liquid culture and newer diagnostic tools/equipments subject to the approval of funds. Once this newer diagnostic tool is introduced at the National TB Reference Laboratory of the PHL, the country will require to train lab staff from NTRL to perform the tests. However, the national TB Reference Laboratory will continue to send the samples from MDR patients to Regional Reference Laboratory in Bangkok for 2nd line DST testing. NTCP is also planning to establish culture facilities at the national referral and two regional referral hospitals to support diagnosis of TB in children and follow up of MDR-TB patients.
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As of today, there is no representative data on levels of drug resistance. However, WHO estimates (2008), 0.6% MDR-TB among newly diagnosed smear positive TB cases. Currently, NTRL, Public Health Laboratory is conducting the Drug Resistance Surveillance in the country to study the drug resistance pattern of 1st line anti-TB drugs. The drug rsistance pattern of this country will only be known upon completion of this surveillance which is expected to be completed within next few months time. The national TB control programme was approved by the Green Light Committee for management of MDR-TB cases in 2009. The National TB control program then initiated procuring the second line anti-TB drugs through GLC and the enrollment of patients had already begun from 2010. In 2010, the National TB Control Program through the financial and technical assistance from WHO has developed the MDR-TB guideline for the management of MDRTB cases in the country. Following that, training on MDR-TB management was conducted to the selected Medical Officers of the district hospitals with high burden TB cases. This training program was also facilitated by the technical assistance from WHO. The diagnosis and management of MDR-TB cases will be done by the National Referral Hospital and the two regional referral hospitals and these three hospitals have been identified as reporting center for MDR-TB since 2011.

