REPORT ON GREEN LIGHT COMMITTEE MONITORING MISSION INDONESIA. January Michael Rich, M.D., M.P.H. Date of mission: January 2017

Transcription

1 REPORT ON GREEN LIGHT COMMITTEE MONITORING MISSION INDONESIA Michael Rich, M.D., M.P.H. Date of mission: January 2017 January 2017 Acknowledgments The monitoring team would like to express gratitude to the National Tuberculosis Control Programme (NTP) Indonesia and the World Health Organization (WHO) Country Office for Indonesia for facilitating this mission. The monitoring team would also like to express gratitude to the patients interviewed, as well as the doctors, nurses and other key personnel from the facilities implementing PMDT. This monitoring mission was embedded in a larger Joint External Monitoring Mission (2017 JEMM) which took place January The 2017 JEMM which had the purpose to make an independent, comprehensive and in-depth analysis of the TB situation, TB control efforts and to provide expert advice and make recommendations for the strengthening of TB control services to reach the endtb strategy targets. Deliverables The principle deliverables of this mission are: 1. rglc Monitoring Report, 2017 (this report). 2. Participation as member and lead assessor of PMDT in the 2017 JEMM. 3. The chapter for the 2017 JEMM Report of the PMDT focal area. List of references accessed for this report: National Action Plan for the Programmatic Management of Drug-resistant TB (Draft). MoH. PMDT guidelines (with annexes for short regimen under development) Monthly monitoring of Xpert scale-up and utilization, Indonesia, December 2016, KNCV/CTB Indonesia Technical Guide Treatment of Patients with Drug-Resistant TB with New Drug Bedaquiline Technical Guide Integrated Management of Tuberculosis Control Drug Resistance Technical Guide Pharmacovigilance Cohort Event-Based Monitoring in PMDT Hospital Referral Standard Operating Procedure - Submission of Payment to Global Fund - Integrated Management of Drug-Resistant TB Integrated Management Training for Drug-Resistant TB Control - Facilitator Guidelines in Training with 5 training modules. Drug-Resistant TB Logistics Communication, Information, and Education for Drug-Resistant TB Assuring high quality care for patients with M/XDR TB Scaling up Enhanced Cohort Review for PMDT. Lisa Chen, Baby Djojonegoro, Philip Hopewell Debriefing: 29 October, 2015 Indonesia TB Patient Pathway Analysis (PPA). January 2017 Indonesia TB Control Update, December (A WHO summary document prepared for the 2017 JEMM). 1

2 Table of Contents PAGE Abbreviations and acronyms Anti-tuberculosis drug abbreviations 3 1. Executive summary (and list of references accessed for this report) 5 2. Summary of Recommendations 6 3. Findings, discussions and recommendations 10 A. Background and introduction 10 B. Information on the burden X/MDR-TB in Indonesia 10 C. Government commitment and partnerships 11 D. Organization, management and coordination 12 E. Case finding, diagnosis and definitions 13 F. Laboratory aspects 19 G. Treatment 21 H. Side-effects and monitoring response to treatment 30 I. Treatment delivery and adherence 31 J. Drug Procurement and management 32 K. Infection control 32 L. Information systems and data management 33 ANNEXES Annex A: Progress made on last year s monitoring mission s recommendations 34 Annex B: The terms of reference for this visit 37 Annex C: Detailed agenda of mission 39 Annex D: List of People Met During the Mission 43 Annex E: Pediatric drug dosage table for the new shorter MDR Regimen 45 2

3 ABBREVIATIONS AND ACRONYMS AIDS Acquired immunodeficiency syndrome ART antiretroviral therapy CET Clinical Experts Team DOT Directly observed treatment DOTS Directly Observed Treatment Short-course DRS Drug resistance survey DR TB Drug-resistant tuberculosis DST Drug susceptibility testing EMR Electronic medical record EXPAND-TB Expanding Access to New Diagnostics for TB. Project funded by UNITAID and implemented by GLI, FIND, WHO and GDF FIND Foundation for Innovative New Diagnostics GDF Global TB Drug Facility GLC Green Light Committee GFATM Global Fund to Fight AIDS, Tuberculosis and Malaria HIV human immunodeficiency virus IUATLD International Union Against Tuberculosis and Lung Disease KNCV Royal Netherlands TB Foundation LPA Line Probe Assay LJ Lowenstein Jensen MDG Millennium Development Goal MDR-TB Multidrug-resistant tuberculosis MOH Ministry of Health NGO Non governmental organization NTP National Tuberculosis Programme NTRL National TB Reference Laboratory PMTCT Prevention of mother-to-child transmission PPM Public-Private or Public-Public Mix SEARO South East Asia Region SLD Second-line anti-tuberculosis drug SOP Standard operating procedures SRL Supranational tuberculosis reference laboratory TB Tuberculosis UNAIDS Joint United Nations Programme on HIV/AIDS UNICEF United Nations International Children Fund Union International Union Against Tuberculosis and Lung Disease UNITAID International facility for the purchase of drugs and laboratory commodities for HIV/AIDS, malaria and tuberculosis WHO World Health Organization XDR-TB Extensive drug-resistant tuberculosis 3

