WHO consolidated guidelines on tuberculosis Module 4: Treatment Online annexes Drug-resistant tuberculosis treatment WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Online annexes ISBN 978-92-4-000706-2 (electronic version) © World Health Organization 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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WHO consolidated guidelines on tuberculosis Drug-resistant tuberculosis treatment Module 4: Treatment Online annexes Contents Abbreviations and acronyms 3 Annex 1: Methods and expert panels 5 Annex 2: Declarations of interest 31 Annex 3: GRADE evidence summary tables 44 Annex 4: GRADE evidence-to-decision tables 64 Annex 5: Summaries of unpublished data 121 Annex 6: Statistical analysis plans 129 Abbreviations and acronyms 3 Abbreviations and acronyms ACSM advocacy, communication and social mobilization ACTG AIDS Clinical Trials Group ATS American Thoracic Society CDC United States Centers for Disease Control and Prevention DALY disability-adjusted life year DoI declaration of interest DR-TB drug-resistant tuberculosis DSMB Data and Safety Monitoring Board DST drug-susceptibility testing EFPIA European Federation of Pharmaceutical Industries and Associations ERG Evidence Review Group EtD evidence-to-decision (framework) EU European Union FDC fixed-dose combination FIND Foundation for Innovative New Diagnostics FTE full-time equivalent GDG Guideline Development Group GRADE Grading of Recommendations Assessment, Development and Evaluation GRC WHO Guideline Review Committee GSK Glaxo SmithKline HALT Hepatitis and Latent TB infection HIV human immunodeficiency virus Hr-TB isoniazid (H)-resistant tuberculosis IDSA United States Infectious Diseases Society of America IPD individual patient data KNCV KNCV Tuberculosis Foundation LAM lipoarabinomannan assay LSHTM London School of Hygiene & Tropical Medicine LTBI latent tuberculosis infection MDR-TB multidrug-resistant tuberculosis WHO consolidated guidelines on tuberculosis: Online annexes4 MDR/RR-TB multidrug- or rifampicin-resistant tuberculosis MSF Médecins Sans Frontières NIAID United States National Institutes of Allergy and Infectious Disease NIH United States National Institutes of Health Opti-Q Efficacy and safety of levofloxacin for the treatment of MDR-TB (study) PICO population, intervention, comparator and outcomes PMDT programmatic management of drug-resistant TB PK/PD pharmacokinetics/pharmacodynamics TB-PRACTECAL Pragmatic clinical trial for more effective, concise and less toxic MDR-TB treatment regimen(s) RCT randomized controlled trial RECRU Respiratory Epidemiology and Clinical Trials Unit (McGill University) RR-TB rifampicin-resistant TB SAE serious adverse event SIAPS Systems for Improved Access to Pharmaceuticals and Services STREAM Evaluation of a standardised treatment regimen of anti-tuberculosis drugs for patients with MDR-TB (trial) TAG Treatment Action Group TB tuberculosis TBTC Tuberculosis Trials Consortium UNION International Union Against Tuberculosis and Lung Disease UNITAID Global investment initiative for TB, HIV, malaria and Hepatitis C USAID United States Agency for International Development WHO World Health Organization WHO/GTB World Health Organization Global TB Programme XDR-TB extensively drug-resistant tuberculosis Annex 1: Methods and expert panels 5 Annex 1: Methods and expert panels A1 Methods Since 2007, the guideline development process within the World Health Organization (WHO) has been overseen by the WHO Guidelines Review Committee (GRC), which follows internationally recognized standards such as the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, to support to a structured and transparent methodology for policy-making. The policy recommendations presented here were developed following the standards and updated procedures described in the WHO handbook for guideline development.1 Initially, a WHO Guideline Steering Group was established to determine specific areas requiring up-to- date evidence, and to bring together experts to synthesize and independently review new evidence and develop recommendations (see Annex 2 and Annex 4). Also, an external review group was assembled to review the updated recommendations based on the input of the Guideline Development Group (GDG; see Annex 4). The GDG comprised researchers, epidemiologists, end-users (clinicians and national tuberculosis [TB] control programme officers), community representatives and experts in evidence synthesis. In compliance with the procedures and practices established by the GRC, declarations of interest (DOI) were managed according to the WHO Conflict of Interest Policy, including review of curricula vitae and critical evaluation of DOI. Additionally, contingent to the assessment of competing interests, the full list of members of the GDG and their biographies were published on the WHO website on 30 September 2019. This was followed by a public notice and comment period, during which WHO allowed members of the public to provide comments pertinent to any interests that might have gone unnoticed or unreported during earlier assessments. During the face-to-face GDG meeting held in Geneva, Switzerland on 12–14 November 2019, the members of the GDG reached decisions through a process of discussion and consensus. Where consensus could not be reached through discussion, the GDG voted on decisions – these decisions were noted in GRADEpro and were made based on the vote of the majority. A1.1 Preparation for evidence assessment The GRADE approach was used to rate the certainty in the estimate of effect (quality of evidence) as high, moderate, low or very low, and to determine the strength of the recommendations (as strong or conditional). A scoping proposal was submitted and approved by the WHO GRC in September 2019. Details about the preparatory work ahead of the update were released to the public through a public comment that focused on the following: the rationale for providing up-to-date guidance, including the scope of the updates; prioritization and formulation of key questions; and the list, affiliations and constituencies of potential members of the GDG undergoing conflict of interest assessments, as per the policies of the WHO Office of Compliance, Risk Management and Ethics policies. 1 WHO handbook for guideline development – 2nd edition Geneva, Switzerland World Health Organization; 2014 (https://apps.who.int/ iris/handle/10665/145714, accessed 20 March 2020). WHO consolidated guidelines on tuberculosis: Online annexes6 In preparation for the GDG meeting, four webinars were held with the group to finalize the scoping and PICO (patients, intervention, comparator and outcomes) questions, score outcomes of interest and discuss preliminary data analysis results. The PICO questions – inclusive of subpopulations, treatment regimen composition and duration, and outcomes – were agreed on by members of the GDG. The questions were framed to capture the effect of novel treatment regimens for specific populations and the value (in terms of effectiveness and safety) of adding, prolonging and combining specific anti-TB agents (see Box A1). Î In MDR/RR-TB patients, does an all-oral treatment regimen lasting <12 months safely improve outcomes when compared with other regimens conforming to current WHO guidelines? Î In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6–9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to current WHO guidelines? Î In MDR/RR-TB patients, does treatment with bedaquiline for more than six months safely improve outcomes when compared with treatment up to six months as part of regimens otherwise conforming to current WHO guidelines? Î In MDR/RR-TB patients, does concurrent use of bedaquiline and delamanid safely improve outcomes when compared with other treatment regimen options otherwise conforming to current WHO guidelines? MDR/RR-TB: multidrug-resistant or rifampicin-resistant tuberculosis; MDR-TB: multidrug-resistant tuberculosis; PICO: patients, intervention, comparator and outcomes; XDR-TB: extensively drug-resistant tuberculosis; WHO: World Health Organization. Box A1. PICO questions The PICO questions looked at the following eight distinct outcomes: successful completion of treatment; bacteriological cure by end of treatment; adherence to treatment (or treatment interruption by non- adherence); treatment failure or relapse; death during treatment; adverse reactions caused by anti-TB medicines; acquisition (amplification) of drug resistance; and sustained bacteriological cure at least 6 months after successful treatment. Members of the GDG were invited to score the outcomes as “critical”, “important” or “not important” for making recommendations on the use of specific regimens under evaluation. The scores are shown in Table A1. Annex 1: Methods and expert panels 7 Table A1. Scoring of outcomes considered relevant by the GDG for the evidence review Outcomes (as outlined in scoping proposal) Rating Survival (or death) 8.33 Relapse-free cure 8.22 Bacteriological cure by end of treatment 8.19 Successful completion of treatment (or lack of successful completion) 7.96 Treatment failure or relapse 7.93 Adherence to treatment (or treatment interruption due to non-adherence) 7.48 Acquisition (amplification) of drug resistance 7.33 Adverse events from anti-TB medicines 7.19 GDG: Guidelines Development Group; TB: tuberculosis. Note: Relative importance was rated on an incremental scale, as follows: 1–3 points: not important for making recommendations; 4–6 points: important but not critical for making recommendations; and 7–9 points: critical for making recommendations on the evaluated interventions. A1.2 Evidence gathering and analysis The evidence to inform the update and development of recommendations resulted from a cooperative effort between WHO, national TB programmes (NTPs) and partner organizations, and close collaboration a with not-for-profit product development partnership (TB Alliance). For this particular update, the following data sources were used: • Programmatic data of multidrug- or rifampicin-resistant TB (MDR/RR-TB) patients from South Africa treated with all-oral bedaquiline-containing shorter regimens, provided by the National TB Control and Management Cluster of the Department of Health of the Republic of South Africa. • Data from a single-arm study [Nix-TB] containing records on patients receiving a novel all-oral regimen consisting of bedaquiline, pretomanid and linezolid, provided by the TB Alliance. • Data for patients with MDR/RR-TB and extensively drug-resistant TB (XDR-TB) from 17 epidemiologically diverse countries treated with bedaquiline or delamanid-containing regimens, from the observational study of the EndTB project provided by the EndTB Consortium (Partners in Health, Médecins Sans Frontières, Interactive Research & Development and Unitaid). • Data from a cohort study that included records of women treated during pregnancy for MDR/RR-TB using bedaquiline-containing regimens, provided by the South African Medical Research Council. • Data resulting from a public call for records on patients from India, Republic of Belarus and Uzbekistan, treated according to WHO-recommended regimens. Only individual patient data (IPD) was used for purposes of this update. Comparator data was assembled as part of an IPD database containing records of more than 13 000 patients with MDR/ RR-TB, from 53 individual datasets from 40 countries. Sample sizes varied according to the availability of IPD for each analysable outcome. Analysable sample sizes are presented in Annex 4. The methods used to minimize bias and confounding, and to make the intervention and comparator groups as similar as possible were exact matching (HIV coinfection or antiretroviral therapy [ART] use, TB treatment history and total number of drugs the strain was resistant to) and propensity score- based matching (on age, sex, and baseline sputum acid-fast bacilli [AFB] smear result). This process was conducted with replacement using a caliper distance of 0.02 during the propensity score-based matching, to estimate the adjusted odds ratios (aORs) of outcomes and their 95% confidence intervals WHO consolidated guidelines on tuberculosis: Online annexes8 (CI). In addition, the distribution of the matched covariates within the intervention and comparator groups was further examined to assess the fidelity of the matching process. The decision process that informs and leads to the making of any recommendations goes beyond the understanding of the magnitude of the desirable and undesirable effects resulting from the implementation of a particular intervention, and beyond the certainty of the evidence assessed. It also takes into account how people who are directly affected value a given intervention in terms of the main outcomes, resource implications, cost–effectiveness, impact on equity, feasibility and acceptability. For this update, the magnitude of the desirable and undesirable effects of the interventions was evaluated through the analysis methods already described. Other critical factors that could help to inform the judgements of the GDG for making an evidence-informed assessment were considered. The evidence reviews on cost–effectiveness, values, preferences and acceptability described below were commissioned to help inform the decision-making process and the conclusions drawn on the interventions under evaluation. Evidence on cost–effectiveness Costs could be affected, for example, through changes in duration of a regimen, use or replacement of newer agents, health care delivery costs, duration of follow-up visits and safety monitoring (and type of monitoring required; e.g. electrocardiography and audiometry). Therefore, a decision analytic model, together with estimates of the efficacy and safety differences between regimens, was used to help inform any considerations for the implementation of these recommendations. The model aimed to assess the cost of changes to recommended regimens for drug-resistant TB; estimate cost–effectiveness; and identify parameters and set specific characteristics that could influence cost or cost–effectiveness, focusing2 on the use of an all-oral bedaquiline-containing shorter regimen of 9–12 months’ duration, and on the use of bedaquiline for longer than 6 months and its concurrent use with delamanid. The modelling approach used projections from existing models, incorporated into certain individual parameter estimates (e.g. transmission models for secondary cases prevented by more effective treatment, and Markov cost–effectiveness models for total costs of MDR-TB cases). Costs were evaluated from a health system perspective (see Annex 4). In addition, an economic evaluation was carried out to estimate the cost–effectiveness of a new regimen containing bedaquiline, pretomanid, and linezolid (BPaL), compared with the standard of care for patients who have XDR-TB, or have failed or are intolerant to their MDR-TB treatments, in three epidemiological settings at a given price. A Markov model was developed to follow a cohort of the intended population for the BPaL regimen. This provided the advantage of modelling both disease and treatment processes, where timing of events was important. Clinical data from the Nix-TB study were used to inform clinical efficacy of the intervention, and costing estimates were obtained through data available in the Global Health Costing Consortium database and from Value-TB (a multicounty TB costing study funded by the Bill & Melinda Gates Foundation). Evidence on values and preferences A qualitative study was undertaken to provide better understanding of the values and preferences for treatment, and perspectives on treatment acceptability, feasibility and equity. Although the goal was to gather evidence representing all individuals who would either use or be affected by the recommendations on each intervention – including policy-makers, health professionals, patients and other key stakeholders – this qualitative study was only able to capture data on patient representatives and MDR/RR-TB survivors. The methodology used to capture relevant data focused on in-depth interviews with stakeholders from high TB burden countries in Asia, Africa, Eastern Europe and South America. Fig. A1 provides an overview of the qualitative themes that reflect the values, preferences and perspectives regarding acceptability, feasibility and equity of the treatment of drug-resistant TB. 2 A separate evaluation of the BPaL regimen for the treatment of patients who have XDR-TB, or have failed or are intolerant to their MDR-TB treatments, was commissioned by the manufacturer and presented to the GDG. Annex 1: Methods and expert panels 9 Fig. A1. Overview of the main qualitative themes Values & Preferences Equity Acceptability Feasibility • Minimal life disruption • Full recovery • Independence • Informed choice • Treatment access • Social and economic burden • Prompt effective treament • Risk-priority balance • Community/ social ties • Community-based treatment • Rigorous monitoring • Individualized treatment A1.3 Certainty of evidence and strength of recommendations In assessing the quality of evidence, several factors can increase or decrease the quality of evidence. The highest quality rating is usually assigned to evidence gathered from randomized, controlled trials (RCTs), whereas evidence from observational studies, including programmatic data, is usually assigned a value of low or very low quality. The higher the quality of evidence, the more likely it is that a strong recommendation can be made (Table A2). The criteria used by the GDG to determine the quality of available evidence are summarized in Annex 4. The certainty in the estimates of effect (quality of evidence) was assessed and rated either down or up on the basis of risk of bias, inconsistency or heterogeneity, indirectness, imprecision and other considerations. Table A2. Certainty of evidence and strength of recommendations Certainty in the evidence Definition High ( ) Further research is very unlikely to change our confidence in the estimate of effect. Moderate ( ) Further research is likely to have an important impact on our confidence in the effect and may change the estimate. Low ( ) Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low ( ) Any estimate of effect is very uncertain. Through the GRADE system, the strength of a recommendation is classified as “strong” or “conditional”. The strength of a recommendation is determined by the balance between desirable and undesirable effects, values and preferences, resource use, equity considerations, acceptability and feasibility to implement the intervention. For strong recommendations, the GDG is confident that the desirable WHO consolidated guidelines on tuberculosis: Online annexes10 effects of adherence to the recommendation outweigh the undesirable effects. For conditional recommendations, the GDG considers that the desirable effects probably outweigh the undesirable effects. The strength of a recommendation has implications for the individuals affected by these guidelines (Table A3). Table A3. Perspective taken, and description of strength and conditionality of recommendations Perspective Strong recommendation Conditional recommendation From patients Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. The majority of individuals in this situation would want the suggested course of action, but many would not. From clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guidelines could be used as a quality criterion or performance indicator. Recognize that different choices will be appropriate for individual patients, and that patients must be helped to arrive at a management decision consistent with their values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences. From policy-makers The recommendation can be adopted as policy in most situations. Policy-making will require substantial debate and involvement of various stakeholders. A1.4 Assessment of the quality of the evidence The WHO guideline development process uses specific criteria to assess the characteristics of a body of evidence, such as within-study bias (methodological quality), consistency, precision, and directness or applicability of the evidence. The evidence reviewed at the November 2019 GDG meeting was primarily programmatic data or data from cohort studies, although one dataset was from an RCT. These data were assessed as having low or very low certainty, based on an assessment of the criteria described above. The low or very low certainty of the evidence reinforced the need for additional high-quality evidence (from carefully executed research studies, including RCTs) to inform policy- making. To ensure proper assessment of the quality of the evidence, quality assurance procedures were performed by the Research Institute of the McGill University Health Centre, assisted by a GRADE methodologist. Analysis of IPD data from studies or programmatic cohorts described in Section A1.1 was used to inform the development of specific recommendations. The IPD-based analyses help to reduce between-study heterogeneity; they also allow the examination of patient-level characteristics, harmonization of outcomes and exploration of variability in effectiveness. Although double-adjustment in propensity score matching analyses was carried out to remove the effects of confounding, there was still potential for bias in the effect estimates to have occurred through residual or unmeasured Annex 1: Methods and expert panels 11 confounding. Residual confounding could also have arisen from unknown factors, associated with both the exposure and the outcome, for which data were not collected. A1.5 Publication, implementation, evaluation and expiry These guidelines were prepared in accordance with the requirements of the GDG.3 They will be published on the WHO website and made freely available to download, as part of a comprehensive set of WHO consolidated guidelines on TB. They will also be communicated widely at international and regional conferences, and at meetings of programme managers in all regions. In 2020, WHO will also release an operational guide with more practical details, to support programmatic implementation of the revised recommendations. National programmes will be supported by WHO and technical and funding partners, to prepare a national plan for the programmatic management of drug-resistant TB. Implementers should create a conducive policy and programmatic environment – including national and local policies, and standard operating procedures – to facilitate implementation of the recommendations in these guidelines. This should include promoting universal health coverage and offering public financing for management of drug-resistant TB. Furthermore, dedicated resources should be allocated, including for staff development and service delivery in the community. It is important to train frontline health care staff and students in critical areas such as diagnosis, designing a regimen, patient support, monitoring response to treatment and management of adverse reactions. National programmes should ensure meaningful engagement with affected populations, their communities, the private sector, other relevant health programmes and ministries in both planning and implementing the recommendations. The uptake of these WHO recommendations will be monitored in the annual data collection of WHO Global TB Data Monitoring. WHO will update the guidelines 5 years after their publication, or earlier if new evidence becomes available that necessitates a revision. 3 WHO handbook for guideline development – 2nd edition Geneva, Switzerland World Health Organization; 2014 (https://apps.who.int/ iris/handle/10665/145714, accessed 20 March 2020). WHO consolidated guidelines on tuberculosis: Online annexes12 A2 Expert panels This section lists the participants at GDG meetings for various updates of the drug-resistant TB treatment guidelines. A2.1 WHO treatment guidelines for drug-resistant TB treatment guidelines, 2020 update GDG members 1. Holger SCHÜNEMANN (Chair) GRADE methodologist Cochrane Canada & McMaster University Hamilton, ON Canada 2. Rafael LANIADO-LABORIN (Co-Chair) Clinician; National TB programme; end-user National TB Programme Tijuana Mexico 3. Susan ABDEL RAHMAN Children’s Mercy Hospital Kansas City, MO United States of America 4. Erlina BURHAN Clinician; end-user Department of Respiratory and Pulmonology, Persahabatan Hospital Jakarta Indonesia 5. Daniela CIRILLO Laboratory specialist San Raffaele Supranational TB Reference Laboratory Milan Italy 6. Charles DALEY Pulmonologist; MDR-TB expert National Jewish Health Denver, CO United States of America 7. Geraint (Gerry) Rhys DAVIES Trials expert; Pharmacologist University of Liverpool Liverpool United Kingdom of Great Britain and Northern Ireland 8. Fernanda DOCKHORN COSTA JOHANSEN National TB programme; end-user; Clinician Ministry of Health MDR-TB referral centre Brasilia Brazil 9. Kelly DOOLEY Clinical pharmacologist; Researcher Johns Hopkins University School of Medicine Baltimore, MD United States of America 10. Bernard FOURIE Clinical trials expert University of Pretoria Pretoria South Africa 11. Agnes GEBHARD Technical agency; end-user; Clinician KNCV Tuberculosis Foundation The Hague Netherlands 12. Elmira GURBANOVA rGLC; Clinician; end-user Lung Clinic, University of Tartu Tartu Estonia 13. Muhammad Amir KHAN Civil society representatitve Association for Social Development Islamabad Pakistan 14. Yuhong LIU Clinician; end-user National Clinical Center on Tuberculosis, China CDC, Beijing Chest Hospital Beijing China (People’s Republic of ) Annex 1: Methods and expert panels 13 15. Marian LOVEDAY Specialist Scientist; maternal health medicine South African Medical Research Council Cape Town South Africa 16. Barend (Ben) MARAIS Paediatrician The University of Sydney School of Medicine Sydney Australia 17. Iqbal MASTER Clinician; MDR-TB physician; end-user King George V Hospital, Kwazulu Natal Durban South Africa 18. Alberto MENDOZA Clinician; end-user National TB Programme Lima Peru 19. Beatrice MUTAYOBA Programme Manager; end-user National TB and Leprosy Programme Dar Es Salaam United Republic of Tanzania 20. Payam NAHID Clinician; Clinical trials expert University of California SF & American Thoracic Society ATS San Francisco, CA United States of America 21. Mahshid NASEHI Programme Manager; end-user National TB and Leprosy Control Programmes Tehran Iran (Islamic Republic of ) 22. Viet Nhung NGUYEN National TB programme; end-user National TB Control Programme, Ministry of Health Hanoi Viet Nam 23. Alberto PIUBELLO Clinician; MDR-TB physician; end-user International Union Against Tuberculosis and Lung Disease Niamey Niger 24. Maria RODRIGUEZ Clinician; National TB programme; end-user Ministry of Health MDR-TB referral centre Santo Domingo Dominican Republic 25. Rohit SARIN Technical agency end-user National Institute of TB & Respiratory Diseases NITRD New Delhi India 26. Ingrid SCHOEMAN Former MDR-TB patient TB PROOF Pretoria South Africa 27. Alena SKRAHINA National TB programme; MDR-TB physician; end-user Republican Research and Practical Centre for Pulmonology and Tuberculosis Minsk Belarus 28. Carrie TUDOR Nursing specialist; Technical agency; end-user International Council of Nurses Durban South Africa 29. Debrah VAMBE National TB programme; end-user National TB Control Program Mbabane Eswatini 30. Andrew VERNON Trials expert; Technical agency end-user US Centers for Disease Control and Prevention Atlanta, GA United States of America WHO consolidated guidelines on tuberculosis: Online annexes14 Evidence reviewers 31. Jonathon CAMPBELL Epidemiologist; health economist. McGill University’s Faculty of Medicine Montreal, QC Canada 32. Amrita DAFTARY Behavioural health scientist Dahdaleh Institute for Global Health Research, York University Toronto, ON Canada 33. Gabriela GOMEZ Honorary Associate Professor London School of Hygiene and Tropical Medicine London United Kingdom of Great Britain and Northern Ireland 34. Emily KENDALL Infectious diseases dynamics; mechanistic modeling Johns Hopkins Bloomberg School of Public Health Baltimore, MD United States of America 35. Richard MENZIES Lead - Evidence reviewer McGill University’s Faculty of Medicine Montreal, QC Canada 36. Rada SAVIC Associate Professor Department of Bioengineering and Therapeutic Sciences, Division of Pulmonary and Critical Care Medicine, Schools of Pharmacy and Medicine, University of California San Francisco San Francisco, CA United States of America 37. Nick WINTERS Research Assistant McGill University’s Faculty of Medicine Montreal, QC Canada Observers 38. Draurio BARREIRA CRAVO NETO Technical manager, TB Unitaid Geneva Switzerland 39. Dan EVERITT Vice President and Senior Medical Officer, Principal Investigator Nix-TB TB Alliance New York, NY United States of America 40. Abdul GHAFOOR National TB Programme Islamabad Pakistan 41. Christopher GILPIN Migration Health Division International Organization for Migration Geneva Switzerland 42. Anisa HAJIZADEH McMaster University Hamilton, ON Canada 43. Brian KAISER Technical Officer Stop TB Partnership’s Global Drug Facility Geneva Switzerland 44. Blessina KUMAR CEO Global Coalition of TB Activists New Delhi India 45. Tamara LOTFI Research Associate Faculty of Medicine, American University of Beirut Beirut Lebanon 46. YaDiul MUKADI Technical Advisor United States Agency for International Development Washington, DC United States of America Annex 1: Methods and expert panels 15 47. Norbert NDJEKA Director, Drug-Resistant TB, TB & HIV Department of Health Pretoria South Africa 48. Eugene SUN Head of R&D TB Alliance New York, NY United States of America 49. Kitty VAN WEEZENBEEK Executive Director KNCV TB Foundation The Hague Netherlands 50. Francis VARAINE Project Lead, EndTB Project Médecins Sans Frontières Paris France 51. Mohammed YASSIN Senior Disease Advisor, TB The Global Fund to Fight AIDS, Tuberculosis and Malaria Geneva Switzerland WHO Regional Offices 52. Askar YEDILBAYEV Regional TB adviser EURO WHO/EURO Copenhagen Denmark 53. Mohammed AKHTAR Regional TB adviser EMRO WHO/EMRO Cairo Egypt 54. Vineet BHATIA representing Regional TB adviser SEARO WHO/SEARO New Delhi India WHO headquarters 55. Tereza KASAEVA, Director, GTB 56. John GROVE, Director, QNS 57. Medea GEGIA,Technical Officer, GTB/TSC 58. Lice GONZÁLEZ-ANGULO, Technical Officer, GTB/LDR 59. Malgorzata GRZEMSKA, Coordinator, GTB/TSC 60. Alexei KOROBITSYN,Technical Officer, GTB/LDR 61. Corinne MERLE, Scientist, IIR 62. Fuad MIRZAYEV, Medical Officer, GTB/LDR 63. Lorenzo MOJA, Technical Officer, IAU 64. Deusdedit MUBANGIZI, Coordinator, PQ 65. Linh Nhat NGUYEN, Technical Officer, GTB/TSC 66. Susan NORRIS, GRC Secretariat 67. Andreas REIS, Senior Ethics Officer, REK 68. Kerri VINEY, Scientist, GTB/LDR 69. Marco VITORIA, Medical Officer, TAC 70. Karin WEYER, Coordinator, GTB/LDR 71. Matteo ZIGNOL, Coordinator, THC/RTE A2.2 WHO treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018 update GDG members 1. Holger SCHÜNEMANN (Chair) Cochrane Canada & McMaster University Canada (GRADE methodologist) 2. Susan ABDEL RAHMAN Children’s Mercy Hospital, Kansas United States of America (Clinician; Pharmacologist (paediatrics)) WHO consolidated guidelines on tuberculosis: Online annexes16 3. Sarabjit S CHADHA The UNION / Regional Green Light Committee India (Technical agency end-user) 4. Daniela CIRILLO San Raffaele Supranational TB Reference Laboratory Italy (Laboratory specialist) 5. Geraint (Gerry) Rhys DAVIES University of Liverpool United Kingdom of Great Britain and Northern Ireland (Trials expert; Pharmacologist) 6. Fernanda DOCKHORN COSTA JOHANSEN Ministry of Health (MDR-TB referral centre) Brazil (National TB programme end-user; Clinician) 7. Bernard FOURIE University of Pretoria South Africa (Clinical trials expert) 8. Edwin HERRERA-FLORES Hospital Nacional (MDR-TB referral centre), Arzobispo Loayza, Lima Peru (Clinician) 9. Ayuko HIRAI Médecins Sans Frontières Papua New Guinea (Technical agency end-user; Clinician) 10. Alexander KAY Baylor Global TB Program, Mbabane Eswatini (Paediatrician) 11. Rafael LANIADO-LABORIN National TB Programme / Regional Green Light Committee Mexico (Clinician; National TB programme end-user) 12. Eden MARIANO SLB Group of TB Activists Philippines (Past MDR-TB patient) 13. Lawrence MBUAGBAW McMaster University Canada (Epidemiologist; Biostatistician) 14. Payam NAHID University of California SF & American Thoracic Society (ATS) United States of America (Clinician; Clinical trials expert) 15. Austin Arinze OBIEFUNA Afro Global Alliance Ghana (Civil society) 16. Cristina POPA Marius Nasta TB institute (MDR-TB referral centre), Bucharest Romania (Clinician) 17. Wipa REECHAIPICHITKUL University of Khon Kaen (MDR-TB referral centre) Thailand (Clinician) 18. Maria RODRIGUEZ Ministry of Health (MDR-TB referral centre) Dominican Republic (Clinician; National TB programme end-user) 19. Adman Skirry SHABANGU National TB Control Programme, Ministry of Health Eswatini (National TB programme end-user) 20. Sabira TAHSEEN National Reference Laboratory, Islamabad Pakistan (Laboratory specialist) 21. Carrie TUDOR International Council of Nursing United States of America (Nursing specialist; Technical agency end-user) 22. Zarir UDWADIA Hinduja Hospital (MDR-TB referral centre), Breach Candy Hospital and Parsee General Hospitals, Mumbai, India (Clinician) Annex 1: Methods and expert panels 17 23. Andrew VERNON US-CDC United States of America (Trials expert; Technical agency end-user) Evidence Reviewers (Observers) 24. Syed ABIDI McGill University, Montréal Canada 25. Faiz A KHAN McGill University, Montréal Canada 26. Jonathon CAMPBELL McGill University, Montréal Canada 27. Zhiyi LAN McGill University, Montréal Canada 28. Dick MENZIES McGill University, Montréal Canada Technical resource persons (observers) 29. Charles DALEY National Jewish Health (MDR-TB referral centre), Denver United States of America (Clinician; Chair of the Global Drug- Resistant TB Initiative) 30. Kelly DOOLEY Johns Hopkins University, Baltimore United States of America (Clinical trials expert; Clinician; Pharmacologist) 31. Gregory KEARNS Arkansas Children’s Hospital Research Institute United States of America (Pharmacologist (paediatrics)) 32. Anneke HESSELING (remote participation) Stellenbosch University, Cape Town South Africa (Paediatrician; Clinical trials expert) 33. Gary MAARTENS