DPR Korea Patients with possible drug resistance are currently not being systematically diagnosed and second-line drug are not available through the programme. There is no reliable data on the extent of MDR-TB in the country. However, re-treatment cases comprise 17% of all notified cases. A preliminary survey of drug resistance among patients failing Category I and II regimens carried out with the assistance of the supranational reference laboratory in Hong Kong showed high levels of resistance. A representative Drug Resistant Survey is proposed to be undertaken in 2012 for which protocol is under development. A programmatic Management of DR-TB guideline in line with WHO recommendations has been developed in 2011. Expansion Plan for DR-TB management has also been prepared through a wide consultative process. Second line drugs are being procured through Global Fund support and by mid 2012 fifty new cases are expected to be initiated with MDR-TB treatment and subsequently more MDR-TB patients will be put on the treatment. Infection control plan and guidelines has been developed and essential renovations are expected to be carried out in the DR-TB treatment facilities. The central TB Institute in Pyongyang is being developed to function as the National Reference Laboratory with capacity to do culture and DST. All necessary equipment for the central lab in Pyongyang to undertake quality assurance of smear microscopy and to do culture, has been procured and is being installed in the renovated premises of the Central reference laboratory at the Central TB Institute in Pyongyang with support from the Stanford group and WHO. Laboratory staff from this laboratory has recently undergone training on culture and drug susceptibility testing, assisted by the technical consultants from supranational reference laboratory in Hong Kong. India Data from two recent state representative drug resistance surveillance (DRS) surveys in India show that multi drug-resistant TB (MDR-TB) amongst new cases is relatively low ( 3%), but is significantly higher (14-17%) among re-treatment cases. Due the very large number of TB patients in India, it is estimated that MDR-TB cases in India represent over 20% of the global burden of MDR-TB, with an estimated 99,000 cases emerging in 2009.
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Extensively drug resistant TB (XDR-TB) has been reported in India, but numbers are as yet uncertain. However high levels of fluoroquinlone resistance among MDR-TB cases have been documented in the DRS survey in Gujarat and the initial cohorts of patients enrolled under RNTCP Category IV treatment. India has prioritized prevention of MDR-TB and XDR-TB through improved DOTS implementation, and through increasing engagement of medical colleges and the private sector. National guidelines for MDR-TB management were developed in 2006. The national programme provides DST to all patients who have failed an initial first line drug treatment (Category I), all patients who remain smear positive after 4 months or more of Category II treatment, and contacts of MDR-TB cases who are found to have smear positive PTB. MDRTB treatment using the standardized regimen is started after DST results confirm MDR-TB. The first MDR-TB suspects were enrolled under RNTCP in March 2007 in the states of Gujarat and Maharashtra. By June 2011, diagnostic services for MDR-TB were established in seventeen states and treatment services in nine states. These states provide predominantly community-based MDR-TB treatment, integrated into the routine TB control programme activities at the district level, with case-management supported by a speciality clinical facility at the state level. By the end of September 11, about 5000 MDR-TB patients had been initiated on RNTCP Category IV treatment. Diagnostic services are currently available through an expanding laboratory network. Currently, 31 C-DST labs are accredited under RNTCP to provide services for the diagnosis and follow up of MDR TB patients. These include 4 NRLs, 17 IRLs and 10 other labs from medical colleges, private sector, NGOs and ICMR. A network of at least 43 accredited laboratories (offering C&DST and line probe assay testing) is planned to be in place by 2012-13. A public-private collaboration mechanism is already in place in order to extend the network through inclusion and accreditation of existing laboratories in medical colleges and in private hospitals. RNTCP will also access culture and DST services through accredited non-public sector laboratories. RNTCP is receiving financial and technical support for the expansion of MDR-TB services through a number of sources. Financial support is provided by the GF (via and approved Rolling Continuation Channel agreement), the World Bank (via a credit agreement) and WHO (utilising USAID funds for laboratory strengthening). Technical support is provided by FIND, GLI, PATH and WHO to the laboratory strengthening activities, and GLC and WHO for the management of MDR-TB cases. In May 2009, UNITAID approved support to RNTCP in relation to laboratory strengthening and procurement of second line anti-TB drugs. A significant component (US $130 million) of Indias application to GFATM Round 9 is intended to support the scale-up of MDR-TB services up till 2015. RNTCP services for MDR-TB and plans for scale-up were recently reviewed during the Joint Government of India / WHO Monitoring Mission of RNTCP in April 2009 and a joint GLC/GLI mission in July/August 2009. However most MDR-TB cases are still being managed outside of the RNTCP. A major concern is that unless MDR-TB management scales-up rapidly in the public sector, an increasing number of MDR-TB cases will be managed by the unregulated private sector, posing risks for increases in XDR-TB in India. The National Consensus Statement on the management of MDR-TB in India, which resulted from a consultative meeting held by RNTCP in late 2007, has been widely disseminated to lay down a national minimum standard for the diagnosis and management of MDR-TB for all public and private providers nationwide treating MDR-TB cases, especially those outside of RNTCP. The programme is closely working with the office of the Drug Controller General of India in regard to the better enforcement of the existing regulatory mechanisms related to anti-TB drug prescription and

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usage, and to explore ways to further strengthen such mechanisms to protect the currently available, and future, anti-TB drugs from misuse and the development of drug resistance.