4 Anti-tuberculosis drug abbreviations (in the format of the WHO new Grouping of second-line TB drugs) Group A: Fluoroquinolones 2 Group B: Second-line injectable agents Group C: Other core second-line agents 2 Group D: Add-on agents (not part of the core MDR-TB regimen) Levofloxacin Moxifloxacin Gatifloxacin Amikacin Capreomycin Kanamycin (Streptomycin) 3 Ethionamide / Prothionamide Cycloserine / Terizidone Linezolid Clofazimine D1 D2 D3 Pyrazinamide Ethambutol High-dose isoniazid Bedaquiline Delamanid p-aminosalicylic acid Imipenem-cilastatin 4 Meropenem 4 Amoxicillinclavulanate 4 (Thioacetazone) 5 1 This grouping is intended to guide the design of conventional regimens. Lfx Mfx Gfx Am Cm Km (S) Eto / Pto Cs / Trd Lzd Cfz Z E H h Bdq Dlm PAS Ipm Mpm Amx-Clv (T) 2 Medicines in Groups A and C are shown by decreasing order of usual preference for use. 3 For the treatment of RR-/MDR-TB, streptomycin is included as a substitute for the second-line injectable agents when aminoglycosides or capreomycin cannot be used and susceptibility is confirmed or highly likely to streptomycin. Resistance to streptomycin alone does not qualify for the definition of extensively drug-resistant TB (XDR-TB). 4 Carbapenems and clavulanate are meant to be used together; clavulanate is only available in formulations combined with amoxicillin 5 HIV-status must be tested and confirmed to be negative before thioacetazone is started 4

5 1. Executive summary Indonesia has a high number of cases of rifampicin resistant/multidrug resistant TB (RR-/MDR-TB), ranking high among the 20 high MDR-TB burden countries in the world. The precise MDR-TB burden in Indonesia is unknown as there is no nationwide representative data on RR-/MDR-TB prevalence. Precise estimates of XDR-TB are also unknown. In the last three years, there has been considerable progress made in PMDT with wider use of Xpert, a steady increase in patient enrollment and stronger patient support. Nonetheless, the progress in falling well short of meeting the needs which include thousands of MDR-TB cases that never get diagnosed and a poor treatment outcomes with high default and death. Progress made on last year s rglc monitoring mission s recommendations (May 2016) can be found in Annex A. There are ambitious plans in place for the scale up of PMDT with many challenges to be overcome. These challenges include: Extremely low proportion of eligible groups receive Xpert testing. Eligible groups such as retreatment after Category I or Category I, contacts of DR-TB patients and patients with TB/HIV are are not always screened for drug-resistance with Xpert. In fact, a very low proportion of the eligible groups are screened. Scaling up the use of Xpert. Xpert testing is very much underutilized. The new algorithm for Xpert that was intended to be implemented starting in May 2016 has not been successfully rolled out. It was estimated that less than 50,000 Xpert tests were performed 2016 and it will be a significant challenge to reach the target utilization of 1.6 million tests in Limited access to PMDT services. The 35 PMDT referral hospitals plus 57 PMDT treatment centers are far from the national target of At least one PMDT Referral Hospital or PMDT Treatment Centre in all 514 districts/municipalities. Second-line DST for all patients with RR-TB/MDR-TB. Second-line phenotypic DST is being done on very few MDR-TB patients. Line probe assay (LPA), a rapid molecular test, for second-line DST is not yet operational. The country plans to have 2 sites operational by mid Two LPA sites could perform the needed number of tests for 2017; however, the country wide specimen transport will prove challenging. LPA DST to second-line drugs is extremely important for identifying who gets the shorter MDR regimen and who gets new TB drugs. Decreasing default of patients on MDR regimens. High early lost to follow up of rifampicin resistant TB (RR-TB) positive patients (approximately 25%) is quite common at most sites. The reasons vary from patients refusing treatment because of fear of adverse events, died before treatment, and simply lost to follow up. Perhaps the main reason is that there is still very limited access to PMDT services and many patients have to spend considerable time and money to reach these limited facilities. It is unclear if one cause is the health staff not explaining the treatment properly. An additional 25% get lost to follow up while on treatment. The sputum and specimen transport system is weak as is getting test results back to the clinician caring for the patient. Resources and systems to do home visits to defaulting patients often not available. The financial support of 750,00 IDR per month is not always enough for the extreme poor and vulnerable. There also can be delays and gaps for months where the support money is late getting to the patient. Transition to the short regimen and use of new TB drugs for those that do not qualify for the shorter regimen. The treatment regimens and the strategy for determining which patients get short MDR regimen needs to be well thought out. The patients that have a contra-indication for a new TB drug will in most cases benefit form a regimen with a new TB drug. Training on the transition should occur nationally and over a short period of time. 5

6 Management of care of the patients on MDR Regimens needs improvement. Even with use of the shorter MDR regimens, supporting and managing care of the patient is a challenge and needs to be improved. Adverse effects for patient on MDR-TB treatment are not aggressively managed. The Puskesmas staff are not always trained well to manage MDR-TB patients. There are long delays in monitoring culture results getting into the patient s chart, which are essential for monitoring effectiveness of treatment. A transition to the shorter MDR regimen is planned for June 2017, but guidelines, training material and changes to the MDR-TB forms are not yet finalized. Most important, in management of care, communications between Clinical Expert Teams (CETs), referral and treatment centres, and satellite sites that treat patients is sub-optimal. 2. Priority recommendations from present rglc Mission (January 2017) (Progress made on last year s rglc monitoring mission s recommendations (May 2016) can be found in Annex A). Section A Recommendations Background and introduction 1. Review and implement the recommendations that are in the 2017 JEMM to further improve TB control and PMDT. Section B Recommandations - Information on M-/XDR-TB 2. Complete the national DRS to better estimate the prevalence of DR-TB. The national DRS should include doing SLD resistance testing in all patients found to have RR-TB in order to determine the rate of fluoroquinolone and second-line injectable drug resistance in patients with RR-/MDR-TB. Section C Recommendations Government commitment and partnerships 3) Finalize and implement the National Action Plan on the Programmatic Management of Drug-resistant TB (PMDT), version January The action plan includes incorporating all WHO endorsed tools to fight MDR-TB including modern molecular diagnostics, decentralized treatment, new shorter MDR regimens, new anti- TB drugs bedaquiline and delamanid for patients not able to receive the shorter MDR regimens, and a robust system of management, supervision and monitoring. The Action plan should be come costed and supported by stakeholders and GoI MoH. The system of human resources to implement the plan should be reviewed and appropriately put in place. Increase engagement of the private sector and consider designing robust public-private mix management of PMDT. Section D Recommendations - Organization, management and coordination (includes recommendations on supervision and monitoring of the programme) 4. Improve the system of treatment delivery and management of the patients on MDR regimens. Establish at least 1 PMDT Referral Hospital or PMDT Treatment Centres in all 514 districts/municipalities as soon as possible, consider accelerating the PMDT National Action Plan that only reaches this goal in Provide regular refresher training to the a PMDT Referral Hospital or PMDT treatment Centre staff with an emphasis on roles and responsibilities. 6