University of Cape Town South Africa (Clinician; TB/HIV specialist; Pharmacologist) 34. Norbert NDJEKA Department of Health, Pretoria South Africa (National TB programme end-user; Clinician) 35. Michael L. RICH Partners in Health, Boston United States of America (Technical agency end-user; Clinician) 36. H Simon SCHAAF (remote participation) Stellenbosch University, Cape Town South Africa (Paediatrician; Clinical trials expert) 37. Valérie SCHWOEBEL The UNION France (Technical agency end-user) 38. Shenjie TANG Beijing Chest Hospital (MDR-TB referral centre), Beijing China (Clinician) 39. Ye TUN National Expert DR-TB Committee & Thingungyun San Pya General Hospital (MDR-TB referral centre) / University of Medicine (2), Yangon Myanmar (Clinician) 40. Kitty VAN WEEZENBEEK KNCV TB Foundation, The Hague Netherlands (Technical agency end-user) 41. Francis VARAINE MSF France, Paris France (Technical agency end-user) 42. Irina VASILYEVA National Medical Research Centre of TB and Infectious Disease, Moscow Russian Federation (National TB programme end-user; Clinician) WHO consolidated guidelines on tuberculosis: Online annexes18 43. Kerri VINEY Meeting Rapporteur Sweden (WHO consultant) Trial investigators (observers; joining via webinar) 44. Lawrence GEITER Otsuka United States of America 45. Chrispin KAMBILI Johnson & Johnson United States of America 46. Carole MITNICK Partners in Health, Boston United States of America 47. Andrew NUNN Medical Research Council United Kingdom of Great Britain and Northern Ireland Other observers 48. Draurio BARREIRA CRAVO NETO UNITAID, Geneva Switzerland 49. Edward M COX US Food and Drugs Administration, Washington DC United States of America 50. Jennifer FURIN Sentinel Project United States of America 51. Brian KAISER Global Drug Facility, Stop TB Partnership, Geneva Switzerland 52. Lindsay McKenna Treatment Action Group United States of America 53. YaDiul MUKADI USAID, Washington United States of America 54. Eric PELFRENE European Medicines Agency, London United Kingdom of Great Britain and Northern Ireland 55. Anna SCARDIGLI Global Fund to Fight AIDS, TB and Malaria, Geneva Switzerland WHO headquarters Deputy Director General for Programmes Soumya SWAMINATHAN Global TB Programme Tereza KASAEVA, Director Nicola COCCO Dennis FALZON Giuliano GARGIONI Medea GEGIA Christopher GILPIN Licé GONZALEZ-ANGULO Malgosia GRZEMSKA Ernesto JARAMILLO Alexei KOROBITSYN Fuad MIRZAYEV Kefas SAMSON Karin WEYER Matteo ZIGNOL Guideline Review Committee Susan NORRIS Tropical Disease Research Piero OLLIARO Corinne MERLE HIV Department Satvinder SINGH Essential Medicines Programme Lorenzo MOJA Research, Ethics and Knowledge Management Andreas Alois REIS WHO Regional Offices Ogtay GOZALOV (EUR) Vineet BHATIA (SEAR) Annex 1: Methods and expert panels 19 A2.3 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018 update GDG members 1. Farhana AMANULLAH Consultant Paediatrician Director Paediatric TB Program The Indus Hospital, Korangi Crossing, Karachi PAKISTAN 2. Tsira CHAKHAIA (via webinar) ACSM Advisor, Civil Society Georgia USAID Georgia TB Prevention Project University Research Co., LLC Tbilisi GEORGIA 3. Daniela Maria CIRILLO Head Emerging Bacterial Pathogens Unit Fondazione Centro San Raffaele Milano ITALY 4. Kelly DOOLEY (Co-chair) Associate Professor of Medicine Pharmacology & Molecular Science Divisions of Clinical Pharmacology & Infectious Diseases Johns Hopkins University Baltimore, MD UNITED STATES 5. Luis Gustavo DO VALLE BASTOS Capacity Building Team Leader Stop TB Partnership’s Global Drug Facility (GDF) SWITZERLAND 6. Philipp DU CROS Research Advisor Médecins Sans Frontières London UNITED KINGDOM 7. Raquel DUARTE TB consultant National HIV/AIDS/TB Programme Medical School, Porto University Institute of Public Health, Porto University Porto PORTUGAL 8. Christopher KUABAN Dean, Faculty of Health Sciences University of Bamenda, Cameroon Bamenda, North West Region CAMEROON 9. Rafael LANIADO-LABORIN Head, TB Clinic, Hospital General de Tijuana Instituto Estatal de Salud de Baja California Tijuana MEXICO 10. Gary MAARTENS Faculty of Health Sciences Division of Clinical Pharmacology Department of Medicine University of Cape Town Cape Town SOUTH AFRICA 11. Andrei MARYANDYSHEV Head of Phthisiopulmonary Department Northern State Medical University Troitsky 51, 163061 - Arkhangelsk RUSSIAN FEDERATION 12. Ignacio MONEDERO-RECUERO MDR-TB and TB-HIV Consultant International Union of TB and Lung Disease (The Union) Paris FRANCE 13. Maria Imelda Josefa QUELAPIO Senior Consultant KNCV TB Foundation The Hague NETHERLANDS 14. Wipa REECHAIPITKUL Professor Department of Medicine Faculty of Medicine Khon Kaen University Khon Kaen THAILAND WHO consolidated guidelines on tuberculosis: Online annexes20 15. Michael RICH Global Health Physician Partners in Health Harvard Medical School Boston, MA UNITED STATES 16. Nancy SANTESSO (Co-chair) Assistant Professor Department of Health Research Methods, Evidence, and Impact McMaster University Hamilton CANADA 17. Rada SAVIC Associate Professor Department of Bioengineering and Therapeutic Sciences Division of Pulmonary and Critical Care Medicine Schools of Pharmacy and Medicine University of California San Francisco San Francisco, CA UNITED STATES 18. Welile SIKHONDZE National Tuberculosis Control Programme Advisor and Research Coordinator Mbabane SWAZILAND 19. Armand VAN DEUN Bacteriology Consultant Department of Biomedical Sciences Mycobacteriology Unit Prince Leopold Institute of Tropical Medicine Antwerpen BELGIUM Observers 20. Giovanni Battista MIGLIORI Director, WHO Collaborating Centre for TB and Lung Diseases Fondazione S. Maugeri, Care and Research Institute Tradate ITALY 21. Ya Diul MUKADI Medical Officer Tuberculosis Division/Infectious Disease Office Global Health Bureau Washington, DC UNITED STATES 22. Payam NAHID Professor of Medicine Division of Pulmonary and Critical Care Medicine University of California San Francisco General Hospital San Francisco CA UNITED STATES 23. Timothy RODWELL Foundation for Innovative New Diagnostics (FIND) Geneva SWITZERLAND 24. Mohammed YASSIN Senior Advisor The Global Fund Geneva SWITZERLAND Evidence Reviewers 25. Dick MENZIES Director, Respiratory Division MUHC and McGill University, Room K1.24 Montréal Chest Institute Montréal, PQ CANADA 26. Federica FREGONESE McGill University Health Centre Montréal, Quebec, CANADA WHO headquarters Secretariat 27. WEYER, Karin, Coordinator, HQ/HTM/GTB/LDR 28. FALZON, Dennis, Medical Officer, HQ/HTM/GTB/LDR 29. GAO Xu, Intern, HQ/HTM/GTB/RTE 30. van GEMERT, Wayne, Technical Officer, HQ/HTM/GTB/LDR Annex 1: Methods and expert panels 21 31. GILPIN, Christopher, Scientist, HQ/HTM/GTB/LDR 32. GONZÁLEZ-ANGULO, Lice Y., Technical Officer, HQ/HTM/GTB/RTE 33. JARAMILLO, Ernesto, Medical Officer, HQ/HTM/GTB/LDR 34. KOROBITSYN, Alexei, Technical Officer, HQ/HTM/GTB/LDR 35. MIRYAZEV, Fuad, Medical Officer, HQ/HTM/GTB/LDR 36. OLLIARO, Piero, Unit Leader, Intervention Research, HQ/HTM/TDR/IIR 37. ZIGNOL, Matteo, Scientist, HQ/HTM/GTB/TM A2.4 WHO guidelines for the treatment of drug-susceptible tuberculosis and patient care, 2017 update GDG members 1. Si Thu AUNG Deputy Director (TB) and National TB Programme Manager Department of Public Health Ministry of Health Nay Pyi Taw, Myanmar (Unable to attend the meeting) 2. Frank BONSU National TB Programme Manager Ministry of Health Accra, Ghana 3. Jeremiah Muhwa CHAKAYA Clinician National TB Programme Manager KEMRI, Nairobi, Kenya 4. Lucy CHESIRE TB ACTION Group Nairobi, Kenya 5. Daniela CIRILLO Head of Emerging Bacterial Pathogens Unit WHO Collaborating Centre and TB Supranational Reference Laboratory San Raffaele Scientific Institute Milano, Italy 6. Poonam DHAVAN Migration Health Programme Coordinator International Organization for Migration Geneva, Switzerland (Unable to attend the meeting) 7. Kelly DOOLEY Associate Professor of Medicine, Pharmacology & Molecular Sciences Divisions of Clinical Pharmacology & Infectious Diseases Center for Tuberculosis Research Faculty Leader, Janeway Firm of the Osler Residency Program Johns Hopkins University School of Medicine Baltimore, MD, United States of America 8. Kathy FIEKERT Senior TB Consultant KNCV Tuberculosis Foundation The Hague, Netherlands 9. Paula FUJIWARA Scientific Director International Union Against Tuberculosis and Lung Disease (The Union) Paris, France 10. Mike FRICK TB/HIV Project Treatment Action Group New York, NY, United States of America 11. Andrei MARYANDYSHEV Head of Phthisiopulmonary Department Arkhangelsk, Russian Federation 12. Nguyen Viet NHUNG Director of National Lung Hospital Vietnam National TB Programme Hanoi, Viet Nam 13. Ejaz QADEER Ministry of Health Islamabad, Pakistan WHO consolidated guidelines on tuberculosis: Online annexes22 14. Abdul Hamid SALIM Advisor to National TB Programme Bangladesh on Global Fund and MDR-TB TB Gate, Leprosy Hospital Compound, Mohakhali Dhaka, Bangladesh 15. Simon SCHAAF Paediatrician Paediatrics and Child Health Faculty of Medicine and Health Sciences University of Stellenbosch Stellenbosch, South Africa 16. Holger SCHÜNEMANN (Chair) Methodologist McMaster University Hamilton, Canada 17. Pedro Guillermo SUAREZ Management Sciences for Health Arlington, VA, United States of America (Unable to attend the meeting) 18. Carrie TUDOR TB Project Director International Council of Nurses Durban, South Africa 19. Justin Wong Yun YAW Head, Disease Control Division Ministry of Health Jalan Menteri Besar Brunei Evidence reviewers 20. Narges ALIPANAH Physician Santa Clara Valley Medical Center San Jose, CA, United States of America 21. Lelia CHAISSON Epidemiologist Infectious Disease Epidemiology Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore, MD, United States of America 22. Jennifer HO Woolcock Institute of Medical Research University of Sydney Australia James JOHNSTON Evaluation Lead, TB Services British Columbia Centre for Disease Control Vancouver British Columbia, Canada 23. Dick MENZIES RECRU/ Montreal Chest Institute Montreal Quebec, Canada 24. Payam NAHID Professor University of California San Francisco San Francisco, CA, United States of America Observers 25. Amy BLOOM Senior Technical Advisor Bureau of Global Health US Agency for International Development Washington, D.C., United States of America 26. Janet GINNARD UNITAID Geneva, Switzerland Members of the External Review Group (area of expertise shown in parentheses for non-WHO staff) 27. Mohammed AZIZ WHO Regional Office for the Eastern Mediterranean 28. Masoud DARA WHO Regional Office for Europe 29. Riitta DLODLO International Union Against Tuberculosis and Lung Disease (Technical agency/ programme implementation) France 30. Celine GARFIN Ministry of Health (National programme/ end-user) Philippines 31. Mirtha del GRANADO WHO Regional Office for the Americas Annex 1: Methods and expert panels 23 32. Daniel KIBUGA WHO Regional Office for Africa 33. Hyder KHURSHID WHO Regional Office for South- East Asia 34. Vaira LEIMANE Riga East University Hospital, Centre of Tuberculosis and Lung Diseases (Clinician/end-user) Latvia 35. Nobuyuki NISHIKIORI WHO Regional Office for the Western Pacific 36. Lee REICHMAN Rutgers New Jersey Medical School (Clinician/end-user) United States of America 37. Rohit SARIN National Institute of TB & Respiratory Diseases, Ministry of Health (National programme/end-user) India 38. Dalene VON DELFT TB Proof (Patient representative) South Africa 39. Fraser WARES Royal Dutch Tuberculosis Foundation (KNCV) (Technical agency/ programme implementation) The Netherlands WHO headquarters Secretariat 40. Annabel BADDELEY, GTB/THC 41. Dennis FALZON, GTB/LDR 42. Giuliano GARGIONI, GTB/TSC 43. Nebiat GEBRESSELASSIE, GTB/RTE 44. Haileyesus GETAHUN, GTB/THC 45. Lice Y. GONZÁLEZ-ANGULO, GTB/RTE 46. Malgorzata GRZEMSKA, GTB/TSC 47. Elizabeth HARAUSZ (GTB/TSC Consultant) 48. Ernesto JARAMILLO, GTB/LDR 49. Avinash KANCHAR, GTB/THC 50. Soleil LABELLE, GTB/TSC 51. Christian LIENHARDT, GTB/RTE 52. Knut LÖNNROTH, GTB/PSI 53. Fuad MIRZAYEV, GTB/LDR 54. Linh NGUYEN, GTB/TSC 55. Marco VITORIA, HIV/TAC 56. Diana WEIL, GTB/PSI 57. Karin WEYER, GTB/LDR 58. Matteo ZIGNOL, GTB/TME A2.5 WHO treatment guidelines for drug-resistant TB, 2016 update GDG members 1. Farhana AMANULLAH Associate Director Pediatric TB Program Indus Hospital Karachi Pakistan 2. Tsira CHAKHAIA ACSM Advisor, Civil Society University Research Co., LLC Tbilisi Georgia 3. Daniela Maria CIRILLO Head Emerging Bacterial Pathogens Unit San Raffaele del Monte Tabor Foundation (hSR) San Raffaele Scientific Institute Milano Italy WHO consolidated guidelines on tuberculosis: Online annexes24 4. Charles L DALEY (Co-Chair) Chief Division of Mycobacterial and Respiratory Infections National Jewish Health Denver, CO USA 5. Luis Gustavo DO VALLE BASTOS Senior Technical Advisor Center for Pharmaceutical Management Management Sciences for Health Arlington, VA USA 6. Kelly DOOLEY Associate Professor of Medicine Pharmacology & Molecular Science Divisions of Clinical Pharmacology & Infectious Diseases Johns Hopkins University School of Medicine Center for Tuberculosis Research Baltimore, MD USA 7. Carlos A TORRES-DUQUE Director Tuberculosis Department Latin American Thoracic Society Bogotá Colombia 8. Michel GASANA Manager National TB & Other Respiratory Communicable Diseases Division Ministry of Health Kigali Rwanda 9. Agnes GEBHARD Senior Consultant Team Leader of ACCESS Team Technical Division KNCV Tuberculosis Foundation The Hague Netherlands 10. Armen HAYRAPETYAN Director National TB Control Centre Ministry of Health Abovyan city Armenia 11. Antonia KWIECIEN Senior Technical Advisor Systems for Improved Access to Pharmaceuticals and Services Program (SIAPS) Management Sciences for Health (MSH) Arlington, VA USA 12. José A CAMINERO LUNA Coordinator MDR-TB Unit, International Union Against Tuberculosis & Lung Disease (UNION) General Hospital of Gran Canaria “Dr. Negrin” Las Palmas de Gran Canaria Spain 13. Sundari MASE Medical Team Lead Field Services and Evaluation Branch Division of Tuberculosis Elimination National Center for HIV, Hepatitis, STD and TB Prevention Centers for Disease Control and Prevention Atlanta, GA USA 14. Lindsay MCKENNA TB/HIV Project Officer Treatment Action Group New York, NY USA 15. Nguyen Viet Nhung Director National Tuberculosis Control Programme Hanoi Viet Nam 16. Maria RODRIGUEZ Coordinator MDR-TB National Technical Unit Ministry of Health Santo Domingo Dominican Republic 17. Holger SCHÜNEMANN (Chair) Chair and Professor Departments of Clinical Epidemiology & Biostatistics and of Medicine McMaster University Hamilton, ON Canada Annex 1: Methods and expert panels 25 18. James SEDDON Clinical Lecturer Department of Paediatrics Imperial College London United Kingdom 19. Thomas SHINNICK Associate Director Global Laboratory Activities Mycobacteriology Laboratory Branch, Division of Tuberculosis Elimination Centers for Disease Control and Prevention Atlanta, GA USA 20. Alena SKRAHINA Scientific Director Republican Scientific & Practical Centre for Pulmonology & Tuberculosis Belarus Research Institute of Pulmonology and Tuberculosis Minsk Belarus Observers (at the GDG meeting in Geneva in November 2015) 21. J Peter CEGIELSKI Team Leader MDR TB International Programs and Research Branch, Division of Tuberculosis Elimination Centers for Disease Control & Prevention Atlanta, GA USA 22. Janet Kristen GINNARD Technical Officer Strategy & Results UNITAID Geneva Switzerland 23. Giovanni BATTISTA MIGLIORI Director WHO Collaborating Centre for Tuberculosis and Lung Diseases Fondazione Salvatore Maugeri Tradate, VA Italy 24. Payam NAHID Professor of Medicine University of California, San Francisco San Francisco General Hospital Division of Pulmonary and Critical Care Medicine San Francisco, CA USA 25. Nobuyuki NISHIKIORI Regional Adviser, TB WHO Western Pacific Regional Office Manila The Philippines 26. Thomas W PIGGOTT Resident Physician McMaster University Hamilton ON Canada 27. Anna SCARDIGLI Disease Advisor, Tuberculosis Technical Advice and Partnership The Global Fund to Fight AIDS, Tuberculosis and Malaria Geneva Switzerland 28. Barbara SEAWORTH Professor of Medicine Director Heartland National TB Center University of Texas Health Science Center, Tyler San Antonio, TX USA 29. Mohammed YASSIN Technical Advisor, Tuberculosis The Global Fund to Fight AIDS, Tuberculosis and Malaria Geneva Switzerland 30. Ya Diul MUKADI Senior TB Technical Advisor Infectious Disease Division, Global Health Bureau US Agency for International Development (USAID) Washington, DC USA WHO consolidated guidelines on tuberculosis: Online annexes26 Resource persons 31. Philipp DU CROS TB Advisor Médecins sans Frontières (MSF) London United Kingdom 32. Michael L RICH Medical Officer Partners in Health Harvard Medical School Boston, MA USA 33. Abdul Hamid SALIM Advisor, NTP Bangladesh TB Gate, Leprosy hospital Compound Mohakhali Dhaka Bangladesh 34. Valérie SCHWOEBEL Medical Officer International Union Against Tuberculosis & Lung Disease (UNION) Paris France 35. Francis VARAINE International Medical Coordinator Médecins sans Frontières (MSF) Paris France 36. Askar B. YEDILBAYEV Medical Officer Partners in Health Boston, MA USA External Review Group 37. Chen-Yuan CHIANG International Union Against Tuberculosis and Lung Disease (UNION) Paris France 38. Celine GARFIN Infectious Diseases for Prevention and Control Division Disease Prevention and Control Bureau Department of Health Manila The Philippines 39. Michael KIMERLING KNCV Tuberculosis Foundation The Hague Netherlands 40. Vaira LEIMANE National TB Programme Ministry of Health Riga Latvia 41. Guy MARKS International Union Against Tuberculosis and Lung Disease (UNION) Paris France 42. Gao MENGQIU Beijing Chest Hospital Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute Beijing China 43. Norbert NDJEKA Drug Resistant TB, TB & HIV Department of Health Pretoria South Africa 44. Ejaz QADEER National TB Programme Ministry of Health Islamabad Pakistan 45. Lee REICHMAN Rutgers University New Jersey, NJ USA 46. Rohit SARIN LRS Institute of TB and Respiratory Diseases Delhi India 47. Irina VASILYEVA Central Tuberculosis Research Institute (CTRI) Moscow Russian Federation 48. Dalene VON DELFT TB Proof South Africa Annex 1: Methods and expert panels 27 Evidence Reviewers 49. Mayara LISBOA SOARES DE BASTOS McGill University Montreal, Qc Canada 50. Gregory J FOX* University of Sydney Spit Junction, NSW Australia 51. Rebecca HARRIS London School of Hygiene and Tropical Medicine London United Kingdom 52. Anneke HESSELING Paediatric TB Research Programme Desmond Tutu TB Centre Department of Paediatrics and Child Health Faculty of Medicine and Health Sciences Stellenbosch University Cape Town South Africa 53. Faiz KHAN Faculty of Medicine, McGill University Montreal Chest Institute McGill University Health Centre Montreal, Qc Canada 54. Mishal KHAN London School of Hygiene and Tropical Medicine London United Kingdom 55. Dick MENZIES Montreal Chest Institute McGill University Health Centre Montreal, Qc Canada WHO Guideline Steering Committee 56. Dennis FALZON, LDR/GTB 57. Nathan FORD, TAC/HIV 58. Giuliano GARGIONI, TSC/GTB 59. Haileyesus GETAHUN, THC/GTB 60. Malgorzata GRZEMSKA, TSC/GTB 61. Ernesto JARAMILLO, LDR/GTB 62. Avinash KANCHAR, THC/GTB 63. Soleil LABELLE, TSC/GTB 64. Christian LIENHARDT, PSI/GTB 65. Knut LÖNNROTH, PSI/GTB 66. Alberto MATTEELLI, THC/GTB 67. Fuad MIRZAYEV, LDR/GTB 68. Linh Nhat NGUYEN, LDR/GTB 69. Marco Antonio VITORIA, TAC/HIV 70. Fraser WARES, LDR/GTB 71. Diana WEIL, PSI/GTB 72. Karin WEYER, LDR/GTB 73. Matteo ZIGNOL, TME/GTB WHO Consultant 74. Elizabeth HARAUSZ A2.6 WHO guidelines for the programmatic management of drug- resistant tuberculosis, 2011 update GDG members (area of expertise shown in parentheses) 1. Jaime BAYONA Socios En Salud Sucursal (Programme management, public health) Peru 2. José A. CAMINERO University General Hospital of Gran Canaria, Spain and The UNION (Clinical practice) Paris, France * Affiliated with McGill University for the evidence reviews done for these guidelines WHO consolidated guidelines on tuberculosis: Online annexes28 3. Charles L. DALEY National Jewish Health, (clinical practice) United States of America 4. Agnes GEBHARD KNCV Tuberculosis Foundation (Programme management) Netherlands 5. Myriam HENKENS, Médecins Sans Frontières (Programme management) France 6. Timothy H. HOLTZ HIV/STD Research Program, United States Centers for Disease Control and Prevention–CDC, Asia Regional Office (Epidemiology, surveillance, programme evaluation) Thailand 7. Joël KERAVEC Management Sciences for Health (Drug management) Brazil 8. Salmaan KESHAVJEE Harvard Medical School (Programme management, public health) United States of America 9. Aamir J. KHAN Indus Hospital TB Program (Epidemiology, programme management) Pakistan 10. Vaira LEIMANE State Infectology Center Clinic of Tuberculosis and Lung Diseases (Programme management, clinical practice) Latvia 11. Andrei MARYANDYSHEV Northern State Medical University Archangelsk (Clinical practice) Russian Federation 12. Carole D. MITNICK Harvard Medical School (Epidemiology, programme support) United States of America 13. Gloria NWAGBONIWE Alliance for Hope, (Civil society) Nigeria 14. Domingo PALMERO Pulmonology Division Hospital Muñiz, (Clinical practice) Argentina 15. Ma. Imelda QUELAPIO Tropical Disease Foundation, (Programme management) Philippines 16. Michael L. RICH Partners In Health (Clinical practice) United States of America 17. Sarah ROYCE PATH (Surveillance, public health) United States of America 18. Sabine RÜSCH-GERDES National Reference Centre for Mycobacteria, (Laboratory specialist) Germany 19. Archil SALAKAIA Management Sciences for Health, (Programme management) United States of America 20. Rohit SARIN LRS Institute of TB and Allied Diseases, (Clinical practice) India 21. Holger SCHÜNEMANN McMaster University (Chairman of the Guideline Development Group; epidemiology, guideline methodology) Canada 22. Elena SKACHKOVA Federal Centre of TB Monitoring, (Surveillance) Russian Federation 23. Francis VARAINE Médecins Sans Frontières (Clinical and programme management) France Annex 1: Methods and expert panels 29 WHO headquarters, Geneva, Switzerland TB Department 24. Léopold BLANC 25. Dennis FALZON 26. Christopher FITZPATRICK 27. Katherine FLOYD 28. Haileyesus GETAHUN 29. Malgorzata GRZEMSKA 30. Christian GUNNEBERG 31. Ernesto JARAMILLO 32. Christian LIENHARDT 33. Fuad MIRZAYEV 34. Paul NUNN 35. Mario C. RAVIGLIONE 36. Delphine SCULIER 37. Fraser WARES 38. Karin WEYER 39. Matteo ZIGNOL HIV Department 40. Chris DUNCOMBE 41. Marco Antonio DE AVILA VITORIA External Review Group (area of expertise shown in parentheses for non-WHO staff) 42. Samiha BAGHDADI WHO Regional Office for the Eastern Mediterranean Egypt 43. Mercedes BECERRA Harvard Medical School (Academia) United States of America 44. Vineet BHATIA WHO Regional Office for South-East Asia India 45. Masoud DARA WHO Regional Office for Europe Denmark 46. Mirtha DEL GRANADO WHO Regional Office for the Americas United States of America 47. Reuben GRANICH WHO HIV Department Switzerland 48. Lindiwe MVUSI Department of Health (Programme management) South Africa 49. Nani NAIR WHO Regional Office for South- East Asia India 50. Norbert NDJEKA Department of Health (Programme management, clinical practice) South Africa 51. Wilfred A.C. NKHOMA WHO Regional Office for Africa, Zimbabwe 52. Katsunori OSUGA WHO Regional Office for the Western Pacific Philippines 53. Hendrik Simon SCHAAF Department of Paediatrics and Child Health, Stellenbosch University and Tygerberg Children’s Hospital (Clinical practice, paediatric MDR-TB, surveillance) South Africa 54. Catharina VAN WEEZENBEEK WHO Regional Office for the Western Pacific, Philippines 55. Irina VASILYEVA Central TB Research Institute of RAMS (Research, clinical practice) Russian Federation 56. Wang Xie XIU Tianjin Centers for Disease Control and Prevention (Surveillance) China 57. Richard ZALESKIS WHO Regional Office for Europe Denmark WHO consolidated guidelines on tuberculosis: Online annexes30 Evidence review teams 58. Chunling LU Harvard Medical School United States of America 59. Carole D. MITNICK Harvard Medical School United States of America 60. Richard A. WHITE Harvard Medical School United States of America 61. Gail KENNEDY University of California (San Francisco) United States of America 62. George RUTHERFORD University of California (San Francisco) United States of America 63. Karen STEINGART University of California (San Francisco) United States of America 64. Matthew ARENTZ University of Washington United States of America 65. David HORNE University of Washington United States of America 66. Patricia PAVLINAC University of Washington United States of America 67. Judd L. WALSON University of Washington United States of America 68. Melissa BAUER McGill University Canada 69. Richard (Dick) MENZIES McGill University Canada 70. Olivia OXLADE McGill University Canada 71. Patricia WHYTE Griffith University Queensland (Guideline development) Australia Annex 2: Declarations of interest 31 Annex 2: Declarations of interest A2.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020 In conformity with WHO guidelines for declaration of interests for WHO experts issued by the WHO Office for Compliance and Risk Management and Ethics, members of the Guideline Development Group, External Review Group and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DOIs) and declare in writing any competing interest (whether academic, financial or other) which could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DOI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Office for Compliance and Risk Management and Ethics was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included as members of the Guideline Development Group. As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public ahead of the meeting (https://www.who. int/tb/areas-of-work/drug-resistant-tb/treatment/drug-resistant-tb-gdg/en/). This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments. Guideline Development Group The following Guideline Development Group members declared no conflicts of interest: Holger Schünemann (Chair); Rafael Laniado-Laborin (Co-Chair); Erlina Burhan; Fernanda Dockhorn Costa Johansen; Bernard Fourie; Elmira Gurbanova; Muhammad Amir Khan; Marian Loveday; Mahshid Nasehi; Ben Marais; Beatrice Mutayoba; Maria Rodríguez; Debrah Vambe; and Nguyen Viet Nhung. One member of the Guideline Development Group submitted additional information, which required no further action as this did not result in any conflict. • Ingrid Schoeman: As an XDR-TB survivor, she went through the side-effects of being on treatment for 2 years. She works at TB Proof, and advocacy organisation which is often invited to attend key stakeholder meetings where they share the experiences of DR-TB survivors and advocated for high-quality TB care. She has been employed by TB Proof since 2017. She is certain that better evidence-based guidelines for treating DR-TB would benefit her colleagues, friends and local communities. Six members of the Guideline Development Group declared interests that were judged non-significant and were believed not to affect the independence and impartiality of the experts during the guideline development process. Therefore, no restrictions to their participation applied: • Charles Daley: Participation in the Data Monitoring Committee (DMC) for delamanid. A total of 5000 USD by Otsuka Pharmaceutical for services rendered in 2016 as the Chairman of the Committee. Participation in the DMC for pediatric trials of delamanid (Role Member). A total of 4000 USD by Otsuka Pharmaceutical for current services as a member of the Committee. WHO consolidated guidelines on tuberculosis: Online annexes32 • Gerry Davies: Participation in the PreDiCT-TB consortium, a public-private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Role as academic coordinator (2012–2017) led to engagement with industrial partners in pre-competitive areas of research into TB drug development. All of these activities were fully supported by public funding from the European Union. No financial support was received from EFPIA. Current collaborator on pharmacokinetic sub-studies deriving from the STREAM Stage 1 trial. Funding support will be provided through research institution [University of Liverpool] to support analysis of pharmacokinetic samples and data later in late 2019/early 2020. This works focuses on evaluating clofazimine and fluoroquinolones. Academic co-supervisor of PhD candidate who is currently involved in the TB-PRACTECAL trial (chief investigator) at the London School of Hygiene and Tropical Medicine. Funding support will be provided through research institution [University of Liverpool] from Médecins Sans Frontières to support analysis of pharmacokinetic samples in early 2020. This work will involve bedaquiline, pretomanid, clofazimine, linezolid and moxifloxacin. • Yuhong Liu: China’s New Drug Introduction and Protection Program (NDIP) was supported by the Bill & Melinda Gates Foundation (BMGF) and Janssen Pharmaceutica. Bedaquiline was provided by Janssen Pharmaceutica through the global donation project (4000 patients) . BMGF and Janssen Pharmaceutica also project support to doctors’ training, project activity implementation, quality control, etc. A total of 500 000 USD were provided for project implementation by BMGF including training, data collection, project supervision, between 2016–2020. Financial interests (resulting from funding source) that could directly affect, or could appear to affect, the professional judgment of the expert were not identified. • Iqbal Master: Non-monetary support provided by Janssen Pharmaceutica to attend the 2016 International Lung conference in Liverpool. Only flights and accommodation were sponsored. No direct or indirect payments were made. As a manger in the MDR unit, I provide a link for the implementation of research studies, including STREAM 1 and the Nix-TB trial from 2013 onwards. I received no monetary support or remuneration for involvement in these studies. My involvement was purely from an altruistic wish to facilitate research in order to improve treatment regimens and outcomes in MDR patients in general. As a Government official, working in at a public health hospital, participation in the roll-out of bedaquiline and delamanid through a Clinical access programme, launched by the National TB programme. Member of the Provincial and National MDR-TB Advisory Committee of South Africa which makes recommendations and advises Government sites on clinical management. • Payam Nahid: Federal CDC contract to support clinical trial units in San Francisco and Hanoi, Vietnam United States Centers for Disease Control and Prevention University of California, San Francisco Federal contract to support clinical trial units in San Francisco and Hanoi, Vietnam. Participation as a member of the DSMB for an MDR-TB clinical trial, TB-PRACTECAL. All DSMB related materials are obviously kept confidential. Discussions are underway with Médecins Sans Frontières (MSF) for future potential participation of Vietnam clinical trial units in Hanoi and HCMC in EndTB MDR -TB clinical trials. No contracts or agreements have been offered, signed or formalized. If agreements are formalized, enrolments into the EndTB trials would be anticipated to begin in 2020. • Carrie Tudor: Grant from Eli Lilly Foundation – Lilly MDR-TB Partnership for TB Project managed by the International Council of Nurses. Award of approximately USD 1 000 000 from 2013–2019. The below-mentioned members of the Guideline Development Group declared interests which were judged to be significant and which required further discussion and assessment by the WHO Office for Compliance and Risk Management and Ethics to outline a management plan: • Susan Abdel-Rahman: (Significant) Research Support from the Thrasher Foundation for an amount of 197 000 USD. Funding ended on 30 October 2017. The Thrasher Research Fund provides grants for paediatric medical research. The Fund is currently supporting over 150 projects, including but not limited to research on childhood blindness, nutritional deficiencies, brain injuries, diabetes, asthma, cancer, genetic diseases and a number of infections including HIV, malaria, TB, schistosomiasis, cytomegalovirus and otitis media. Employment & Consultancies: WHO Agreement Annex 2: Declarations of interest 33 for performance of work to conduct a summary review of preclinical and EBA data on pretomanid use. Financial interests (resulting from research support) that could directly affect, or could appear to affect, the professional judgment of the expert were not identified. Financial interest resulting from WHO Agreement for performance of work may be perceived to compromise the expert’s objectivity or independent professional judgment in the discharge of GDG duties and responsibilities led to partial exclusion from decision-making and voting limited to BPaL regimen. • Daniela Cirillo: Research grant to measure minimum inhibitory concentrations (MIC) for bedaquiline. Work sponsored through the Ospedale San Raffaele by Janssen Therapeutics. The amount granted was 50 000 USD in 2018. Research grant to study MIC distributions for new TB drugs. Work sponsored through the Ospedale San Raffaele by the TB Alliance. The amount granted was 30 000 USD in 2018. Payment for MIC work for new TB drugs was done through Ospedale San Raffaele and not direct to the individual. Although these interests are tangentially related to the subject of the current guideline development meeting (i.e. diagnostics), a significant conflict of interest was identified for participation in the decision-making process and voting related to funding from the TB Alliance, leading to partial exclusion from decision-making and voting limited to BPaL regimen. • Kelly Dooley: Participation as PI of the “Assessing Pretomanid for TB (APT)” trial, assessing pretomanid for treatment of drug-sensitive TB. Support and funding is from the U.S. FDA. Drug donation from TB Alliance (pretomanid) and Pfizer (rifabutin). No salary support. Participation as investigator on trials sponsored by the NIH, FDA, the U.S. CDC or UNITAID, assessing: Use of rifapentine for TB infection in pregnant women, young children, patients with HIV co-infection; use of rifapentine for treatment shortening in patients with pulmonary TB (rifapentine