Indonesia The drug resistance survey in Central Java has been completed. The MDR-TB rate is 1.9 % among the new cases and 17.1 % re-treatment cases. Another DRS survey is in progress in East Java province. The national MDR-TB prevalence is estimated to be 2 % of all TB cases, which is lower than the estimated regional average of 4.0%. Efforts to expand and strengthen the national laboratory network are underway, with assistance from the Supra National Reference Laboratory IMVS, in Adelaide, Australia. Reference laboratories for quality assurance for AFB direct smear microscopy examination are already established in 26 provinces out of the existing 33 provinces in Indonesia. The reference laboratories for quality assurance are being established in seven new provinces, for AFB direct smear microscopy examination. Five Laboratories have been quality assured for drug susceptibility test (DST) for first line anti TB drugs (FLD) in 2008 and in 2009 for second line anti TB drug (SLD). The five quality assured laboratories are the Persahabatan Hospital Laboratory in Jakarta, The Microbiology Department of University Indonesia in Jakarta, the provincial Laboratory the BLK Bandung in Bandung, the provincial laboratory the BBLK Surabaya in Surabaya and the Microbiology Department of University Hasanuddin, the NEHCRI, in Makassar, South Sulawesi province. The Microbiology Department University Indonesia and the NEHCRI are using the liquid media method; while the other three are using conventional solid media method. However, not all providers in private sector and hospitals are linked yet with the services of the NTP; they are not following the DOTS Strategy. TB cases in these settings usually receive un-standardized treatment and without proper supervised treatment. Treatment success rates among TB patients treated in hospitals, and private clinics/sectors are generally lower, except for those hospitals which have been successfully linked to NTP. DOTS expansion to hospitals and private providers remains a challenge and a priority. A GLC application was approved in September 2007. National programmatic and treatment guidelines for the management of MDR-TB and training materials for health staff are in place. Two sites of PMDT pilot have started providing service for MDR TB cases in mid 2009. The two pilot sites are the East Jakarta City with Persahabatan Hospital as its referral center for MDR TB; and Surabaya city with Dr. Soetomo Hospital as its referral center for MDR TB. During the pilot phase in order to speed up the diagnosis, it was agreed the drug-susceptibility testing (DST) of the pilot sites was to be conducted in Microbiology University Indonesia, while the treatment follow up laboratory examination is being conducted in Persahabatan Hospital for East Jakarta pilot site and the BBLK Surabaya for Surabaya city pilot site. For expansion policy, all five quality assured laboratory will be utilized to conduct DST for diagnosis purposes. The rapid test to diagnosis TB is being introduced in the country. The line probe assay (LPA), the Hain test, is in operational research phase-2 and the newest rapid diagnostic, the GeneXpert, is being processed for pilot purposes and operational research in 17 sites. In May 2010, preparation of PMDT expansion was planned for three new sites: Makassar city in South Sulawesi, with Labuang Baji Hospital as the referral hospital for MDR TB; Surakarta city in Central Java with Dr. Muwardi Hospital as the referral hospital for MDR TB and Malang city in East Java with Dr. Saiful Anwar as the referral hospital for MDR TB. The three new sites started treating MDR TB patients by end 2010.
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Cumulatively MDR TB patients intake until end of September 2011 was: 1585 MDR TB suspects were detected. 1109 MDR TB suspects completed laboratory examination. 471 confirmed MDR TB patients. 332 (70 %) are put on treatment. 32 (6 %) pre-enrolment. 10 (2 %) excluded for various reason. 45 (11 %) died while waiting for DST result. 39 (8 %) refused to be enrolled. 13 (3 %) lost. More than 20 % of the confirmed MDR TB cases were not put on treatment due to various reasons as stated. Efforts are being conducted to improve the rate of enrollment. Preparation for four new sites are in progress: Denpasar city, Bali province, with Sanglah hospital as referral hospital for MDR TB; Jogjakarta city, DIY Province with Sardjito hospital as referral hospital for MDR TB, Bandung city, West Java province with Hasan Sadikin hospital as referral hospital for MDR TB and Medan city, North Sumatra province with Adam Malik hospital as referral hospital for MDR TB. Hopefully the four new sites will be in function by the end of 2011. Maldives The national TB programme in the Maldives has achieved and sustained full coverage with DOTS, fully involving the private sector in the country. Case detection and treatment success rates of over 90% have consistently been achieved over several years. A few cases of drug resistance have been reported by the programme since 1998. However, MDR-TB is currently a growing concern in the Maldives. Drug susceptibility testing (DST) as deemed clinically necessary, is undertaken by sending samples to regional reference laboratories in the region. Currently the samples are sent to the National Tuberculosis Institute in Bangalore, India. Patients diagnosed with MDR-TB are managed clinically at the tertiary care hospital Indira Gandhi Memorial Hospital (IGMH) in Mal, and treatment is based on individualized regimens. Eight patients have so far been identified as MDR-TB, of which 3 were cured and 2 are on treatment. Second-line drugs for the management of these cases are procured by the Ministry of Health and Family on a case-by-case basis.