7 Re-design the way a satellite site gets trained and manages MDR-TB patients. Consider organizing a community-based DOT option for patients. Improve communication between the Clinical Expert Teams (CETs), PMDT Referral Hospital or PMDT treatment Centre, and PMDT satellite sites Section E Recommendations - Case-finding Strategy 5) Improve and scale-up the diagnosis of DR-TB through: Assure that every patient that belongs to an eligible groups for DR-TB screening (such as retreatment after Category I or Category I, contacts of DR-TB patients and patients with TB/HIV are always screened for drug resistance with Xpert. Continue to scale up the use of Xpert as the initial test to determine DR-TB and implement the new diagnostic algorithm at all Xpert sites. Increase number of Xpert sites per the PMDT National Action Plan (approximately 1000 Xpert MTB/RIF machines employed and 2.3 million test performed in 2018; 2000 Xpert MTB/RIF machines employed and 4.5 million test performed in 2020). Perform Xpert in all hospitalized patients with respiratory symptoms (this recommendation will help with infection control and case finding for both DS-TB and DR-TB). Assure that private clinicians have access to Xpert testing, free of charge to the patient. Establish a robust network of sputum/specimen transport to Xpert facilities and referral laboratory with a system of reporting results back to the ordering facility. This should be done for Xpert, monitoring cultures, and DST. Revise the projected number of cartridges need for the new algorithm for TB diagnosis and number of DR-TB cases to be detected for 2017 to account for slow adaptation of the new Algorithm for TB diagnosis. Keep goals for 2018, 2019, and 2020 similar in ambition. Perform a second algorithm using line probe assay (LPA) for diagnosing prexdr and XDR-TB in all patients with RR-/MDR-TB. Section F Recommendations- Laboratory services 6) Improve and scale-up the diagnosis of DR-TB, monitoring of cultures and DST to isoniazid and secondline drugs. Continue to scale up the use of Xpert as the initial test to determine DR-TB and implement the new diagnostic algorithm at all Xpert sites. Strengthen the system of monitoring cultures. Perform second-line DST in all patients with RR/MDR-TB, initially with LPA to 1 st and 2 nd line drugs and then phenotypic testing to isoniazid, kanamycin (or amikacin), capreomycin, and the flouroqunolones (ofloxacin and moxifloxacin at 0.5 and 2.0 mg/dl concentrations). The WHO is coming out with new recommendations on critical concentrations for DST of second-line TB drugs in the latter half of 2017, so please look for them and adapt protocols as indicated. 7

8 Section G Recommendations- Treatment strategies 7. Modify treatment regimens to be up-to-date with the latest WHO 2016 Guidelines on treatment of DR-TB. 1. Update all PMDT guides for new shorter MDR regimens and for the use of new TB drugs, bedaquiline and delamanid, when MDR shorter regimens cannot be used. 2. Implement the new shorter MDR regimen in patients that have no contraindications to it and implement individualized conventional MDR regimens in patients with a contraindication to the shorter MDR regimen. 3. Fast track the regulatory approval for delamanid use in Indonesia. 8. Specific design of regimens are listed below and are consistant with the Indonesian National Action Plan for PMDT (see above discussion for more details). Simple MDR-TB (no SLD resistance): Standardized regimen to be used until July 2017: 8-12 Km-LFX-Eto-Cs-Z-(E)-H / LFX-Eto-Cs-Z-(E)-H The suggested shorter MDR regimen to be started after July 2017, or sooner if possible, is: 4-6 Km-Mfx HD -Pto-Cfz-Z-H HD / 5 Mfx HD -Cfz-Z-E The use of Pto (or Eto) in the continuation phase is up to the NTPs. There is not clear evidence on whether Pto in the continuation phase improves outcomes or makes outcomes worse as default could be higher do to added adverse effects. This consultant has a slight preference for not using Pto (or Eto) throughout the shorter MDR regimen but the final decision is left to the NTP. The observational study on 500 patients from Bangladesh had excellent results and did not use Pto in the continuation phase. Pre-XDR TB: Resistance or severe toxicity to the injectable agent (PreXDR Injectable). Confidence in Eto and Cs: 8-12 Bdq(or Dlm)-Lfx-Eto-Cs-Z / Lfx-Eto-Cs-Z Resistance or severe toxicity to the flouroquinolones (FQs) (PreXDR-FQ). Confidence in Eto and Cs Km-Bdq(or Dlm)-Lzd-(Lfx)-Eto-Cs / Lzd-(Lfx)-Eto-Cs XDR-TB: New case of XDR-TB or failure to the standard conventional MDR regimen: 6 Bdq(or Dlm)-Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS / 14 Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS A case of XDR-TB after taking the shorter MDR regimen or failure of the shorter MDR regimen (or close contact of a person that failed the shorter MDR regimen): 8 (Cm)-Dlm-Lzd-(Cfz)-Cs-PAS / 16 (Dlm)-Lzd-(Cfz)-Cs-PAS 8