donated by Sanofi); use of high-dose rifampin and levofloxacin for pediatric TB meningitis (NIH funded); use of high-dose isoniazid for MDR-TB (NIH funded, ACTG A5312); delamanid for MDR-TB in children with HIV infection (NIH funded, IMPAACT 2005; drug donation by Otsuka); bedaquiline for children with MDR-TB and HIV infection (NIH Funded, IMPAACT 1108); meropenem/amox/clav for drug- sensitive- and MDR-TB (FDA funded). No salary support. Protocol Co-Chair ACTG study A5343 assessing use of delamanid and bedaquiline among patients with MDR-TB. Drug donation by Otsuka, Janssen and ViiV Healthcare. Support and funding for this trial are provided by the U.S. NIH, Division of AIDS (DAIDS); no salary support. Involvement in the DELamanId BEdaquiline for ResistAnt TubErculosis study (A53439) led to partial exclusion limited to discussions and voting processes related to the combined use of bedaquiline and delamanid. • Agnes Gebhard: Research grant provided to KNCV by the TB Alliance to conduct a situational analysis in 3 countries (Indonesia, Kyrgyzstan, Nigeria) to understand the current infrastructure, resources, and practices for management of all forms of TB, and potential hurdles for integrating regimens (BPaL, BPaMZ, separately and together as a comprehensive solution to TB treatment). Research grant provided by the TB Alliance (305 000 USD – Between 2018 and 2019) to develop a country roadmap for introduction of new regimens. Four countries were chosen as examples (Kazakhstan, Kyrgyzstan, Uzbekistan and Indonesia). These roadmaps are flexible for use with any new (DR) TB regimen. Public support for the approval of Pretomanid in combination with bedaquiline and linezolid submitted to the U.S. FDA Antimicrobial Drugs Advisory Committee in response to a request for comments. The letter is in the public domain (https://www.regulations.gov/ docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=0&dct=PS&D=FDA-2019-N-1317). Financial interest (Institutional) resulting from research grants provided by the TB Alliance led to partial exclusion from decision-making and voting limited to BPaL regimen. • Alberto Piubello: Involvement in the Union-sponsored study “Treatment Regimen of Anti- tuberculosis Drugs for Patients With Multi-Drug-Resistant TB (STREAM), Stage 2” led to partial exclusion from decision-making and voting limited to the all-oral bedaquiline-containing shorter regimen. • Alena Skrahina: Principal Investigator in the Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) led to partial led to partial exclusion from decision-making and voting limited to BPaL regimen. WHO consolidated guidelines on tuberculosis: Online annexes34 • Andrew Vernon: Work in the Division of TB Elimination at CDC which involved collaboration with NIH and Sanofi on the conduct of a multinational phase 3 trial of TB treatment using daily rifapentine. Sanofi provided medications for the trial, and has supported costs of PK testing. Total contribution to CDC Foundation was ~$3million (from 2007–17). No payment was received through these funds. Moreover, these funds were only a small proportion of overall trial costs, the vast majority of which were borne by CDC as the trial sponsor. In his capacity as a TB researcher and clinician at CDC, Andrew participated in meetings, both internal and external, concerned with the development of guidelines for the treatment of active TB and of LTBI in the United States. Role of the U.S. CDC as temporary voting members within the U.S. FDA’s Antimicrobial Drugs Advisory Committee Meeting. The latter interest led to partial exclusion from decision-making and voting limited to BPaL regimen. External Review Group The following External Review Group members declared no conflicts of interest: Heather ALEXANDER, Sarabjit Singh CHADHA, Lisa CHEN, Edwin H HERRERA-FLORES, Anna Marie Celina GARFIN, Mathilde JACHYM, Giovanni Battista MIGLIORI, Thato MOSIDI, Welile SIKHONDZE, Bhabana SHRESTHA, Ivan SOLOVIC, Carlos TORRES, Zarir UDWADIA. The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines: • Amanullah FARHANA: Declared that she has been employed and undertaken consultancy work for WHO and that she has had research activities funded by WHO and the Global Fund. • Guy MARKS: Is the President of The Union (IUATLD), which undertakes projects and work in the field of MDR-TB. He is an investigator on the VQUIN trial, an investigated-initiated, publicly funded study on preventive therapy for contacts of patients with MDR-TB. • Andrei MARYANDYSHEV: Declared research undertaken on MDR/RR-TB. The new TB drugs were investigated in the clinical trials in the hospital where Dr Maryandyshev works, i.e. Arkhangelsk clinical antituberculosis dispensary, Russian Federation where he was a main investigator. He participated in the clinical trials of new TB drugs: TMC207-TiDP13-C209 and TMC207TBC3001 phase II-III from 1.02.2012 to 3.10.2016; “An international, multicenter, prospective, randomized, double-blind, controlled study evaluating the efficacy and tolerability of a chemotherapy regimen including SQ 109 in pulmonary tuberculosis patients with multiple drug-resistant M. tuberculosis (phase IIc-III) from 19.08.2014 to 13.07.2016; PBTZ169-A15-C2b-1 “An international multicenter, double- blind, placebo-controlled, randomized trial to evaluate the efficacy, safety, and pharmacokinetics of PBTZ169 when used in combination therapy for patients with respiratory tuberculosis with bacterial excretion and drug resistance, phase IIb-III” from 13.12.2016 to 29.05.2017; Compassionate use of Delamanid (OPC-6768) for patients MDR TB, 6.12.2016 his hospital has received Delamanid for 5 patients from Otsuka company. • Lawrence MBUAGBAW: Undertook a biostatistical consultation to support FDA reporting requirements for the use of bedaquiline, for Janssen Pharmaceuticals for which he received payment. • Anuj K BHATNAGAR: Is the Co-Principal investigator for the STREAM 2 trial (Medical Research Council Clinical Trials Unit, London), for the Rajan Babu Institute of Pulmonary Medicine and Tuberculosis (RBIPMT) site, Delhi in India. The trial was initiated in this site in March 2019. The monetary aspects of the trial are being looked after by Vital Strategies as an affiliate of IUATLD for refurbishment of the ward, equipment, hiring of staff, upgrading laboratory facilities, access to all laboratory tests and patient support including monetary compensation. No money has been transferred to the institute for this trial. In addition, the National Institute for Research in Tuberculosis, Chennai (NIRT), an organization of the Indian Council of Medical Research (ICMR), Ministry of Health and Family Welfare, Government of India has initiated a Phase 3 trial – called BEAT TB, to study the efficacy and tolerability of a combination of newer drugs for shortening the treatment for pre-XDR and XDR-TB in 5 sites of India. At the RBIPMT site, of which Dr Bhatnagar is the Principal Investigator for this trial, they have just completed a site initiation visit and recruitment of personnel. Annex 2: Declarations of interest 35 The first instalment of the grant for the initiation of this trial by NIRT Chennai has been given for recruitment of staff, equipment, laboratory reagents and patient and DOT provider support. Evidence reviewers: The following experts who conducted the evidence for to inform the revision of the recommendations declared the below interests, which require no action beyond reporting for transparency purposes. • Amrita Daftary: Columbia University Consultancy (2016–2021) – This is an ongoing consultancy to provide qualitative expertise to the design and evaluation of an adherence intervention in people with XDRTB-HIV in KwaZulu Natal, South Africa. Commissioned qualitative research for current GDG meeting. IC-IMPACTS funded grant (2015 – 2018) – study has been completed at McGill University; this was an intervention to engage pharmacy providers in Patna, India, to screen and refer TB symptomatic persons for a chest x-ray and doctor for timely TB detection. BMGF funded grant (2017–2020) – This study is held at McGill University where she was based until June 2019; this is an observational study using standardized patients to assess quality of clinical care for TB diagnosis in Cape Town and Durban, South Africa. NIH funded grant (2018 – 2020) – study is based at CAPRISA and Columbia University; this is an intervention to reduce XDRTB-HIV stigma in coinfected patients in KwaZulu Natal, South Africa. • David Dowdy: Research grant Bill and Melinda Gates Foundation Grant to Institution (not owned by me) approx $300,000 current year interest, approximately $50,000. Travel to meetings Bill and Melinda Gates Foundation Travel paid for me to attend, approx. $10,000. • Gabriela Gomez: Consultant providing modelling results for an investment case on a universal drug regimen for TB. Direct funding granted through BMGF for an amount of USD 40000. Funding concluded in 2018. Managed research grant to LSHTM for an economic evaluation of TB-PRACTECAL. Funding provided through MSF to research unit. Approximately £ 150 000. Her involvement stopped August 2019, although the project continues. In addition, a second grant from TB Alliance was granted to conduct an economic evaluation of the BPaL regimen. Approximately £ 60 000. Since 12 August 2019, she has been employed by Sanofi Pasteur. She is the lead for Europe in Vaccine Epidemiology and Modelling. There is no TB vaccine in the commercial pipeline of Sanofi Pasteur to her knowledge currently. She was not representing Sanofi Pasteur at this meeting, but only presenting work done as part of her previous position as Associate Professor at LSHTM. • Richard Menzies: Commissioned WHO evidence reviews (2016-current) to identify, assess and synthesize the evidence for the development of guidelines for treatment of MDR-TB. • Rada Savic: She received research funding from NIH, UNITAID and BMGF. Research funding to her institution (UCSF) where she is a principal investigator. She serves on Scientific Advisory Committee for TB Alliance, but receives no income for that role. She is a member of Core Science Group for NIH clinical trial network (ACTG) and for CDC clinical trial consortia (TBTC). A2.2 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 Guideline Development Group The scope of the guidelines update and the composition of the Guidelines Development Group (GDG), including the biographies of the members, were made public for comment ahead of the meeting, in line with WHO requirements (https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg- meeting-mdr-rr-tb-treatment-2018-update/en/). All GDG members completed the WHO Declaration of interest (DoI) form and agreed to the confidentiality undertaking. The WHO Guideline Steering Committee reviewed the completed forms. The following GDG members declared no interests conflicting with the objectives of the guidelines: Eden ABADIANO MARIANO, Sarabjit S CHADHA, Fernanda DOCKHORN COSTA JOHANSEN, Edwin WHO consolidated guidelines on tuberculosis: Online annexes36 HERRERA-FLORES, Ayuko HIRAI, Alexander KAY, Rafael LANIADO-LABORIN, Lawrence MBUAGBAW, Austin Arinze OBIEFUNA, Cristina POPA, Wipa REECHAIPICHITKUL, Maria RODRIGUEZ, Holger SCHÜNEMANN, Adman Skirry SHABANGU and Sabira TAHSEEN. The following GDG members declared interests that were judged not to be in conflict with the objectives of the guidelines: Susan ABDEL-RAHMAN declared that a research grant (US$ 196 356) was received by her institution from the Thrasher Foundation in September 2017 for her role as Principal Investigator to study whether second-line TB medicines can be accurately quantified from dried blood spots (funding ongoing). Daniela CIRILLO declared that a grant (US$ 26 000) was provided to her research unit by the Foundation for Innovative New Diagnostics (FIND) to evaluate new TB diagnostics (funding ongoing). In 2014, she received funding from Janssen (US$ 10 000) and Otsuka (US$ 25 000) for work on drug-susceptibility testing (DST) of new drugs. In 2014, Janssen Italy funded her participation in an expert working group on the use of bedaquiline in Italy (US$ 1000). Geraint (Gerry) Rhys DAVIES declared that he was until November 2017 the academic coordinator of the PreDiCT-TB consortium, a public–private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Although this role involved engagement with industrial partners (GSK, Sanofi, Janssen) in pre-competitive areas of research into TB drug development, these activities were fully supported by public funding from the European Union (EU) and neither he nor his research institution have received any funding from EFPIA or from the individual industrial partners. He has been asked and intends to provide advice to the STREAM study team on possible PK studies, which may be carried out in future using existing or further prospectively collected samples (no payment or research support has been offered for this activity). In 2017, he was paid fees by WHO for expert consultancies (US$ 5000). He is a member of a steering group convened by Critical Path to TB Regimens to advise on development of the lipoarabinomannan (LAM) biomarker developed by Otsuka in the context of adaptive clinical trials (receives no payment for this activity). Bernard FOURIE declares receiving US$ 16 000 per year (ongoing) to act as a non-executive director and member of the Board of the National Bioproducts Institute in South Africa, which is exclusively involved in the production and marketing of blood- and plasma-derived products. Payam NAHID declares an ongoing Federal US Centers for Disease Control and Prevention (CDC) contract to the University of California San Francisco to support clinical trial units in San Francisco and Viet Nam (total amount not specified). Carrie TUDOR declares that her employer receives funding from the Eli Lilly Foundation (~US$ 1000 000 for 2013–2017; ongoing at US$ 243 000 in 2018) to run the International Council of Nurses’ TB/MDR-TB project. The project focuses on building the capacity of nurses and allied professionals on TB and DR-TB care through training and currently operates in China, Eswatini, Ethiopia, Lesotho, Malawi, the Russian Federation, Uganda and Zambia. She also received US$ 20 000 from the KwaZulu Natal Research Institute for TB & HIV (South Africa) and Fogarty/NIH (US) for her dissertation and postdoctoral research on TB until 2014. Zarir UDWADIA declares that he has supported about 40 patients to access bedaquiline and three patients to access delamanid through the compassionate use programmes of Janssen and Otsuka, respectively. He declares that he did not charge fees to the patients involved and there were no financial transactions with the manufacturers. Andrew VERNON declares that he heads a clinical research group at US CDC (Tuberculosis Trials Consortium [TBTC]) doing TB trials. TBTC often collaborates with pharmaceutical companies, which may provide modest support, e.g. drug supplies, funding for PK sub-studies. Sanofi Aventis awarded ~US$ 2.8 million in six unrestricted grants to CDC Foundation in 2007–2015 to facilitate or support TBTC work on rifapentine (e.g. PK studies, staff contracts, travel for invited speakers, preparation of data to support regulatory filings). These funds have not otherwise benefited the research group. TBTC has studies under way with rifapentine (TBTC Study 31) and levofloxacin (Opti-Q, TBTC Study 32). He declares that his branch has supported studies of drug-susceptible TB that have included moxifloxacin (TBTC Study 27, Study 28 and Study 31). His branch has also supported enrolment at two of the three sites involved in the Opti-Q Study. This study evaluates different doses of levofloxacin in the treatment of DR-TB and has no comparator arm. There is no involvement with drug procurement. The principal investigator and management of the study, including data handling, analysis and drug Annex 2: Declarations of interest 37 procurement, are at Boston University. The Opti-Q outcomes are not yet known and the final analysis has yet to start. The majority of the study was funded by the US NIH (National Institutes of Allergy and Infectious Diseases [NIAID]). The following GDG member declared an interest that was judged to conflict with the objectives of the guidelines (funding for new medicines for use in MDR-TB regimens). He therefore withdrew from the GDG panel and participated as a technical resource. Gary MAARTENS declared that his laboratory will receive US$ 2 184 608 from the US NIH (NIAID) to undertake drug assays for a trial on the safety, tolerability and PK of bedaquiline and delamanid, alone and in combination, among patients on MDR-TB treatment (AIDS Clinical Trials Group study A5343). He will receive no salary support. External Review Group (ERG) The following ERG members declared no interest conflicting with the objectives of the guidelines: Essam ELMOGHAZI, Mildred FERNANDO-PANCHO, Anna Marie Celina GARFIN, Barend (Ben) MARAIS, Andrei MARYANDYSHEV, Alberto MATTEELLI, Giovanni Battista MIGLIORI, Nguyen Viet NHUNG, Rohit SARIN, Welile SIKHONDZE, Ivan SOLOVIC, Pedro SUAREZ and Carlos TORRES. The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines: Thato MOSIDI declares that she represents people affected by and living with TB on the Global Fund Country Coordinating Mechanism in South Africa. She is also an active member of TB Proof, a not- for-profit organization that advocates for patient access to TB medicines. The following evidence reviewers were from McGill University, Montréal, Canada – Syed ABIDI, Jonathon CAMPBELL, Zhiyi LAN and Dick MENZIES. They declared no interest conflicting with the objectives of the guidelines. The following evidence reviewer declared interests that were judged not to be in conflict with the objectives of the guidelines: Faiz Ahmad KHAN declared payment by WHO to collect data and carry out a meta-analysis on the shorter MDR-TB regimens for the 2016 guidelines (CAD$ 4080) and travel fees to present these findings at a GDG meeting in 2015. He also declares undertaking an update of the same analysis in 2016–2018 for the ATS guidelines for which he receives no remuneration. A2.3 WHO treatment guidelines for isoniazid- resistant tuberculosis, 2018 In conformity with the WHO guidelines for declarations of interest1 for WHO experts issued by the WHO Compliance, Risk Management and Ethics Office, members of the Guideline Development Group (GDG), Evidence Review Group (ERG) and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DoIs) and declare in writing any competing interest (whether academic, financial or other) that could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DoI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Compliance, Risk Management and Ethics Office was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included in the GDG. ERG members were also requested to declare interests and these were also assessed for potential conflict. As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public 4 weeks ahead of the meeting (https:// www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-izoniazid-resistant-tb/en/). WHO consolidated guidelines on tuberculosis: Online annexes38 This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments. Guideline Development Group The following GDG members declared no interests: Daniela CIRILLO, Kelly DOOLEY (Co-Chair), Gustavo DO VALLE BASTOS, Raquel DUARTE, Christopher KUABAN, Rafael LANIADO-LABORIN, Gary MAARTENS, Andrei MARYANDYSHEV, Ignacio MONEDERO-RECUERO, Maria Imelda Josefa QUELAPIO, Wipa REECHAIPICHITKUL, Nancy SANTESSO (Co-Chair), Welile SIKHONDZE and Armand VAN DEUN. Five GDG members declared interests that were judged non-significant and not affecting the neutrality of the guideline development process. Therefore, no restrictions to their participation applied: Farhana AMANULLAH: (1b) paediatric expert for WHO TB monitoring mission in Indonesia (value US$ 600/day, 14–27 January 2017); (2a) paediatric TB expert for Harvard Medical School Global Health Delivery grant (20% full-time equivalent [FTE]; June 2016–June 2018); (2b) paediatric TB expert for Global Fund grant (20% FTE; June 2016–December 2017). Tsira CHAKHAIA: (1b) Research coordinator for TB Alliance NC-006 clinical trial (2016); community engagement project coordinator for TB Alliance (current); research coordinator for NiX-TB (from May 2017). Philipp DU CROS: (2a) Member of the protocol writing committee and steering committee of the TB-PRACTECAL Clinical Trial, which has received a grant of €6.8 million from the Dutch Postcode Lottery to Médecins Sans Frontières, Operational Centre Amsterdam (currently active). Michael RICH: (1a) employed by Partners in Health to work on clinical care guidelines and in the programmatic management of DR-TB; (1a) WHO consultancies on treatment of drug-resistant TB to national TB programmes; (2a) conduct research and develop regimens for drug-resistant tuberculosis (DR-TB) as a recipient of the UNITAID’s Expand new drug markets for TB [EndTB] grant (all active during the development of the present recommendations). Rada SAVIC: (1b) Member of the panel of the WHO Meeting on Target Regimen Profiles (value US$ 2500); grant reviewer for European and Developing Countries Clinical Trials Partnership (value US$ 1000); (2a) principal investigator or co-principal investigator of research grants by United States National Institutes of Health (NIH) and Gates Foundation on improving TB treatment options (all currently active). External Review Group The following ERG members declared no interests related to the objectives of this meeting: Essam ELMOGHAZI, James JOHNSTON, Enos MASINI, Rohit SARIN, Kitty VAN WEEZENBEEK, Irina VASILYEVA and Piret VIIKLEPP. The below-mentioned ERG members declared interests that were judged not to be significant to the topic of the guideline. Some of the ERG members were involved in clinical trials not related to the treatment of Hr-TB and therefore no restrictions applied to their participation as expert reviewers. Charles L. DALEY: (1b) Chair and member of data monitoring committees for delamanid studies (US$ 45 000 provided by Otsuka Pharmaceutical over 8 years; ongoing); Chair of data monitoring committee for clofazimine studies (US$ 2500 provided by Novartis; finished in 2016). Ingrid OXLEY: (5b) at the Union Conference 2015 in Cape Town, TB Proof campaigns advocated for treatment of latent TB infection (LTBI) among health care workers. She is a health care worker and has had two episodes of TB. Many members of TB Proof who are health care workers may have benefited Annex 2: Declarations of interest 39 from the WHO guidelines for the treatment of LTBI or received funding for LTBI treatment. This was not the focus of the current guideline. Simon SCHAAF: (2a) research support to employer for pharmacokinetics work on second-line TB medicines in children from the NIH and Otsuka Pharmaceutical (approximately ZAR 5 million/year). NIH grant ceased in 2015; Otsuka Pharmaceutical grant is still active. Helen STAGG: (1b) grant to employer for consultancy work on MDR-TB clinical pathways in eastern Europe (Otsuka Pharmaceutical: £59 925; 2013–2015); (2a) grant to employer for Hepatitis and Latent TB Infection (HALT) study (Department of Health of the United Kingdom; National Institute for Health Research, United Kingdom; £86 000 for HALT study (2014); £315 265 for fellowship, salary, research costs; 2015–2017); (2b) non-monetary support for HALT study (Sanofi provides free rifapentine to the research study participants; 2014–2017); (6d) received International Trainee Scholarship Award (US$ 1000 value) at the American Thoracic Society (ATS) conference 2016 where she presented the results of a review she conducted (1). Carlos A. TORRES-DUQUE: (5a) & (5b) as member of the National Advisory Committee for Tuberculosis (Ministry of Health of Colombia) participates in the updates of national TB treatment guidelines. His expert opinion is based upon evidence and local/international experience and does not generate any profits for him. Evidence reviewers The independent experts who undertook the systematic reviews of evidence for this revision declared no interests related to the topic of the policy guideline objectives. This information is included in the Declaration of interest section in the WHO treatment guidelines for isoniazid-resistant tuberculosis, pages ix–xi, available at: https://apps.who.int/iris/bitstream/han dle/10665/260494/9789241550079-eng.pdf A2.4 WHO guidelines for the treatment of drug- susceptible tuberculosis and patient care, 2017 update The scope for the update of the Guidelines for treatment of drug-susceptible tuberculosis and patient care and the composition of the Guideline Development Group (GDG), as well as the External Review Group, were established in line with WHO’s policy on conflict of interest. All contributors completed a WHO Declaration of Interest form. All stated declarations of interest were evaluated by three members of the steering group for the existence of any possible financial or intellectual conflict of interest. In some cases there was possible conflict of interest justifying the exclusion from membership of the GDG, and the Director of the WHO Global TB Programme, the WHO Guideline Review Committee and the WHO Legal Office were consulted on this and a decision was made. Diversity and broad representation in the GDG were sought in an effort to address and overcome any potential intellectual conflicts of interest. The GDG was composed of representatives of technical partners and academia, a GRADE methodologist, national TB programme managers from different WHO regions, representatives of civil society organizations, experts from WHO collaborating centres, professional organizations and a representative from the International Organization for Migration (see web Annex 1). The biographies of the GDG members were made public ahead of the meeting, and the WHO Guidelines Steering Committee, which was formed in preparation for the update of the guidelines, reviewed the completed forms at the beginning of the meeting with everyone present. WHO consolidated guidelines on tuberculosis: Online annexes40 Guideline Development Group The following members declared no interests: Si Thu AUNG; Frank BONSU; Jeremiah CHAKAYA; Lucy CHESIRE; Daniela CIRILLO; Poonam DHAVAN; Kathy FIEKERT; Andrei MARYANDYSHEV; Nguyen Viet NHUNG; Ejaz QADEER; Abdul Hamid SALIM; Holger SCHÜNEMANN; Pedro SUAREZ; Justin Wong Yun YAW. The following GDG members declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting: Kelly DOOLEY declared that she did not receive any salary support from drug companies for her work in the following roles and activities: Co-chair of the AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid for MDR-TB; principal investigator, assessing pretomanid for tuberculosis trial, assessing pretomanid (PA-824, investigational drug) for treatment of drug-sensitive TB; investigator on trials assessing rifapentine for pregnant women with latent TB infection, rifapentine for treatment shortening in patients with pulmonary TB, high-dose rifampicin and levofloxacin for paediatric TB meningitis, high-dose isoniazid for MDR-TB, and delamanid for MDR-TB in children with and without HIV. Mike FRICK declared that his organization received non-commercial support (1) to track investment made in TB research and development; (2) to host a symposium at the UNION meeting; (3) advocate for increased funding for TB research and development, research and access to evidence-based interventions; and (4) management of community research advisors group. Simon SCHAAF declared receiving grants for pharmacokinetic drug studies in children of second-line drugs and for studying preventive therapy in MDR-TB. Carrie TUDOR declared that her organization receives funding from Eli Lilly Foundation for activities related to TB and MDR-TB projects. External Review Group The following External Review Group members declared no interest related to the objectives of this meeting: Riitta DLODLO, Celine GARFIN, Lee REICHMAN, Vaira LEIMANE, Rohit SARIN, Dalene VON DELFT and Fraser WARES. The following WHO staff from the regional offices reviewed the final draft of the guideline document: Masoud DARA (Europe), Mirtha DEL GRANADO (Americas), Daniel KIBUGA (Africa), Hyder KHURSHID (South-East Asia), Mohamed AZIZ (Eastern Mediterranean), and Nobuyuki NISHIKIORI (Western Pacific). Evidence Reviewers The researchers who undertook the systematic reviews of evidence for this revision were the following: Narges ALIPANAH, Cecily MILLER, Payam NAHID (team leader for PICO 1, 2 & 7–10), University of California, San Francisco, United States of America; and Lelia CHAISSON, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America. Richard MENZIES, McGill University, Montreal, Canada (team leader for PICO 3, 4 & 6); and James JOHNSTON, University of British Columbia, Vancouver, Canada. Gregory FOX (team leader for PICO 11) and Jennifer HO, University of Sydney, Sydney, Australia. The evidence reviewers did not participate in the formulation of the policy recommendations. The following reviewers declared no interest related to the objectives of and their attendance at the meeting: Narges ALIPANAH, Jennifer HO and James JOHNSTON. The following reviewer declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting: Payam NAHID declared that his research unit received support from the United States Centers for Disease Control and Prevention through a federal contract to support clinical trial units in San Francisco, USA, and in Hanoi, Viet Nam. Annex 2: Declarations of interest 41 This information is included in the Declaration and management of conflict of interest section in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update, pages 6–7, available at: https://apps.who.int/iris/bitstream/handle/10665/255052/9789241550000-eng.pdf A2.