Myanmar Public-public and public-private mix initiatives are being scaled up to increasingly engage general practitioners and specialists in DOTS implementation, in order to avoid the further development of M/XDR-TB. In 2010, almost 15% of TB cases were notified by general practitioners though the collaboration with the Myanmar Medical Association and Population Services International. Anti-TB drugs are available over the counter including for second-line drugs kanamycin and the fluoroquinolones. A nationwide drug resistance survey carried out in 2007-2008, showed an MDR-TB prevalence of 4.2% among newly diagnosed and 10% among previously treated cases. To date, five XDR-TB case have been confirmed. The third nationwide drug resistance survey will commence in early 2012. The national reference laboratory in Yangon performs cultures and first-line DST. Second-line DST is being undertaken at the SNRL at Bangkok. Culture and DST facilities have been established at the facility in Mandalay in 2009. The launching ceremony for
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Biosafety level-3 Laboratories for TB Diagnosis (NTRL Yangon and Upper Myanmar TB Laboratory Mandalay) was held in NTRL building in Yangon on 12.7.2010. Since the beginning of 2011, the two laboratories are performing liquid culture and line probe assay for rapid diagnosis of MDR-TB. As of November 2011, Xpert MTB/RIF is not being used but equipment is being brought in by international NGOs in collaboration with the NTP. The Ministry of Health has established a National Committee on Drug-Resistant TB, including hospital specialists, staff of the NTP, WHO and implementing partners, to oversee the national response. The Green Light Committee approved DOTS-Plus pilot project started patient enrollment in 10 pilot sites in Yangon and Mandalay in July 2009. From July 2009 to end August 2011, 291 MDR-TB patients have initiated treatment. A total of 28 MDR-TB patients have completed the treatment out of which 71% have been cured. These initial results are very promising, especially since all enrolled patients were chronic TB patients that had been on a waiting list for treatment with second-line anti-TB drugs. With support from WHO, the 2009 MDR-TB management guidelines are being revised. In April 2011, the Green Light Committee approved the expansion of MDR-TB management to treat an additional 1,800 patients under Global Fund Round 9 support. An ambitious MDR-TB scale-up plan has been finalized for 2011-2015. Diagnosis, treatment and care will be offered to an additional 10,000 MDR-TB patients over five years. All States and Regions will have MDR-TB treatment centres with the possibility to hospitalize MDR-TB patients. Rapid MDR-TB diagnosis will be ensured by Xpert MTB/RIF availability in each State/Region and a specimen transportation system will allow for additional laboratory investigations at the two existing state-of-the art reference laboratories. MDR-TB diagnosis will be offered to previously treated TB patients, contacts of MDR-TB patients and HIVassociated TB patients. All confirmed MDR-TB cases will be treated according to WHO guidelines. The NTP will rely on community-based MDR-TB care but patients can be hospitalized for about two weeks to ensure that the second-line anti-TB drug treatment is tolerated. As a result, community-based organizations and volunteers will have a much expanded role for MDR-TB management and national and international NGOs are committed to support community-care programmes based on the newly developed NTP community care guidelines. Efforts are now being made to attract financial resources from Global Fund Round 11, USAID, Three Diseases Fund and UNITAID to support the MDR-TB scale-up plan (funding needs amount to US$ 53 million over five years).

Nepal Nepal and Thailand are the only two countries reporting trends in drug resistance on a national scale. However, the proportion of MDR-TB among new cases in Nepal has fluctuated from a little over 1.0% to 3.0%, in the four surveys that have been conducted since 1996, making it difficult to interpret the trends. The current estimate is 2.9% (1.8-3.2) among new cases and 11.7% (7.1-18.32) among retreatment cases. MDR-TB management under the national programme commenced in September 2005 following WHO Green Light Committee approval. Currently, culture and DST facilities are being provided through a unique public-private partnership with GENETUP (German Nepal Tuberculosis Project) an NGO-run laboratory, actively supported by the SNRL at Gauting, Germany. The national reference laboratory has been accredited by SLR Gauting Germany in 2010. NTP has plan to extend culture facilities to all five regions while DST service will be available in one additional region. With WHO support NTP has revised the DR TB Guidelines, training modules and specific recording reporting forms and registers in 2011.