9 Section H Recommendations - Side-effects and monitoring response to treatment 9. Aggressively treat and manage all side-effects with a special focus on nausea and vomiting. 10. Implement a stronger strategy to have zero hearing loss from MDR-TB treatment. Baseline audiometry testing for all MDR TB cases at initiation of treatment. Repeat audiogram for any mild symptom of hearing loss, tinnitus, or dizziness and routinely at month 3 and 5 (or monthly while on injectable agents if resources are available). Consider the use of handheld audiometry devices that run on android phones or tablets, such as HearScreen. Use new TB drugs bedaquiline or delamanid in cases of moderate or severe hearing loss. In cases of suspected lack of response to the regimen and hearing loss, re-design the whole regimen with the inclusion of a new TB drug; In the case of moderate or severe hearing loss on the new shorter regimen, if the patient has gotten more than 3 months of treatment consider suspension of the injectable agent and continuing the rest of the treatment. If the patient has gotten less than 3 months, consider redesign of using a conventional regimen and new TB drug and no injectable. 11. Establish a robust network of sputum/specimen transport with the referral laboratory with a system of reporting results back to the ordering facility. This should be done for Xpert, monitoring cultures, and DST to first and second-line drugs. (See Sections E and F above). Section I Recommendations - Treatment Delivery and adherence 12. Treatment delivery and adherence can be improved through: Re-designing how a satellite site gets trained and manages MDR-TB patients, with an emphasis on ways to improve adherence. Consider more provisions for community-based DOTs Consider increasing the 750,000 IDR monthly support for all PMDT patients and consider an additional social support package for the extremely poor and vulnerable patients. Design a system that allows for a robust public-private treatment of MDR-TB that assures high adherence and patient support. Section J Recommendations - Drug management 13. See the 2017 GDF report for all recommendations concerning drug procurement of SLDs. 14. Fast track the regulatory approval for delamanid use in Indonesia. Section K Recommendations - Infection control 15. See 2017 JEMM recommendations. Continue to emphasize and fully fund infection control protocols. 16. Improve contact tracing for MDR-TB cases. Section L Recommendations - Recording and reporting, and data management 17. Continue etb Manager for PMDT. Assure all satellite treatment sites have access to etb Manager. Complete XPERT MTB/RIFAlert and etb Manager linkage. 9

10 Link etb Manager with the National medical information system (MIS). 3. Findings, discussions and recommendations A. Background and introduction Indonesia consists of 34 provinces, each with a governor and legislature. Provinces are composed of districts and municipalities ( ), responsible for government services. The Sub-districts or Kecamatan (7,094) are divided into villages or Desa/ Kelurahan (74,093/ 8,412), which are in turn divided into citizen groups (RW/RT) and, finally, neighborhoods (ten household groups). A large Joint External Monitoring Mission (JEMM) took place in 2017, led by both national and international reviewers, which undertook a comprehensive appraisal of the NTP and TB control in Indonesia. Please see the 2017 JEMM Report for further discussion on the existing TB control activities in Indonesia. There has been substantial progress since the last rglc visit of May 2016, especially in terms of establishing a National Action Plan for PMDT and a new diagnostic algorithm for TB that uses Xpert; still much remains to be done. An evaluation of the progress made on the recommendations from the May 2016 rglc report is provided in Annex A. The terms of reference for this visit are described in Annex B, and the visit agenda, places visited, and people met are described in Annex C. Section A Recommendations Background and introduction 1. Review and implement the recommendations that are in the 2017 JEMM to further improve TB control and PMDT. B. Information on the burden X/MDR-TB in Indonesia Indonesia has a high number of cases of rifampicin resistant/multidrug resistant TB (RR-/MDR-TB), ranking high among the 20 high MDR-TB burden countries in the world. The precise MDR-TB burden in Indonesia is unknown as there is no nationwide representative data on RR-/MDR-TB prevalence. Precise estimates of XDR-TB are also unknown. The NTP and National Institute of Research and Development (NIHRD) have initiated a nationwide resistance survey in 2016 with results expected in Based on data from the small resistance surveys, the WHO estimates there could be as many as 32,000 cases of incident cases of TB corresponding to around 10,000 cases among the notified cases (see Table 1 and 2). Table 1. Epidemiology of RR-/MDR-TB in Indonesia Indicador Estimates DR-TB incidence 12 cases/100,000 population (32,000 cases) Estimated MDR/RR-TB cases among 10,000 cases notified pulmonary TB cases in 2015: Estimated % of TB cases with MDR/RR-TB 2.8% (New) and 16% (previously treated). 10

11 Table 2. Estimated proportion of MDR-TB cases among notified TB cases in Indonesia in 2015 Notified cases 2015 Drug resistance estimates New pulmonary TB cases 295, % 8,300 Re-treatment cases 10,325 16% 1,700 Extra-pulmonary TB cases 24,623 Not known - Total 330,729 10,000 Estimated DR-TB cases (WHO) Section B Recommendations - Information on M-/XDR-TB 2. Complete the national DRS to better estimate the prevalence of DR-TB. The national DRS should include doing SLD resistance testing in all patients found to have RR-TB in order to determine the rate of fluoroquinolone and second-line injectable drug resistance in patients with RR-/MDR-TB. C. Government commitment and partnerships See the 2017 JEMM for a more thorough discussion on government commitment, political will and the extensive list of partnerships in respect to TB control and PMDT. There is now national health insurance coverage being rolled out through the BPJS (National Health Insurance). The BPJS will cover the cost of MDR-TB treatment however, it is not clear if it sufficient and is likely only complimentary to the GF funding, government programmatic funding, and other funding (NGOs). There is little interaction with private sector on PMDT. A National Action Plan for PMDT has been updated and exists in draft form. Highlights of the plan are to scale up PMDT care aggressively with the following 2020 goals: At least one PMDT Referral Hospital or PMDT Treatment Centre in all 514 districts/municipalities Over 2000 operating Xpert machines that will be performing over 4.5 million Xpert tests per year. A completed transition to the short regimen (transition to start in full force mid-2017) and the use of the new TB drugs bedaquiline and delamanid for cases that cannot take the short regimen. A more capable and skilled staff for the management of MDR regimens. Multiple options of managing MDR-TB that include better engagement with private hospitals and more options in the public sector for decentralized clinic-based and community-based care. Section C Recommendations Government commitment and partnerships 3. Finalize and implement the National Action Plan on the Programmatic Management of Drug-resistant TB (PMDT), version January The action plan includes incorporating all WHO endorsed tools to fight MDR-TB including modern molecular diagnostics, decentralized treatment, new shorter MDR regimens, new anti- TB drugs bedaquiline and delamanid for patients not able to receive the shorter MDR regimens, and a robust system of management, supervision and monitoring. The Action plan should be come costed and supported by stakeholders and GoI MoH. The system of human resources to implement the plan should be reviewed and appropriately put in place. Increase engagement of the private sector and consider designing robust public-private mix management of PMDT. 11