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 update Guideline Development Group The scope of the guidelines update, and the composition of the GDG, including their biographies, were made public for comment ahead of the meeting in line with WHO’s conflict of interest policy. All GDG members completed the WHO Declaration of Interest forms. The WHO Guideline Steering Committee, in preparation for the update of the guidelines and the GDG meeting, reviewed the completed forms. The following GDG members declared no conflicting interests: Luis Gustavo do Valle BASTOS, José A CAMINERO, Tsira CHAKHAIA, Michel GASANA, Armen HAYRAPETYAN, Antonia KWIECIEN, Sundari MASE, Nguyen Viet NHUNG, Maria RODRIGUEZ, Holger SCHÜNEMANN, James SEDDON and Alena SKRAHINA. The following GDG members declared interests that were judged not to be in conflict with the objectives of the meeting: Farhana AMANULLAH declared having received funding for consultancies (US$ 500/ day) and travel from WHO; and grants from the Global Fund and TB-REACH to cover her salary (10% full-time equivalent). Daniela CIRILLO declared having received funding from FIND to conduct evaluation of drug- susceptibility testing (DST) for new drugs (US$ 16 000), and from Otsuka to evaluate DST for delamanid (US$ 25 000). She also declared being the head of a supranational TB reference laboratory in Italy involved in country capacity-building in DST technologies for second-line drugs and new diagnostics for drug-resistant TB; and being a member of the Italian national committee for the use of bedaquiline. Charles L. DALEY declared having received funding from Otsuka to serve as chair of the data monitoring committee for trials of delamanid (US$ 47 000 over 7 years–current). Kelly DOOLEY declared having received funding to provide expert advice on a trial design for TB/HI (US$ 2000/ year paid to the university/ employer); she also declared the following activities and roles: co-chair AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid; principal investigator for adjuvant paclitaxel and trastuzumab (APT) trial assessing pretomanid (PA-824); and investigator in trials assessing high-dose isoniazid for MDR-TB, rifapentine for pregnant women and children with latent TB infection (LTBI), high- dose rifampicin and levofloxacin for paediatric TB meningitis, as well as bedaquiline and delamanid for children with MDR-TB and HIV infection. Agnes GEBHARD declared that she works for the KNCV TB Foundation, which has two projects funded by the Eli Lilly and Company Foundation: (i) engaging the private sector in diagnosis and treatment of TB and MDR-TB with quality-assured second-line TB drugs, and (ii) the roll-out of QuanTB (a drug forecasting tool) in countries not supported by the Systems for Improved Access to Pharmaceuticals and Services (SIAPS) implemented by Management Sciences for Health. In addition, she declared that the KNCV TB Foundation has a collaborative project with Cepheid in two countries (Nigeria, Viet Nam), with KCNV providing services for the installation and initial training on the use of GeneXpert machines. Carlos TORRES-DUQUE declared having received honoraria from Janssen Pharmaceuticals for presentations on TB prevention and WHO policy on bedaquiline at a Latin American Meeting on MDR-TB held in 2014 (US$ 2000). Tom SHINNICK declared being an employee of the United States Centers for Disease Control and Prevention (CDC). CDC supports his travel and research related to his work on laboratory services needed for TB control. He declared having often represented CDC’s position on laboratory services needed for TB diagnosis, treatment and control. As part of his official duties for CDC, he served on the Data and Safety Monitoring Board (DSMB) organized by Otsuka WHO consolidated guidelines on tuberculosis: Online annexes42 for the clinical trial of delamanid. He did not receive any remuneration for serving on the DSMB nor for travel expenses (CDC paid for all travel expenses related to serving on the DSMB). The DSMB has completed its work for the trial. The following GDG members declared interests that were judged to be in conflict with some of the objectives of the meeting and were thus recused from some of the discussions: Lindsay MCKENNA declared non-commercial support to Treatment Action Group (TAG), her employer, from Stop TB Partnership; Bill & Melinda Gates Foundation; the US Department of Veteran Affairs (on behalf of CDC); Janssen Therapeutics for Hepatitis C and HIV projects and the Global Alliance for TB Drug Development (a public–private entity developing new drugs and regimens for TB treatment). She was thus recused from participating in the 9 November 2015 meeting session on Patients, Intervention, Comparator and Outcomes (PICO) question 1 on MDR-TB regimen composition for adults and children. José A CAMINERO stated in his biosketch that he is a staff consultant of the International Union Against Tuberculosis and Lung Disease (UNION), an agency directly involved in the implementation and evaluation of programmes using shorter MDR-TB regimens. He was therefore recused from the 10 November 2015 meeting session on PICO question 3 on shorter regimens for MDR-TB. External Review Group The following ERG members declared no interest related to the objectives of this meeting: Chen-Yuan CHIANG, Celine GARFIN, Michael KIMERLING, Vaira LEIMANE, Gao MENGQIU, Norbert NDJEKA, Ejaz QADEER, Lee REICHMAN, Rohit SARIN and Irina VASILYEVA. The following two ERG members declared interests which were judged not to be in conflict with the objectives of the guidelines. Guy MARKS declared research support from AERAS (US$ 450 000) related to the evaluation of latent TB infection and the rate of recurrence of TB after initial treatment in Viet Nam. He also declared being the Vice-President (and a board member) of the UNION and Editor-in-Chief of the International Journal of Tuberculosis and Lung Disease (for which he receives an honorarium). Dalene VON DELFT declared having received support from TAG, USAID, UNITAID, Janssen Pharmaceuticals, Critical Path to TB Drug Regimens (CPTR) and AERAS to cover travel costs and accommodation to give presentations/speeches on drug-resistant TB. She declared that in 2011 she received bedaquiline as part of her MDR-TB treatment through a compassionate use access programme. Evidence Reviewers The following reviewers declared interests that were judged not to be in conflict with the objectives of the meeting: Gregory J FOX declared having received research and non-monetary support from the UNION (sponsored by Otsuka) valued at about US$ 5000 to attend the 2015 International UNION Conference and to receive the Young Innovator Award (he declares no work for Otsuka or any relationship of this award with any commercial or research activities with Otsuka). Katherine FIELDING declared that her employer (LSHTM) was a recipient of an award from Médecins Sans Frontières (MSF) (£26 890) for the period February–December 2015 to provide statistical support for the TB-PRACTECAL study on which she is a co-investigator. The study is a Phase II–III randomized controlled trial (RCT) to evaluate the efficacy and safety of shorter MDR-TB regimens for adults. Rebecca HARRIS declared she is consulting for a clinical research organization (Cromsource) working for Glaxo SmithKline (GSK) vaccines (~£90 000 in 2013); and on GSK vaccines not related to TB (~£10 000 since 2013) for Manpower Solutions. David MOORE declared receiving research support from the Wellcome Trust Research Training Fellowship Programme to supervise a PhD student to study MDR-TB in Peru (£207 056 in 2014). Annex 2: Declarations of interest 43 Anneke HESSELING declared that her employer (Stellenbosch University) is a recipient of an award from Otsuka Pharmaceutical (~US$ 70 000 to date) for her work on the Phase III delamanid clinical trials in children. This information is included in the Declaration of interest section in the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update, pages 2–5, available at: https://www.who.int/tb/areas- of-work/drug-resistant-tb/Annexes_8-10.pdf A2.6 WHO guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update Funding for the meetings and reviews involved in the updating of the guidelines came entirely from the United States Agency for International Development (USAID). The experts on the Guideline Development Group (GDG) and the institutions where they work contributed time for the various discussions and other activities involved in the update process. The Declaration of interest forms were completed by all non-WHO members of the GDG and the External Review Group, as well as the members of the academic centres who were involved in the reviews. Four members of the GDG declared interests that were judged to represent a potential conflict and were excused from the sessions of the meeting on 25–27 October 2010 during which recommendations relating to the drug regimens were discussed. Jaime BAYONA was a consultant for the development of clinical trial design for studies of an anti-tuberculosis drug manufactured by Otsuka Pharmaceutical Co. Ltd (OPC-67683). Charles L. DALEY was chairperson of drug-safety monitoring for two trials conducted by Otsuka Pharmaceutical Co. Ltd. Carole D. MITNICK served as a member of the Scientific Advisory Board of Otsuka Pharmaceutical Co. Ltd and had an advisory role on drug OPC-67683. Ma. Imelda QUELAPIO received support (monetary and non-monetary) for research from Otsuka Pharmaceutical Co. Ltd. The following members of the academic centres, who performed the reviews of evidence from which the recommendations contained in these guidelines are derived, presented their findings at the meeting: Matthew ARENTZ, Melissa BAUER, Richard MENZIES, Carole D. MITNICK, Olivia OXLADE, Patricia PAVLINAC and Judd L. WALSON. They did not participate in the formulation of recommendations related to the respective reviews of evidence that they performed. This information is included in the Funding and declarations of interest section in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update, page 2, available at: https://apps.who.int/iris/bitstream/handle/10665/44597/9789241501583_eng.pdf WHO consolidated guidelines on tuberculosis: Online annexes44 An ne x 3: G RA D E ev id en ce s um m ar y ta bl es A 3. 1 W H O tr ea tm en t g ui de lin es fo r m ul tid ru g- a nd ri fa m pi ci n- re si st an t tu be rc ul os is , 2 02 0 up da te A ut ho r( s) : Re se ar ch In st itu te o f t he M cG ill Un iv er sit y H ea lth C en tre Q ue st io n: Sh ou ld a n al l-o ra l s ho rt er r eg im en o f 9 –1 2 m on th s’ du ra tio n in clu di ng b ed aq ui lin e vs a s ho rt er r eg im en r ec om m en de d by W H O (w ith in je ct ab le ) b e us ed fo r M D R/ RR -T B pa tie nt s to s af el y im pr ov e ou tc om es ? Se tt in g: In te rn at io na l D at e: Ap ril 2 02 0 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Sh or te r r eg im en re co m m en de d by W H O (w ith in je ct ab le ) Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 65 3 (9 6. 6% ) 57 3/ 62 1 (9 2. 3% ) O R 2. 1 (1 .1 to 4. 0) 3 m or e pe r 1 00 (fr om 1 m or e to 6 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 79 1 (7 9. 8% ) 57 3/ 79 2 (7 2. 3% ) O R 1. 6 (1 .2 to 2. 1) 8 m or e pe r 1 00 (fr om 3 m or e to 13 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 81 3 (7 7. 6% ) 57 3/ 84 0 (6 8. 2% ) O R 1. 7 (1 .3 to 2. 2) 10 m or e pe r 1 00 (fr om 5 m or e to 15 m or e) b, c VE RY LO W CR IT IC AL Annex 3: GRADE evidence summary tables 45 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Sh or te r r eg im en re co m m en de d by W H O (w ith in je ct ab le ) Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 89 1 (7 0. 8% ) 57 3/ 98 7 (5 8. 1% ) O R 1. 9 (1 .6 to 2. 4) 14 m or e pe r 1 00 (fr om 9 m or e to 19 m or e) b, c VE RY LO W CR IT IC AL Lo st v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 88 /8 91 (9 .9 % ) 17 1/ 98 7 (1 7. 3% ) O R 0. 5 (0 .4 to 0. 7) 7 fe w er pe r 1 00 (fr om 11 fe w er to 4 fe w er )b, c VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 27 4 (9 7. 4% ) 19 7/ 22 1 (8 9. 1% ) O R 4. 4 (1 .6 to 11 .9 ) 8 m or e pe r 1 00 (fr om 3 m or e to 13 m or e) b VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 34 1 (7 8. 3% ) 19 7/ 26 9 (7 3. 2% ) O R 1. 3 (0 .8 to 2. 1) 5 m or e pe r 1 00 (fr om 3 fe w er to 12 m or e) b VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 34 8 (7 6. 7% ) 19 7/ 29 3 (6 7. 2% ) O R 1. 7 (1 .1 to 2. 6) 10 m or e pe r 1 00 (fr om 2 m or e to 17 m or e) b VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 37 8 (7 0. 6% ) 19 7/ 34 5 (5 7. 1% ) O R 2. 3 (1 .6 to 3. 3) 16 m or e pe r 1 00 (fr om 9 m or e to 24 m or e) b VE RY LO W CR IT IC AL WHO consolidated guidelines on tuberculosis: Online annexes46 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Sh or te r r eg im en re co m m en de d by W H O (w ith in je ct ab le ) Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) A FB S m ea r P os iti ve : L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 33 /3 78 (8 .7 % ) 63 /3 45 (1 8. 3% ) O R 0. 4 (0 .2 to 0. 6) 11 fe w er pe r 1 00 (fr om 16 fe w er to 5 fe w er )b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 44 6 (9 6. 2% ) 34 6/ 36 8 (9 4. 0% ) O R 1. 4 (0 .7 to 2. 9) 2 m or e pe r 1 00 (fr om 2 fe w er to 5 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 54 1 (7 9. 3% ) 34 6/ 49 2 (7 0. 3% ) O R 1. 6 (1 .2 to 2. 3) 8 m or e pe r 1 00 (fr om 3 m or e to 14 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 55 8 (7 6. 9% ) 34 6/ 51 4 (6 7. 3% ) O R 1. 6 (1 .2 to 2. 2) 9 m or e pe r 1 00 (fr om 3 m or e to 15 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. A ll O th er U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 61 3 (7 0. 0% ) 34 6/ 59 9 (5 7. 8% ) O R 1. 9 (1 .4 to 2. 4) 14 m or e pe r 1 00 (fr om 8 m or e to 19 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 /6 13 (1 0. 3% ) 97 /5 99 (1 6. 2% ) O R 0. 6 (0 .4 to 0. 8) 6 fe w er pe r 1 00 (fr om 10 fe w er to 2 fe w er )b VE RY LO W CR IT IC AL Annex 3: GRADE evidence summary tables 47 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Sh or te r r eg im en re co m m en de d by W H O (w ith in je ct ab le ) Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) H IV N eg at iv e: S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 19 9 (9 8. 0% ) 20 5/ 22 8 (8 9. 9% ) O R 6. 5 (1 .4 to 29 .5 ) 7 m or e pe r 1 00 (fr om 2 m or e to 12 m or e) b VE RY LO W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 23 4 (8 3. 3% ) 20 5/ 25 4 (8 0. 7% ) O R 1. 9 (1 .1 to 3. 5) 10 m or e pe r 1 00 (fr om 1 m or e to 18 m or e) b VE RY LO W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 23 8 (8 1. 9% ) 20 5/ 27 7 (7 4. 0% ) O R 2. 1 (1 .3 to 3. 6) 13 m or e pe r 1 00 (fr om 4 m or e to 21 m or e) b VE RY LO W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 25 5 (7 6. 5% ) 20 5/ 32 7 (6 2. 7% ) O R 2. 7 (1 .7 to 4. 3) 20 m or e pe r 1 00 (fr om 11 m or e to 29 m or e) b VE RY LO W CR IT IC AL H IV N eg at iv e: L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 18 /2 55 (7 .1 % ) 61 /3 27 (1 8. 7% ) O R 0. 3 (0 .2 to 0. 7) 10 fe w er pe r 1 00 (fr om 17 fe w er to 4 fe w er )b VE RY LO W CR IT IC AL AF B: a cid -f as t b ac illi ; a O R: a dj us te d od ds ra tio ; A RT : a nt ire tro vi ra l t he ra py ; C I: co nf id en ce in te rv al ; H IV : h um an im m un od ef ici en cy v iru s; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t T B; O R: o dd s ra tio ; W H O : W or ld H ea lth O rg an iz at io n. Ex pl an at io ns a. F or s om e pa tie nt s, in fo rm at io n w as m iss in g on A FB s m ea r r es ul t a nd c ul tu re re su lt in th e an al ys is. P at ie nt s w ith u nk no w n ag e, s ex , o r H IV s ta tu s w er e ex clu de d fro m a ll an al ys es . b. O ut co m es a nd c os ts a re s im ul at ed u sin g a m od el th at d ra w s pa ra m et er e st im at es fr om m ul tip le s ou rc es , i nc lu di ng th e aO Rs fo r s uc ce ss v er su s de at h/ fa ilu re d es cr ib ed a bo ve . c. T he a bs ol ut e ef fe ct is c al cu la te d af te r m at ch in g in te rv en tio n an d co m pa ra to r p op ul at io ns , a nd p er fo rm in g bi no m ia l r eg re ss io n w ith a n id en tit y lin k. WHO consolidated guidelines on tuberculosis: Online annexes48 A ut ho r( s) : Re se ar ch In st itu te o f t he M cG ill Un iv er sit y H ea lth C en tre Q ue st io n: Sh ou ld a n al l-o ra l s ho rt er re gi m en o f 9 –1 2 m on th s’ du ra tio n in clu di ng b ed aq ui lin e vs lo ng er re gi m en s w ith ou t n ew T B dr ug s be u se d fo r M D R/ RR -T B pa tie nt s to s af el y im pr ov e ou tc om es ? Se tt in g: In te rn at io na l D at e: Ap ril 2 02 0 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s w ith ou t n ew T B dr ug s Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 65 3 (9 6. 6% ) 67 9/ 77 1 (8 8. 1% ) O R 3. 7 (2 .2 to 6. 3) 8 m or e pe r 1 00 (fr om 5 m or e to 11 m or e) b, c VE RY L O W CR IT IC AL Su cc es s vs . D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 79 1 (7 9. 8% ) 67 9/ 10 44 (6 5. 0% ) O R 2. 3 (1 .8 to 3. 0) 15 m or e pe r 1 00 (fr om 10 m or e to 19 m or e) b, c VE RY L O W CR IT IC AL Su cc es s vs . F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 81 3 (7 7. 6% ) 67 9/ 11 36 (5 9. 8% ) O R 2. 6 (2 .0 to 3. 3) 18 m or e pe r 1 00 (fr om 14 m or e to 23 m or e) b, c VE RY L O W CR IT IC AL Su cc es s vs . A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 89 1 (7 0. 8% ) 67 9/ 14 37 (4 7. 3% ) O R 2. 8 (2 .3 to 3. 5) 23 m or e pe r 1 00 (fr om 18 m or e to 27 m or e) b, c VE RY L O W CR IT IC AL Annex 3: GRADE evidence summary tables 49 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s w ith ou t n ew T B dr ug s Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Lo st v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 88 /8 91 (9 .9 % ) 36 8/ 14 37 (2 5. 6% ) O R 0. 4 (0 .3 to 0. 5) 14 fe w er pe r 1 00 (fr om 17 fe w er to 10 fe w er )b, c VE RY L O W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 27 4 (9 7. 4% ) 24 8/ 28 8 (8 6. 1% ) O R 8. 9 (3 .4 to 23 .7 ) 12 m or e pe r 1 00 (fr om 7 m or e to 17 m or e) b VE RY L O W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 34 1 (7 8. 3% ) 24 8/ 37 8 (6 5. 6% ) O R 2. 1 (1 .5 to 3. 1) 13 m or e pe r 1 00 (fr om 6 m or e to 20 m or e) b VE RY L O W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 34 8 (7 6. 7% ) 24 8/ 41 8 (5 9. 3% ) O R 3. 0 (2 .1 to 4. 4) 19 m or e pe r 1 00 (fr om 12 m or e to 26 m or e) b VE RY L O W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 37 8 (7 0. 6% ) 24 8/ 52 9 (4 6. 9% ) O R 2. 9 (2 .1 to 4. 0) 24 m or e pe r 1 00 (fr om 17 m or e t o 31 m or e) b VE RY L O W CR IT IC AL A FB S m ea r P os iti ve : L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 33 /3 78 (8 .7 % ) 13 1/ 52 9 (2 4. 8% ) O R 0. 3 (0 .2 to 0. 6) 15 fe w er pe r 1 00 (fr om 20 fe w er to 9 fe w er )b VE RY L O W CR IT IC AL WHO consolidated guidelines on tuberculosis: Online annexes50 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s w ith ou t n ew T B dr ug s Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 44 6 (9 6. 2% ) 43 2/ 49 1 (8 8. 0% ) O R 4. 5 (2 .4 to 8. 4) 8 m or e pe r 1 00 (fr om 4 m or e to 11 m or e) b VE RY L O W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 54 1 (7 9. 3% ) 43 2/ 68 9 (6 2. 7% ) O R 2. 7 (2 .0 to 3. 7) 18 m or e pe r 1 00 (fr om 12 m or e t o 23 m or e) b VE RY L O W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 55 8 (7 6. 9% ) 43 2/ 74 8 (5 7. 8% ) O R 2. 9 (2 .2 to 3. 9) 21 m or e pe r 1 00 (fr om 15 m or e t o 26 m or e) b VE RY L O W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 61 3 (7 0. 0% ) 43 2/ 91 9 (4 7. 0% ) O R 2. 7 (2 .1 to 3. 5) 23 m or e pe r 1 00 (fr om 17 m or e t o 28 m or e) b VE RY L O W CR IT IC AL H IV -P os iti ve o n A RT : L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 /6 13 (1 0. 3% ) 21 4/ 91 9 (2 3. 3% ) O R 0. 4 (0 .3 to 0. 6) 11 fe w er pe r 1 00 (fr om 15 fe w er to 7 fe w er )b VE RY L O W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 19 9 (9 8. 0% ) 22 7/ 25 8 (8 8. 0% ) O R 6. 7 (2 .2 to 20 .8 ) 12 m or e pe r 1 00 (fr om 6 m or e to 18 m or e) b VE RY L O W CR IT IC AL Annex 3: GRADE evidence summary tables 51 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s w ith ou t n ew T B dr ug s Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) H IV N eg at iv e: S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 23 4 (8 3. 3% ) 22 7/ 30 2 (7 5. 2% ) O R 2. 1 (1 .2 to 3. 8) 13 m or e pe r 1 00 (fr om 5 m or e to 21 m or e) b VE RY L O W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 23 8 (8 1. 9% ) 22 7/ 33 3 (6 8. 2% ) O R 2. 5 (1 .6 to 3. 8) 17 m or e pe r 1 00 (fr om 9 m or e to 26 m or e) b VE RY L O W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 25 5 (7 6. 5% ) 22 7/ 44 0 (5 1. 6% ) O R 3. 5 (2 .4 to 5. 2) 28 m or e pe r 1 00 (fr om 20 m or e to 37 m or e) b VE RY L O W CR IT IC AL H IV N eg at iv e: L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 18 /2 55 (7 .1 % ) 13 0/ 44 0 (2 9. 5% ) O R 0. 2 (0 .1 to 0. 4) 21 fe w er pe r 1 00 (fr om 28 fe w er to 14 fe w er )b VE RY L O W CR IT IC AL AF B: a cid -f as t b ac illi ; a O R: a dj us te d od ds ra tio ; A RT : a nt ire tro vi ra l t he ra py ; C I: co nf id en ce in te rv al ; H IV : h um an im m un od ef ici en cy v iru s; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t T B: O R: o dd s ra tio ; W H O : W or ld H ea lth O rg an iz at io n. Ex pl an at io ns a. F or s om e pa tie nt s, in fo rm at io n w as m iss in g on A FB s m ea r r es ul t a nd c ul tu re re su lt in th e an al ys is. P at ie nt s w ith u nk no w n ag e, s ex , o r H IV s ta tu s w er e ex clu de d fro m a ll an al ys es . b. O ut co m es a nd c os ts a re s im ul at ed u sin g a m od el th at d ra w s pa ra m et er e st im at es fr om m ul tip le s ou rc es , i nc lu di ng th e aO Rs fo r s uc ce ss v er su s de at h/ fa ilu re d es cr ib ed a bo ve . c. T he a bs ol ut e ef fe ct is c al cu la te d af te r m at ch in g in te rv en tio n an d co m pa ra to r p op ul at io ns , a nd p er fo rm in g bi no m ia l r eg re ss io n w ith a n id en tit y lin k. WHO consolidated guidelines on tuberculosis: Online annexes52 A ut ho r( s) : Re se ar ch In st itu te o f t he M cG ill Un iv er sit y H ea lth C en tre Q ue st io n: Sh ou ld a n al l-o ra l s ho rt er re gi m en o f 9 –1 2 m on th s’ du ra tio n in clu di ng b ed aq ui lin e vs lo ng er re gi m en s c on ta in in g be da qu ilin e be u se d in M D R/ RR -T B pa tie nt s to s af el y im pr ov e ou tc om es ? Se tt in g: In te rn at io na l D at e: Ap ril 2 02 0 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s co nt ai ni ng be da qu ili ne Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 65 3 (9 6. 6% ) 26 8/ 29 2 (9 1. 8% ) O R 3. 9 (1 .7 to 9. 1) 5 m or e pe r 1 00 (fr om 1 m or e to 9 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 79 1 (7 9. 8% ) 26 8/ 33 8 (7 9. 3% ) O R 1. 0 (0 .6 to 1. 5) 4 fe w er pe r 1 00 (fr om 10 fe w er to 3 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 81 3 (7 7. 6% ) 26 8/ 36 2 (7 4. 0% ) O R 1. 4 (0 .9 to 2. 0) 2 m or e pe r 1 00 (fr om 4 fe w er to 9 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 89 1 (7 0. 8% ) 26 8/ 44 0 (6 0. 9% ) O R 1. 6 (1 .2 to 2. 2) 7 m or e pe r 1 00 (fr om 1 m or e to 14 m or e) b, c VE RY LO W CR IT IC AL Annex 3: GRADE evidence summary tables 53 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s co nt ai ni ng be da qu ili ne Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Lo st v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 88 /8 91 (9 .9 % ) 88 /4 40 (2 0. 0% ) O R 0. 5 (0 .4 to 0. 8) 8 fe w er pe r 1 00 (fr om 13 fe w er to 3 fe w er )b, c VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 27 4 (9 7. 4% ) 13 3/ 14 8 (8 9. 9% ) O R 4. 1 (1 .4 to 12 .2 ) 6 m or e pe r 1 00 (fr om 1 fe w er to 12 m or e) b VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 34 1 (7 8. 3% ) 13 3/ 17 1 (7 7. 8% ) O R 0. 8 (0 .5 to 1. 4) 4 fe w er pe r 1 00 (fr om 13 fe w er to 5 m or e) b VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 34 8 (7 6. 7% ) 13 3/ 18 6 (7 1. 5% ) O R 1. 5 (0 .9 to 2. 5) 4 m or e pe r 1 00 (fr om 5 fe w er to 13 m or e) b VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : S uc ce ss v s. A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 26 7/ 37 8 (7 0. 6% ) 13 3/ 22 3 (5 9. 6% ) O R 2. 0 (1 .3 to 3. 1) 12 m or e pe r 1 00 (fr om 3 m or e to 21 m or e) b VE RY LO W CR IT IC AL A FB S m ea r P os iti ve : L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 33 /3 78 (8 .7 % ) 41 /2 23 (1 8. 4% ) O R 0. 3 (0 .2 to 0. 6) 11 fe w er pe r 1 00 (fr om 17 fe w er to 5 fe w er )b VE RY LO W CR IT IC AL WHO consolidated guidelines on tuberculosis: Online annexes54 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s co nt ai ni ng be da qu ili ne Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 44 6 (9 6. 2% ) 19 1/ 20 5 (9 3. 2% ) O R 2. 8 (1 .0 to 8. 2) 4 m or e pe r 1 00 (fr om 0 fe w er to 8 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 54 1 (7 9. 3% ) 19 1/ 24 4 (7 8. 3% ) O R 1. 0 (0 .6 to 1. 6) 1 fe w er pe r 1 00 (fr om 9 fe w er to 6 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 55 8 (7 6. 9% ) 19 1/ 25 8 (7 4. 0% ) O R 1. 2 (0 .8 to 1. 9) 1 m or e pe r 1 00 (fr om 6 fe w er to 9 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 61 3 (7 0. 0% ) 19 1/ 31 1 (6 1. 4% ) O R 2. 1 (1 .4 to 3. 1) 12 m or e pe r 1 00 (fr om 5 m or e to 20 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 /6 13 (1 0. 3% ) 62 /3 11 (1 9. 9% ) O R 0. 3 (0 .2 to 0. 6) 12 fe w er pe r 1 00 (fr om 18 fe w er to 7 fe w er )b VE RY LO W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 19 9 (9 8. 0% ) 73 /8 2 (8 9. 0% ) O R 3. 5 (0 .8 to 15 .4 ) 8 m or e pe r 1 00 (fr om 1 fe w er to 16 m or e) b VE RY LO W CR IT IC AL Annex 3: GRADE evidence summary tables 55 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng sh or te r r eg im en of 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s co nt ai ni ng be da qu ili ne Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) H IV N eg at iv e: S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 23 4 (8 3. 3% ) 73 /8 7 (8 3. 9% ) O R 1. 3 (0 .5 to 3. 3) 1 m or e pe r 1 00 (fr om 11 fe we r to 13 m or e) b VE RY LO W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 23 8 (8 1. 9% ) 73 /9 6 (7 6. 0% ) O R 1. 7 (0 .8 to 3. 7) 6 m or e pe r 1 00 (fr om 7 fe w er to 18 m or e) b VE RY LO W CR IT IC AL H IV N eg at iv e: S uc ce ss v s. A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 19 5/ 25 5 (7 6. 5% ) 73 /1 17 (6 2. 4% ) O R 1. 8 (0 .9 to 3. 4) 11 m or e pe r 1 00 (fr om 1 fe w er to 24 m or e) b VE RY LO W CR IT IC AL H IV N eg at iv e: L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 18 /2 55 (7 .1 % ) 22 /1 17 (1 8. 8% ) O R 0. 4 (0 .2 to 0. 9) 11 fe w er pe r 1 00 (fr om 20 fe w er to 2 fe w er )b VE RY LO W CR IT IC AL AF B: a cid -f as t b ac illi ; a O R: a dj us te d od ds ra tio ; A RT : a nt ire tro vi ra l t he ra py ; C I: co nf id en ce in te rv al ; H IV : h um an im m un od ef ici en cy v iru s; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t T B; O R: o dd s ra tio . Ex pl an at io ns a. F or s om e pa tie nt s, in fo rm at io n w as m iss in g on A FB s m ea r r es ul t a nd c ul tu re re su lt in th e an al ys is. P at ie nt s w ith u nk no w n ag e, s ex , o r H IV s ta tu s w er e ex clu de d fro m a ll an al ys es . b. O ut co m es a nd c os ts a re s im ul at ed u sin g a m od el th at d ra w s pa ra m et er e st im at es fr om m ul tip le s ou rc es , i nc lu di ng th e aO Rs fo r s uc ce ss v er su s de at h or fa ilu re d es cr ib ed a bo ve . c. T he a bs ol ut e ef fe ct is c al cu la te d af te r m at ch in g in te rv en tio n an d co m pa ra to r p op ul at io ns , a nd p er fo rm in g bi no m ia l r eg re ss io n w ith a n id en tit y lin k. WHO consolidated guidelines on tuberculosis: Online annexes56 A ut ho r( s) : Re se ar ch In st itu te o f t he M cG ill Un iv er sit y H ea lth C en tre Q ue st io n: Sh ou ld a n al l-o ra l s ho rt er re gi m en o f 9 –1 2 m on th s d ur at io n in clu di ng b ed aq ui lin e vs lo ng er re gi m en s c on ta in in g be da qu ilin e an d lin ez ol id be u se d in M D R/ RR -T B pa tie nt s to s af el y im pr ov e ou tc om es ? Se tt in g: In te rn at io na l D at e: Ap ril 2 02 0 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 65 3 (9 6. 6% ) 10 3/ 11 0 (9 3. 6% ) O R 1. 8 (0 .5 to 6. 3) 3 m or e pe r 1 00 (fr om 3 fe w er to 9 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 79 1 (7 9. 8% ) 10 3/ 11 8 (8 7. 3% ) O R 1. 1 (0 .5 to 2. 6) 1 fe w er pe r 1 00 (fr om 10 fe w er to 8 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 81 3 (7 7. 6% ) 10 3/ 12 5 (8 2. 4% ) O R 0. 9 (0 .5 to 1. 8) 5 fe w er pe r 1 00 (fr om 15 fe w er to 5 m or e) b, c VE RY LO W CR IT IC AL Su cc es s vs . A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 63 1/ 89 1 (7 0. 8% ) 10 3/ 15 7 (6 5. 6% ) O R 2. 1 (1 .2 to 3. 7) 13 m or e pe r 1 00 (fr om 3 m or e to 23 m or e) b, c VE RY LO W CR IT IC AL Lo st v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 88 /8 91 (9 .9 % ) 36 /1 57 (2 2. 9% ) O R 0. 4 (0 .1 to 0. 6) 15 fe w er pe r 1 00 (fr om 23 fe w er to 7 fe w er )b, c VE RY LO W CR IT IC AL Annex 3: GRADE evidence summary tables 57 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns A ll- or al be da qu ili ne - co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n Lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 44 6 (9 6. 2% ) 80 /8 5 (9 4. 1% ) O R 2. 6 (0 .5 to 13 .8 ) 4 m or e pe r 1 00 (fr om 2 fe w er to 10 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 54 1 (7 9. 3% ) 80 /9 1 (8 7. 9% ) O R 0. 6 (0 .2 to 1. 4) 9 fe w er pe r 1 00 (fr om 20 fe w er to 2 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : S uc ce ss v s. F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 55 8 (7 6. 9% ) 80 /9 6 (8 3. 3% ) O R 1. 0 (0 .4 to 2. 3) 3 fe w er pe r 1 00 (fr om 14 fe w er to 8 m or e) b VE RY LO W H IV -P os iti ve o n A RT : S uc ce ss v s. A ll U nf av or ab le (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us no ne 42 9/ 61 3 (7 0. 0% ) 80 /1 19 (6 7. 2% ) O R 1. 8 (0 .9 to 3. 6) 11 m or e pe r 1 00 (fr om 0 fe w er to 23 m or e) b VE RY LO W CR IT IC AL H IV -P os iti ve o n A RT : L os t v s. A ll O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) 1 ob se rv at io na l st ud ie s se rio us a no t s er io us no t s er io us no t s er io us st ro ng as so cia tio n 63 /6 13 (1 0. 3% ) 26 /1 19 (2 1. 8% ) O R 0. 3 (0 .1 to 0. 7) 15 fe w er pe r 1 00 (fr om 24 fe w er to 6 fe w er )b VE RY LO W CR IT IC AL aO R: a dj us te d od ds ra tio ; A RT : a nt ire tro vi ra l t he ra py ; C I: co nf id en ce in te rv al ; H IV : h um an im m un od ef ici en cy v iru s; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t T B; O R: o dd s ra tio . Ex pl an at io ns a. F or s om e pa tie nt s, in fo rm at io n w as m iss in g on A FB s m ea r r es ul t a nd c ul tu re re su lt in th e an al ys is. P at ie nt s w ith u nk no w n ag e, s ex , o r H IV s ta tu s w er e ex clu de d fro m a ll an al ys es . b. O ut co m es a nd c os ts a re s im ul at ed u sin g a m od el th at d ra w s pa ra m et er e st im at es fr om m ul tip le s ou rc es , i nc lu di ng th e aO Rs fo r s uc ce ss v er su s de at h or fa ilu re d es cr ib ed a bo ve . c. T he a bs ol ut e ef fe ct is c al cu la te d af te r m at ch in g in te rv en tio n an d co m pa ra to r p op ul at io ns , a nd p er fo rm in g bi no m ia l r eg re ss io n w ith a n id en tit y lin k. WHO consolidated guidelines on tuberculosis: Online annexes58 A ut ho r( s) : TB A llia nc e Q ue st io n: Sh ou ld tr ea tm en t r eg im en la st in g 6– 9 m on th s c om po se d of b ed aq ui lin e, p re to m an id a nd lin ez ol id v s. lo ng er re gi m en s c on ta in in g be da qu ilin e an d lin ez ol id in a dd iti on to o th er a nt i-T B dr ug s b e us ed fo r X D R- TB p at ie nt s o r p at ie nt s w ho a re tr ea tm en t i nt ol er an t o r w ith n on -r es po ns ive M D R- TB ? Se tt in g: Fi ve s ite s in S ou th A fri ca Bi bl io gr ap hy : Co nr ad ie F , D ia co n AH , N gu ba ne N e t a l. Tr ea tm en t o f h ig hl y dr ug -r es ist an t p ul m on ar y tu be rc ul os is, N ew E ng la nd Jo ur na l o f M ed ici ne . 20 20 ; 3 82 (1 0) : 8 93 –9 02 . Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns tr ea tm en t re gi m en la st in g 6– 9 m on th s co m po se d of be da qu ili ne , pr et om an id a nd lin ez ol id lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id in a dd iti on to ot he r a nt i- TB dr ug s Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . F ai lu re /R ec ur re nc e (f ol lo w u p: m ea n 24 m on th s) 1a ob se rv at io na l st ud ie s ve ry se rio us b se rio us c se rio us d ve ry s er io us e no ne 96 /9 9 (9 7. 0% ) 37 5/ 40 9 (9 1. 7% ) O R 3. 3 (0 .8 to 13 .7 ) 6 m or e pe r 1 00 (fr om 2 fe w er to 14 m or e) f,g VE RY LO W CR IT IC AL Su cc es s vs . D ea th (f ol lo w u p: m ea n 24 m on th s) 1a ob se rv at io na l st ud ie s ve ry se rio us b se rio us c se rio us d ve ry s er io us e no ne 96 /1 03 (9 3. 2% ) 37 5/ 40 8 (9 1. 9% ) O R 1. 0 (0 .1 to 8. 2) 1 m or e pe r 1 00 (fr om 7 fe w er to 8 m or e) f,g VE RY LO W CR IT IC AL Su cc es s vs . F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 24 m on th s) 1a ob se rv at io na l st ud ie s ve ry se rio us b se rio us c se rio us d ve ry s er io us e no ne 96 /1 06 (9 0. 6% ) 37 5/ 44 2 (8 4. 8% ) O R 1. 8 (0 .7 to 4. 4) 6 m or e pe r 1 00 (fr om 4 fe w er to 16 m or e) f,g VE RY LO W CR IT IC AL Su cc es s vs . A ll U nf av or ab le (f ol lo w u p: m ea n 24 m on th s) 1a ob se rv at io na l st ud ie s ve ry se rio us b se rio us c se rio us d ve ry s er io us e no ne 96 /1 08 (8 8. 9% ) 37 5/ 45 6 (8 2. 2% ) O R 1. 2 (0 .5 to 3. 1) 2 m or e pe r 1 00 (fr om 7 fe w er to 12 m or e) f,g VE RY LO W CR IT IC AL Annex 3: GRADE evidence summary tables 59 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns tr ea tm en t re gi m en la st in g 6– 9 m on th s co m po se d of be da qu ili ne , pr et om an id a nd lin ez ol id lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id in a dd iti on to ot he r a nt i- TB dr ug s Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) A dv er se e ve nt s 1 h ob se rv at io na l st ud ie s ve ry se rio us i no t s er io us se rio us ve ry s er io us j no ne BP aL r eg im en : 1 (0 .9 % ) pa tie nt d ie d, 2 7 (2 5% ) pa tie nt s ex pe rie nc ed ot he r se rio us ad ve rs e ev en ts in cl ud in g ho sp ita liz at io ns a nd li fe t hr ea te ni ng e ve nt s, an d 53 ( 49 % ) pa tie nt s ex pe rie nc ed a t l ea st o ne G ra de 3 –4 a dv er se e ve nt s. D ru g di sc on tin ua tio n fo r ad ve rs e ev en ts : r el at ed to a ll th re e dr ug s in 1 p at ie nt , a nd re la te d to li ne zo lid (i ni tia l d os e 12 00 m g/ da y) d isc on tin ue d in a no th er 3 5 (3 2% ) p at ie nt s. O nl y 20 (1 8% ) p at ie nt s c om pl et ed a fu ll c ou rs e of 1 20 0 m g/ da y. In th e IP D st ud ie s ( 90 % re ce ive d 60 0 m g/ da y or le ss ), th e po ol ed ra te of L ZD p er m an en t d isc on tin ua tio n w as 1 7. 9% , a nd in th e En dT B st ud y (a ll p at ie nt s r ec ei ve d 60 0m g/ da y or le ss ), th e ra te o f L ZD di sc on tin ua tio n w as 1 3. 1% . I n En dT B: 9 p er so ns o ut o f 1 09 4 (0 .8 % ) d ie d of a p os sib ly/ pr ob ab ly dr ug re la te d AE , i nc lu di ng tw o pe rs on s w ith su dd en c ar di ac d ea th a nd Q T pr ol on ga tio n. VE RY LO W CR IT IC AL AE : a dv er se e ve nt ; B Pa L: b ed aq ui lin e, p re to m an id a nd li ne zo lid ; C I: co nf id en ce in te rv al ; I PD : i nd iv id ua l p at ie nt d at a; L ZD : l in ez ol id ; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t T B; O R: o dd s ra tio . Ex pl an at io ns a. O ne c oh or t s tu dy c om pa re d w ith IP D m et a- an al ys is of 5 5 st ud ie s. b. T hi s w as a s m al l a nd o ne -a rm ed u nb lin de d co ho rt s tu dy w ith s ub st an tia l s el ec tio n in to t he c oh or t; fo llo w -u p da ta t o 24 m on th s w er e no t av ai la bl e fo r al l p at ie nt s, so e nd -p oi nt s of c lin ica l f ai lu re m ay b e un de re st im at ed . c. T he re w er e m aj or d iff er en ce s be tw ee n th e in te rv en tio n an d co m pa ra to r g ro up s (in s el ec tio n, c ha ra ct er ist ics a nd in te ns ity o f c ar e) , a ll of w hi ch c ou ld h av e af fe ct ed th e co m pa ris on . d. T hi s w as a s m al l, w el l-r es ou rc ed , o ne -a rm ed , u nb lin de d co ho rt s tu dy th at w as c om pa re d w ith c oh or ts a nd ro ut in el y co lle ct ed p ro gr am m at ic da ta in th e IP D. A ll co m pa ris on s be tw ee n th e in te rv en tio n an d th e co m pa ra to r w er e in di re ct . e. T hi s w as a sm al l s tu dy (1 08 p at ie nt s i n to ta l in m od ifi ed in te nt io n- to -t re at a na lys is) . I t w as d iff icu lt to p er fo rm a de qu at e m at ch in g in th e an al ys is, so so m e se co nd ar y an al ys es w er e ev en m or e lim ite d by sm al l n um be rs . f. O ut co m es a nd c os ts w er e sim ul at ed u sin g a m od el th at d ra w s pa ra m et er e st im at es fr om m ul tip le s ou rc es , i nc lu di ng th e ad ju st ed o dd s ra tio s fo r s uc ce ss v er su s de at h or fa ilu re d es cr ib ed a bo ve . g. T he a bs ol ut e ef fe ct is c al cu la te d af te r m at ch in g in te rv en tio n an d co m pa ra to r p op ul at io ns , a nd p er fo rm in g bi no m ia l r eg re ss io n w ith a n id en tit y lin k. h. O ne c oh or t s tu dy (c om pa re d w ith IP D m et a- an al ys is of 3 0 st ud ie s co nt ai ni ng a dv er se e ve nt in fo rm at io n an d th e En dT B ob se rv at io na l s tu dy ) i. W ith in th e IP D, a dv er se e ve nt d at a ar e on ly c on sis te nt ly re po rt ed fo r i nd iv id ua ls w ho p er m an en tly s to pp ed th e dr ug o f i nt er es t; al so , c er ta in d ru gs m ay b e m or e clo se ly m on ito re d fo r t ox ici tie s (e .g . b ed aq ui lin e an d lin ez ol id ). j. Th is w as a s m al l s tu dy (1 09 p at ie nt s in th e sa fe ty a na ly sis ) c om pa re d w ith 3 0 di ffe re nt s tu di es in th e IP D, w hi ch m ay v ar y in th e in te ns ity a nd c om pl et en es s of a dv er se e ve nt re po rt in g. WHO consolidated guidelines on tuberculosis: Online annexes60 A ut ho r( s) : Re se ar ch In st itu te o f t he M cG ill Un iv er sit y H ea lth C en tre Q ue st io n: Sh ou ld b ed aq ui lin e fo r m or e th an s ix m on th s vs . b ed aq ui lin e fo r u p to s ix m on th s be u se d in M D R/ RR -T B pa tie nt s as p ar t o f t he lo ng er tre at m en t r eg im en s? Se tt in g: In te rn at io na l Bi bl io gr ap hy : Un pu bl ish ed d at a fro m th e in di vi du al p at ie nt d at as et , 2 01 9 (h el d by M cG ill Un iv er sit y) Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns be da qu ili ne fo r m or e th an s ix m on th s be da qu ili ne fo r u p to s ix m on th s Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . F ai lu re (f ol lo w u p: m ea n 21 m on th s) 1 ob se rv at io na l st ud ie s ve ry se rio us a no t s er io us no t s er io us se rio us b no ne 18 8/ 21 2 (8 8. 