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MDR-TB management services are available in all five regions of the country. By mid-July 2011, twelve treatment centers and 54 sub-centers were offering MDR-TB treatment and follow up services. Treatment progress is monitored with sputum culture examinations every month during intensive phase (first 8 to 12 months) and bi-monthly during the continuation phase (9 to 24/32 months). By July 2011, the NTP had registered over 1,150 MDR-TB cases for treatment. The largest number of MDR-TB cases registered belong to failures of category 2 (89%) followed by category I failures. Male MDR-TB cases have accounted for almost 64% of all registered cases. This trend corresponds with ratio of male to female registered under the DOTS programme. The largest number and proportion of MDR-TB patient belong to 15-54 age group, with almost half of the registered patients in the age group between 15-34 years. This trend is also in line with age groups of new TB patients registered under DOTS. Cure rates among MDR-TB patients registered during first four year of the programme (2005 - 2008) was 67%, while 7% of patients failed treatment, 9% died and 17% defaulted. One of the key reason for high default rate is lack of sufficient hospital beds or alternate accommodation. However, default rates have declined as number of MDR-TB treatment sites were nearly doubled and NTP also managed to provide financial support for transportation (NRs 300/month) through Government resources. This support has subsequently been increased to NRs 1,500 through Global Fund support, which has resulted in a significant decrease in default rates at most of the MDR TB management sites. The Green Light Committee of WHO initially approved the NTP to register 350 MDR-TB patients for treatment. Following five consecutive international annual reviews by the WHO Green Light Committee, the NTP has received approval for continuation of the programme till 2012. During this phase, the NTP plans to treat 300 MDR-TB patients each year up till 2015. Nepal NTP started XDR TB management in Feb. 2010, since then 26 patients have been registered for treatment. During next five-year plan period (July 2010 July 2015) the NTP plans to increase the number of treatment centers/sub treatment centers to 80. This expansion will involve partners in both the public and private sectors. Currently culture facilities are limited to the Kathmandu Valley. The NTP plans to expand culture facilities to at least four additional regions in the coming five years, while drug susceptibility testing, presently available at only one site (GENTUP), will be extended to one additional regional site.