12 D. Organization, management and coordination The are ambitious plans for the expansion of PMDT as described in the National Action Plan for PMDT that include a description of the organization, management and organization of the program. The National Action Plan for PMDT in respect to supervision and human resource capacity building should be followed.. PMDT services are offered in a fraction of health care facilities in centralized centres called PMDT Referral Hospitals and PMDT Treatment Centres with DOT of the regimens being decentralized to identified treatment satellite sites. As of end of 2016, the PMDT services have expanded to 35 PMDT referral hospitals, 57 PMDT treatment centres (previously call sub-referral centres ) and 1,238 Treatment sites (treatment satellite) in 33 provinces. Table 3 describes the PMDT activities performed in each of the different facilities involved in PMDT. Table 3. PMDT activity by PMDT treatment facility type PMDT Activity PMDT Referral Hospitals PMDT treatment facility type PMDT Treatment Centres Treatment Satellite sites Clinical expert team Diagnosing Establish treatment Initiation of treatment Continuing treatment Inpatient + +/- - Outpatient Establish treatment outcome All patients are started at the PMDT Referral Hospitals or PMDT Treatment Centres and after it has been documented the patient is tolerating the treatment, treatment under clinic-based DOT is arranged at a satellite site, often a puskesmas close to the patient s residence. Some patients prefer continue care 12

13 and DOT at the referral and sub-referral level for their whole treatment, and this option is available to patients. Most patients do not require hospitalization for the start of treatment. The satellite site (usually a puskesmas) does the bulk of the DOT, which is clinic-based DOT (the patient travels to the clinic daily for the DOT). The monthly follow-up visits and all follow-up examinations and tests (smear, cultures, blood laboratory tests, hearing tests and specialty consults) and outcome assignments are done through the PMDT Referral Hospitals and PMDT Treatment Centres. Basic adverse events are managed by the satellite sites with more complicated adverse events and regimen adjustment done at the PMDT Referral hospitals and PMDT Treatment Centres. Only the PMDT referral hospitals have Clinical Expert Teams (CETs). The staff at the satellite sites that supervise the outpatient treatment are generally under-trained in the management of DR-TB. Several grassroots patient support groups help patients adhere to treatment, but most of these groups are underfunded. The expansion of PMDT facilities is described in Table 4. Table 4. Expansion of PMDT Facilities (actual) Provinces that have at least one DR-TB referral site Development of DR-TB treatment referral sites Regency / City that have at least 1 DR-TB treatment site Development of DR-TB treatment sites (12%) (40%) (60%) (80%) (100%) Primary healthcare (PHC) Development of the satellite DR TB treatment sites (13%) (25%) (50%) (75%) (100%) Section D Recommendations - Organization, management and coordination (includes recommendations on supervision and monitoring of the programme) 4. Improve the system of treatment delivery and management of the patients on MDR regimens. Establish at least 1 PMDT Referral Hospital or PMDT Treatment Centres in all 514 districts/municipalities as soon as possible, consider accelerating the PMDT National Action Plan that only reaches this goal in Provide regular refresher training to the a PMDT Referral Hospital or PMDT treatment Centre staff with an emphasis on roles and responsibilities. Re-design the way a satellite site gets trained and manages MDR-TB patients. Consider organizing a community-based DOT option for patients. Improve communication between the Clinical Expert Teams (CETs), PMDT Referral Hospital or 13

14 PMDT treatment Centre, and PMDT satellite sites E. Case finding, diagnosis and definitions Diagnostic capacity for drug-resistant TB (DR-TB) is steadily increasing, up to November 2016, there were 83 Xpert MTB/RIF machines operational in 33 provinces. Currently 330 machines are in the process of placement using the Global Fund grant, with the Government of Indonesia also procuring XPERT 201 machines in 2016 and more to come in near future. There are 16 labs for culture where 8 labs are certified for first-line DST and 5 labs are certified for first- and second-line DST. A new algorithm for TB diagnosis that includes the use of Xpert as a primary diagnostic for TB for all patients with symptoms suggestive of TB was designed and disseminated to the provinces in May An interim letter from the Director General forms the basis for implementation of this new algorithm with a new ministerial decree that is to be signed soon. Xpert will also continue to be used as the primary and initial diagnostic for DR-TB. The addition of it being used as a diagnostic tool for drugsusceptible TB (DS-TB) will increase the number of cases of DR-TB found. There was no data on average turn-round time of request of Xpert testing to return of results to the ordering facility; however, all 2017 JEMM teams reported the system specimen transport and reporting poor functioning and with delays. In addition, in most cases patients are requested to travel to the Xpert testing site rather than sending a specimen. Furthermore, all teams reported low to no update of the new Xpert algorithm. According to NTP data (from etb Manager) average turn-around time of DST is 81 days (median 77 days); however, this is based on the time the specimen spent in the laboratory and does not include specimen transit times or time taken to return results back to the treatment centres or entry into etb Manager. The referral networking for culture and DST testing are updated annually based on updated capacity of culture and DST laboratories. The NTP has conducted the piloting of specimen transportation in 9 provinces using courier mechanism. The guideline for specimen transportation has been finalized. Enrollment numbers are low (Figure 1) and outcomes are sub-optimal with a success rate in the low 50 percentage range for most years (Table 3). The program is enrolling only 1848 cases out of the 10,000 notified cases (18.5%), estimated to be 6% of the 32,000 prevalent RR-.MDR-TB cases. Figure 1. Total number of DR-TB patients in Indonesia