7% ) 23 5/ 25 5 (9 2. 2% ) O R 1. 4 (0 .7 to 2. 7) 5 m or e pe r 1 00 (fr om 1 fe w er to 11 m or e) c, d VE RY LO W CR IT IC AL Su cc es s vs . D ea th (f ol lo w u p: m ea n 21 m on th s) 1 ob se rv at io na l st ud ie s ve ry se rio us a no t s er io us no t s er io us se rio us b no ne 18 8/ 20 0 (9 4. 0% ) 23 5/ 24 2 (9 7. 1% ) O R 0. 8 (0 .2 to 2. 4) 4 fe w er pe r 1 00 (fr om 8 fe w er to 1 m or e) c, d VE RY LO W CR IT IC AL Su cc es s vs . F ai lu re /D ea th (f ol lo w u p: m ea n 21 m on th s) 1 ob se rv at io na l st ud ie s ve ry se rio us a no t s er io us no t s er io us se rio us b no ne 18 8/ 22 4 (8 3. 9% ) 23 5/ 26 2 (8 9. 7% ) O R 1. 0 (0 .5 to 1. 7) 1 m or e pe r 1 00 (fr om 6 fe w er to 7 m or e) c, d VE RY LO W CR IT IC AL Su cc es s vs . A ll U nf av or ab le (f ol lo w u p: m ea n 21 m on th s) 1 ob se rv at io na l st ud ie s ve ry se rio us a no t s er io us no t s er io us se rio us b no ne 18 8/ 24 2 (7 7. 7% ) 23 5/ 27 3 (8 6. 1% ) O R 0. 8 (0 .5 to 1. 2) 1 fe w er pe r 1 00 (fr om 8 fe w er to 6 m or e) c, d VE RY LO W CR IT IC AL CI : c on fid en ce in te rv al ; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t t ub er cu lo sis ; O R: o dd s ra tio . Ex pl an at io ns a. D at a fro m a si ng le c oh or t s tu dy w ith e xc el le nt q ua lit y of in fo rm at io n, b ut re as on s f or b ed aq ui lin e ex te ns io n va rie d by p ro vid er a nd si te , w ith m an y de cis io ns in di vid ua liz ed . S om e sit es ra re ly ga ve b ed aq ui lin e fo r m or e th an 6 m on th s a nd o th er s r ar el y ga ve b ed aq ui lin e fo r l es s t ha n or e qu al to 6 m on th s. In m os t s ite s, ho w ev er , d ur at io n ap pe ar ed to b e ba se d at le as t p ar tly o n po or re sp on se to th er ap y, cr ea tin g su bs ta nt ia l s el ec tio n bi as . b. S tu dy in vo lv ed re la tiv el y sm al l n um be rs w ith b ed aq ui lin e ex te ns io n, w ith li m ite d ev en ts . c. O ut co m es a nd c os ts a re s im ul at ed u sin g a m od el th at d ra w s pa ra m et er e st im at es fr om m ul tip le s ou rc es , i nc lu di ng th e ad ju st ed o dd s ra tio s fo r s uc ce ss v er su s de at h/ fa ilu re d es cr ib ed a bo ve . d. T he a bs ol ut e ef fe ct is c al cu la te d af te r m at ch in g in te rv en tio n an d co m pa ra to r p op ul at io ns , a nd p er fo rm in g bi no m ia l r eg re ss io n w ith a n id en tit y lin k. Annex 3: GRADE evidence summary tables 61 A ut ho r( s) : Re se ar ch In st itu te o f t he M cG ill Un iv er sit y H ea lth C en tre a nd P ro fe ss or K el ly D oo le y, Jo hn s H op kin s Un iv er sit y Q ue st io n: Sh ou ld c on cu rre nt u se o f b ed aq ui lin e an d de la m an id v s. no c on cu rre nt u se o f b ed aq ui lin e an d de la m an id b e us ed in M D R/ RR -T B pa tie nt s as p ar t o f t he lo ng er tr ea tm en t r eg im en s? Se tt in g: In te rn at io na l ( fo r t he d at as et fr om M cG ill Un iv er sit y) a nd S ou th A fri ca a nd P er u fo r t he d at as et fr om Jo hn s H op kin s Un iv er sit y Bi bl io gr ap hy : Un pu bl ish ed d at a fro m th e in di vid ua l p at ie nt d at as et , 2 01 9 (h el d by M cG ill Un ive rs ity ) a nd u np ub lis he d da ta fr om th e D EL am an Id B Ed aq ui lin e fo r R es ist An t T ub Er cu lo sis (D EL IB ER AT E) tr ia l, Jo hn s H op kin s Un iv er sit y Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns co nc ur re nt u se of b ed aq ui lin e an d de la m an id no c on cu rr en t us e of be da qu ili ne a nd de la m an id Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su cc es s vs . F ai lu re (f ol lo w u p: m ea n 17 .5 m on th s) 4 ob se rv at io na l st ud ie s ve ry se rio us a se rio us b no t s er io us se rio us c no ne 52 /5 8 (8 9. 7% ) 28 5/ 30 6 (9 3. 1% ) O R 1. 6 (0 .5 to 5. 4) 6 m or e pe r 1 00 (fr om 6 fe w er to 18 m or e) d, e VE RY LO W CR IT IC AL Su cc es s vs . D ea th (f ol lo w u p: m ea n 17 .5 m on th s) 4 ob se rv at io na l st ud ie s ve ry se rio us a se rio us b no t s er io us se rio us c no ne 52 /6 9 (7 5. 4% ) 28 5/ 33 3 (8 5. 6% ) O R 0. 8 (0 .3 to 2. 1) 1 fe w er pe r 1 00 (fr om 15 fe w er to 12 m or e) d, e VE RY LO W CR IT IC AL Su cc es s vs . F ai lu re /D ea th (f ol lo w u p: m ea n 17 .5 m on th s) 4 ob se rv at io na l st ud ie s ve ry se rio us a se rio us b no t s er io us se rio us c no ne 52 /7 5 (6 9. 3% ) 28 5/ 35 4 (8 0. 5% ) O R 1. 2 (0 .6 to 2. 5) 5 m or e pe r 1 00 (fr om 10 fe w er to 20 m or e) d, e VE RY LO W CR IT IC AL Su cc es s vs . A ll U nf av or ab le (f ol lo w u p: m ea n 17 .5 m on th s) 4 ob se rv at io na l st ud ie s ve ry se rio us a se rio us b no t s er io us se rio us c no ne 52 /8 4 (6 1. 9% ) 28 5/ 40 1 (7 1. 1% ) O R 0. 6 (0 .3 to 1. 1) 11 fe w er pe r 1 00 (fr om 25 fe w er to 2 m or e) d, e VE RY LO W CR IT IC AL WHO consolidated guidelines on tuberculosis: Online annexes62 Ce rt ai nt y as se ss m en t № o f p at ie nt s Ef fe ct Ce rt ai nt y Im po rt an ce № o f st ud ie s St ud y de si gn Ri sk o f bi as In co ns is te nc y In di re ct ne ss Im pr ec is io n O th er co ns id er at io ns co nc ur re nt u se of b ed aq ui lin e an d de la m an id no c on cu rr en t us e of be da qu ili ne a nd de la m an id Re la tiv e (9 5% C I) A bs ol ut e (9 5% C I) Su dd en c ar di ac d ea th (f ol lo w u p: m ea n 24 w ee ks ; a ss es se d w ith : Q Tc F pr ol on ga tio n m ea su re d in m ill is ec on ds c ha ng e fr om b as el in e) 1 ra nd om ise d tri al s no t se rio us no t s er io us se rio us se rio us f no ne Th e pr im ar y ai m o f t he D EL IB ER AT E tri al w as to c om pa re th e m ea n ch an ge fr om b as el in e (a ve ra ge d ov er w ee ks 8 –2 4) in Q Tc F w he n be da qu ilin e an d de la m an id a re c o- ad m in ist er ed to th e m ea n ch an ge o bs er ve d w he n ea ch d ru g is ad m in ist er ed al on e. A t w ee k 24 , in 2 8 pa tie nt s w ho re ce ive d be da qu ilin e as pa rt o f t he ir M D R -T B tre at m en t r eg im en th e m ea n in cr ea se in Q Tc F w as 1 1. 9 m s (9 5% C I 7 .4 –1 6. 4 m s) . F or 2 8 pa tie nt s w ho re ce iv ed d el am an id a s pa rt o f t he ir M D R- TB tr ea tm en t re gi m en th e m ea n in cr ea se in Q Tc F w as 8 .6 m s (9 5% C I 4 .0 – 13 .2 m s) . W he n 28 p at ie nt s re ce iv ed c on cu rre nt b ed aq ui lin e an d de la m an id a s pa rt o f t he ir M D R- TB tr ea tm en t r eg im en th e m ea n in cr ea se in Q Tc F w as 2 0. 7 m s ( 95 % C I 1 6. 1– 25 .4 m s). Th e ad di tiv e ef fe ct o f a dd in g de la m an id t o a re gi m en t ha t al re ad y co nt ai ne d be da qu ilin e w as d et er m in ed to b e a m ea n of 8 .8 m s (9 5% C I 2 .3 –1 5. 3 m s) , w he re as th e ad di tiv e ef fe ct of a dd in g be da qu ilin e to a r eg im en t ha t al re ad y co nt ai ne d de la m an id w as a m ea n of 1 2. 1 m s ( 95 % C I 5 .6 –1 8. 6 m s). T he re w er e no G ra de 3 o r G ra de 4 Q T ad ve rs e ev en ts re co rd ed in al l t hr ee p at ie nt g ro up s, in clu di ng a m on g th os e w ho re ce ive d be da qu ilin e an d de la m an id c on cu rre nt ly. LO W CR IT IC AL CI : c on fid en ce in te rv al ; M D R- TB : m ul tid ru g- re sis ta nt tu be rc ul os is; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t t ub er cu lo sis ; O R: o dd s ra tio . Ex pl an at io ns a. Fo r th e tw o co ho rt s tu di es w ith th e in te rv en tio n, th e sm al l n um be r of p at ie nt s re pr es en ts le ss th an 3 % o f a ll pa tie nt s in o ne c oh or t s tu dy w ith e xc el le nt q ua lit y of in fo rm at io n; h en ce , t he re is a p os sib ilit y of su bs ta nt ia l s el ec tio n bi as . T he s ec on d co ho rt a lso h ad s m al l n um be rs , b ut th e pa tie nt s re pr es en t a lm os t h al f o f a ll co ho rt m em be rs ; h en ce , t he re is le ss p os sib ilit y of s el ec tio n bi as . b. Pa tie nt s fo r t he in te rv en tio n w er e tre at ed in tw o ve ry d iff er en t c oh or t s tu di es , w ith d iff er en t c en tre s or p ro vi de rs a nd p ro to co ls. P at ie nt s fo r t he c om pa ra to r w er e tre at ed in fo ur v er y di ffe re nt c oh or t s tu di es . c. Th er e ar e se rio us c on ce rn s ab ou t t hi s st ud y, gi ve n th at s m al l n um be rs re ce iv ed b ed aq ui lin e an d de la m an id c on co m ita nt ly (n =8 4) . d. O ut co m es a nd c os ts a re s im ul at ed u sin g a m od el th at d ra w s pa ra m et er e st im at es fr om m ul tip le s ou rc es , i nc lu di ng th e ad ju st ed o dd s ra tio s fo r s uc ce ss v er su s de at h/ fa ilu re d es cr ib ed a bo ve . e. Th e ab so lu te e ffe ct is c al cu la te d af te r m at ch in g in te rv en tio n an d co m pa ra to r p op ul at io ns , a nd p er fo rm in g bi no m ia l r eg re ss io n w ith a n id en tit y lin k. f. I m pr ec isi on is se co nd ar y to th e sm al l n um be r o f i nd iv id ua ls en ro lle d. T yp ica lly , f or c on tin uo us o ut co m es , a sa m pl e siz e of 4 00 m ak es it p os sib le to d ra w c on clu sio ns w ith c on fid en ce , a lth ou gh th is is a ge ne ra l r ul e. Annex 3: GRADE evidence summary tables 63 A3.2 WHO treatment guidelines for isoniazid- resistant tuberculosis, 2018 Refer to Annex 5: GRADE evidence summary tables in the WHO treatment guidelines for isoniazid- resistant tuberculosis (https://www.who.int/tb/publications/2018/WHO_treatment_guidelines_ isoniazid_resistant_TB_Online_GRADE_tables_Annexes.pdf, accessed 2 March 2019). A3.3 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update Refer to Annex 8: GRADE evidence summary tables in the WHO treatment guidelines for multidrug-and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/ Annexes_8–10.pdf, accessed 2 March 2019). A3.4 Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update Refer to Annex 2: GRADE glossary and summary of evidence tables (questions 6 and 7) in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update (https:// apps.who.int/ iris/bitstream/handle/10665/70677/WHO_HTM_TB_2011.6b_eng.pdf, accessed 2 March 2019). A3.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 update Refer to Annex 4: GRADE tables (question 4) in the WHO treatment guidelines for drug- resistant tuberculosis, 2016 update (https://apps.who.int/iris/bitstream/handle/10665/250125/ 9789241549639-webannexes-eng.pdf, accessed 2 March 2019). A3.6 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update Refer to Annex 3: GRADE evidence profiles (questions 10 and 11) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/ dstb_guidance_2017/en/, accessed 2 March 2019). WHO consolidated guidelines on tuberculosis: Online annexes64 An ne x 4: G RA D E ev id en ce -t o- de ci sio n ta bl es A 4. 1 W H O tr ea tm en t g ui de lin es fo r m ul tid ru g- o r r ifa m pi ci n- re si st an t tu be rc ul os is , 2 02 0 up da te Sh ou ld a n al l- or al s ho rt er re gi m en o f 9 –1 2 m on th s’ d ur at io n in cl ud in g be da qu ili ne v s a sh or te r r eg im en re co m m en de d by W H O (w ith in je ct ab le ) b e us ed fo r M D R/ RR -T B pa tie nt s to s af el y im pr ov e ou tc om es ? PO PU LA TI O N : M D R- /R R- TB p at ie nt s to s af el y im pr ov e ou tc om es IN TE RV EN TI O N : Al l-o ra l b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) CO M PA RI SO N : Sh or te r r eg im en re co m m en de d by W H O (w ith a n in je ct ab le a ge nt ) M AI N O UT CO M ES : Su cc es s vs . F ai lu re /R ec ur re nc e; S uc ce ss v s. D ea th ; S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; S uc ce ss v s. Al l U nf av ou ra bl e; L os t v s. Al l O th er O ut co m es ; A FB S m ea r Po sit iv e: S uc ce ss v s. Fa ilu re /R ec ur re nc e; A FB S m ea r P os iti ve : S uc ce ss v s. D ea th ; A FB S m ea r P os iti ve : S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; A FB S m ea r P os iti ve : Su cc es s vs . A ll Un fa vo ur ab le ; A FB S m ea r P os iti ve : L os t v s. Al l O th er O ut co m es ; H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e; H IV -P os iti ve o n AR T: S uc ce ss vs . D ea th ; H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; H IV -P os iti ve o n AR T: S uc ce ss v s. Al l O th er U nf av ou ra bl e; H IV -P os iti ve o n AR T: L os t v s. Al l O th er O ut co m es ; H IV N eg at iv e: S uc ce ss v s. Fa ilu re /R ec ur re nc e; H IV N eg at iv e: S uc ce ss v s. D ea th ; H IV N eg at iv e: S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; H IV N eg at iv e: S uc ce ss v s. Al l O th er O ut co m es ; H IV N eg at iv e: L os t v s. Al l O th er O ut co m es . SE TT IN G : So ut h Af ric a. PE RS PE CT IV E: Pu bl ic he al th a nd h ea lth s ys te m s pe rs pe ct iv e BA CK G RO UN D : M ul tid ru g- re sis ta nt (M D R- ) a nd ri fa m pi cin -r es ist an t t ub er cu lo sis (M D R- /R R- TB ) i s em er gi ng a s a m aj or p ro bl em d ue to p oo r m an ag em en t o f d ru g- se ns iti ve a s w el l as d ru g- re sis ta nt T B. M D R- /R R- TB is tr ea ta bl e, b ut h as re qu ire d th e us e of lo ng er tr ea tm en t r eg im en s w hi ch c on ta in p ot en tia lly to xic d ru gs . T he in te re st in re du cin g th e du ra tio n of tr ea tm en t f or M D R- TB m ot iv at ed a n um be r o f i ni tia tiv es in re ce nt y ea rs to tr ea t p at ie nt s w ith s ho rt er re gi m en s un de r p ro gr am m at ic as w el l a s tri al co nd iti on s. In 2 01 6, o n th e ba sis o f d at a fro m o bs er va tio na l s tu di es o f t he s ho rt er re gi m en s in d iff er en t A sia n an d Af ric an c ou nt rie s, W H O s ta rt ed to re co m m en d a st an da rd iz ed s ho rt er M D R- TB re gi m en , c on ta in in g an in je ct ab le a ge nt , b as ed o n th e on es u nd er s tu dy fo r e lig ib le p at ie nt s. In 2 01 8, fu rt he r m od ifi ca tio ns w er e m ad e to th e ea rli er re co m m en de d sh or te r r eg im en , r ep la cin g ka na m yc in b y am ika cin (b as ed o n ev id en ce fr om th e co m pa ra tiv e ef fe ct iv en es s of th es e tw o in je ct ab le a ge nt s) . Ev id en ce o f p er m an en t e ffe ct s at tri bu te d to th e to xic ity o f i nj ec ta bl e ag en ts , h av e pr om pt ed fu rt he r a dv an ce s in th e de ve lo pm en t o f n ew tr ea tm en ts s uc h as sh or te r i nj ec ta bl e- sp ar in g re gi m en s. In p ar tic ul ar , o bs er va tio na l d at a on a n al l-o ra l b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n be ca m e av ai la bl e. T hi s is of p ar tic ul ar im po rt an ce g iv en th at th e re gi m en m ay o ffe r p at ie nt s th e lik el ih oo d of b et te r t ol er at in g tre at m en t w ith ou t s ig ni fic an t t ox ici ty. CO N FL IC T O F IN TE RE ST S: Al be rt o Pi ub el lo . Annex 4: GRADE evidence-to-decision tables 65 A ss es sm en t Pr ob le m Is th e pr ob le m a p rio rit y? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow Tu be rc ul os is (T B) re m ai ns a th re at to g lo ba l p ub lic h ea lth a nd is th e to pm os t i nf ec tio us c au se of d ea th in th e w or ld . I n 20 18 , a n es tim at ed 1 0 m illi on p eo pl e de ve lo pe d TB a nd 1 .4 m illi on di ed fr om th e di se as e. A bo ut 5 00 0 00 n ew c as es o f m ul tid ru g- o r r ifa m pi cin -r es ist an t T B (M D R/ RR -T B) w er e es tim at ed to e m er ge in 2 01 8. A lth ou gh a ll of th es e w ou ld h av e be en el ig ib le fo r a s ec on d- lin e TB tr ea tm en t r eg im en , o nl y 15 6 07 1 en ro lm en ts o n tre at m en t w er e re po rt ed b y co un tri es in 2 01 8 – ab ou t 3 0% o f t he e st im at ed c as el oa d. D es pi te th is, s ig ni fic an t im pr ov em en ts in th e av ai la bi lit y of e nh an ce d di ag no st ics a nd m or e ef fe ct iv e m ed ici ne s ha ve oc cu rre d in re ce nt y ea rs a nd h av e le d to e ar lie r d et ec tio n an d hi gh er s uc ce ss ra te s am on g pa tie nt s w ith M D R/ RR -T B in a n um be r o f n at io na l p ro gr am m es . H ow ev er , t he se s uc ce ss es h av e no t b ee n re pr od uc ed in th e re st o f t he w or ld , a nd th e ov er al l t re at m en t s uc ce ss ra te w or ld w id e re ac he d on ly 5 6% fo r p at ie nt s w ith M D R/ RR -T B w ho s ta rt ed o n tre at m en t i n 20 16 , a nd o nl y 39 % fo r p at ie nt s w ith e xt en siv el y dr ug -r es ist an t T B (X D R- TB ). WHO consolidated guidelines on tuberculosis: Online annexes66 D es ir ab le E ff ec ts H ow s ub st an tia l a re th e de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Tr iv ia l ○ S m al l ○ M od er at e ● La rg e ○ V ar ie s ○ D on ’t kn ow O ut co m es Ef fe ct Re la tiv e A bs ol ut e Su cc es s vs . F ai lu re /R ec ur re nc e (fo llo w u p: m ea n 18 m on th s) O R 2. 1 (1 .1 to 4 .0 ) 3 m or e pe r 1 00 (1 m or e to 6 m or e) Su cc es s vs . D ea th (f ol lo w u p: m ea n 18 m on th s) O R 1. 6 (1 .2 to 2 .1 ) 8 m or e pe r 1 00 (3 m or e to 1 3 m or e) Su cc es s vs . F ai lu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) O R 1. 7 (1 .3 to 2 .2 ) 10 m or e pe r 1 00 (5 m or e to 1 5 m or e) Su cc es s vs . A ll Un fa vo ra bl e (fo llo w u p: m ea n 18 m on th s) O R 1. 9 (1 .6 to 2 .4 ) 14 m or e pe r 1 00 (9 m or e to 1 9 m or e) Lo st v s. Al l O th er O ut co m es (f ol lo w u p: m ea n 18 m on th s) O R 0. 5 (0 .4 to 0 .7 ) 7 fe w er p er 1 00 (1 1 fe w er to 4 fe w er ) AF B Sm ea r P os iti ve : S uc ce ss v s. Fa ilu re /R ec ur re nc e (fo llo w u p: m ea n 18 m on th s) O R 4. 4 (1 .6 to 1 1. 9) 8 m or e pe r 1 00 (3 m or e to 1 3 m or e) AF B Sm ea r P os iti ve : S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) O R 1. 3 (0 .8 to 2 .1 ) 5 m or e pe r 1 00 (3 fe w er to 1 2 m or e) AF B Sm ea r P os iti ve : S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) O R 1. 7 (1 .1 to 2 .6 ) 10 m or e pe r 1 00 (2 m or e to 1 7 m or e) AF B Sm ea r P os iti ve : S uc ce ss v s. Al l U nf av or ab le (fo llo w u p: m ea n 18 m on th s) O R 2. 3 (1 .6 to 3 .3 ) 16 m or e pe r 1 00 (9 m or e to 2 4 m or e) AF B Sm ea r P os iti ve : L os t v s. Al l O th er O ut co m es (fo llo w u p: m ea n 18 m on th s) O R 0. 4 (0 .2 to 0 .6 ) 11 fe w er p er 1 00 (1 6 fe w er to 5 fe w er ) H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e (fo llo w u p: m ea n 18 m on th s) O R 1. 4 (0 .7 to 2 .9 ) 2 m or e pe r 1 00 (2 fe w er to 5 m or e) H IV -P os iti ve o n AR T: S uc ce ss v s. D ea th (f ol lo w u p: m ea n 18 m on th s) O R 1. 6 (1 .2 to 2 .3 ) 8 m or e pe r 1 00 (3 m or e to 1 4 m or e) H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th (f ol lo w u p: m ea n 18 m on th s) O R 1. 6 (1 .2 to 2 .2 ) 9 m or e pe r 1 00 (3 m or e to 1 5 m or e) H IV -P os iti ve o n AR T: S uc ce ss v s. Al l O th er Un fa vo ra bl e (fo llo w u p: m ea n 18 m on th s) O R 1. 9 (1 .4 to 2 .4 ) 14 m or e pe r 1 00 (8 m or e to 1 9 m or e) H IV -P os iti ve o n AR T: L os t v s. Al l O th er O ut co m es (fo llo w u p: m ea n 18 m on th s) O R 0. 6 (0 .4 to 0 .8 ) 6 fe w er p er 1 00 (1 0 fe w er to 2 fe w er ) Re su lts fr om th e da ta a ss es sm en t c om m iss io ne d to in fo rm th es e re co m m en da tio ns s ho w th at fa vo ur ab le o ut co m es w er e sig ni fic an tly b et te r f or th e al l-o ra l s ho rt er b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en th an fo r a s ho rt er re gi m en re co m m en de d by W H O (w ith in je ct ab le ). Annex 4: GRADE evidence-to-decision tables 67 U nd es ir ab le E ff ec ts H ow s ub st an tia l a re th e un de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge ○ M od er at e ○ S m al l ○ Tr iv ia l ○ V ar ie s ● D on ’t kn ow Th e G ui de lin e D ev el op m en t G ro up (G D G ) d isc us se d ea rli er re su lts o f t he in di vi du al -p at ie nt da ta (I PD ) m et a- an al ys is co nd uc te d to a ss es s th e ov er al l b al an ce b et w ee n be ne fit s an d ha rm s of in di vi du al a ge nt s. In th e an al ys is, 1 99 5 pa tie nt s re ce iv ed k an am yc in a nd 2 68 (1 3. 4% ) ex pe rie nc ed a n ad ve rs e ev en t c au sin g pe rm an en t d ru g di sc on tin ua tio n; 4 10 6 pa tie nt s re ce iv ed a m ika cin , o f w ho m 2 35 (5 .7 % ) e xp er ie nc ed a n ad ve rs e ev en t c au sin g pe rm an en t dr ug d isc on tin ua tio n; a dd iti on al ly, 1 93 2 re ce iv ed c ap re om yc in a nd 1 61 (8 .3 % ) e xp er ie nc ed an a dv er se e ve nt c au sin g pe rm an en t d ru g di sc on tin ua tio n. In c on tra st , 4 64 p at ie nt s re ce iv ed b ed aq ui lin e, o f w ho m 9 (1 .9 % ) e xp er ie nc ed a n ad ve rs e ev en t c au sin g pe rm an en t dr ug d isc on tin ua tio n. Th ou gh n o m aj or s ig na ls of ri sk w er e ob se rv ed w ith th e us e of th e al l-o ra l b ed aq ui lin e- ba se d sh or te r r eg im en , t he G D G ac kn ow le dg ed th at s om e un ce rt ai nt ie s re m ai ne d gi ve n th e la ck o f s ys te m at ic co lle ct io n of d at a, a nd la ck o f c la rit y as to an y ch an ge s in th e re gi m en th at c ou ld h av e be en in fo rm ed by th e pr es en ce o f a dv er se e ve nt s. H ow ev er , t he G D G re co gn iz ed th at th e an al ys is w as n ot c om pl et el y ag no st ic ab ou t s af et y, in p ar tic ul ar th e ba la nc e be tw ee n de sir ab le v er su s un de sir ab le e ffe ct s, an d th e gr ou p w as s om ew ha t r ea ss ur ed th at e ar lie r s ig na ls at tri bu te d to th e us e of b ed aq ui lin e w er e no t ob se rv ed , p re se nt in g no a dd iti on al s af et y co nc er ns . T he g ro up re -e m ph as iz ed th at a lth ou gh 1 .9 % o f p at ie nt s us in g be da qu ilin e ex pe rie nc e an a dv er se e ve nt th at le ad s to th e di sc on tin ua tio n of th e dr ug , t hi s co ns eq ue nc e is no t t o be c on sid er ed a s“ tri vi al ”, an d th at fo r n ow , s af et y da ta a re n ee de d to b et te r u nd er st an d [s af et y] a sp ec ts o f t he a ll- or al b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en . s af et y da ta a re n ee de d to b et te r u nd er st an d [s af et y] as pe ct s of th e al l-o ra l b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en . Ce rt ai nt y of e vi de nc e W ha t i s th e ov er al l c er ta in ty o f t he e vi de nc e of e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ● Ve ry lo w ○ L ow ○ M od er at e ○ H ig h ○ N o in clu de d st ud ie s Th e G D G p oi nt ed o ut th at , o n th e ba sis o f t he e vi de nc e as se ss ed – n am el y, ob se rv at io na l d at a an d po te nt ia l r es id ua l co nf ou nd in g – th e ov er al l c er ta in ty re ga rd in g th e es tim at es of e ffe ct b as ed w as ju dg ed to b e ve ry lo w, w ith th e ef fe ct s fo r a ll ou tc om es a lso ra te d as “v er y lo w ”. Al th ou gh d ou bl e- ad ju st m en t i n pr op en sit y sc or e m at ch in g an al ys es w as c ar rie d ou t t o re m ov e th e ef fe ct s of c on fo un di ng , m em be rs o f t he G D G fu rt he r d isc us se d th at a lth ou gh th es e ef fo rt s co m pe ns at ed fo r s om e po te nt ia l c on fo un de rs , r es id ua l b ia s is lik el y to b e pr es en t. Th e gr ou p ac kn ow le dg ed th at a lth ou gh th e us e of pr og ra m m at ic da ta h ol ds g re at p ro m ise b ec au se th ey b et te r re fle ct re al p ra ct ice , s om e co ns id er at io ns in te rm s of th e ex te nt to w hi ch th es e fin di ng s co ul d be a pp lie d to o th er s et tin gs a re to b e co nt em pl at ed . F or in st an ce , s pe cif ic cli ni ca l c ha ra ct er ist ics of th e po pu la tio n (e .g . H IV p re va le nc e an d dr ug -r es ist an ce pa tte rn s) a s w el l a s qu al ity o f h ea lth c ar e se rv ice s, m od el s of ca re , a nd tr ea tm en t a dh er en ce s tra te gi es . WHO consolidated guidelines on tuberculosis: Online annexes68 Va lu es Is th er e im po rt an t u nc er ta in ty a bo ut o r v ar ia bi lit y in h ow m uc h pe op le v al ue th e m ai n ou tc om es ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Im po rt an t un ce rt ai nt y or va ria bi lit y ○ P os sib ly im po rt an t un ce rt ai nt y or va ria bi lit y ○ P ro ba bl y no im po rt an t u nc er ta in ty or v ar ia bi lit y ● N o im po rt an t un ce rt ai nt y or va ria bi lit y A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y, pa tie nt an d civ il so cie ty re pr es en ta tiv es (n = 1 6) lo ok ed a t g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se of in je ct ab le a ge nt s an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . Pa rt ici pa nt s ha d th e op po rt un ity to d isc us s im po rt an t a dv er se e ffe ct s, in clu di ng p er m an en t se ns or in eu ra l h ea rin g lo ss , n ep hr ot ox ici ty , e le ct ro ly te a bn or m al iti es , i nj ec tio n pa in a nd lo ca l in je ct io n- sit e co m pl ica tio ns . F ro m a p at ie nt p er sp ec tiv e, a dv er se e ve nt s su ch a s op tic n eu rit is, he ar in g im pa irm en t, m en ta l s ta tu s ch an ge s du e to u re m ia , a nd e le ct ro ly te a bn or m al iti es a re la te e ffe ct s am on g ot he rs a ss oc ia te d w ith th e us e of s pe cif ic se co nd -li ne a ge nt s, in clu di ng in je ct ab le a ge nt s, an d w er e de em ed u na cc ep ta bl e. . Pr ef er en ce s ab ou t t re at m en t a pp ea re d to b e ro ot ed in c or e va lu es , i nc lu di ng m in im al d isr up tio n to n or m al li fe . R el at iv el y fe w p at ie nt s se em ed to p re fe r a s ho rt re gi m en th at w as ti ed to m or e se rio us s id e- ef fe ct s, bu t o nl y if th e sid e- ef fe ct s w er e ra re or re ve rs ib le . I n ad di tio n, in te rm s of th e du ra tio n of tr ea tm en t, pr ef er en ce s se em ed to b e gu id ed fi rs t b y sid e- ef fe ct s an d se co nd b y ef fic ac y of tr ea tm en t r eg im en s. Ba la nc e of e ff ec ts D oe s th e ba la nc e be tw ee n de si ra bl e an d un de si ra bl e ef fe ct s fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on ○ P ro ba bl y fa vo rs th e in te rv en tio n ● Fa vo rs th e in te rv en tio n ○ V ar ie s ○ D on ’t kn ow Th e G D G c on sid er ed w he th er th e ba la nc e be tw ee n de sir ab le an d un de sir ab le e ffe ct s fa vo ur ed th e in te rv en tio n. D at a as se ss m en t s ho w ed th at th e ov er al l r at e of a dv er se e ve nt s at tri bu te d to b ed aq ui lin e as c om pa re d w ith in je ct ab le a ge nt s w as tw o tim es le ss . A t t he s am e tim e, th e G D G n ot ed a 5 0% re du ct io n in d ea th , a ttr ib ut in g th is ef fe ct to th e ad di tio n of be da qu ilin e. H ow ev er , t he g ro up e m ph as iz ed th e po te nt ia l ha rm s if th is be da qu ilin e- co nt ai ni ng re gi m en w er e to b e im pl em en te d w ith ou t e ns ur in g pr op er d ru g- su sc ep tib ilit y te st in g (D ST ), an d th e po te nt ia l f or a m pl ifi ca tio n of re sis ta nc e pa tte rn s. W he n de cid in g on w he th er o r n ot th e ba la nc e of ef fe ct s fa vo ur ed th e in te rv en tio n or th e co m pa ra to r, th e gr ou p pr oc ee de d to v ot e. To ta l v ot in g m em be rs p re se nt : 2 9 ex pe rt s (p lu s 1 co nf lic t o f i nt er es t). V ot in g pr oc ee de d as fo llo w s: Pr ob ab ly, 1 3; fa vo ur s th e in te rv en tio n, 1 4; v ar ie s, 1; a bs te nt io n, 1; p lu s on e vo tin g m em be r w ho a bs ta in ed d ue to c on fli ct of in te re st . Annex 4: GRADE evidence-to-decision tables 69 Re so ur ce s re qu ir ed H ow la rg e ar e th e re so ur ce re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge c os ts ○ M od er at e co st s ○ N eg lig ib le c os ts an d sa vi ng s ● M od er at e sa vi ng s ○ L ar ge s av in gs ○ V ar ie s ○ D on ’t kn ow Co m pa re d w ith th e in je ct ab le -c on ta in in g sh or te r r eg im en , t he 9 –1 2- m on th a ll- or al re gi m en is pr oj ec te d to b e bo th c os t- sa vi ng a nd m or e ef fe ct iv e th an th e in je ct ab le -c on ta in in g sh or te r re gi m en u nd er n ea rly a ll m od el le d co nd iti on s. Th e pr oj ec te d co st s av in gs a ve ra ge U S$ 1 00 0 (2 01 9) in S ou th A fri ca a nd d ep en d pr im ar ily o n th e ex te nt to w hi ch h ig he r d ru g co st s ar e ou tw ei gh ed b y th e re du ce d co st s of d el iv er in g in je ct ab le a ge nt s, an d tre at in g re cu rre nt a nd se co nd ar y ca se s (a bo ut U S$ 2 00 0 pe r p at ie nt is s av ed in s et tin gs w ith tw o- tim es -h ig he r h ea lth ca re c os ts , v er su s <U S$ 1 00 s av ed in s et tin gs w ith h ig h dr ug c os ts b ut lo w h ea lth c ar e co st s) . An im po rt an t i ss ue a ck no w le dg ed b y th e G D G w as th at al th ou gh th e al l-o ra l b ed aq ui lin e- co nt ai ni ng re gi m en s ee m ed to b e bo th c os t-s av in g an d m or e ef fe ct iv e as c om pa re d w ith th e sh or te r r eg im en re co m m en de d by W H O (w ith a n in je ct ab le ), co st s ar e no t e xp ec te d to a ut om at ica lly e lim in at ed o r de cr ea se d. S ev er al o th er k ey fa ct or s m us t a lso b e co ns id er ed , in clu di ng th e ex ist in g st oc k of s ec on d- lin e m ed ica tio ns w hi le tra ns iti on in g fro m a n in je ct ab le -b as ed re gi m en to a n al l-o ra l on e, d ia gn os tic c ap ac ity to id en tif y el ig ib le in di vi du al s in to cu rre nt ly re co m m en de d re gi m en s (b as ed o n dr ug -s us ce pt ib ilit y pa tte rn s, et c. ), an d ca pa cit y to c on du ct re gu la r a ct iv e TB d ru g sa fe ty m on ito rin g an d m an ag em en t. H ow ev er , t he re w er e no d at a fo r d et er m in in g th e ex ac t r es ou rc es th at w ou ld b e co ns um ed w ith th e im pl em en ta tio n of th is al l-o ra l b ed aq ui lin e- co nt ai ni ng re gi m en . Th e G D G d id a gr ee th at , o ve ra ll, sa vi ng s ca n be c on sid er ed in te rm s of fu tu re re tre at m en ts p re ve nt ed , a s w el l a s re du ce d ho sp ita liz at io n ra te s re su lti ng fr om le ss a dv er se re ac tio ns . Ce rt ai nt y of e vi de nc e of r eq ui re d re so ur ce s W ha t i s th e ce rt ai nt y of th e ev id en ce o f r es ou rc e re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ V er y lo w ○ L ow ● M od er at e ○ H ig h ○ N o in clu de d st ud ie s Th e co st s av in gs re la tiv e to a s ho rt in je ct ab le -c on ta in in g re gi m en a re a lso ro bu st , e xc ep t at e xt re m es w ith d ru g co st s, he al th c ar e co st s or th e co st o f b ed aq ui lin e an d ot he r co m pa ni on d ru gs . Th ou gh th e un ce rt ai nt y ar ou nd th e es tim at es o f e ffe ct w as ac kn ow le dg ed , t he G D G a gr ee d th at th er e se em ed to b e m od er at e co st s av in gs , b ec au se o f r ed uc ed h os pi ta liz at io n ra te s re su lti ng fr om fe w er a dv er se re ac tio ns , l es s m on ito rin g/ vi sit s (fo r in je ct ab le u se ), an d fe w er tr ea tm en t i nt er ru pt io ns b ec au se o f be tte r a dh er en ce . WHO consolidated guidelines on tuberculosis: Online annexes70 Co st e ff ec ti ve ne ss D oe s th e co st -e ff ec tiv en es s of th e in te rv en tio n fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on ● Pr ob ab ly fa vo rs th e in te rv en tio n ○ F av or s th e in te rv en tio n ○ V ar ie s ○ N o in clu de d st ud ie s A co st –e ffe ct iv en es s m od el w as d ev el op ed , i nc or po ra tin g es tim at ed h ea lth s ys te m c os ts w ith dr ug p ro cu re m en t, he al th c ar e de liv er y, ad ve rs e ev en ts , r et re at m en ts , s ec on da ry c as es , a nd m or bi di ty a nd m or ta lit y as so cia te d w ith T B m or ta lit y an d re cu rre nc e, tr ea tm en t d ur at io n, d ru g to xic ity a nd T B tra ns m iss io n. C os ts a nd c os t– ef fe ct iv en es s w er e ev al ua te d in S ou th A fri ca , w ith s en sit iv ity a na ly se s re pr es en tin g a ra ng e of d ru g an d he al th c ar e co st s, hi gh a nd lo w H IV c o- pr ev al en ce , 9 5% C Is fo r e st im at es o f r el at iv e ef fic ac y de riv ed fr om s ta tis tic al a na ly sis of p at ie nt c oh or t d at a, a nd u nc er ta in ty in th e va lu es o f p ar am et er s re pr es en tin g th e na tu ra l hi st or y of T B. Co m pa re d w ith th e in je ct ab le -c on ta in in g sh or te r r eg im en , t he 9 –1 2- m on th a ll- or al re gi m en is pr oj ec te d to b e bo th c os t s av in g an d m or e ef fe ct iv e th an th e in je ct ab le -c on ta in in g sh or te r r eg im en u nd er n ea rly a ll m od el le d co nd iti on s. Th e pr oj ec te d co st s av in gs a ve ra ge US $ 10 00 (2 01 9) in S ou th A fri ca a nd d ep en d pr im ar ily o n th e ex te nt to w hi ch h ig he r d ru g co st s ar e ou tw ei gh ed b y re du ce d co st s of d el iv er in g in je ct ab le a ge nt s, an d tre at in g re cu rre nt a nd se co nd ar y ca se s (a bo ut U S$ 2 00 0 sa ve d pe r p at ie nt is s av ed in s et tin gs w ith tw o- tim es -h ig he r he al th c ar e co st s, ve rs us < US $ 10 0 sa ve d in s et tin gs w ith h ig h dr ug c os ts b ut lo w h ea lth c ar e co st s) . I n a sc en ar io w he re th e al l-o ra l r eg im en w as n o lo ng er c os t-s av in g be ca us e be da qu ilin e pr ice s w er e fo ur fo ld h ig he r t ha n cu rre nt p ric in g in S ou th A fri ca o r v ia th e G D F, th e in cr em en ta l co st –e ffe ct iv en es s ra tio o f t he a ll- or al re gi m en w as U S$ 4 00 p er d isa bi lit y ad ju st ed li fe -y ea r av er te d (ra ng e: U S$ 1 00 –U S$ 9 00 a cr os s 95 % C I f or re la tiv e re gi m en e ffi ca cy ). Eq ui ty W ha t w ou ld b e th e im pa ct o n he al th e qu ity ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ R ed uc ed ○ P ro ba bl y re du ce d ○ P ro ba bl y no im pa ct ○ P ro ba bl y in cr ea se d ● In cr ea se d ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y, pa tie nt an d civ il so cie ty re pr es en ta tiv es (n =1 6) lo ok ed a t g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B tre at m en t, su ch a s du ra tio n, p ill bu rd en , u se o f i nj ec ta bl e ag en ts a nd p ot en tia l f or e xp er ie nc in g ad ve rs e ev en ts . Pa rt ici pa nt s co ns id er ed a ny th in g le ss th an u ni ve rs al a nd im m ed ia te a cc es s to n ew tr ea tm en ts to be u ne th ica l, bu t w he n pr om pt ed to c on sid er th is pr ef er en ce a ga in st a li m ite d su pp ly o f d ru gs , a fe w w ou ld p rio rit iz e th e yo un ge st a nd s ick es t, as w el l a s th os e w ho a re a dh er en t a nd c ou ld be m on ito re d fo r a dv er se e ve nt s. Pa tie nt s w ho fa ce s oc io ec on om ic ch al le ng es to a dh er en ce , or w ho li ve in re m ot e, ru ra l o r p oo re r c om m un iti es th at la ck te ch ni ca l s kil l o r e qu ip m en t f or tre at m en t m on ito rin g, c ou ld th en b e di sp ro po rt io na te ly a nd u nj us tly p