Sri Lanka Drug resistance survey in 2007 showed exceptionally low rates of drug resistance. The next national drug resistance survey is planned to commence in 2012. The protocol for the drug resistance survey has been already developed with the technical assistance from WHO. Culture and DST is performed for all patients who fail Category I regimens, at the time of initiation of treatment for all retreatment patients (commencing Category II regimens), contacts of known MDR-TB cases and other high risk groups such as prisoners, drug addicts, people living with HIV/AIDS, overseas returnees etc. The national reference laboratory is supported by the designated supranational laboratory at TRC Chennai, and by staff from WHO/SEARO. Guidelines for Programmatic Management of Drug Resistant TB have been developed. MDR-TB is diagnosed at the national reference laboratory located at the premises of the Chest Hospital at Welisara. Patients are treated primarily at this referral hospital, though other hospitals also manage these cases. In addition to the Chest Hospital
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Welisara, there are 12 hospitals throughout the country with wards for patients with chest diseases. Second-line anti-TB drugs are received as a grant from the Green Light Committee. Enrolment of patients was started in 2010. No stock-outs have been reported. The success rate among MDR-TB cases is not known since systematic collection of data on MDR-TB patients was commenced only recently. Thailand The third national drug resistance survey (DRS) was completed in 2006. The survey revealed a low rate of 1.65% multi-drug resistance among newly diagnosed cases and 34.5% among previously treated cases, slightly higher than the rate of MDR-TB among new cases reported in the survey conducted in 2002 (0.93%). The fourth DRS is conducting in 2010-2011 under the financial support from the GFATM Round 6. According to the National guideline, five groups of patients are targeted for culture and drug susceptibility testing (DST) at start of treatment: re-treatment cases, migrant workers, prisoners, HIV positive patients and close contacts of MDR-TB patients but with the limitation of budget the NHSO would support funding for culture and DST in patients mentioned above except the migrant and prisoners. Cultures are performed in 65 laboratories of which 15 laboratories are presently accredited for culture and first line DST, including 5 of the 12 regional laboratories. Culture, DST and second line drugs are performed free of charge for Thai citizens, utilizing funding from the National Health Security Office. But since MDR records and reports have been implemented since 2009, the first report should come to the NTP by the end of 2010. MDR-TB treatment is presently provided at about 100 treatment units throughout the country, based on the national guidelines for the programmatic management of MDR-TB, adapted from the WHO guidelines. MDR recording and reporting system was just developed nationwide in 2009. In 2009, estimated MDR-TB cases among notified pulmonary TB cases by World Health Organization were 2,300. However, only 376 confirmed MDR cases and 189 suspected MDR cases were reported to the central level. These numbers included 23 confirmed MDR cases and 68 suspected MDR cases in prison settings. Recording and reporting system is the most challenging issue because the MDR national guideline has been on the process of revision and the recording and reporting system is not finalized. Model facilities have been selected based on their performance in DOTS implementation, the presence of a good referral system and measures for infection control. The selected sites will serve as centres of excellence for the management of MDR-TB. A GLC mission assessed four selected sites in March 2009 and a GLC application was approved in May 2009 to enroll 50 cases in Years 1 (2009) and 2 (2010) at the four sites, followed by up to 290 cases by Year 5 at 25 sites. These four sites are the Chest Disease Institute, the Bamrasnaradura Infectious Disease Institute, the Chest clinic at TB Bureau, and the Medical Correctional Institute. This application is funded through the Global Fund Round 8, with additional funding received through Round 6 for laboratory strengthening.

Timor-Leste The Green Light Committee approved project for management of MDR-TB in Timor-Leste was formally launched in June 2008. MDR-TB guidelines have been developed and a national coordination committee has also been established. Sputum samples of suspected MDR-TB are transported for culture and drug susceptibility testing to SA Pathology (formally IMVS), Adelaide, Australia which is the designated supra-national reference laboratory for Timor-Leste. Treatment for MDR TB patients is initiated through an NGO, Klibur Domin which supports the NTP for MDR-TB treatment, admitting patients in their facility during
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intensive phase. Continuation phase of treatment is ambulatory. NTP coordinates with PMDT coordination committee and the Cuban Doctors Brigade to ensure regular follow-up of patients by expert clinicians. The results for PMDT in Timor Leste up to March 2011 are as follows: Culture and DST testing, Timor Leste 2008-2011: 2008 No of cases tested for MDR-TB at IMVS (including DST) No of cases detected to be MDRTB by IMVS No of cases started on treatment by the NTP 13 4 3 2009 14 4 1 2010 33 3 3 2011 March) 3 1 0 (upto

Three patients are currently undergoing treatment. Support for drugs has been received from UNITAID and from Global Fund Rd 7 grant.

Milestones for 2011 Regional and national costed plans for MDR-TB and XDR-TB management and infection control developed in all countries; MDR-TB sites further expanded in Bangladesh, India, Myanmar, Nepal, Indonesia and Timor-Leste; established in Bhutan, DPR Korea, Sri Lanka and Thailand; At least over 3000 MDR-TB patients initiated on treatment by end-2010.

Implications for the Regional Offices collaborative activities with countries Intensified technical assistance to Member countries to build laboratory and case management capacity for the diagnosis and case management of M/XDR-TB; Building capacity at both Regional and country offices to effectively support countries in implementing, monitoring performance, and assessing the impact of these more complex interventions; Strengthening linkages with centres of excellence, and identifying additional experts including from WHO Collaborating Centres, to assist countries; Greater coordination and collaboration with all technical and development partners to harmonize support and to ensure capacity is built in countries, in a sustainable way.

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