15 The planned increase in Xpert facilities and number of cartridges needed is projected in Table 6, note the numbers for 2016 in Table 6 are projections and were not met. Because the new algorithm for TB diagnosis with Xpert has not yet been implemented widely, the number of Xpert tests performed in Indonesia were mostly done to diagnose DR-TB, with approximately 27,000 tests performed in This is many times lower than the projected goal of 1 million Xpert tests for It is expected in 2017 the number of Xpert tests will greatly increase and hence greatly improve case finding of RR-TB. Table 7 illustrates the projected number of DR-TB to be found if the new algorithm for TB diagnosis is used. 15

16 Table 5. Expected number of Xpert machines and cartridges need for new algorithm for TB diagnosis Baseline Target TB case finding 335, Probable TB targets 10: 1 3,350,000 4,113,800 5,155,560 6,772,650 6,484, Plans for diagnostic examinations a. Microscopic 99.8% 68% 60% 55% 45% 30% b. Xpert 0.2% 32% 40% 45% 55% 70% 2. Load diagnostic tests a. Microscopic 2,278,000 2,468,280 2,835,558 3,047,693 1,945,392 b. Xpert cartridges 10% 1,072,000 1,645,520 2,320,002 3,724,958 4,539, DR-TB diagnostic facilities Number of Xpert machines , ,167 Scope Laboratory cultures DST laboratory LPA laboratory 1 st and 2 nd Line. Province District / City (1 st line) 2 (1 st line)

17 Table 7 - Projected number of DR-TB to be found if the new algorithm for TB diagnosis is used % Case Discovery Number of TB case finding targets (all forms) 330, , , , , , Pulmonary TB 306, , , , , , - New treatment , , , , , ,775 - Re-treatment 5 10,325 16,750 18, , , , Extra-pulmonary TB 24,623 21,809 27,788 37,135 41,954 42,370 Estimated MDR-TB/RR-TB among notified pulmonary TB cases New treatments 2.8 8,282 8,287 9,820 13,123 14,826 14,974 Re-treatment 16 1,652 2,680 2,954 3,947 4,459 4,503 TOTAL 9,934 10,967 12,774 17,070 19,285 19,477 Target MDR-TB/RR-TB cases to be treated % Annual Target 40% 60% 70% 80% 80% 80% Number of patients 3,974 6,580 8,942 13,656 15,428 15,582 Actual number of patients 1,589 1,757 N / A N / A N / A N / A % achievements 16% 16% N / A N / A N / A N / A % revised target, National Action Plan for PMDT, Revised target number of RR- /MDR-TB patients 16% 16% 40% 60% 70% 80% 5, , The NTP should anticipate that a massive and robust system of specimen transport and information system of returning laboratory results will be needed. Figure 2 illustrates the anticipated system, with the projected 2020 numbers of laboratories and facilities as per the National Action Plan for PMDT

18 Figure 2. Illustration of the flow of specimens and information as per National Action Plan for PMDT with approximate projection numbers of treatment and laboratory facilities for year A description of the flow of specimens and information is as follows: From the PHC, send specimens to an Xpert testing/lab with information going back to PHC. if Rifampicin resistance is found, the PHC refers patients to PMDT referral/treatment site. The PMDT referral/treatment site then sends 1 specimen to an LPA for direct second line DST (if the specimen is smear positive) and sends 2 specimens to a laboratory for culture and first-line DST. If mycobacterium grows on culture, then refer the isolate to a laboratory for SLD DST (if LPA for SLD not yet performed, do both SLD phenotypic testing and LPA from culture). All LPA, culture and phenotypic DST laboratory results are reported back to PMDT referral/treatment sites in a timely manner. Section E Recommendations - Case-finding Strategy 5) Improve and scale-up the diagnosis of DR-TB through: Assure that every patient that belongs to an eligible groups for DR-TB screening (such as retreatment after Category I or Category I, contacts of DR-TB patients and patients with TB/HIV are always screened for drug resistance with Xpert. Continue to scale up the use of Xpert as the initial test to determine DR-TB and implement the new diagnostic algorithm at all Xpert sites. Increase number of Xpert sites per the PMDT National Action Plan (approximately 1000 Xpert MTB/RIF machines employed and 2.3 million test performed in 2018; 2000 Xpert MTB/RIF machines employed and 4.5 million test performed in 2020). 18

19 Perform Xpert in all hospitalized patients with respiratory symptoms (this recommendation will help with infection control and case finding for both DS-TB and DR-TB). Assure that private clinicians have access to Xpert testing, free of charge to the patient. Establish a robust network of sputum/specimen transport to Xpert facilities and referral laboratory with a system of reporting results back to the ordering facility. This should be done for Xpert, monitoring cultures, and DST. Revise the projected number of cartridges need for the new algorithm for TB diagnosis and number of DR-TB cases to be detected for 2017 to account for slow adaptation of the new Algorithm for TB diagnosis. Keep goals for 2018, 2019, and 2020 similar in ambition. Perform a second algorithm using line probe assay (LPA) for diagnosing prexdr and XDR-TB in all patients with RR-/MDR-TB. 19

20 F. Laboratory aspects Review of the laboratory network took place as part of the 2018 JEMM, from which Figure 2 and 3 are taken and describes the present situation for culture and DST. Figure 2. Culture and DST laboratories Figure 3. Map of certified culture laboratories,