la ce d at a d isa dv an ta ge Th e G D G a gr ee d th at in je ct ab le -s pa rin g re gi m en s w ou ld be e as ie r t o de ce nt ra liz e an d, th er ef or e, in re m ot e an d un de rs er vi ce d se tti ng s an d di sa dv an ta ge d po pu la tio ns , w ou ld h el p to a lle vi at e he al th in eq ui tie s, w ith ou t a nt ici pa tin g di ffe re nc es in o ut co m es in s pe cif ic po pu la tio ns . F ur th er , t he gr ou p al so n ot ed th at b ec au se a ud io m et ry w ou ld n ot b e re qu ire d, it m ig ht b e ea sie r t o m on ito r i nd iv id ua ls in s pi te o f in cr ea se d re qu ire m en ts fo r e le ct ro ca rd io gr ap hy , w hi ch is a pr er eq ui sit e fo r t he u se o f b ed aq ui lin e- co nt ai ni ng re gi m en s. H ow ev er , t he g ro up s tre ss ed th at th e us e of e le ct ro ca rd io gr ap hy sh ou ld n ot b e a di ffe re nt ia tin g el em en t b et w ee n th es e tw o re gi m en s, be ca us e pa tie nt s re ce iv in g in je ct ab le a ge nt s su ch as a m ika cin s ho ul d al so h av e re gu la r c ar di ac m on ito rin g. T he gr ou p ac kn ow le dg ed th at it is p os sib le th at , i n so m e se tti ng sk no t a ll pa tie nt s w ill be a bl e to u nd er go e le ct ro ca rd io gr ap hi c m on ito rin g; h ow ev er , i t w as a lso n ot ed th at th e in cr ea sin g ac ce ss to e le ct ro ca rd io gr ap hy a t p er ip he ry le ve ls m ig ht im pr ov e eq ui ty. Annex 4: GRADE evidence-to-decision tables 71 Co st e ff ec ti ve ne ss D oe s th e co st -e ff ec tiv en es s of th e in te rv en tio n fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on ● Pr ob ab ly fa vo rs th e in te rv en tio n ○ F av or s th e in te rv en tio n ○ V ar ie s ○ N o in clu de d st ud ie s A co st –e ffe ct iv en es s m od el w as d ev el op ed , i nc or po ra tin g es tim at ed h ea lth s ys te m c os ts w ith dr ug p ro cu re m en t, he al th c ar e de liv er y, ad ve rs e ev en ts , r et re at m en ts , s ec on da ry c as es , a nd m or bi di ty a nd m or ta lit y as so cia te d w ith T B m or ta lit y an d re cu rre nc e, tr ea tm en t d ur at io n, d ru g to xic ity a nd T B tra ns m iss io n. C os ts a nd c os t– ef fe ct iv en es s w er e ev al ua te d in S ou th A fri ca , w ith s en sit iv ity a na ly se s re pr es en tin g a ra ng e of d ru g an d he al th c ar e co st s, hi gh a nd lo w H IV c o- pr ev al en ce , 9 5% C Is fo r e st im at es o f r el at iv e ef fic ac y de riv ed fr om s ta tis tic al a na ly sis of p at ie nt c oh or t d at a, a nd u nc er ta in ty in th e va lu es o f p ar am et er s re pr es en tin g th e na tu ra l hi st or y of T B. Co m pa re d w ith th e in je ct ab le -c on ta in in g sh or te r r eg im en , t he 9 –1 2- m on th a ll- or al re gi m en is pr oj ec te d to b e bo th c os t s av in g an d m or e ef fe ct iv e th an th e in je ct ab le -c on ta in in g sh or te r r eg im en u nd er n ea rly a ll m od el le d co nd iti on s. Th e pr oj ec te d co st s av in gs a ve ra ge US $ 10 00 (2 01 9) in S ou th A fri ca a nd d ep en d pr im ar ily o n th e ex te nt to w hi ch h ig he r d ru g co st s ar e ou tw ei gh ed b y re du ce d co st s of d el iv er in g in je ct ab le a ge nt s, an d tre at in g re cu rre nt a nd se co nd ar y ca se s (a bo ut U S$ 2 00 0 sa ve d pe r p at ie nt is s av ed in s et tin gs w ith tw o- tim es -h ig he r he al th c ar e co st s, ve rs us < US $ 10 0 sa ve d in s et tin gs w ith h ig h dr ug c os ts b ut lo w h ea lth c ar e co st s) . I n a sc en ar io w he re th e al l-o ra l r eg im en w as n o lo ng er c os t-s av in g be ca us e be da qu ilin e pr ice s w er e fo ur fo ld h ig he r t ha n cu rre nt p ric in g in S ou th A fri ca o r v ia th e G D F, th e in cr em en ta l co st –e ffe ct iv en es s ra tio o f t he a ll- or al re gi m en w as U S$ 4 00 p er d isa bi lit y ad ju st ed li fe -y ea r av er te d (ra ng e: U S$ 1 00 –U S$ 9 00 a cr os s 95 % C I f or re la tiv e re gi m en e ffi ca cy ). Eq ui ty W ha t w ou ld b e th e im pa ct o n he al th e qu ity ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ R ed uc ed ○ P ro ba bl y re du ce d ○ P ro ba bl y no im pa ct ○ P ro ba bl y in cr ea se d ● In cr ea se d ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y, pa tie nt an d civ il so cie ty re pr es en ta tiv es (n =1 6) lo ok ed a t g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B tre at m en t, su ch a s du ra tio n, p ill bu rd en , u se o f i nj ec ta bl e ag en ts a nd p ot en tia l f or e xp er ie nc in g ad ve rs e ev en ts . Pa rt ici pa nt s co ns id er ed a ny th in g le ss th an u ni ve rs al a nd im m ed ia te a cc es s to n ew tr ea tm en ts to be u ne th ica l, bu t w he n pr om pt ed to c on sid er th is pr ef er en ce a ga in st a li m ite d su pp ly o f d ru gs , a fe w w ou ld p rio rit iz e th e yo un ge st a nd s ick es t, as w el l a s th os e w ho a re a dh er en t a nd c ou ld be m on ito re d fo r a dv er se e ve nt s. Pa tie nt s w ho fa ce s oc io ec on om ic ch al le ng es to a dh er en ce , or w ho li ve in re m ot e, ru ra l o r p oo re r c om m un iti es th at la ck te ch ni ca l s kil l o r e qu ip m en t f or tre at m en t m on ito rin g, c ou ld th en b e di sp ro po rt io na te ly a nd u nj us tly p la ce d at a d isa dv an ta ge Th e G D G a gr ee d th at in je ct ab le -s pa rin g re gi m en s w ou ld be e as ie r t o de ce nt ra liz e an d, th er ef or e, in re m ot e an d un de rs er vi ce d se tti ng s an d di sa dv an ta ge d po pu la tio ns , w ou ld h el p to a lle vi at e he al th in eq ui tie s, w ith ou t a nt ici pa tin g di ffe re nc es in o ut co m es in s pe cif ic po pu la tio ns . F ur th er , t he gr ou p al so n ot ed th at b ec au se a ud io m et ry w ou ld n ot b e re qu ire d, it m ig ht b e ea sie r t o m on ito r i nd iv id ua ls in s pi te o f in cr ea se d re qu ire m en ts fo r e le ct ro ca rd io gr ap hy , w hi ch is a pr er eq ui sit e fo r t he u se o f b ed aq ui lin e- co nt ai ni ng re gi m en s. H ow ev er , t he g ro up s tre ss ed th at th e us e of e le ct ro ca rd io gr ap hy sh ou ld n ot b e a di ffe re nt ia tin g el em en t b et w ee n th es e tw o re gi m en s, be ca us e pa tie nt s re ce iv in g in je ct ab le a ge nt s su ch as a m ika cin s ho ul d al so h av e re gu la r c ar di ac m on ito rin g. T he gr ou p ac kn ow le dg ed th at it is p os sib le th at , i n so m e se tti ng sk no t a ll pa tie nt s w ill be a bl e to u nd er go e le ct ro ca rd io gr ap hi c m on ito rin g; h ow ev er , i t w as a lso n ot ed th at th e in cr ea sin g ac ce ss to e le ct ro ca rd io gr ap hy a t p er ip he ry le ve ls m ig ht im pr ov e eq ui ty. A cc ep ta bi lit y Is th e in te rv en tio n ac ce pt ab le to k ey s ta ke ho ld er s? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt a nd c iv il so cie ty re pr es en ta tiv es (n = 1 6) , l oo ke d at g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se o f i nj ec ta bl e ag en ts a nd p ot en tia l f or e xp er ie nc in g ad ve rs e ev en ts . T he re su lts of th is qu al ita tiv e an al ys is su gg es te d th at m os t p at ie nt s w ou ld p rio rit iz e a re gi m en w ith fe w er an d le ss -s ev er e sid e- ef fe ct s ab ov e al l e lse , b ec au se it w ou ld a llo w th em to c on tin ue ro ut in e ac tiv iti es . O f n ot e, s ur vi vo rs o f d ru g- re sis ta nt T B re m ar ke d th at th ey w ou ld a cc ep t a lo ng er tre at m en t t ha t p ro m ise d fe w er s ev er e ad ve rs e ef fe ct s ov er a s ho rt er re gi m en ti ed to m or e se ve re s id e- ef fe ct s, ev en if tr ea tm en t w as e xp er im en ta l o r e ffi ca cy w as u nc le ar . T hi s co nt ra st ed w ith c om pa ra tiv el y fe w p ar tic ip an ts w ho p rio rit iz ed ra pi d re tu rn to n or m al li fe a nd w ou ld ra th er as su m e th e ris k of m or e se rio us s id e- ef fe ct s w ith in a s ho rt er re gi m en , e ve n if tre at m en t w as ex pe rim en ta l a nd e ffi ca cy u nc le ar . Th e G D G n ot ed th at p at ie nt s re co gn iz e th at th ei r e xp er ie nc es an d pe rc ep tio ns a re h ig hl y pe rs on - an d co nt ex t-d ep en de nt , th ou gh p re fe re nc e fo r t hi s [s ho rt er ] r eg im en s ee m ed to b e co nd iti on al u po n ad ve rs e ev en ts b ei ng ra re o r r ev er sib le . N ev er th el es s, ov er al l, a sh or t, in je ct io n- fre e re gi m en w ith fe w to no p hy sic al a nd m en ta l h ea lth s id e- ef fe ct s an d a lo w p ill bu rd en ap pe ar ed to b e th e m os t a cc ep ta bl e. WHO consolidated guidelines on tuberculosis: Online annexes72 Fe as ib ili ty Is th e in te rv en tio n fe as ib le to im pl em en t? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ○ Y es ● Va rie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n = 1 6) lo ok ed a t g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se of in je ct ab le a ge nt s an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . Th is st ud y re ve al ed th at a s th e re gi m en , i n pa rt icu la r t he e xp an sio n of b ed aq ui lin e ac ce ss to al l p at ie nt s, is he ld b ac k in s om e se tti ng s as a re su lt of re st ric tiv e el ig ib ilit y (i. e. p rio rit iz at io n of s pe cif ic gr ou ps ) c rit er ia , l ac k of fu nd in g, o r l ac k of a de qu at e in fra st ru ct ur e in p la ce (e .g . di ag no st ics ), th e op er at io na liz at io n an d im m ed ia te ro llo ut o f t he a ll- or al b ed aq ui lin e- co nt ai ni ng re gi m en m ay b e ha m pe re d. O ne im po rt an t r eq ui re m en t h ig hl ig ht ed b y th e G D G w as th at of e ns ur in g th e ca re fu l s el ec tio n of p at ie nt s w ho a re to b en ef it fro m th is re gi m en , c on du ct in g ra pi d an d ac cu ra te D ST , a nd th e m on ito rin g of b ed aq ui lin e re sis ta nc e. T he im pl em en ta tio n of th e re gi m en m ay b e lim ite d by th e ne ed fo r i m pr ov ed la bo ra to ry in fra st ru ct ur e. A lth ou gh c ou nt rie s ar e im pl em en tin g ra pi d m ol ec ul ar te st s to id en tif y rif am pi cin re sis ta nc e, la bo ra to ry ca pa cit y ne ed s to b e ef fe ct iv el y es ta bl ish ed to c on du ct ge no ty pi c an d ph en ot yp ic te st in g fo r o th er im po rt an t a ge nt s in th e re gi m en . A lso , a lth ou gh th e pr ev al en ce o f i de nt ifi ed m ut at io ns c on fe rr in g lo w -le ve l d ru g re sis ta nc e is ve ry lo w, co un tri es a re to s tre ng th en la bo ra to ry c ap ac ity a nd to m on ito r th e ac qu isi tio n of re sis ta nc e to b ed aq ui lin e th ou gh th ei r n at io na l re fe re nc e la bo ra to rie s or T B su pr an at io na l r ef er en ce s ite s. Th is is es pe cia lly im po rt an t g iv en th e pi pe lin e of n ew a nt i-T B re gi m en s th at a re re ly in g on b ed aq ui lin e as a b ac kb on e. Th e re m ov al o f i nj ec ta bl e ag en ts , a s di sc us se d by th e G D G , al so p oi nt ed to w ar ds th e co nv en ie nc e (fo r h ea lth c ar e w or ke rs ) of n ot h av in g to d el iv er d ai ly in je ct io ns , a nd m or e so , f or pa tie nt s no t h av in g to e nd ur e th e pa in a nd o th er s ig ni fic an t ad ve rs e ev en ts . Th e im pl em en ta tio n of th e re gi m en is p er ce iv ed to g o be yo nd se cu rin g of fu nd in g, b ut it fu rt he r r eq ui re s m ak in g lo ng - te rm , s us ta in ab le s ys te m s ch an ge to e ns ur e ra pi d tra ns iti on , co ns id er in g th e re gi st ra tio n of b ed aq ui lin e an d ot he r n ew ag en ts , u ni nt er ru pt ed s up pl y of q ua lit y- as su re d dr ug s an d ac tiv e TB d ru g sa fe ty m on ito rin g an d m an ag em en t s ys te m in co or di na tio n w ith e xis tin g ph ar m ac ov ig ila nc e st ru ct ur es a t t he co un tr y le ve l. Al so , t he im pl em en ta tio n of th is re gi m en (a nd a ny o th er n ov el re gi m en ) w ill re qu ire d ec isi on -m ak in g to w ar ds m ul tis ec to ra l po lic ie s, ta ilo rin g pa tie nt c en tre d pr og ra m m es w hi ch a lso co ns id er a sp ec ts s uc h as m en ta l h ea lth a nd m an ag em en t o f ot he r c om or bi di tie s, fa cil ita tin g co un se llin g an d su pp or t d ur in g tre at m en t, an d af te r c om pl et io n, fa cil ita tin g fu ll re co ve ry . Annex 4: GRADE evidence-to-decision tables 73 Su m m ar y of ju dg em en ts JU D G EM EN T PR O BL EM Ye s Va rie s D on ’t kn ow D ES IR AB LE E FF EC TS Tr iv ia l Sm al l M od er at e La rg e Va rie s D on ’t kn ow UN D ES IR AB LE E FF EC TS La rg e M od er at e Sm al l Tr iv ia l Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s VA LU ES Im po rt an t un ce rt ai nt y or va ria bi lit y Po ss ib ly im po rt an t un ce rt ai nt y or va ria bi lit y Pr ob ab ly n o im po rt an t un ce rt ai nt y or va ria bi lit y N o im po rt an t un ce rt ai nt y or va ria bi lit y BA LA N CE O F EF FE CT S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s D on ’t kn ow RE SO UR CE S RE Q UI RE D La rg e co st s M od er at e co st s N eg lig ib le c os ts a nd sa vi ng s M od er at e sa vi ng s La rg e sa vi ng s Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE O F RE Q UI RE D R ES O UR CE S Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s CO ST E FF EC TI VE N ES S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s N o in clu de d st ud ie s EQ UI TY Re du ce d Pr ob ab ly re du ce d Pr ob ab ly n o im pa ct Pr ob ab ly in cr ea se d In cr ea se d Va rie s D on ’t kn ow AC CE PT AB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow FE AS IB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow Ty pe o f r ec om m en da tio n St ro ng re co m m en da tio n ag ai ns t th e in te rv en tio n ○ Co nd iti on al re co m m en da tio n ag ai ns t t he in te rv en tio n ○ Co nd iti on al re co m m en da tio n fo r e ith er th e in te rv en tio n or th e co m pa ris on ○ Co nd iti on al re co m m en da tio n fo r t he in te rv en tio n ● St ro ng re co m m en da tio n fo r t he in te rv en tio n ○ WHO consolidated guidelines on tuberculosis: Online annexes74 Co nc lu si on s Re co m m en da tio n A sh or te r, al l-o ra l, be da qu ilin e- co nt ai ni ng re gi m en o f 9 –1 2 m on th s’ du ra tio n is re co m m en de d in e lig ib le p at ie nt s w ith c on fir m ed M D R/ RR -T B w ho h av e no t b ee n ex po se d to tr ea tm en t w ith s ec on d- lin e TB m ed ici ne s us ed in th is re gi m en fo r m or e th an 1 m on th a nd in w ho m re sis ta nc e to fl uo ro qu in ol on es h as b ee n ex clu de d. (C on di tio na l r ec om m en da tio n, v er y lo w c er ta in ty in th e ev id en ce ) Ju st ifi ca tio n O ve ra ll, th e G D G n ot ed th at th e ce rt ai nt y of th e ev id en ce o n th e ef fic ac y of th e al l-o ra l s ho rt er re gi m en w as v er y lo w, a ttr ib ut ab le n am el y to c on ce rn s of s er io us ri sk o f b ia s, de sp ite ef fo rt s to b al an ce b as el in e co va ria te s. H ow ev er , t he g ro up re co gn iz ed th at th e cu rre nt e vi de nc e as se ss m en t o f t he a ll- or al , b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en s ho w ed a b et te r ra tio o f s uc ce ss v er su s un fa vo ur ab le o ut co m es a nd a s ig ni fic an t r ed uc tio n in lo ss to fo llo w -u p. W he n de cid in g on th e st re ng th o f t he re co m m en da tio n, th e G D G re ac he d a un an im ou s de cis io n on th e co nd iti on al ity o f t he re co m m en da tio n, m ai nl y at tri bu te d to th e ve ry lo w c er ta in ty in th e ev id en ce a nd re qu ire m en ts to b ui ld la bo ra to ry c ap ac ity a nd e ns ur e D ST . O th er g ro un ds fo r t he s tre ng th a nd d ire ct io n of th is re co m m en da tio n ar e as fo llo w s: • Th e an al ys is co nd uc te d to in fo rm th e de ve lo pm en t o f t hi s re co m m en da tio n w as b as ed o n ob se rv at io na l p ro gr am m at ic da ta fr om S ou th A fri ca w he re th e st an da rd iz ed s ho rt er , a ll- or al , be da qu ilin e- co nt ai ni ng re gi m en (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) w as u se d fo r p at ie nt s w ith M D R/ RR -T B. • Th ou gh n o m aj or s ig na ls of ri sk w er e ob se rv ed w ith th e us e of th e al l-o ra l b ed aq ui lin e- ba se d sh or te r r eg im en , t he re a lso re m ai ne d so m e un ce rt ai nt ie s, gi ve n th e la ck o f s ys te m at ic co lle ct io n of d at a, a nd g iv en th e la ck o f c la rit y as to a ny c ha ng es in th e re gi m en th at c ou ld h av e be en in fo rm ed b y th e pr es en ce o f a dv er se e ve nt s. • Co st –e ffe ct iv en es s m od el lin g of th e al l-o ra l, sh or te r, be da qu ilin e- co nt ai ni ng re gi m en s ho w ed ro bu st c os t s av in gs re la tiv e to e ith er a lo ng er o ra l r eg im en o r a s ho rt in je ct ab le - co nt ai ni ng re gi m en . – Th e G D G ju dg ed th at m an y el ig ib le p at ie nt s w ou ld p re fe r t he a ll- or al , b ed aq ui lin e- co nt ai ni ng re gi m en o f 9 –1 2 m on th s’ du ra tio n. T hi s is su pp or te d by li m ite d ob se rv at io ns in vo lv in g 16 s ur vi vo rs o f d ru g- re sis ta nt T B. In a dd iti on , t hi s re gi m en m ay h el p pr om ot e he al th e qu ity o r m iti ga te th e w or se ni ng o f h ea lth in eq ui tie s. Al th ou gh th e pa ne l r ec og ni ze d th at im pl em en ta tio n an d sc al e- up o f t hi s re gi m en m ay b e slo w d ue p re re qu isi te s on la bo ra to ry c ap ac ity a nd m on ito rin g. Su bg ro up c on si de ra tio ns Th e an al ys is at te m pt ed to d es cr ib e th e ba la nc e of e ffe ct s an d co ns id er at io ns fo r v ar io us s ub gr ou ps o r s pe cia l p op ul at io ns . H ow ev er , t he e vi de nc e re vi ew ed s up po rt ed th e us e of th is on th e fo llo w in g, w ith s pe cif ic ca ve at s: • Pe op le li vi ng w ith H IV in fe ct io n: T he d at a ev al ua te d co rre sp on de d to a s et tin g w ith a h ig h pr ev al en ce o f H IV , a nd o f p ar tic ul ar s ig ni fic an ce , m os t P LH IV (> 95 % ) w ho s ta rt ed th e al l- or al b ed aq ui lin e- co nt ai ni ng re gi m en w er e re ce iv in g an tir et ro vi ra l t he ra py (A RT ). In v ie w o f t he tr ea tm en t o ut co m es d es cr ib ed in th e an al ys is, th er e w er e no g ro un ds to b el ie ve th at th e re gi m en w ou ld p er fo rm a ny d iff er en tly in P LH IV . I t i s ne ce ss ar y to c on sid er s ig ni fic an t c lin ica l i nt er ac tio ns th at m ay in cr ea se b ed aq ui lin e ex po su re o r t ha t o f o th er a ge nt s w ith p ot en tia l fo r c ar di ot ox ici ty w he n th es e ar e co -a dm in ist er ed w ith a nt ire tro vi ra ls. • Ch ild re n: A lth ou gh n o di re ct o ut co m e es tim at io ns c ou ld b e dr aw n fo r t hi s po pu la tio n, e xt ra po la tio n w as d ee m ed re as on ab le . H ow ev er , b ec au se b ed aq ui lin e is cu rre nt ly re co m m en de d fo r c hi ld re n an d ad ol es ce nt s ag ed 6 –1 7 ye ar s, th e G D G c on clu de d th at th e al l-o ra l b ed aq ui lin e- co nt ai ni ng re gi m en m ay b e us ed in e lig ib le c hi ld re n w ith in th is ag e gr ou p, ta kin g in to ac co un t s pe cif ica tio ns fo r r eg im en c om pa ni on d ru gs – in p ar tic ul ar , b ed aq ui lin e. • Pr eg na nt a nd la ct at in g w om en : M or e ev id en ce is n ee de d to b et te r i nf or m th e us e of th e al l-o ra l, be da qu ilin e- co nt ai ni ng s ho rt er re gi m en (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) . O ne of th e ag en ts in th is al l-o ra l s ho rt er re gi m en , e th io na m id e, is u su al ly c on tra in di ca te d in p re gn an cy , a nd w ith ho ld in g th is ag en t o r r ep la cin g it w ith a no th er o ne c ou ld s er io us ly co m pr om ise th e ef fe ct iv en es s of th e re gi m en . I n th e ca se o f p re gn an t a nd la ct at in g w om en , i t i s th er ef or e re co m m en de d th at a n in di vi du al iz ed , a ll- or al lo ng er re gi m en (w ith in clu sio n of b ed aq ui lin e) is u se d in th is po pu la tio n (s ee R ec om m en da tio ns o n th e us e of lo ng er re gi m en s fo r M D R/ RR -T B) . – Ex tra pu lm on ar y di se as e: In v ie w o f t he u na va ila bi lit y of e vi de nc e on s ur ro ga te s fo r s ev er ity o r e xt en t o f d ise as e, c lin ica l j ud ge m en t i s ad vi se d to d ec id e on th e us e of th is re gi m en in pa tie nt s w ith e xt en siv e TB d ise as e or s ev er e fo rm s of e xt ra pu lm on ar y TB . Annex 4: GRADE evidence-to-decision tables 75 Im pl em en ta tio n co ns id er at io ns Th e in te re st in re du cin g th e du ra tio n of tr ea tm en t f or M D R/ RR -T B ha s m ot iv at ed a n um be r o f s tu di es in re ce nt y ea rs to tr ea t p at ie nt s w ith s ho rt er re gi m en s un de r p ro gr am m at ic as w el l as tr ia l c on di tio ns . F ol lo w in g ex pe rie nc es in v ar io us s et tin gs , [ el ig ib le ] p at ie nt s no w h av e an o pt io n to b e tre at ed w ith a s ho rt er , i nj ec ta bl e- sp ar in g re gi m en o f 9 –1 2 m on th s’ du ra tio n. To en su re th at th e re gi m en a ch ie ve s its d es ira bl e ef fe ct s, pr ev en t t he a cq ui sit io n (o r a m pl ifi ca tio n) o f a dd iti on al d ru g re sis ta nc e, w hi le re gi m en c om po ne nt s ar e pr ot ec te d, c ou nt rie s ar e to co ns id er th e fo llo w in g: • Pa tie nt s el ec tio n an d de cis io ns to s ta rt th e al l-o ra l s ho rt er re gi m en : P at ie nt s w ith c on fir m ed M D R/ RR -T B an d w ith re sis ta nc e to fl uo ro qu in ol on es ru le d ou t a re e xp ec te d to b en ef it th e m os t f ro m th is re gi m en . P ro pe r p at ie nt s el ec tio n w ou ld n ot o nl y le ad to im pr ov ed tr ea tm en t o ut co m es b ut w ill al so c on tri bu te to p ro te ct in g ag ai ns t t he d ev el op m en t o f b ed aq ui lin e re sis ta nc e. In th is re sp ec t, th e re gi m en is to o nl y be im pl em en te d in s et tin gs w he re ro ut in e D ST fo r r ifa m pi cin a nd fl uo ro qu in ol on es c an b e gu ar an te ed . It is ve ry im po rt an t t ha t t he im pl em en ta tio n of th es e re co m m en da tio ns is a cc om pa ni ed b y co nt in ue d ef fo rt s to in cr ea se a cc es s to D ST fo r a ll m ed ici ne s fo r w hi ch re lia bl e m et ho ds ex ist , a s w el l a s fo r t he d ev el op m en t a nd ro llo ut o f D ST m et ho ds fo r n ew er m ed ici ne s. In th e ab se nc e of a d ru g- su sc ep tib ilit y te st , a ss ay s sp ec ifi c fo r b ed aq ui lin e re sis ta nc e sh ou ld b e m on ito re d th ro ug h as se ss m en t o f M IC s of b ed aq ui lin e. • Re sis ta nc e to o th er a nt i-T B dr ug s sh ou ld b e m on ito re d in a cc or da nc e to W H O re co m m en da tio ns . • Us e of li ne zo lid : T he e vi de nc e m ad e av ai la bl e to in fo rm th is re co m m en da tio n fo cu se d on th e as se ss m en t o f a re gi m en c om po se d of b ed aq ui lin e, le vo flo xa cin /m ox ifl ox ac in , et hi on am id e, e th am bu to l, py ra zi na m id e, h ig h- do se is on ia zi d, c lo fa zi m in e an d py ra zi na m id e. H ow ev er , s ec on da ry a na ly se s (o nl y in lo ng er re gi m en s co nt ai ni ng b ed aq ui lin e an d be da qu ilin e pl us li ne zo lid ) s ho w ed fa vo ur ab le o ut co m es w he n tre at m en t r eg im en s in clu de d bo th li ne zo lid a nd b ed aq ui lin e. T he b as is fo r t he a dd iti on o f l in ez ol id w as to p ro te ct th e re gi m en – in p ar tic ul ar , b ed aq ui lin e – w hi le a w ai tin g su sc ep tib ilit y re su lts o n ad di tio na l r es ist an ce to fl uo ro qu in ol on es a nd o th er d ru gs . T he G D G d ec id ed th at , u nt il ne w e vi de nc e is av ai la bl e on s ho rt er re gi m en s th at in clu de b ot h of th es e ag en ts , t he a ll- or al b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en a dv ise d he re in s ho ul d no t i nc lu de li ne zo lid . H ow ev er , t he g ro up en co ur ag ed c ou nt rie s to c on sid er th e us e of a m od ifi ed a ll- or al b ed aq ui lin e- a nd li ne zo lid -c on ta in in g re gi m en o nl y un de r op er at io na l r es ea rc h un til n ew e vi de nc e be co m es a va ila ble . • Pa tie nt -c en tre d ap pr oa ch : E ffo rt s ar e re qu ire d to p ro vi de p at ie nt s up po rt to e na bl e fu ll ad he re nc e to tr ea tm en t. M on ito rin g an d ev al ua tio n • Th e im pl em en ta tio n of th is re gi m en re qu ire s th e us e of ro ut in e D ST n ot o nl y fo r p at ie nt s el ec tio n bu t a lso to m on ito r t he a cq ui sit io n of re sis ta nc e. • Al th ou gh th e da ta a ss es se d di d no t u ne ar th a ny m aj or s ig na ls of ri sk , a ct iv e TB d ru g sa fe ty m on ito rin g an d m an ag em en t s ys te m s m us t b e fu nc tio na l i n or de r t o co nd uc t r ig or ou s ac tiv e m on ito rin g of a dv er se e ve nt s an d to d et ec t, m an ag e, a nd re po rt s us pe ct ed o r c on fir m ed d ru g to xic iti es in a ti m el y m an ne r. Re se ar ch p rio rit ie s M em be rs o f t he G D G d isc us se d th e re se ar ch g ap s to in fo rm th e de ve lo pm en t o f p ub lic h ea lth re co m m en da tio ns fo r t he m an ag em en t a nd c ar e of o f p at ie nt s w ith M D R/ RR -T B, a nd hi gh lig ht ed th e fo llo w in g pr io rit ie s: • st ud ie s as se ss in g co m pa ris on s of a ll- or al s ho rt er re gi m en s w hi ch in clu de b ot h be da qu ilin e an d lin ez ol id , i n ad di tio n to o th er c om pa ni on d ru gs ; • st ud ie s as se ss in g co m pa ris on s of a ll- or al s ho rt er re gi m en s am on g di ffe re nt s ub gr ou ps a nd s pe cia l p op ul at io ns , i nc lu di ng p re gn an t a nd la ct at in g w om en ; • ra nd om iz ed , c on tro lle d tri al s or o pe ra tio na l r es ea rc h of th e ef fe ct iv en es s an d sa fe ty o f a ll- or al s ho rt er re gi m en s, in cr ea sin g th e ce rt ai nt y in th e ev id en ce ; • st ud ie s ex pl or in g m ec ha ni sm s of a cq ui sit io n of re sis ta nc e to b ed aq ui lin e an d ge ne tic m ar ke rs to id en tif y re sis ta nc e; a nd • ef fo rt s to d et er m in e be st w ay s to s ta nd ar di ze d at a co lle ct io n so th at c ou nt rie s ca n co nt rib ut e to d ev el op m en t o f g lo ba l r ec om m en da tio ns . AR T: a nt ire tro vi ra l t he ra py ; D ST : d ru g- su sc ep tib ilit y te st in g; G D F: G lo ba l D ru g Fa cil ity ; G D G : G ui de lin e D ev el op m en t G ro up ; M D R/ RR -T B: m ul tid ru g- re sis ta nt o r rif am pi cin -r es ist an t tu be rc ul os is; M IC : m in im um in hi bi to ry c on ce nt ra tio n; W H O : W or ld H ea lth O rg an iz at io n. WHO consolidated guidelines on tuberculosis: Online annexes76 Sh ou ld a n al l- or al s ho rt er re gi m en o f 9 –1 2 m on th s’ d ur at io n in cl ud in g be da qu ili ne v s lo ng er re gi m en s co nt ai ni ng b ed aq ui lin e be u se d fo r M D R/ RR -T B pa tie nt s to s af el y im pr ov e ou tc om es ? PO PU LA TI O N : M D R- /R R- TB p at ie nt s to s af el y im pr ov e ou tc om es IN TE RV EN TI O N : Al l-o ra l b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) CO M PA RI SO N : Lo ng er b ed aq ui lin e- co nt ai ni ng re gi m en M AI N O UT CO M ES : Su cc es s vs . F ai lu re /R ec ur re nc e; S uc ce ss v s. D ea th ; S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; S uc ce ss v s. Al l U nf av ou ra bl e; L os t v s. Al l O th er O ut co m es ; AF B Sm ea r P os iti ve : S uc ce ss v s. Fa ilu re /R ec ur re nc e; A FB S m ea r P os iti ve : S uc ce ss v s. D ea th ; A FB S m ea r P os iti ve : S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; A FB S m ea r P os iti ve : S uc ce ss v s. Al l U nf av ou ra bl e; A FB S m ea r P os iti ve : L os t v s. Al l O th er O ut co m es ; H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e; H IV -P os iti ve o n AR T: S uc ce ss v s. D ea th ; H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; H IV -P os iti ve o n AR T: Su cc es s vs . A ll O th er U nf av ou ra bl e; H IV -P os iti ve o n AR T: L os t v s. Al l O th er O ut co m es ; H IV N eg at iv e: S uc ce ss v s. Fa ilu re /R ec ur re nc e; H IV N eg at iv e: Su cc es s vs . D ea th ; H IV N eg at iv e: S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; H IV N eg at iv e: S uc ce ss v s. Al l O th er O ut co m es ; H IV N eg at iv e: L os t v s. Al l O th er O ut co m es . SE TT IN G : So ut h Af ric a. PE RS PE CT IV E: Pu bl ic he al th a nd h ea lth s ys te m s pe rs pe ct iv e BA CK G RO UN D : M ul tid ru g- re sis ta nt (M D R- ) a nd ri fa m pi cin -r es ist an t t ub er cu lo sis (M D R- /R R- TB ) i s em er gi ng a s a m aj or p ro bl em d ue to p oo r m an ag em en t o f d ru g- se ns iti ve a s w el l a s dr ug -r es ist an ce T B. M D R- /R R- TB is tr ea ta bl e, b ut h as re qu ire d th e us e of lo ng er tr ea tm en t r eg im en s w hi ch c on ta in p ot en tia lly to xic d ru gs . T he in te re st in re du cin g th e du ra tio n of tr ea tm en t f or M D R- TB m ot iv at ed a n um be r o f i ni tia tiv es in re ce nt y ea rs to tr ea t p at ie nt s w ith sh or te r r eg im en s un de r p ro gr am m at ic as w el l a s tri al c on di tio ns . I n 20 16 , o n th e ba sis o f d at a fro m o bs er va tio na l s tu di es o f t he s ho rt er re gi m en s in di ffe re nt A sia n an d Af ric an c ou nt rie s, W H O s ta rt ed to re co m m en d a st an da rd ise d sh or te r M D R- TB re gi m en , c on ta in in g an in je ct ab le a ge nt , b as ed on th e on es u nd er s tu dy fo r e lig ib le p at ie nt s. In 2 01 8, fu rt he r m od ifi ca tio ns w er e m ad e to th e ea rli er re co m m en de d sh or te r r eg im en , r ep la cin g ka na m yc in b y am ika cin (b as ed o n ev id en ce fr om th e co m pa ra tiv e ef fe ct iv en es s of th es e tw o in je ct ab le a ge nt s) . Ev id en ce o f p er m an en t e ffe ct s at tri bu te d to th e to xic ity o f i nj ec ta bl e ag en ts , h av e pr om pt ed fu rt he r a dv an ce s in th e de ve lo pm en t o f n ew tr ea tm en ts su ch a s sh or te r i nj ec ta bl e- sp ar in g re gi m en s. In p ar tic ul ar , o bs er va tio na l d at a on a n al l-o ra l b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n be ca m e av ai la bl e. T hi s is of p ar tic ul ar im po rt an ce g iv en th at th e re gi m en m ay o ffe r p at ie nt s th e lik el ih oo d of b et te r t ol er at in g tre at m en t w ith ou t s ig ni fic an t t ox ici ty. CO N FL IC T O F IN TE RE ST S: Al be rt o Pi ub el lo . Annex 4: GRADE evidence-to-decision tables 77 A ss es sm en t Pr ob le m Is th e pr ob le m a p rio rit y? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow TB re m ai ns a th re at to g lo ba l p ub lic h ea lth a nd is th e to p in fe ct io us c au se o f d ea th in th e w or ld . In 2 01 8, a n es tim at ed 1 0 m illi on p eo pl e de ve lo pe d TB a nd 1 .4 m illi on d ie d fro m th e di se as e. Ab ou t 5 00 0 00 n ew c as es o f m ul tid ru g- o r r ifa m pi cin -r es ist an t T B (M D R/ RR -T B) w er e es tim at ed to e m er ge in 2 01 8. A lth ou gh a ll of th es e w ou ld h av e be en e lig ib le fo r a s ec on d- lin e TB tr ea tm en t re gi m en , o nl y 15 6 07 1 en ro lm en ts in tr ea tm en t w er e re po rt ed b y co un tri es in 2 01 8 – ab ou t 3 0% of th e es tim at ed c as el oa d. D es pi te th is, s ig ni fic an t i m pr ov em en ts in th e av ai la bi lit y of e nh an ce d di ag no st ics a nd m or e ef fe ct iv e m ed ici ne s ha ve o cc ur re d in re ce nt y ea rs , a nd h av e le d to e ar lie r de te ct io n an d hi gh er s uc ce ss ra te s am on g pa tie nt s w ith M D R/ RR -T B in a n um be r o f n at io na l pr og ra m m es . H ow ev er , t he se s uc ce ss es h av e no t b ee n re pr od uc ed in th e re st o f t he w or ld , a nd th e ov er al l t re at m en t s uc ce ss ra te w or ld w id e re ac he d on ly 5 6% fo r p at ie nt s w ith M D R/ RR -T B w ho st ar te d tre at m en t i n 20 16 , a nd o nl y 39 % fo r p at ie nt s w ith e xt en siv el y dr ug -r es ist an t T B (X D R- TB ). WHO consolidated guidelines on tuberculosis: Online annexes78 D es ir ab le E ff ec ts H ow s ub st an tia l a re th e de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Tr iv ia l ● Sm al l ○ M od er at e ○ L ar ge ○ V ar ie s ○ D on ’t kn ow Th e an al ys is al so s ug ge st ed th at w he n th e al l-o ra l s ho rt er re gi m en w as c om pa re d w ith a n in je ct ab le -f re e lo ng er 4 re gi m en c on ta in in g be da qu ilin e, th er e se em ed to b e no m ar ke d di ffe re nc es in th e ou tc om es o bs er ve d ea rli er ; h ow ev er , r el at iv el y m od es t b en ef ici al e ffe ct s w er e no te d in th e di re ct io n of th e in te rv en tio n; in p ar tic ul ar , s uc ce ss v s fa ilu re /r ec ur re nc e (a O R 3. 9, 9 5% C I 1 .7 –9 .1 ), su cc es s vs a ll un fa vo ur ab le o ut co m es (a O R 1. 6, 9 5% C I 1 .2 –2 .2 ) a nd lo ss to fo llo w u p (a O R 0. 5, 95 % C I 0 .4 –0 .8 ), al l f av ou rin g th e us e of th e al l-o ra l s ho rt er re gi m en . O ut co m e n/ N (B dq s ho rt ) n/ N (L on g, ne w d ru gs ) N um be r of Pa irs aO R (9 5% C I) aR D (9 5% C I) Su cc es s vs . Fa ilu re /R ec ur re nc e 63 1/ 65 3 26 8/ 29 2 28 5 3. 9 (1 .7 , 9 .1 ) 5 (1 , 9 ) Su cc es s vs . D ea th 63 1/ 79 1 26 8/ 33 8 32 8 1. 0 (0 .6 , 1 .5 ) -4 (- 10 , 3 ) Su cc es s vs . F ai lu re / Re cu rre nc e/ D ea th * 63 1/ 81 3 26 8/ 36 2 35 2 1. 4 (0 .9 , 2 .0 ) 2 (- 4, 9 ) Su cc es s vs . A ll Un fa vo ra bl e 63 1/ 89 1 26 8/ 44 0 42 7 1. 6 (1 .2 , 2 .2 ) 7 (1 , 1 4) Lo st v s. Al l O th er O ut co m es 88 /8 91 88 /4 40 42 7 0. 