21 Table 6 above describes the NTPS s ambitious plan to scale up rapid molecular testing for TB diagnosis and support for MDR-TB treatment with culture and additional phenotypic and genotypic (LPA) DST. Further laboratory recommendations can be found in the 2017 JEMM report. Phenotypic DST should no longer be done to Ofloxacin. The WHO is coming out with new guidance on critical concentrations and clinical breakpoints for the FQs, so anticipate that the lab should start to be prepared for this. Fuad Mirzayev at the WHO Geneva can be contacted for suggested concentrations, and for which FQs should have DST. The laboratory should start the transition as soon as possible, so that a full transition can be made by the end of the year. Section F recommendations- Laboratory services 6) Improve and scale-up the diagnosis of DR-TB, monitoring of cultures and DST to isoniazid and second-line drugs. Continue to scale up the use of Xpert as the initial test to determine DR-TB and implement the new diagnostic algorithm at all Xpert sites. Strengthen the system of monitoring cultures. Perform second-line DST in all patients with RR/MDR-TB, initially with LPA to 1 st and 2 nd line drugs and then phenotypic testing to isoniazid, kanamycin (or amikacin), capreomycin, and the flouroqunolones (levofloxacin and moxifloxacin at 0.5 and 2.0 mg/dl concentrations). G. Treatment The present treatment regimen used in Indonesia is a standardized conventional regimen: 8-12 Km-LFX-Eto-Cs-Z-(E)-H / LFX-Eto-Cs-Z-(E)-H The regimen can be modified slightly for serious adverse events or resistance patterns (i.e. with CM, or PAS), but this is not commonly done. The program has sub-optimal results from the use of the present regimen (Table 8) and has decided to transition to the new shorter MDR regimen and to individualized conventional regimens for those that do not qualify for the new shorter MDR regimen Table 8. Outcomes of DR-TB Treatment, Number of cases: ,301 1,590 1,848 OOutcomesutcomes Cured (%) 52.6% 62.9% 56.5% 53.5% 48.8% 43.4% 6.9% 0% Complete (%) 5.3% 5% 1.6% 1.2% 1.3% 2.4% 0.2% 0% Defaulted (%) 10.5% 10.7% 25.1% 26.9% 28.7% 27.1% 24.7% 9.5% Failed (%) 5.3% 4.3% 1.2% 3.2% 3% 2.2% 2.3% 0.3% Deaths (%) 10.5% 12.9% 15.3% 15.3% 16.7% 17.3% 14.2% 8.7% Not evaluated/other 15.8% 4.3% 0.4% 0% 0% 1% 2% 1.2% Still in treatment 0% 0% 0% 0% 0% 6.5% 49.7% 80.2% source: MDR TB 08 etb Manager accessed January 11,

22 There is a planned transition to the new short MDR regimen. The new regimen is not finalized in fine detail (i.e. in terms of the dose of moxifloxacin or whether ethionamide or prothionamide will be used). On January 21 st of the JEMM an ad hoc meeting Partners meeting on country preparedness for introduction of the short treatment regimen (STR) took place. This consultant has reviewed the short regimen plan and the transition is planned to start in July 2017 and is a solid plan. Only patients that meet the inclusion criteria will be given the short regimen. The program is using the recommended WHO criteria for who gets the short MDR regimen, which is reproduced in Figure 2. The plan for the individualized conventional regimens are not finalized and recommendations of the individualized regimens will come at the end of this section. Figure 4. WHO recommended algorithm for identifying which patients receive the new shorter MDR regimen and which patients receive and individualized conventional regimen. In addition to the transition to the short regimen, the country has had three pilot sites for the use of bedaquiline and has enrolled 50 patients in There is also one UNITAID endtb Project site at Cempaka Putih Islamic Hospital, where one patient was enrolled on bedaquiline in late 2016 and more are planned for To date, no patients have been enrolled on delamanid and the drug has not been imported to Indonesia. 22

23 DETAILED RECOMMENDATIONS ON REGIMEN DESIGN FOR INDONESIA: The following is a detailed summary of the regimens to be used under the transition including recommendations in areas of where existing guidance in the Indonesian program is lacking in respect to the shorter MDR regimen and for the design of the individualized conventional regimens. Patient will continue to be placed on the standardized conventional regimen until the transition date, which should be as soon as drugs are in country and personnel are trained, expected no later than July 2017, but can be sooner in areas. Simple MDR-TB (no SLD resistance): Standardized regimen to be used until July 2017: 8-12 Km-LFX-Eto-Cs-Z-(E)-H / LFX-Eto-Cs-Z-(E)-H New TB drugs may be used if there is severe toxicity to any of the second-line TB drugs. As PAS is now grouped now in Group D-3, the lowest group in the hierarchy of TB drugs. Most programs use Bdq or Dlm as the first choice of drug if there is a toxicity to any of the second-line drugs. If the patient is responding well to the regimen (clinical and culture evidence of improving) then a simple substitution can be made replacing the drug causing the toxicity with a new TB drug. If it is unclear if the patient with a drug toxicity is responding to the regimen, it is best to replace the drug causing the drug toxicity with a new TB drug plus another Group C drug or completely redesign the regimen. This is to avoid adding a single drug to a failing regimen. This consultant recommends the use of a new TB drug (Bdq or Dlm) plus linezolid when two drugs are needed. This preserves the use of Cfz for the shorter MDR regimen. If the patient is failing a regimen and has toxicity, it is best to design a whole new regimen. If the inha mutation is detected by LPA, there is no need to use Eto or Pto in the regimen; the drugs will have no efficacy and will only add toxicity. It is suggested by this consultant to use Dlm, or Bdq, or Lzd, or PAS (the drugs are in the order of preference of this consultant). Again, if making a substitution, never add a single drug to a failing regimen. If Eto or Pto is resulting in recalcitrant vomiting. If LPA for second-line drugs has the rrs mutation, use no injectable (substitute a new TB drug); if the eis promotor mutation is present use Cm. The suggested shorter MDR regimen to be started as of July 2017, or sooner if possible, is: 4-6 Km-Mfx HD -Pto-Cfz-Z-H HD / 5 Mfx HD -Cfz-Z-E Only patients that meet the criteria for the new shorter MDR regimen should receive it. This consultant strongly prefers high-dose moxifloxacn (Mfx HD) ). SLD DST with LPA to the injectable agents and fluoroquinolones should be done in all RR-TB patients to determine if the patient meets the criteria for the new shorter MDR regimen. As the widespread availability of SLD DST with LPA is not presently available, it should be allowable to at the start of the program to start a patient on the new shorter MDR regimen if they have no history of failing an MDR regimen and are not a contact of someone that failed an MDR regimen or has SLD resistance (especially if the contact had prexdr or XDR TB). Because there is a large stock Eto in country (and more coming in transit) the country should use Eto at the start of the transition. No new orders for Eto are suggested as Pto is considered to have fewer side effects. The use of Pto (or Eto) in the continuation phase is up to the NTPs. There is no clear evidence on whether Pto in the continuation phase improves outcomes or makes outcomes worse as default could be higher do to added adverse effects. This consultant has a slight preference for not using Pto (or Eto) in the later phase in the shorter MDR regimen; but the final decision is left 23

24 to the NTP. The observational study on 500 patients from Bangladesh had excellent results and did not use Pto in the continuation phase. Pyridoxine at a dose of 25 mg/day will be added to the regimen as prophylaxis for peripheral neuropathy (increased risk in HIV co-infected patients, malnourished, diabetic, alcoholics, and pregnant women) with the use of high dose Isoniazid. If neuropathy appears it should be treated with higher dose of pyridoxine (from mg/day). If the inha mutation is detected by LPA, there is no need to use Eto or Pto in the regimen; the drugs will have no efficacy and will only add toxicity. Also, the high-dose H in the short regimenb will be highly effective. Moxifloxacin must be administered separately from antacids, iron, magnesium, and vitamins (by 4 hours). Use weight-based high-dose Mfx and Table 9 is the suggested dosing (Annex E is a suggested dosing of the new shorter MDR regimen for children). 24

25 Table 9. Weight-based dosing of anti-tb drugs in the 9-month MDR Regimen Month of treatment Taken daily for months 1-4; may be prolonged if not responding to therapy Drug Weight in KG* kg kg >50** kg Moxifloxacin (Mfx) 400 mg 600 mg 800 mg (400 mg) Pyrazinamide (Z) 1000 mg 1200 mg 1600 mg (500 mg) Ethambutol (E) 600 mg 800 mg 1200 mg (400 mg) Isoniazid (H) 300 mg 450 mg (>55 kg)** 600 mg (300 mg) Ethionamide (Eto) # 250 mg 500 mg (>55 kg)** 750 mg (250 mg) Clofazimine (Cfz) 50 mg 100 mg 100 mg (100 mg) Kanamycin (Km) 500 mg 750 mg 1000 mg 1000 mg (1 g vial) $ Taken daily for months 5-9 Moxifloxacin (Mfx) (400 mg) Pyrazinamide (Z) (500 mg) Ethambutol (E) (400 mg) Ethionamide (Eto) # (250 mg) Clofazimine (Cfz) (100 mg) 400 mg 600 mg 800 mg 1000 mg 1200 mg 1600 mg 600 mg 800 mg 1200 mg 250 mg 500 mg (>55 kg)** 750 mg 50 mg 100 mg 100 mg *For weight less than 24 kg, the regimen will be individually designed based on the pediatric doses in the PIH Guide for the Medical Management for MDR-TB, **Pto/Eto and H highest doses are given above 55kg, rather than above 50kg like the other drugs. # Pto/Eto can be given twice a day in the intensive phase if maximum doses are used and the patient has major GI side effects not responsive to anti-emetics. $ If resistant to Kanamycin and susceptible to Capreomycin, Capreomycin can be used at the same dose as Kanamycin. 25

26 Table 10 is a suggested monitoring schedule. Table 10. Monitoring schedule Monitoring & Evaluation Evaluation by a clinician specialized in PMDT Screening by DOT provider Sputum smear and culture Weight Drug susceptibility test (DST) Chest radiograph Serum creatinine and Serum potassium Thyroid stimulating Hormone (TSH) Liver serum enzymes HIV screening Pregnancy tests Hemoglobin and white blood count 9 to 11 month shorter MDR Regimen At baseline, then monthly clinical follow ups at follow up facility and quarterly at at the PMDT Referral Hospitals or PMDT Treatment Centres. At every DOT encounter. Often done at the Puskesmas as clinic-based DOT. Monthly for the full treatment. At baseline and then monthly (adjust doses if weight changes) At baseline, the minimum required DST is rifampicin by Xpert MTB/RIF. Additional DST is recommended at baseline for H, Lfx, Km, and Cm in all RR-TB patients if possible. DST to H, Lfx, Km, and Cm is recommended for all patients that remain or become culture positive despite treatment for >3 months. At baseline, and then repeat if only clinically indicated. At baseline, then monthly while receiving injectable drugs. Every 1 to 3 weeks in HIV infected patients, diabetics and other high risk patients or when indicated. Monitor monthly for signs/symptoms of hypothyroidism, obtain a TSH if signs are present. Routine screening TSH at month 3 and 6 is recommended. In patients at risk for or with symptoms of hepatitis. Monthly for HIV-infected. At baseline, and repeat if clinically indicated At baseline for women of childbearing age, and repeat when indicated For HIV-infected patients on AZT monitor monthly initially and then as needed based on symptoms for anemia Patients that do not convert by 6 months or who are determined to be clinically deteriorating at any time will be switched off the regimen and placed on an individually designed MDR-TB regimen that will include the option of using the new TB drugs (bedaquiline or delamanid). Table 11 describes a suggested strategy to determine the duration of treatment for the new shorter MDR regimen, which lasts 9 to 11 months long depending on smear microscopy. 26