5 (0 .4 , 0 .8 ) -8 (- 13 , - 3) Th e G D G ju dg ed th e de sir ab le a nt ici pa te d ef fe ct s to be s m al l. Th e gr ou p ar gu ed th at w he n a dr ug s uc h as be da qu ilin e is in clu de d in a re gi m en – a s se en in th e an al ys is – th e ou tc om es in th e in te rv en tio n an d co m pa ris on gr ou ps a re n ot to o di st an t. In a ct ua lit y, th e da ta e va lu at ed se em ed to in di ca te th at th e al l-o ra l b ed aq ui lin e- co nt ai ni ng sh or te r r eg im en o f 9 –1 2 m on th s’ du ra tio n w as ju st a s go od a s al l-o ra l l on ge r r eg im en s co nt ai ni ng b ed aq ui lin e. Th e m ai n ad va nt ag es o f t he a ll- or al s ho rt er re gi m en a s ob se rv ed in th e an al ys is w as m os tly in te rm s of d ec re as ed ra te s of lo ss to fo llo w -u p. U nd es ir ab le E ff ec ts H ow s ub st an tia l a re th e un de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge ○ M od er at e ○ S m al l ○ Tr iv ia l ● Va rie s ○ D on ’t kn ow In p as t y ea rs , t he in cr ea se d us e of b ed aq ui lin e ha s re as su re d th e TB c om m un ity o f t he p ot en tia l f or a dv er se ev en ts a ss oc ia te d w ith th is ag en t. Th e G D G a nt ici pa te d th at th e un de sir ab le a nt ici pa te d ef fe ct s on th e us e of re gi m en s m ay n ot b e so d iff er en t be tw ee n an a ll- or al s ho rt er a nd a n al l-o ra l l on ge r r eg im en w he n bo th c on ta in b ed aq ui lin e. H ow ev er , t he se e ffe ct s m ay v ar y, de pe nd in g on , f or e xa m pl e, th e se le ct io n or al lo ca tio n of p at ie nt s in to re gi m en s co nt ai ni ng b ed aq ui lin e, se ve rit y of d ise as e, d ru g- re sis ta nc e pa tte rn s, qu al ity o f c ar e an d m on ito rin g. 4 Re co m m en da tio ns re le as ed b y W H O in D ec em be r 2 01 8 em ph as iz ed th at fu lly o ra l [ lo ng er ] r eg im en s sh ou ld b e pr io rit iz ed a nd b ec om e th e pr ef er re d op tio n fo r m os t p at ie nt s, an d th at in je ct ab le a ge nt s w er e no lo ng er a m on g th e pr io rit y m ed ici ne s to c on sid er w he n de sig ni ng lo ng er M D R- TB re gi m en s. Annex 4: GRADE evidence-to-decision tables 79 Ce rt ai nt y of e vi de nc e W ha t i s th e ov er al l c er ta in ty o f t he e vi de nc e of e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ● Ve ry lo w ○ L ow ○ M od er at e ○ H ig h ○ N o in clu de d st ud ie s Th e G D G p oi nt ed o ut th at o n th e ba sis o f t he e vi de nc e as se ss ed – n am el y, ob se rv at io na l d at a an d po te nt ia l re sid ua l c on fo un di ng – th e ov er al l c er ta in ty in th e es tim at es of e ffe ct w as ju dg ed to b e ve ry lo w, w ith th e ef fe ct s fo r al l o ut co m es a lso ra te d as “v er y lo w ”. Al th ou gh d ou bl e ad ju st m en t i n pr op en sit y sc or e m at ch in g an al ys es w as ca rr ie d ou t t o re m ov e th e ef fe ct s of c on fo un di ng , m em be rs of th e G D G fu rt he r n ot ed th at a lth ou gh th es e ef fo rt s co m pe ns at ed fo r s om e po te nt ia l c on fo un de rs , r es id ua l bi as is li ke ly to b e pr es en t. Th e gr ou p ac kn ow le dg ed th at a lth ou gh th e us e of p ro gr am m at ic da ta h ol ds g re at pr om ise b ec au se th ey b et te r r ef le ct re al p ra ct ice , s om e co ns id er at io ns in te rm s of th e ex te nt to w hi ch th es e fin di ng s co ul d be a pp lie d to o th er s et tin gs a re to b e co nt em pl at ed . F or in st an ce , s pe cif ic cli ni ca l c ha ra ct er ist ics of th e po pu la tio n (e .g . H IV p re va le nc e an d dr ug - re sis ta nc e pa tte rn s) m ay h av e an e ffe ct , a s m ay q ua lit y of h ea lth c ar e se rv ice s, m od el s of c ar e, a nd tr ea tm en t ad he re nc e st ra te gi es . Va lu es Is th er e im po rt an t u nc er ta in ty a bo ut o r v ar ia bi lit y in h ow m uc h pe op le v al ue th e m ai n ou tc om es ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Im po rt an t un ce rt ai nt y or va ria bi lit y ○ P os sib ly im po rt an t un ce rt ai nt y or va ria bi lit y ○ P ro ba bl y no im po rt an t u nc er ta in ty or v ar ia bi lit y ● N o im po rt an t un ce rt ai nt y or va ria bi lit y A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt a nd civ il so cie ty re pr es en ta tiv es (n =1 6) lo ok ed a t g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt as pe ct s of d ru g- re sis ta nt T B tre at m en t r eg im en s, su ch a s du ra tio n, p ill bu rd en , u se o f i nj ec ta bl e ag en ts a nd p ot en tia l f or e xp er ie nc in g ad ve rs e ev en ts . Pa rt ici pa nt s ha d th e op po rt un ity to d isc us s im po rt an t a dv er se e ffe ct s in clu di ng p er m an en t se ns or in eu ra l h ea rin g lo ss , n ep hr ot ox ici ty , e le ct ro ly te a bn or m al iti es , i nj ec tio n pa in a nd lo ca l in je ct io n- sit e co m pl ica tio ns . F ro m a p at ie nt p er sp ec tiv e, a dv er se e ve nt s (e .g . o pt ic ne ur iti s, he ar in g im pa irm en t a nd m en ta l s ta tu s ch an ge s du e to u re m ia o r e le ct ro ly te a bn or m al iti es ) a ss oc ia te d w ith th e us e of s pe cif ic se co nd -li ne a ge nt s, in clu di ng in je ct ab le a ge nt s, w er e de em ed u na cc ep ta bl e. Pr ef er en ce s re ga rd in g tre at m en t a pp ea re d to b e ro ot ed in c or e va lu es , i nc lu di ng m in im al d isr up tio n to n or m al li fe . Re la tiv el y fe w p at ie nt s se em ed to p re fe r a s ho rt re gi m en th at is ti ed to m or e se rio us s id e- ef fe ct s, an d th en o nl y if th e sid e- ef fe ct s w er e ra re o r r ev er sib le . I n ad di tio n, in te rm s of tr ea tm en t d ur at io n, p re fe re nc es s ee m ed to b e gu id ed fi rs t b y sid e- ef fe ct s an d se co nd b y ef fic ac y of tre at m en t r eg im en s. WHO consolidated guidelines on tuberculosis: Online annexes80 Ba la nc e of e ff ec ts D oe s th e ba la nc e be tw ee n de si ra bl e an d un de si ra bl e ef fe ct s fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on ● Pr ob ab ly fa vo rs th e in te rv en tio n ○ F av or s th e in te rv en tio n ○ V ar ie s ○ D on ’t kn ow Re so ur ce s re qu ir ed H ow la rg e ar e th e re so ur ce re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge c os ts ○ M od er at e co st s ○ N eg lig ib le c os ts an d sa vi ng s ● M od er at e sa vi ng s ○ L ar ge s av in gs ○ V ar ie s ○ D on ’t kn ow Th e pr oj ec te d co st s av in g is ne ar ly U S$ 3 00 0 (2 01 9 US $) in S ou th A fri ca , a nd v ar ie s ac ro ss s et tin gs , la rg el y in p ro po rt io n to h ea lth c ar e an d dr ug c os ts (w ith s av in gs o f > US $ 20 00 e ve n in a lo w - in co m e se tti ng a nd a fte r r ed uc tio n in d ru g co st s to h al f o f c ur re nt G lo ba l D ru g Fa cil ity [G D F] p ric es ). Sm al le r i f l in ez ol id is n ot in clu de d. Ce rt ai nt y of e vi de nc e of r eq ui re d re so ur ce s W ha t i s th e ce rt ai nt y of th e ev id en ce o f r es ou rc e re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ V er y lo w ○ L ow ○ M od er at e ○ H ig h ● N o in clu de d st ud ie s Annex 4: GRADE evidence-to-decision tables 81 Co st e ff ec ti ve ne ss D oe s th e co st -e ff ec tiv en es s of th e in te rv en tio n fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on ● Pr ob ab ly fa vo rs th e in te rv en tio n ○ F av or s th e in te rv en tio n ○ V ar ie s ○ N o in clu de d st ud ie s A co st –e ffe ct iv en es s m od el w as d ev el op ed , i nc or po ra tin g es tim at ed h ea lth s ys te m c os ts w ith d ru g pr oc ur em en t, he al th c ar e de liv er y, ad ve rs e ev en ts , r et re at m en ts , s ec on da ry c as es , a nd m or bi di ty an d m or ta lit y as so cia te d w ith T B m or ta lit y an d re cu rre nc e, tr ea tm en t d ur at io n, d ru g to xic ity , a nd TB tr an sm iss io n. C os ts a nd c os t– ef fe ct iv en es s w er e ev al ua te d in S ou th A fri ca , w ith s en sit iv ity an al ys es re pr es en tin g a ra ng e of d ru g an d he al th c ar e co st s, hi gh a nd lo w H IV c o- pr ev al en ce , 95 % c on fid en ce in te rv al s (C is) fo r e st im at es o f r el at iv e ef fic ac y de riv ed fr om s ta tis tic al a na ly sis o f pa tie nt c oh or t d at a, a nd u nc er ta in ty in th e va lu es o f p ar am et er s re pr es en tin g TB n at ur al h ist or y. Co m pa re d an 1 8– 20 -m on th a ll- or al re gi m en (m od el le d as c on ta in in g W H O g ro up A d ru gs in clu di ng b ed aq ui lin e an d lin ez ol id ), a 9– 12 -m on th a ll- or al , b ed aq ui lin e- co nt ai ni ng re gi m en is pr oj ec te d to b e bo th c os t s av in g an d ef fe ct iv e un de r a ll m od el le d sc en ar io s. Be ca us e th e sh or te r or al re gi m en d om in at ed o ve r t he lo ng er re gi m en in a ll sc en ar io s m od el le d, c os t– ef fe ct iv en es s w as no t c al cu la te d. Eq ui ty W ha t w ou ld b e th e im pa ct o n he al th e qu ity ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ R ed uc ed ○ P ro ba bl y re du ce d ○ P ro ba bl y no im pa ct ○ P ro ba bl y in cr ea se d ● In cr ea se d ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n = 1 6) , l oo ke d at g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se o f in je ct ab le a ge nt s, an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . Pa rt ici pa nt s co ns id er ed a ny th in g le ss th an u ni ve rs al a nd im m ed ia te a cc es s to n ew tr ea tm en ts to be u ne th ica l, bu t w he n pr om pt ed to c on sid er th is pr ef er en ce a ga in st a li m ite d su pp ly o f d ru gs , a fe w w ou ld p rio rit iz e th e yo un ge st a nd s ick es t, as w el l a s th os e w ho w er e ad he re nt a nd c ou ld b e m on ito re d fo r a dv er se e ve nt s. Pa tie nt s w ho fa ce s oc io ec on om ic ch al le ng es to a dh er en ce o r w ho liv e in re m ot e, ru ra l o r p oo re r c om m un iti es th at la ck te ch ni ca l s kil l o r e qu ip m en t f or tr ea tm en t m on ito rin g, c ou ld th en b e di sp ro po rt io na te ly a nd u nj us tly p la ce d at a d isa dv an ta ge . Th e G D G a gr ee d th at in je ct ab le -s pa rin g re gi m en s w ou ld be e as ie r t o de ce nt ra liz e an d th er ef or e to u se in re m ot e an d un de rs er vi ce d se tti ng s an d di sa dv an ta ge d po pu la tio ns , he lp in g to a lle vi at e he al th in eq ui tie s, w ith ou t a nt ici pa tin g di ffe re nc es in o ut co m es in s pe cif ic po pu la tio ns . T he gr ou p al so n ot ed th at b ec au se a ud io m et ry w ou ld n ot b e re qu ire d, it m ig ht b e ea sie r t o m on ito r i nd iv id ua ls, in s pi te of in cr ea se d re qu ire m en ts fo r e le ct ro ca rd io gr ap hy , w hi ch is a pr er eq ui sit e fo r t he u se o f b ed aq ui lin e- co nt ai ni ng re gi m en s. H ow ev er , t he g ro up s tre ss ed th at th e us e of el ec tro ca rd io gr ap hy s ho ul d no t b e a di ffe re nt ia tin g el em en t be tw ee n th es e tw o re gi m en s, be ca us e pa tie nt s re ce iv in g in je ct ab le a ge nt s su ch a s am ika cin s ho ul d al so h av e re gu la r c ar di ac m on ito rin g. T he g ro up a ck no w le dg ed th at it is po ss ib le th at in s om e se tti ng s no t a ll pa tie nt s w ou ld be a bl e to u nd er go e le ct ro ca rd io gr ap hi c m on ito rin g; ho w ev er , t he g ro up a lso n ot ed th at th e in cr ea sin g ac ce ss to e le ct ro ca rd io gr ap hy a t p er ip he ra l l ev el s m ig ht im pr ov e eq ui ty. WHO consolidated guidelines on tuberculosis: Online annexes82 A cc ep ta bi lit y Is th e in te rv en tio n ac ce pt ab le to k ey s ta ke ho ld er s? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n = 1 6) , l oo ke d at g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se of in je ct ab le a ge nt s, an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . T he re su lts o f t hi s qu al ita tiv e an al ys is su gg es te d th at m os t p at ie nt s w ou ld p rio rit iz e a re gi m en w ith fe w er a nd le ss s ev er e sid e- ef fe ct s ab ov e al l e lse , b ec au se it w ou ld a llo w th em to c on tin ue ro ut in e ac tiv iti es . O f n ot e, s ur vi vo rs of d ru g- re sis ta nt T B re m ar ke d th at th ey w ou ld a cc ep t a lo ng er tr ea tm en t t ha t p ro m ise d le ss se ve re a dv er se e ff ec ts o ve r a s ho rt er re gi m en ti ed to m or e se ve re s id e- ef fe ct s, ev en if tr ea tm en t w as e xp er im en ta l o r e ffi ca cy u nc le ar . T hi s co nt ra st ed w ith th e co m pa ra tiv el y fe w p ar tic ip an ts w ho pr io rit iz ed ra pi d re tu rn to n or m al li fe a nd w ou ld ra th er a ss um e th e ris k of m or e se rio us s id e- ef fe ct s w ith in a s ho rt er re gi m en , e ve n if tre at m en t w as e xp er im en ta l a nd e ffi ca cy u nc le ar . Th e G D G n ot ed th at p at ie nt s re co gn iz e th at th ei r ex pe rie nc es a nd p er ce pt io ns a re h ig hl y pe rs on - an d co nt ex t-d ep en de nt , t ho ug h pr ef er en ce fo r t hi s [s ho rt er ] re gi m en s ee m ed to b e co nd iti on al u po n ad ve rs e ev en ts be in g ra re o r r ev er sib le . N ev er th el es s, ov er al l, a sh or t, in je ct io n- fre e re gi m en w ith fe w to n o ph ys ica l a nd m en ta l h ea lth s id e- ef fe ct s an d a lo w pi ll bu rd en a pp ea re d to b e th e m os t a cc ep ta bl e. Annex 4: GRADE evidence-to-decision tables 83 Fe as ib ili ty Is th e in te rv en tio n fe as ib le to im pl em en t? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n =1 6) lo ok ed a t g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt as pe ct s of d ru g- re sis ta nt T B tre at m en t r eg im en s, su ch a s du ra tio n, p ill bu rd en , u se o f i nj ec ta bl e ag en ts a nd p ot en tia l f or e xp er ie nc in g ad ve rs e ev en ts . Th is st ud y re ve al ed th at a s th e re gi m en , i n pa rt icu la r t he e xp an sio n of b ed aq ui lin e ac ce ss to a ll pa tie nt s is he ld b ac k is so m e se tti ng s as a re su lt of re st ric tiv e el ig ib ilit y (i. e. p rio rit iz at io n of s pe cif ic gr ou ps ) c rit er ia , l ac k of fu nd in g or la ck o f a de qu at e in fra st ru ct ur e in p la ce (e .g . d ia gn os tic s) ; th er ef or e, th e op er at io na liz at io n an d im m ed ia te ro ll- ou t o f t he a ll- or al b ed aq ui lin e- co nt ai ni ng re gi m en m ay b e ha m pe re d. O ne im po rt an t r eq ui re m en t h ig hl ig ht ed b y th e G D G w as th at o f e ns ur in g th e ca re fu l s el ec tio n of p at ie nt s w ho ar e to b en ef it fro m th is re gi m en , c on du ct in g ra pi d an d ac cu ra te D ST , a nd m on ito rin g be da qu ilin e re sis ta nc e. T he im pl em en ta tio n of th e re gi m en m ay b e lim ite d by th e ne ed fo r i m pr ov ed la bo ra to ry in fra st ru ct ur e. A lth ou gh co un tri es a re im pl em en tin g ra pi d m ol ec ul ar te st s to id en tif y rif am pi cin re sis ta nc e, la bo ra to ry c ap ac ity n ee ds to b e ef fe ct iv el y es ta bl ish ed to c on du ct g en ot yp ic an d ph en ot yp ic te st in g fo r o th er im po rt an t a ge nt s in th e re gi m en . A lso , a lth ou gh th e pr ev al en ce o f i de nt ifi ed m ut at io ns c on fe rr in g lo w -le ve l d ru g re sis ta nc e is ve ry lo w, co un tri es a re to s tre ng th en la bo ra to ry c ap ac ity a nd to m on ito r t he a cq ui sit io n of re sis ta nc e to b ed aq ui lin e th ou gh th ei r n at io na l r ef er en ce la bo ra to rie s or T B su pr an at io na l re fe re nc e ne tw or k sit es . T hi s is es pe cia lly im po rt an t g iv en th e pi pe lin e of n ew a nt i-T B re gi m en s th at a re re ly in g on be da qu ilin e as a b ac kb on e. Th e re m ov al o f i nj ec ta bl e ag en ts , a s di sc us se d by th e G D G , a lso p oi nt ed to w ar ds th e co nv en ie nc e (fo r h ea lth ca re w or ke rs ) o f n ot h av in g to d el iv er d ai ly in je ct io ns , a nd m or e so , f or p at ie nt s no t h av in g to e nd ur e pa in a nd o th er sig ni fic an t a dv er se e ve nt s. Th e im pl em en ta tio n of th e re gi m en is p er ce iv ed to g o be yo nd s ec ur in g of fu nd in g, b ut it fu rt he r r eq ui re s m ak in g lo ng -t er m , s us ta in ab le s ys te m s ch an ge s to e ns ur e ra pi d tra ns iti on , c on sid er in g th e re gi st ra tio n of b ed aq ui lin e an d ot he r n ew a ge nt s, un in te rr up te d su pp ly o f q ua lit y- as su re d dr ug s, an d ac tiv e TB d ru g sa fe ty m on ito rin g an d m an ag em en t s ys te m in c oo rd in at io n w ith e xis tin g ph ar m ac ov ig ila nc e st ru ct ur es a t t he c ou nt ry le ve l. Al so , t he im pl em en ta tio n of th is re gi m en (a nd a ny o th er no ve l r eg im en ) w ill re qu ire d ec isi on -m ak in g to w ar ds m ul tis ec to ra l p ol ici es , t ai lo rin g pa tie nt -c en tre d pr og ra m m es th at a lso c on sid er a sp ec ts s uc h as m en ta l h ea lth a nd m an ag em en t o f o th er c om or bi di tie s, fa cil ita tin g co un se llin g an d su pp or t d ur in g tre at m en t, an d af te r c om pl et io n, fa cil ita tin g fu ll re co ve ry . WHO consolidated guidelines on tuberculosis: Online annexes84 Su m m ar y of ju dg em en ts JU D G EM EN T PR O BL EM N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow D ES IR AB LE E FF EC TS Tr iv ia l Sm al l M od er at e La rg e Va rie s D on ’t kn ow UN D ES IR AB LE E FF EC TS La rg e M od er at e Sm al l Tr iv ia l Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s VA LU ES Im po rt an t un ce rt ai nt y or va ria bi lit y Po ss ib ly im po rt an t un ce rt ai nt y or va ria bi lit y Pr ob ab ly n o im po rt an t un ce rt ai nt y or va ria bi lit y N o im po rt an t un ce rt ai nt y or va ria bi lit y BA LA N CE O F EF FE CT S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s n ot fa vo r e ith er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s D on ’t kn ow RE SO UR CE S RE Q UI RE D La rg e co st s M od er at e co st s N eg lig ib le c os ts a nd sa vi ng s M od er at e sa vi ng s La rg e sa vi ng s Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE O F RE Q UI RE D R ES O UR CE S Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s CO ST E FF EC TI VE N ES S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s n ot fa vo r e ith er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s N o in clu de d st ud ie s EQ UI TY Re du ce d Pr ob ab ly re du ce d Pr ob ab ly n o im pa ct Pr ob ab ly in cr ea se d In cr ea se d Va rie s D on ’t kn ow AC CE PT AB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow FE AS IB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow Ty pe o f r ec om m en da tio n St ro ng re co m m en da tio n ag ai ns t th e in te rv en tio n ○ Co nd iti on al re co m m en da tio n ag ai ns t t he in te rv en tio n ○ Co nd iti on al re co m m en da tio n fo r e ith er th e in te rv en tio n or th e co m pa ris on ○ Co nd iti on al re co m m en da tio n fo r t he in te rv en tio n ● St ro ng re co m m en da tio n fo r t he in te rv en tio n ○ Annex 4: GRADE evidence-to-decision tables 85 Co nc lu si on s Re co m m en da tio n A sh or te r, al l-o ra l, be da qu ilin e- co nt ai ni ng re gi m en o f 9 –1 2 m on th s du ra tio n is re co m m en de d in e lig ib le p at ie nt s w ith c on fir m ed M D R/ RR -T B w ho h av e no t b ee n ex po se d to tr ea tm en t w ith s ec on d- lin e TB m ed ici ne s us ed in th is re gi m en fo r m or e th an o ne m on th a nd in w ho m re sis ta nc e to fl uo ro qu in ol on es h as b ee n ex clu de d. (C on di tio na l r ec om m en da tio n, v er y lo w c er ta in ty in th e ev id en ce ) Ju st ifi ca tio n O ve ra ll, th e G D G n ot ed th at th e ce rt ai nt y of th e ev id en ce re ga rd in g th e ef fic ac y of th e al l-o ra l s ho rt er re gi m en w as “v er y lo w ”, at tri bu ta bl e to c on ce rn s of s er io us ri sk o f b ia s, de sp ite ef fo rt s to b al an ce b as el in e co va ria te s. H ow ev er , t he g ro up re co gn iz ed th at th e cu rre nt e vi de nc e as se ss m en t o f t he a ll- or al , b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en h as s om e ad di tio na l ad va nt ag es a s co m pa re d w ith a ll- or al lo ng er re gi m en s, na m el y in te rm s of lo w er lo ss to fo llo w -u p (d es ira bl e ef fe ct ) a nd o bv io us s ho rt er d ur at io n (a cc ep ta bi lit y) . W he n de cid in g on th e st re ng th o f t he re co m m en da tio n, th e G D G re ac he d a un an im ou s de cis io n on th e co nd iti on al ity o f t he re co m m en da tio n, m ai nl y at tri bu te d to th e ve ry lo w c er ta in ty in th e ev id en ce a nd re qu ire m en ts to b ui ld la bo ra to ry c ap ac ity a nd e ns ur e D ST . O th er g ro un ds fo r t he s tre ng th a nd d ire ct io n of th is re co m m en da tio n ar e as fo llo w s: • Th e an al ys is co nd uc te d to in fo rm th e de ve lo pm en t o f t hi s re co m m en da tio n w as b as ed o n ob se rv at io na l p ro gr am m at ic da ta fr om S ou th A fri ca w he re th e st an da rd iz ed s ho rt er , a ll- or al , be da qu ilin e- co nt ai ni ng re gi m en (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) w as u se d fo r p at ie nt s w ith M D R/ RR -T B. • Th ou gh n o m aj or s ig na ls of ri sk w er e ob se rv ed w ith th e us e of th e al l-o ra l b ed aq ui lin e- ba se d sh or te r r eg im en , t he re a lso re m ai ne d so m e un ce rt ai nt ie s gi ve n th e la ck o f s ys te m at ic co lle ct io n of d at a, a nd th e la ck o f c la rit y as to a ny c ha ng es in th e re gi m en th at c ou ld h av e be en in fo rm ed b y th e pr es en ce o f a dv er se e ve nt s. • Co st –e ffe ct iv en es s m od el lin g of th e al l-o ra l, sh or te r, be da qu ilin e- co nt ai ni ng re gi m en s ho w ed ro bu st c os t s av in gs re la tiv e to e ith er a lo ng er o ra l r eg im en o r a s ho rt in je ct ab le - co nt ai ni ng re gi m en . • Th e G D G ju dg ed th at m an y el ig ib le p at ie nt s w ou ld p re fe r t he a ll- or al , b ed aq ui lin e- co nt ai ni ng re gi m en o f 9 –1 2 m on th s’ du ra tio n. T hi s is su pp or te d by li m ite d ob se rv at io ns in vo lv in g 16 s ur vi vo rs o f d ru g- re sis ta nt T B. In a dd iti on , t hi s re gi m en m ay h el p pr om ot e he al th e qu ity o r m iti ga te th e w or se ni ng o f h ea lth in eq ui tie s. H ow ev er , t he p an el re co gn iz ed th at im pl em en ta tio n an d sc al e- up o f t hi s re gi m en m ig ht b e slo w b ec au se o f p re re qu isi te s re ga rd in g la bo ra to ry c ap ac ity a nd m on ito rin g. Su bg ro up c on si de ra tio ns Th e at te m pt ed to d es cr ib e th e ba la nc e of e ffe ct s an d co ns id er at io ns fo r v ar io us s ub gr ou ps o r s pe cia l p op ul at io ns . H ow ev er , t he e vi de nc e re vi ew ed s up po rt ed th e us e of th is in th e fo llo w in g se tti ng s, w ith s pe cif ic ca ve at s: • Pe op le li vi ng w ith H IV in fe ct io n (P LH IV ): Th e da ta e va lu at ed c or re sp on de d to a s et tin g w ith a h ig h pr ev al en ce o f H IV , a nd o f p ar tic ul ar s ig ni fic an ce , m os t P LH IV (> 95 % ) w ho s ta rt ed th e al l-o ra l b ed aq ui lin e- co nt ai ni ng re gi m en w er e re ce iv in g an tir et ro vi ra l t he ra py (A RT ). In v ie w o f t he tr ea tm en t o ut co m es d es cr ib ed in th e an al ys is, th er e w er e no g ro un ds to b el ie ve th at th e re gi m en w ou ld p er fo rm a ny d iff er en tly in P LH IV . I t i s ne ce ss ar y to c on sid er s ig ni fic an t c lin ica l i nt er ac tio ns th at m ay in cr ea se b ed aq ui lin e ex po su re o r t ha t o f o th er a ge nt s w ith po te nt ia l f or c ar di ot ox ici ty w he n th es e ar e co -a dm in ist er ed w ith a nt ire tro vi ra ls. • Ch ild re n: A lth ou gh n o di re ct o ut co m e es tim at io ns c ou ld b e dr aw n fo r t hi s po pu la tio n, e xt ra po la tio n w as d ee m ed re as on ab le . H ow ev er , b ec au se b ed aq ui lin e is cu rre nt ly re co m m en de d fo r c hi ld re n an d ad ol es ce nt s ag ed 6 –1 7 ye ar s, th e G D G c on clu de d th at th e al l-o ra l b ed aq ui lin e- co nt ai ni ng re gi m en m ay b e us ed in e lig ib le c hi ld re n w ith in th is ag e gr ou p, ta kin g in to ac co un t s pe cif ica tio ns fo r r eg im en c om pa ni on d ru gs , i n pa rt icu la r, be da qu ilin e. • Pr eg na nt a nd la ct at in g w om en : M or e ev id en ce is n ee de d to b et te r i nf or m th e us e of th e al l-o ra l, be da qu ilin e- co nt ai ni ng s ho rt er re gi m en (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) . O ne of th e ag en ts in th is al l-o ra l s ho rt er re gi m en , e th io na m id e, is u su al ly c on tra in di ca te d in p re gn an cy , a nd w ith ho ld in g th is ag en t o r r ep la cin g it w ith a no th er o ne c ou ld s er io us ly co m pr om ise th e ef fe ct iv en es s of th e re gi m en . F or p re gn an t a nd la ct at in g w om en , i t i s th er ef or e re co m m en de d th at a n in di vi du al iz ed , a ll- or al lo ng er re gi m en (i nc lu di ng b ed aq ui lin e) be u se d (s ee R ec om m en da tio ns o n th e us e of lo ng er re gi m en s fo r M D R/ RR -T B) . • Ex tra pu lm on ar y di se as e: In v ie w o f t he u na va ila bi lit y of e vi de nc e re ga rd in g su rro ga te s fo r s ev er ity o r e xt en t o f d ise as e, it is a dv isa bl e to u se c lin ica l j ud ge m en t t o de cid e on th e us e of th is re gi m en in p at ie nt s w ith e xt en siv e TB d ise as e or s ev er e fo rm s of e xt ra pu lm on ar y TB . WHO consolidated guidelines on tuberculosis: Online annexes86 Im pl em en ta tio n co ns id er at io ns Th e in te re st in re du cin g th e du ra tio n of tr ea tm en t f or M D R/ RR -T B ha s m ot iv at ed a n um be r o f s tu di es in re ce nt y ea rs o f t re at in g pa tie nt s w ith s ho rt er re gi m en s un de r p ro gr am m at ic as w el l a s tri al c on di tio ns . B ec au se o f e xp er ie nc es in v ar io us s et tin gs , [ el ig ib le ] p at ie nt s no w h av e an o pt io n to b e tre at ed w ith a s ho rt er , i nj ec ta bl e- sp ar in g re gi m en o f 9 –1 2 m on th s’ du ra tio n. To e ns ur e th at th e re gi m en a ch ie ve s its d es ira bl e ef fe ct s an d to p re ve nt th e ac qu isi tio n (o r a m pl ifi ca tio n) o f a dd iti on al d ru g re sis ta nc e (w hi le p ro te ct in g re gi m en c om po ne nt s) , co un tri es a re to c on sid er th e fo llo w in g: • Pa tie nt s el ec tio n an d de cis io ns to s ta rt th e al l-o ra l s ho rt er re gi m en : P at ie nt s w ith c on fir m ed M D R/ RR -T B an d w ith re sis ta nc e to fl uo ro qu in ol on es ru le d ou t a re e xp ec te d to b en ef it th e m os t f ro m th is re gi m en . P ro pe r p at ie nt s el ec tio n w ill no t o nl y le ad to im pr ov ed tr ea tm en t o ut co m es , b ut w ill al so c on tri bu te to a vo id in g th e de ve lo pm en t o f r es ist an ce to b ed aq ui lin e. In th is re sp ec t, th e re gi m en is to o nl y be im pl em en te d in s et tin gs w he re ro ut in e D ST fo r r ifa m pi cin a nd fl uo ro qu in ol on es c an b e gu ar an te ed . – It is ve ry im po rt an t t ha t t he im pl em en ta tio n of th es e re co m m en da tio ns is a cc om pa ni ed b y co nt in ue d ef fo rt s to in cr ea se a cc es s to D ST fo r a ll m ed ici ne s fo r w hi ch re lia bl e m et ho ds ex ist , a s w el l a s fo r t he d ev el op m en t a nd ro llo ut o f D ST m et ho ds fo r n ew er m ed ici ne s. In th e ab se nc e of a d ru g- su sc ep tib ilit y te st , a ss ay s sp ec ifi c fo r b ed aq ui lin e re sis ta nc e sh ou ld be m on ito re d th ro ug h as se ss m en t o f m in im um in hi bi to ry c on ce nt ra tio ns (M IC s) o f b ed aq ui lin e. – Re sis ta nc e to o th er a nt i-T B dr ug s sh ou ld b e m on ito re d in a cc or da nc e w ith W H O re co m m en da tio ns . • Us e of li ne zo lid : T he e vi de nc e m ad e av ai la bl e to in fo rm th is re co m m en da tio n fo cu se d on th e as se ss m en t o f a re gi m en c om po se d of b ed aq ui lin e, le vo flo xa cin /m ox ifl ox ac in , et hi on am id e, e th am bu to l, py ra zi na m id e, h ig h- do se is on ia zi d, c lo fa zi m in e, a nd p yr az in am id e. H ow ev er , s ec on da ry a na ly se s (o nl y in lo ng er re gi m en s co nt ai ni ng b ed aq ui lin e an d be da qu ilin e pl us li ne zo lid ) s ho w ed fa vo ur ab le o ut co m es w he n tre at m en t r eg im en s in clu de d bo th li ne zo lid a nd b ed aq ui lin e. T he b as is fo r t he a dd iti on o f l in ez ol id w as to p ro te ct th e re gi m en , i n pa rt icu la r, be da qu ilin e, w hi le a w ai tin g su sc ep tib ilit y re su lts o n ad di tio na l r es ist an ce to fl uo ro qu in ol on es a nd o th er d ru gs . T he G D G d ec id ed th at u nt il ne w e vi de nc e is av ai la bl e on s ho rt er re gi m en s th at in clu de b ot h of th es e ag en ts , t he a ll- or al b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en a dv ise d he re in s ho ul d no t i nc lu de li ne zo lid . H ow ev er , t he g ro up en co ur ag ed c ou nt rie s to c on sid er th e us e of a m od ifi ed a ll- or al b ed aq ui lin e- a nd li ne zo lid -c on ta in in g on ly u nd er o pe ra tio na l r es ea rc h un til n ew e vi de nc e be co m es a va ila ble . • Pa tie nt -c en tre d ap pr oa ch : E ffo rt s ar e re qu ire d to p ro vi de p at ie nt s up po rt to e na bl e fu ll ad he re nc e to tr ea tm en t. M on ito rin g an d ev al ua tio n • Th e im pl em en ta tio n of th is re gi m en re qu ire s th e us e of ro ut in e D ST n ot o nl y fo r p at ie nt s el ec tio n, b ut a lso fo r m on ito rin g of th e ac qu isi tio n of re sis ta nc e. • Al th ou gh th e da ta a ss es se d di d no t u ne ar th a ny m aj or s ig na ls of ri sk , a ct iv e TB d ru g sa fe ty m on ito rin g an d m an ag em en t s ys te m s m us t b e fu nc tio na l i n or de r t o co nd uc t r ig or ou s ac tiv e m on ito rin g of a dv er se e ve nt s an d to d et ec t, m an ag e an d re po rt s us pe ct ed o r c on fir m ed d ru g to xic iti es in a ti m el y m an ne r. Re se ar ch p rio rit ie s M em be rs o f t he G D G d isc us se d th e re se ar ch g ap s to in fo rm th e de ve lo pm en t o f p ub lic h ea lth re co m m en da tio ns fo r t he m an ag em en t o f M D R/ RR -T B, a nd h ig hl ig ht ed th e fo llo w in g pr io rit ie s: • st ud ie s as se ss in g co m pa ris on s of a ll- or al s ho rt er re gi m en s w hi ch in clu de b ed aq ui lin e an d lin ez ol id , i n ad di tio n to o th er c om pa ni on d ru gs ; • st ud ie s as se ss in g co m pa ris on s of a ll- or al s ho rt er re gi m en s am on g di ffe re nt s ub gr ou ps a nd s pe cia l p op ul at io ns , i nc lu di ng p re gn an t a nd la ct at in g w om en ; • ra nd om iz ed -c on tro lle d tri al s or o pe ra tio na l r es ea rc h of th e ef fe ct iv en es s an d sa fe ty o f a ll- or al s ho rt er re gi m en s, in cr ea sin g th e ce rt ai nt y of th e ev id en ce ; • st ud ie s ex pl or in g m ec ha ni sm s of a cq ui sit io n of re sis ta nc e to b ed aq ui lin e an d ge ne tic m ar ke rs to id en tif y re sis ta nc e; a nd • ef fo rt s to d et er m in e be st w ay s to s ta nd ar di ze th e co lle ct io n of d at a so th at c ou nt rie s ca n co nt rib ut e to th e de ve lo pm en t o f g lo ba l r ec om m en da tio ns . aO R: a dj us te d od ds ra tio ; A RT : a nt ire tro vi ra l t he ra py ; d ru g- su sc ep tib ilit y te st in g; G D F: G lo ba l D ru g Fa cil ity ; G D G : G ui de lin e D ev el op m en t G ro up ; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t T B; M IC : m in im um in hi bi to ry c on ce nt ra tio n; P LH IV : p eo pl e liv in g w ith h um an im m un od ef ici en cy v iru s; TB : t ub er cu lo sis ; W H O : W or ld H ea lth O rg an iz at io n. Annex 4: GRADE evidence-to-decision tables 87 Sh ou ld a n al l- or al s ho rt er re gi m en o f 9 –1 2 m on th s’ d ur at io n in cl ud in g be da qu ili ne v s lo ng er re gi m en s w ith ou t n ew T B dr ug s be u se d fo r M D R- /R R- TB p at ie nt s to s af el y im pr ov e ou tc om es ? PO PU LA TI O N : M D R- /R R- TB p at ie nt s to s af el y im pr ov e ou tc om es IN TE RV EN TI O N : Al l-o ra l b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) CO M PA RI SO N : Lo ng er re gi m en s w ith ou t n ew T B dr ug s M AI N O UT CO M ES : Su cc es s vs . F ai lu re /R ec ur re nc e; S uc ce ss v s. D ea th ; S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; S uc ce ss v s. Al l U nf av ou ra bl e; L os t v s. Al l O th er O ut co m es ; A FB Sm ea r P os iti ve : S uc ce ss v s. Fa ilu re /R ec ur re nc e; A FB S m ea r P os iti ve : S uc ce ss v s. D ea th ; A FB S m ea r P os iti ve : S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; A FB S m ea r Po sit iv e: S uc ce ss v s. Al l U nf av ou ra bl e; A FB S m ea r P os iti ve : L os t v s. Al l O th er O ut co m es ; H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e; H IV -P os iti ve o n AR T: S uc ce ss v s. D ea th ; H IV -P os iti ve o n AR T: S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; H IV -P os iti ve o n AR T: S uc ce ss v s. Al l O th er U nf av ou ra bl e; H IV -P os iti ve on A RT : L os t v s. Al l O th er O ut co m es ; H IV N eg at iv e: S uc ce ss v s. Fa ilu re /R ec ur re nc e; H IV N eg at iv e: S uc ce ss v s. D ea th ; H IV N eg at iv e: S uc ce ss v s. Fa ilu re / Re cu rre nc e/ D ea th ; H IV N eg at iv e: S uc ce ss v s. Al l O th er O ut co m es ; H IV N eg at iv e: L os t v s. Al l O th er O ut co m es . SE TT IN G : So ut h Af ric a. PE RS PE CT IV E: Pu bl ic he al th a nd h ea lth s ys te m s pe rs pe ct iv e BA CK G RO UN D : M ul tid ru g- re sis ta nt (M D R- ) a nd ri fa m pi cin -r es ist an t t ub er cu lo sis (M D R- /R R- TB ) i s em er gi ng a s a m aj or p ro bl em d ue to p oo r m an ag em en t o f d ru g- se ns iti ve as w el l a s dr ug -r es ist an t T B. M D R- /R R- TB is tr ea ta bl e, b ut h as re qu ire d th e us e of lo ng er tr ea tm en t r eg im en s w hi ch c on ta in p ot en tia lly to xic d ru gs . T he in te re st in re du cin g th e du ra tio n of tr ea tm en t f or M D R- TB m ot iv at ed a n um be r o f i ni tia tiv es in re ce nt y ea rs to tr ea t p at ie nt s w ith s ho rt er re gi m en s un de r pr og ra m m at ic as w el l a s tri al c on di tio ns . I n 20 16 , o n th e ba sis o f d at a fro m o bs er va tio na l s tu di es o f t he s ho rt er re gi m en s in d iff er en t A sia n an d Af ric an co un tri es , W H O s ta rt ed to re co m m en d a st an da rd iz ed s ho rt er M D R- TB re gi m en , c on ta in in g an in je ct ab le a ge nt , b as ed o n th e on es u nd er s tu dy fo r e lig ib le pa tie nt s. In 2 01 8, fu rt he r m od ifi ca tio ns w er e m ad e to th e ea rli er re co m m en de d sh or te r r eg im en , r ep la cin g ka na m yc in b y am ika cin (b as ed o n ev id en ce fr om th e co m pa ra tiv e ef fe ct iv en es s of th es e tw o in je ct ab le a ge nt s) . Ev id en ce o f p er m an en t e ffe ct s at tri bu te d to th e to xic ity o f i nj ec ta bl e ag en ts , h av e pr om pt ed fu rt he r a dv an ce s in th e de ve lo pm en t o f n ew tr ea tm en ts su ch a s sh or te r i nj ec ta bl e- sp ar in g re gi m en s. In p ar tic ul ar , o bs er va tio na l d at a on a n al l-o ra l b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en o f 9 –1 2 m on th s du ra tio n be ca m e av ai la bl e. T hi s is of p ar tic ul ar im po rt an ce g iv en th at th e re gi m en m ay o ffe r p at ie nt s th e lik el ih oo d of b et te r t ol er at in g tre at m en t w ith ou t sig ni fic an t t ox ici ty. CO N FL IC T O F IN TE RE ST S: Al be rt o Pi ub el lo . A ss es sm en t Pr ob le m Is th e pr ob le m a p rio rit y? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow Tu be rc ul os is (T B) re m ai ns a th re at to g lo ba l p ub lic h ea lth a nd is th e to pm os t i nf ec tio us c au se o f de at h in th e w or ld . I n 20 18 , a n es tim at ed 1 0 m illi on p eo pl e de ve lo pe d TB a nd 1 .4 m illi on d ie d fro m th e di se as e. A bo ut 5 00 0 00 n ew c as es o f m ul tid ru g- o r r ifa m pi cin -r es ist an t T B (M D R/ RR -T B) w er e es tim at ed to e m er ge in 2 01 8. A lth ou gh a ll of th es e w ou ld h av e be en e lig ib le fo r a s ec on d- lin e TB tr ea tm en t r eg im en , o nl y 15 6 07 1 en ro lm en ts in tr ea tm en t w er e re po rt ed b y co un tri es in 2 01 8 – ab ou t 3 0% o f t he e st im at ed c as el oa d. D es pi te th is, s ig ni fic an t i m pr ov em en ts in th e av ai la bi lit y of e nh an ce d di ag no st ics a nd m or e ef fe ct iv e m ed ici ne s ha s oc cu rre d in re ce nt y ea rs an d ha s le d to e ar lie r d et ec tio n an d hi gh er s uc ce ss ra te s am on g pa tie nt s w ith M D R/ RR -T B in a nu m be r o f n at io na l p ro gr am m es . H ow ev er , t he se s uc ce ss es h av e no t b ee n re pr od uc ed in th e re st o f t he w or ld , a nd th e ov er al l t re at m en t s uc ce ss ra te w or ld w id e re ac he d on ly 5 6% fo r p at ie nt s w ith M D R/ RR -T B w ho s ta rt ed tr ea tm en t i n 20 16 , a nd o nl y 39 % fo r p at ie nt s w ith e xt re m el y dr ug - re sis ta nt T B (X D R- TB ). WHO consolidated guidelines on tuberculosis: Online annexes88 D es ir ab le E ff ec ts H ow s ub st an tia l a re th e de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Tr iv ia l ○ S m al l ○ M od er at e ● La rg e ○ V ar ie s ○ D on ’t kn ow Th e pr im ar y an al ys is al so il lu st ra te d th e ef fe ct o f a n al l-o ra l s ho rt er b ed aq ui lin e- ba se d re gi m en as c om pa re d w ith lo ng re gi m en s th at d id n ot c on ta in a ny n ew d ru gs . T he s ho rt er re gi m en pe rfo rm ed s ig ni fic an tly b et te r a cr os s al l o ut co m es a nd a ll su bg ro up s as c om pa re d w ith tr ea tm en t ou tc om es w he n lo ng er re gi m es w ith ou t n ew d ru gs w er e im pl em en te d. O ut co m e n/ N (B dq s ho rt ) n/ N (L on g, n o ne w d ru gs ) N um be r of Pa irs aO R (9 5% CI ) aR D (9 5% CI ) Su cc es s vs . F ai lu re / Re cu rre nc e 63 1/ 65 3 67 9/ 77 1 58 0 3. 7 (2 .2 , 6 .3 ) 8 (5 , 1 1) Su cc es s vs . D ea th 63 1/ 79 1 67 9/ 10 44 74 7 2. 3 (1 .8 , 3 .0 ) 15 (1 0, 1 9) Su cc es s vs . F ai lu re /R ec ./ D ea th 63 1/ 81 3 67 9/ 11 36 77 1 2. 6 (2 .0 , 3 .3 ) 18 (1 4, 2 3) Su cc es s vs . A ll Un fa vo ra bl e 63 1/ 89 1 67 9/ 14 37 85 9 2. 8 (2 .3 , 3 .5 ) 23 (1 8, 2 7) Lo st v s. Al l O th er O ut co m es 88 /8 91 36 8/ 14 37 85 9 0. 4 (0 .3 , 0 .5 ) -1 4 (- 17 , - 10 ) U nd es ir ab le E ff ec ts H ow s ub st an tia l a re th e un de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge ○ M od er at e ○ S m al l ● Tr iv ia l ○ V ar ie s ○ D on ’t kn ow Th e G D G d isc us se d ea rli er re su lts o f t he in di vi du al -p at ie nt d at a (IP D ) m et a- an al ys is co nd uc te d to as se ss th e ov er al l b al an ce b et w ee n be ne fit s an d ha rm s of in di vi du al a ge nt s. In th e an al ys is, 1 99 5 pa tie nt s re ce iv ed k an am yc in a nd 2 68 (1 3. 4% ) e xp er ie nc ed a n ad ve rs e ev en t c au sin g pe rm an en t dr ug d isc on tin ua tio n; 4 10 6 pa tie nt s re ce iv ed a m ika cin , o f w ho m 2 35 (5 .7 % ) e xp er ie nc ed a n ad ve rs e ev en t c au sin g pe rm an en t d ru g di sc on tin ua tio n; a dd iti on al ly, 1 93 2 re ce iv ed c ap re om yc in an d 16 1 (8 .3 % ) e xp er ie nc ed a n ad ve rs e ev en t c au sin g pe rm an en t d ru g di sc on tin ua tio n. In co nt ra st , 4 64 p at ie nt s re ce iv ed b ed aq ui lin e, o f w ho m n in e (1 .9 % ), ni ne (1 .9 % ) e xp er ie nc ed a n ad ve rs e ev en t c au sin g pe rm an en t d ru g di sc on tin ua tio n. Th e G D G a gr ee d th at th er e is ev id en ce o f p at ie nt s ex pe rie nc in g ad ve rs e ev en ts a fte r t he u se o f b ed aq ui lin e. H ow ev er , i t w as em ph as iz ed th at c om pa re d w ith th e al te rn at iv e, a nd o n th e ba sis o f t he IP D m et a- an al ys is, th es e ev en ts s ee m to b e sig ni fic an tly fe w er . So m e m em be rs o f t he G D G d id e m ph as iz e th at a lth ou gh th e un de sir ab le e ffe ct s of th e al l-o ra l b ed aq ui lin e- co nt ai ni ng sh or te r r eg im en s ee m ed to b e tri vi al c om pa re d w ith th os e of lo ng er re gi m en s w ith ou t n ew T B dr ug s, th er e w er e st ill ad ve rs e ev en ts a ss oc ia te d w ith th e dr ug s us ed in th e al l-o ra l r eg im en . Annex 4: GRADE evidence-to-decision tables 89 Ce rt ai nt y of e vi de nc e W ha t i s th e ov er al l c er ta in ty o f t he e vi de nc e of e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ● Ve ry lo w ○ L ow ○ M od er at e ○ H ig h ○ N o in clu de d st ud ie s Th e G D G p oi nt ed o ut th at o n th e ba sis o f t he e vi de nc e as se ss ed – n am el y ob se rv at io na l d at a an d po te nt ia l r es id ua l co nf ou nd in g – th e ov er al l c er ta in ty o f t he e st im at es o f e ffe ct w as ju dg ed to b e “v er y lo w ”, w ith th e ef fe ct s fo r a ll ou tc om es al so ra te d as “v er y lo w ”. Al th ou gh d ou bl e ad ju st m en t i n pr op en sit y sc or e m at ch in g an al ys es w as c ar rie d ou t t o re m ov e th e ef fe ct s of c on fo un di ng , m em be rs o f t he G D G fu rt he r n ot ed th at a lth ou gh th es e ef fo rt s co m pe ns at ed fo r s om e po te nt ia l c on fo un de rs , r es id ua l b ia s w as lik el y to b e pr es en t. Th e gr ou p ac kn ow le dg ed th at a lth ou gh th e us e of p ro gr am m at ic da ta h ol ds g re at p ro m ise b ec au se th ey b et te r r ef le ct re al p ra ct ice , s om e co ns id er at io ns in te rm s of th e ex te nt to w hi ch th es e fin di ng s co ul d be a pp lie d to ot he r s et tin gs a re to b e co nt em pl at ed , s uc h as s pe cif ic cli ni ca l ch ar ac te ris tic s of th e po pu la tio n (e .g . H IV p re va le nc e; d ru g- re sis ta nc e pa tte rn s) , a s w el l a s qu al ity o f h ea lth c ar e se rv ice s, m od el s of c ar e, a nd tr ea tm en t a dh er en ce s tra te gi es . Va lu es Is th er e im po rt an t u nc er ta in ty a bo ut o r v ar ia bi lit y in h ow m uc h pe op le v al ue th e m ai n ou tc om es ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Im po rt an t un ce rt ai nt y or va ria bi lit y ○ P os sib ly im po rt an t un ce rt ai nt y or va ria bi lit y ○ P ro ba bl y no im po rt an t un ce rt ai nt y or va ria bi lit y ● N o im po rt an t un ce rt ai nt y or va ria bi lit y A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n = 1 6) , l oo ke d at g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se o f in je ct ab le a ge nt s, an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . Pr ef er en ce s fo r t re at m en t d ur at io n se em ed to b e gu id ed fi rs t b y sid e- ef fe ct s an d se co nd b y ef fic ac y. Th e qu al ita tiv e st ud y, th ou gh s m al l, hi gh lig ht ed h ow m os t p at ie nt s w ou ld p re fe r a lo ng er re gi m en w ith le ss s ev er e sid e- ef fe ct s ov er a s ho rt er re gi m en w ith m or e se ve re s id e- ef fe ct s.. Pr ef er en ce s re ga rd in g tre at m en t a pp ea re d to b e ro ot ed in c or e va lu es , i nc lu di ng m in im al d isr up tio n to n or m al li fe . R el at iv el y fe w p at ie nt s se em ed to p re fe r a s ho rt re gi m en th at w as ti ed to m or e se rio us s id e- ef fe ct s, an d th en o nl y if th e sid e- ef fe ct s w er e ra re o r r ev er sib le . I n ad di tio n, in te rm s of th e du ra tio n of tr ea tm en t, pr ef er en ce s se em ed to b e gu id ed fi rs t b y sid e- ef fe ct s an d se co nd b y ef fic ac y of tr ea tm en t r eg im en s. WHO consolidated guidelines on tuberculosis: Online annexes90 Ba la nc e of e ff ec ts D oe s th e ba la nc e be tw ee n de si ra bl e an d un de si ra bl e ef fe ct s fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t fa vo r e ith er th e in te rv en tio n or th e co m pa ris on ○ P ro ba bl y fa vo rs th e in te rv en tio n ● Fa vo rs th e in te rv en tio n ○ V ar ie s ○ D on ’t kn ow Th e di sc us se d w he th er th e ba la nc e be tw ee n de sir ab le a nd un de sir ab le e ffe ct s fa vo ur ed th e in te rv en tio n. D at a as se ss ed sh ow ed th at th e ov er al l r at e of a dv er se e ve nt s at tri bu te d to be da qu ilin e as c om pa re d w ith in je ct ab le a ge nt s w as tw o tim e le ss . A t t he s am e tim e, th e G D G n ot ed a 5 0% re du ct io n in de at hs , a ttr ib ut in g th is ef fe ct to th e ad di tio n of b ed aq ui lin e. H ow ev er , t he g ro up e m ph as iz ed th e po te nt ia l h ar m s if th is be da qu ilin e- co nt ai ni ng re gi m en w er e to b e im pl em en te d w ith ou t e ns ur in g pr op er D ST , a nd th e po te nt ia l f or a m pl ifi ca tio n of re sis ta nc e pa tte rn s. Re so ur ce s re qu ir ed H ow la rg e ar e th e re so ur ce re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge c os ts ○ M od er at e co st s ○ N eg lig ib le c os ts an d sa vi ng s ● M od er at e sa vi ng s ○ L ar ge s av in gs ○ V ar ie s ○ D on ’t kn ow Th e G D G d id a gr ee th at , o ve ra ll, sa vi ng s ca n be c on sid er ed in te rm s of fu tu re re tre at m en ts p re ve nt ed , a s w el l a s re du ce d ho sp ita liz at io n ra te s re su lti ng fr om fe w er a dv er se re ac tio ns . Ce rt ai nt y of e vi de nc e of r eq ui re d re so ur ce s W ha t i s th e ce rt ai nt y of th e ev id en ce o f r es ou rc e re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ V er y lo w ○ L ow ● M od er at e ○ H ig h ○ N o in clu de d st ud ie s Th e G D G a nt ici pa te d th e co st s av in gs to b e ro bu st , w ith s av in gs on d ru gs , h ea lth c ar e de liv er y, fe w er a dv er se e ve nt s an d lo w er re tre at m en t a nd lo ss -t o- fo llo w -u p ra te s. Annex 4: GRADE evidence-to-decision tables 91 Co st e ff ec ti ve ne ss D oe s th e co st -e ff ec tiv en es s of th e in te rv en tio n fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t fa vo r e ith er th e in te rv en tio n or th e co m pa ris on ○ P ro ba bl y fa vo rs th e in te rv en tio n ● Fa vo rs th e in te rv en tio n ○ V ar ie s ○ N o in clu de d st ud ie s N o co st –e ffe ct iv en es s an al ys is w as p er fo rm ed o nl y fo r c ur re nt ly re co m m en de d co m pa ra to r re gi m en s. A lo ng er re gi m en c on ta in in g no n ew T B dr ug s w as n ot s ep ar at el y m od el le d. Al th ou gh th e an al yt ic- de cis io n m od el d id n ot fo cu s on co m pa rin g co st s av in gs a nd c os t– ef fe ct iv en es s re la tiv e to lo ng er re gi m en s w ith ou t t he u se o f a ny n ew d ru gs , t he G D G di d ac kn ow le dg e th at th e sh or te ni ng o f t he re gi m en a nd th e sw itc h fro m in je ct ab le s to o ra l d ru gs a re e st im at ed to b e re so ur ce s av in g as a re su lt of s av in gs o n dr ug s, he al th c ar e de liv er y, an d re du ce d ra te s of a dv er se e ve nt s. Eq ui ty W ha t w ou ld b e th e im pa ct o n he al th e qu ity ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ R ed uc ed ○ P ro ba bl y re du ce d ○ P ro ba bl y no im pa ct ○ P ro ba bl y in cr ea se d ● In cr ea se d ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n = 1 6) , l oo ke d at g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se o f in je ct ab le a ge nt s, an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . Pa rt ici pa nt s co ns id er ed a ny th in g le ss th an u ni ve rs al a nd im m ed ia te a cc es s to n ew tr ea tm en ts to be u ne th ica l, bu t w he n pr om pt ed to c on sid er th is pr ef er en ce a ga in st a li m ite d su pp ly o f d ru gs , a fe w w ou ld p rio rit iz e th e yo un ge st a nd s ick es t, as w el l a s th os e w ho w er e ad he re nt a nd c ou ld b e m on ito re d fo r a dv er se e ve nt s. Pa tie nt s w ho fa ce s oc io ec on om ic ch al le ng es to a dh er en ce o r w ho liv e in re m ot e, ru ra l, or p oo re r c om m un iti es th at la ck te ch ni ca l s kil l o r e qu ip m en t f or tr ea tm en t m on ito rin g co ul d th en b e di sp ro po rt io na te ly a nd u nj us tly p la ce d at a d isa dv an ta ge . Th e G D G a gr ee d th at th e al l-o ra l s ho rt er re gi m en w ou ld b e ea sie r t o de ce nt ra liz e an d th er ef or e m ak e av ai la bl e to re m ot e an d un de rs er vi ce d se tti ng s an d di sa dv an ta ge d po pu la tio ns , he lp in g to a lle vi at e he al th in eq ui tie s, w ith ou t a nt ici pa tin g di ffe re nc es in o ut co m es in s pe cif ic po pu la tio ns . F ur th er , t he gr ou p no te d th at b ec au se a ud io m et ry w ou ld n ot b e re qu ire d, it m ig ht b e ea sie r t o m on ito r i nd iv id ua ls, in s pi te o f i nc re as ed re qu ire m en ts fo r e le ct ro ca rd io gr ap hy , w hi ch is a p re re qu isi te fo r t he u se o f b ed aq ui lin e- co nt ai ni ng re gi m en s. H ow ev er , th e gr ou p st re ss ed th at th e us e of e le ct ro ca rd io gr ap hy sh ou ld n ot b e a di ffe re nt ia tin g el em en t b et w ee n th es e tw o re gi m en s, be ca us e pa tie nt s re ce iv in g in je ct ab le a ge nt s su ch as a m ika cin s ho ul d al so h av e re gu la r c ar di ac m on ito rin g. T he gr ou p ac kn ow le dg ed th at it is p os sib le th at , i n so m e se tti ng s, no t a ll pa tie nt s w ill be a bl e to u nd er go e le ct ro ca rd io gr ap hi c m on ito rin g; h ow ev er , m em be rs a lso n ot ed th at th e in cr ea sin g ac ce ss to e le ct ro ca rd io gr ap hy a t p er ip he ra l l ev el s m ig ht im pr ov e eq ui ty. WHO consolidated guidelines on tuberculosis: Online annexes92 A cc ep ta bi lit y Is th e in te rv en tio n ac ce pt ab le to k ey s ta ke ho ld er s? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n = 1 6) , l oo ke d at g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , us e of in je ct ab le a ge nt s, an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . T he re su lts o f t hi s qu al ita tiv e an al ys is su gg es te d th at m os t p at ie nt s w ou ld p rio rit iz e a re gi m en w ith fe w er a nd le ss se ve re s id e- ef fe ct s ab ov e al l e lse , b ec au se it w ou ld a llo w th em to c on tin ue ro ut in e ac tiv iti es . O f no te , s ur vi vo rs o f d ru g- re sis ta nt T B re m ar ke d th at th ey w ou ld a cc ep t a lo ng er tr ea tm en t t ha t pr om ise d le ss s ev er e ad ve rs e ef fe ct s ov er a s ho rt er re gi m en ti ed to m or e se ve re s id e- ef fe ct s, ev en if tr ea tm en t w as e xp er im en ta l o r e ffi ca cy w as u nc le ar . T hi s co nt ra st ed w ith c om pa ra tiv el y fe w p ar tic ip an ts w ho p rio rit iz ed a ra pi d re tu rn to n or m al li fe a nd w ou ld ra th er a ss um e th e ris k of m or e se rio us s id e- ef fe ct s w ith in a s ho rt er re gi m en , e ve n if tre at m en t w as e xp er im en ta l a nd ef fic ac y w as u nc le ar . Th e G D G n ot ed th at p at ie nt s re co gn iz e th at th ei r e xp er ie nc es an d pe rc ep tio ns a re h ig hl y pe rs on - an d co nt ex t-d ep en de nt , th ou gh p re fe re nc e ov er th is [s ho rt er ] r eg im en s ee m ed to b e co nd iti on al u po n ad ve rs e ev en ts b ei ng ra re o r r ev er sib le . N ev er th el es s, ov er al l, a sh or t, in je ct io n- fre e re gi m en w ith fe w to no p hy sic al a nd m en ta l h ea lth s id e- ef fe ct s an d a lo w p ill bu rd en ap pe ar ed to b e th e m os t a cc ep ta bl e. Annex 4: GRADE evidence-to-decision tables 93 Fe as ib ili ty Is th e in te rv en tio n fe as ib le to im pl em en t? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ○ Y es ● Va rie s ○ D on ’t kn ow A qu al ita tiv e st ud y un de rt ak en to h ig hl ig ht th e pe rs pe ct iv es o f k ey s ta ke ho ld er s, m ai nl y pa tie nt s an d civ il so cie ty re pr es en ta tiv es (n = 1 6) , l oo ke d at g en er al p re fe re nc es a nd v al ue s re ga rd in g di ffe re nt a sp ec ts o f t re at m en t r eg im en s fo r d ru g- re sis ta nt T B, s uc h as d ur at io n, p ill bu rd en , u se o f in je ct ab le a ge nt s, an d po te nt ia l f or e xp er ie nc in g ad ve rs e ev en ts . Th is st ud y re ve al ed th at b ec au se th e re gi m en – in p ar tic ul ar th e ex pa ns io n of b ed aq ui lin e ac ce ss to a ll pa tie nt s – is he ld b ac k in s om e se tti ng s as a re su lt of re st ric tiv e el ig ib ilit y (i. e. p rio rit iz at io n of s pe cif ic gr ou ps ) c rit er ia , l ac k of fu nd in g, o r l ac k of a de qu at e in fra st ru ct ur e in p la ce (e .g . di ag no st ics ), th e op er at io na liz at io n an d im m ed ia te ro llo ut o f t he a ll- or al b ed aq ui lin e- co nt ai ni ng re gi m en m ig ht b e ha m pe re d. O ne im po rt an t r eq ui re m en t h ig hl ig ht ed b y th e G D G w as th at of e ns ur in g th e ca re fu l s el ec tio n of p at ie nt s w ho a re to b en ef it fro m th is re gi m en , c on du ct in g ra pi d an d ac cu ra te D ST , a nd m on ito rin g be da qu ilin e re sis ta nc e. T he im pl em en ta tio n of th e re gi m en m ay b e lim ite d by th e ne ed fo r i m pr ov ed la bo ra to ry in fra st ru ct ur e. A lth ou gh c ou nt rie s ar e im pl em en tin g ra pi d m ol ec ul ar te st s to id en tif y rif am pi cin re sis ta nc e, la bo ra to ry ca pa cit y ne ed s to b e ef fe ct iv el y es ta bl ish ed to c on du ct ge no ty pi c an d ph en ot yp ic te st in g fo r o th er im po rt an t a ge nt s in th e re gi m en . A lso , a lth ou gh th e pr ev al en ce o f i de nt ifi ed m ut at io ns c on fe rr in g lo w -le ve l d ru g re sis ta nc e is ve ry lo w, co un tri es a re to s tre ng th en la bo ra to ry c ap ac ity a nd to m on ito r th e ac qu isi tio n of re sis ta nc e to b ed aq ui lin e th ou gh th ei r na tio na l r ef er en ce la bo ra to rie s or T B su pr an at io na l r ef er en ce ne tw or k sit es . T hi s is es pe cia lly im po rt an t g iv en th e pi pe lin e of n ew a nt i-T B re gi m en s th at a re re ly in g on b ed aq ui lin e as a ba ck bo ne . Th e re m ov al o f i nj ec ta bl e ag en ts , a s di sc us se d by th e G D G , a lso po in te d to w ar ds th e co nv en ie nc e (fo r h ea lth c ar e w or ke rs ) o f no t h av in g to d el iv er d ai ly in je ct io ns , a nd m or e so , f or p at ie nt s no t h av in g to e nd ur e pa in a nd o th er s ig ni fic an t a dv er se e ve nt s. Th e im pl em en ta tio n of th e re gi m en is p er ce iv ed to g o be yo nd se cu rin g of fu nd in g, b ut it fu rt he r r eq ui re s m ak in g lo ng - te rm , s us ta in ab le s ys te m s ch an ge s to e ns ur e ra pi d tra ns iti on , co ns id er in g th e re gi st ra tio n of b ed aq ui lin e an d ot he r n ew ag en ts , u ni nt er ru pt ed s up pl y of q ua lit y- as su re d dr ug s, an d ac tiv e TB d ru g sa fe ty m on ito rin g an d m an ag em en t s ys te m in co or di na tio n w ith e xis tin g ph ar m ac ov ig ila nc e st ru ct ur es a t t he co un tr y le ve l. Al so , t he im pl em en ta tio n of th is re gi m en (a nd a ny o th er n ov el re gi m en ) w ill re qu ire d ec isi on -m ak in g to w ar ds m ul tis ec to ra l po lic ie s, ta ilo rin g pa tie nt -c en tre d pr og ra m m es th at a lso co ns id er a sp ec ts s uc h as m en ta l h ea lth a nd m an ag em en t o f ot he r c om or bi di tie s, fa cil ita tin g co un se llin g an d su pp or t d ur in g tre at m en t, an d af te r c om pl et io n, fa cil ita tin g fu ll re co ve ry . WHO consolidated guidelines on tuberculosis: Online annexes94 Su m m ar y of ju dg em en ts JU D G EM EN TS PR O BL EM N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow D ES IR AB LE E FF EC TS Tr iv ia l Sm al l M od er at e La rg e Va rie s D on ’t kn ow UN D ES IR AB LE E FF EC TS La rg e M od er at e Sm al l Tr iv ia l Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s VA LU ES Im po rt an t un ce rt ai nt y or va ria bi lit y Po ss ib ly im po rt an t un ce rt ai nt y or va ria bi lit y Pr ob ab ly n o im po rt an t un ce rt ai nt y or va ria bi lit y N o im po rt an t un ce rt ai nt y or va ria bi lit y BA LA N CE O F EF FE CT S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s D on ’t kn ow RE SO UR CE S RE Q UI RE D La rg e co st s M od er at e co st s N eg lig ib le c os ts a nd sa vi ng s M od er at e sa vi ng s La rg e sa vi ng s Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE O F RE Q UI RE D R ES O UR CE S Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s CO ST E FF EC TI VE N ES S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s N o in clu de d st ud ie s EQ UI TY Re du ce d Pr ob ab ly re du ce d Pr ob ab ly n o im pa ct Pr ob ab ly in cr ea se d In cr ea se d Va rie s D on ’t kn ow AC CE PT AB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow FE AS IB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow Ty pe o f r ec om m en da tio n St ro ng re co m m en da tio n ag ai ns t th e in te rv en tio n ○ Co nd iti on al re co m m en da tio n ag ai ns t t he in te rv en tio n ○ Co nd iti on al re co m m en da tio n fo r e ith er th e in te rv en tio n or th e co m pa ris on ○ Co nd iti on al re co m m en da tio n fo r th e in te rv en tio n ● St ro ng re co m m en da tio n fo r t he in te rv en tio n ○ Annex 4: GRADE evidence-to-decision tables 95 Co nc lu si on s Re co m m en da tio n A sh or te r, al l-o ra l, be da qu ilin e- co nt ai ni ng re gi m en o f 9 –1 2 m on th s’ du ra tio n is re co m m en de d in e lig ib le p at ie nt s w ith c on fir m ed M D R/ RR -T B w ho h av e no t b ee n ex po se d to tr ea tm en t w ith s ec on d- lin e TB m ed ici ne s us ed in th is re gi m en fo r m or e th an o ne m on th a nd in w ho m re sis ta nc e to fl uo ro qu in ol on es h as b ee n ex clu de d. (C on di tio na l r ec om m en da tio n, v er y lo w c er ta in ty in th e ev id en ce ) Ju st ifi ca tio n O ve ra ll, th e G D G n ot ed th at th e ce rt ai nt y of th e ev id en ce re ga rd in g th e ef fic ac y of th e al l-o ra l s ho rt er re gi m en w as “v er y lo w ”, at tri bu ta bl e na m el y to c on ce rn s of s er io us ri sk o f b ia s, de sp ite e ffo rt s to b al an ce b as el in e co va ria te s. H ow ev er , t he g ro up re co gn iz ed th at th e cu rre nt e vi de nc e as se ss m en t o f t he a ll- or al , b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en h as s om e ad di tio na l a dv an ta ge s as c om pa re d w ith a ll- or al lo ng er re gi m en s, na m el y in te rm s of lo w er lo ss to fo llo w -u p (d es ira bl e ef fe ct ) a nd o bv io us s ho rt er d ur at io n (a cc ep ta bi lit y) . W he n de cid in g on th e st re ng th o f t he re co m m en da tio n, th e G D G re ac he d a un an im ou s de cis io n on th e co nd iti on al ity o f t he re co m m en da tio n, m ai nl y at tri bu te d to th e ve ry lo w c er ta in ty in th e ev id en ce a nd re qu ire m en ts to b ui ld la bo ra to ry c ap ac ity a nd e ns ur e D ST . O th er g ro un ds fo r t he s tre ng th a nd d ire ct io n of th is re co m m en da tio n ar e as fo llo w s: • Th e an al ys is co nd uc te d to in fo rm th e de ve lo pm en t o f t hi s re co m m en da tio n w as b as ed o n ob se rv at io na l p ro gr am m at ic da ta fr om S ou th A fri ca w he re th e st an da rd iz ed s ho rt er , a ll- or al , be da qu ilin e- co nt ai ni ng re gi m en (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) w as u se d fo r p at ie nt s w ith M D R/ RR -T B. • Th ou gh n o m aj or s ig na ls of ri sk w er e ob se rv ed w ith th e us e of th e al l-o ra l b ed aq ui lin e- ba se d sh or te r r eg im en , t he re a lso re m ai ne d so m e un ce rt ai nt ie s gi ve n th e la ck o f s ys te m at ic co lle ct io n of d at a, a nd th e la ck o f c la rit y as to a ny c ha ng es in th e re gi m en th at c ou ld h av e be en in fo rm ed b y th e pr es en ce o f a dv er se e ve nt s. • Co st –e ffe ct iv en es s m od el lin g of th e al l-o ra l, sh or te r, be da qu ilin e- co nt ai ni ng re gi m en s ho w ed ro bu st c os t s av in gs re la tiv e to e ith er a lo ng er o ra l r eg im en o r a s ho rt in je ct ab le - co nt ai ni ng re gi m en . • Th e G D G ju dg ed th at m an y el ig ib le p at ie nt s w ou ld p re fe r t he a ll- or al , b ed aq ui lin e- co nt ai ni ng re gi m en o f 9 –1 2 m on th s’ du ra tio n. T hi s is su pp or te d by li m ite d ob se rv at io ns in vo lv in g 16 s ur vi vo rs o f d ru g- re sis ta nt T B. In a dd iti on , t hi s re gi m en m ay h el p pr om ot e he al th e qu ity o r m iti ga te th e w or se ni ng o f h ea lth in eq ui tie s. H ow ev er , t he p an el re co gn iz ed th at im pl em en ta tio n an d sc al e- up o f t hi s re gi m en m ig ht b e slo w b ec au se o f p re re qu isi te s re ga rd in g la bo ra to ry c ap ac ity a nd m on ito rin g. Su bg ro up c on si de ra tio ns Th e an al ys is at te m pt ed to d es cr ib e th e ba la nc e of e ffe ct s an d co ns id er at io ns fo r v ar io us s ub gr ou ps o r s pe cia l p op ul at io ns . H ow ev er , t he e vi de nc e re vi ew ed s up po rt ed th e us e of th is in th e fo llo w in g se tti ng s, w ith s pe cif ic ca ve at s: • Pe op le li vi ng w ith H IV in fe ct io n (P LH IV ): Th e da ta e va lu at ed c or re sp on de d to a s et tin g w ith a h ig h pr ev al en ce o f H IV , a nd o f p ar tic ul ar s ig ni fic an ce , m os t P LH IV (> 95 % ) w ho s ta rt ed th e al l-o ra l b ed aq ui lin e- co nt ai ni ng re gi m en w er e re ce iv in g an tir et ro vi ra l t he ra py (A RT ).. In v ie w o f t he tr ea tm en t o ut co m es d es cr ib ed in th e an al ys is, th er e w er e no g ro un ds to b el ie ve th at th e re gi m en w ou ld p er fo rm a ny d iff er en tly in P LH IV . I t i s ne ce ss ar y to c on sid er s ig ni fic an t c lin ica l i nt er ac tio ns th at m ay in cr ea se b ed aq ui lin e ex po su re o r t ha t o f o th er a ge nt s w ith po te nt ia l f or c ar di ot ox ici ty w he n th es e ar e co -a dm in ist er ed w ith a nt ire tro vi ra ls. • Ch ild re n: A lth ou gh n o di re ct o ut co m e es tim at io ns c ou ld b e dr aw n fo r t hi s po pu la tio n, e xt ra po la tio n w as d ee m ed re as on ab le . H ow ev er , b ec au se b ed aq ui lin e is cu rre nt ly re co m m en de d fo r c hi ld re n an d ad ol es ce nt s ag ed 6 –1 7 ye ar s, th e G D G c on clu de d th at th e al l-o ra l b ed aq ui lin e- co nt ai ni ng re gi m en m ay b e us ed in e lig ib le c hi ld re n w ith in th is ag e gr ou p, ta kin g in to ac co un t s pe cif ica tio ns fo r r eg im en c om pa ni on d ru gs , i n pa rt icu la r, be da qu ilin e. • Pr eg na nt a nd la ct at in g w om en : M or e ev id en ce is n ee de d to b et te r i nf or m th e us e of th e al l-o ra l, be da qu ilin e- co nt ai ni ng s ho rt er re gi m en (B D Q -L FX /M FX -E TO -E -Z -H h - CF Z) . O ne of th e ag en ts in th is al l-o ra l s ho rt er re gi m en , e th io na m id e, is u su al ly c on tra in di ca te d in p re gn an cy , a nd w ith ho ld in g th is ag en t o r r ep la cin g it w ith a no th er o ne c ou ld s er io us ly co m pr om ise th e ef fe ct iv en es s of th e re gi m en . F or p re gn an t a nd la ct at in g w om en , i t i s th er ef or e re co m m en de d th at a n in di vi du al iz ed , a ll- or al lo ng er re gi m en (w ith in clu sio n of be da qu ilin e) b e us ed (s ee R ec om m en da tio ns o n th e us e of lo ng er re gi m en s fo r M D R/ RR -T B) . – Ex tra pu lm on ar y di se as e: In v ie w o f t he u na va ila bi lit y of e vi de nc e re ga rd in g su rro ga te s fo r s ev er ity o r e xt en t o f d ise as e, it is a dv isa bl e to u se c lin ica l j ud ge m en t t o de cid e on th e us e of th is re gi m en in p at ie nt s w ith e xt en siv e TB d ise as e or s ev er e fo rm s of e xt ra pu lm on ar y TB . WHO consolidated guidelines on tuberculosis: Online annexes96 Im pl em en ta tio n co ns id er at io ns Th e in te re st in re du cin g th e du ra tio n of tr ea tm en t f or M D R/ RR -T B ha s m ot iv at ed a n um be r o f s tu di es in re ce nt y ea rs to tr ea t p at ie nt s w ith s ho rt er re gi m en s un de r p ro gr am m at ic as w el l as tr ia l c on di tio ns . B ec au se o f e xp er ie nc es in v ar io us s et tin gs , [ el ig ib le ] p at ie nt s no w h av e an o pt io n to b e tre at ed w ith a s ho rt er , i nj ec ta bl e- sp ar in g re gi m en o f 9 –1 2 m on th s’ du ra tio n. To en su re th at th e re gi m en a ch ie ve s its d es ira bl e ef fe ct s an d pr ev en t t he a cq ui sit io n (o r a m pl ifi ca tio n) o f a dd iti on al d ru g re sis ta nc e (w hi le p ro te ct in g re gi m en c om po ne nt s) , c ou nt rie s ar e to co ns id er th e fo llo w in g: • Pa tie nt s el ec tio n an d de cis io ns to s ta rt th e al l-o ra l s ho rt er re gi m en : P at ie nt s w ith c on fir m ed M D R/ RR -T B an d w ith re sis ta nc e to fl uo ro qu in ol on es ru le d ou t a re e xp ec te d to b en ef it th e m os t f ro m th is re gi m en . P ro pe r p at ie nt s el ec tio n w ill no t o nl y le ad to im pr ov ed tr ea tm en t o ut co m es , b ut w ill al so c on tri bu te to a vo id in g th e de ve lo pm en t o f r es ist an ce to b ed aq ui lin e. In th is re sp ec t, th e re gi m en is to o nl y be im pl em en te d in s et tin gs w he re ro ut in e D ST fo r r ifa m pi cin a nd fl uo ro qu in ol on es c an b e gu ar an te ed . It is ve ry im po rt an t t ha t t he im pl em en ta tio n of th es e re co m m en da tio ns is a cc om pa ni ed b y co nt in ue d ef fo rt s to in cr ea se a cc es s to D ST fo r a ll m ed ici ne s fo r w hi ch re lia bl e m et ho ds ex ist , a s w el l a s fo r t he d ev el op m en t a nd ro llo ut o f D ST m et ho ds fo r n ew er m ed ici ne s. In th e ab se nc e of a d ru g- su sc ep tib ilit y te st , a ss ay s sp ec ifi c fo r b ed aq ui lin e re sis ta nc e sh ou ld b e m on ito re d th ro ug h as se ss m en t o f m in im um in hi bi to ry c on ce nt ra tio ns (M IC s) o f b ed aq ui lin e. Re sis ta nc e to o th er a nt i-T B dr ug s sh ou ld b e m on ito re d in a cc or da nc e w ith W H O re co m m en da tio ns . • Us e of li ne zo lid : T he e vi de nc e m ad e av ai la bl e to in fo rm th is re co m m en da tio n fo cu se d on th e as se ss m en t o f a re gi m en c om po se d of b ed aq ui lin e, le vo flo xa cin /m ox ifl ox ac in , et hi on am id e, e th am bu to l, py ra zi na m id e, h ig h- do se is on ia zi d, c lo fa zi m in e, a nd p yr az in am id e. H ow ev er , s ec on da ry a na ly se s (o nl y in lo ng er re gi m en s co nt ai ni ng b ed aq ui lin e an d be da qu ilin e pl us li ne zo lid ) s ho w ed fa vo ur ab le o ut co m es w he n tre at m en t r eg im en s in clu de d bo th li ne zo lid a nd b ed aq ui lin e. T he b as is fo r t he a dd iti on o f l in ez ol id w as to p ro te ct th e re gi m en – in p ar tic ul ar , b ed aq ui lin e – w hi le a w ai tin g su sc ep tib ilit y re su lts o n ad di tio na l r es ist an ce to fl uo ro qu in ol on es a nd o th er d ru gs . T he G D G d ec id ed th at u nt il ne w e vi de nc e is av ai la bl e on s ho rt er re gi m en s th at in clu de b ot h of th es e ag en ts , t he a ll- or al b ed aq ui lin e- co nt ai ni ng s ho rt er re gi m en a dv ise d he re in s ho ul d no t i nc lu de li ne zo lid . H ow ev er , t he g ro up en co ur ag ed c ou nt rie s to c on sid er th e us e of a m od ifi ed a ll- or al b ed aq ui lin e- a nd li ne zo lid -c on ta in in g on ly u nd er o pe ra tio na l r es ea rc h un til n ew e vi de nc e be co m es a va ila ble . • Pa tie nt -c en tre d ap pr oa ch : E ffo rt s ar e re qu ire d to p ro vi de p at ie nt s up po rt to e na bl e fu ll ad he re nc e to tr ea tm en t. M on ito rin g an d ev al ua tio n • Th e im pl em en ta tio n of th is re gi m en re qu ire s th e us e of ro ut in e D ST n ot o nl y fo r p at ie nt s el ec tio n, b ut a lso fo r m on ito rin g of th e ac qu isi tio n of re sis ta nc e. • Al th ou gh th e da ta a ss es se d di d no t u ne ar th a ny m aj or s ig na ls of ri sk , a ct iv e TB d ru g sa fe ty m on ito rin g an d m an ag em en t s ys te m s m us t b e fu nc tio na l i n or de r t o co nd uc t r ig or ou s ac tiv e m on ito rin g of a dv er se e ve nt s an d to d et ec t, m an ag e an d re po rt s us pe ct ed o r c on fir m ed d ru g to xic iti es in a ti m el y m an ne r. Re se ar ch p rio rit ie s M em be rs o f t he G D G d isc us se d th e re se ar ch g ap s to in fo rm th e de ve lo pm en t o f p ub lic h ea lth re co m m en da tio ns fo r t he m an ag em en t a nd c ar e of p at ie nt s w ith M D R/ RR -T B, a nd hi gh lig ht ed th e fo llo w in g pr io rit ie s: • st ud ie s as se ss in g co m pa ris on s of a ll- or al s ho rt er re gi m en s w hi ch in clu de b ed aq ui lin e an d lin ez ol id , i n ad di tio n to o th er c om pa ni on d ru gs ; • st ud ie s as se ss in g co m pa ris on s of a ll- or al s ho rt er re gi m en s am on g di ffe re nt s ub gr ou ps a nd s pe cia l p op ul at io ns , i nc lu di ng p re gn an t a nd la ct at in g w om en ; • ra nd om iz ed -c on tro lle d tri al s or o pe ra tio na l r es ea rc h of th e ef fe ct iv en es s an d sa fe ty o f a ll- or al s ho rt er re gi m en s, in cr ea sin g th e ce rt ai nt y of th e ev id en ce ; • st ud ie s ex pl or in g m ec ha ni sm s of a cq ui sit io n of re sis ta nc e to b ed aq ui lin e an d ge ne tic m ar ke rs to id en tif y re sis ta nc e; a nd • ef fo rt s to d et er m in e be st w ay s to s ta nd ar di ze th e co lle ct io n of d at a so th at c ou nt rie s ca n co nt rib ut e to th e de ve lo pm en t o f g lo ba l r ec om m en da tio ns . aO R: a dj us te d od ds ra tio ; A RT : a nt ire tro vi ra l t he ra py ; d ru g- su sc ep tib ilit y te st in g; G D F: G lo ba l D ru g Fa cil ity ; G D G : G ui de lin e D ev el op m en t G ro up ; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t T B; M IC : m in im um in hi bi to ry c on ce nt ra tio n; P LH IV : p eo pl e liv in g w ith h um an im m un od ef ici en cy v iru s; TB : t ub er cu lo sis ; W H O : W or ld H ea lth O rg an iz at io n. Annex 4: GRADE evidence-to-decision tables 97 Sh ou ld a tr ea tm en t r eg im en la st in g 6– 9 m on th s co m po se d of b ed aq ui lin e, p re to m an id a nd li ne zo lid v s lo ng er re gi m en s co nt ai ni ng b ed aq ui lin e an d lin ez ol id in a dd iti on to o th er a nt i- TB d ru gs b e us ed fo r X D R- TB p at ie nt s or p at ie nt s w ho a re tr ea tm en t i nt ol er an t o r w ith n on -r es po ns iv e M D R- TB ? PO PU LA TI O N : XD R- TB p at ie nt s or p at ie nt s w ho a re tr ea tm en t i nt ol er an t o r w ith n on -r es po ns iv e M D R- TB IN TE RV EN TI O N : Tr ea tm en t r eg im en la st in g 6– 9 m on th s co m po se d of b ed aq ui lin e, p re to m an id a nd li ne zo lid CO M PA RI SO N : Lo ng er re gi m en s co nt ai ni ng b ed aq ui lin e an d lin ez ol id in a dd iti on to o th er a nt i-T B dr ug s M AI N O UT CO M ES : Su cc es s vs . F ai lu re /R ec ur re nc e; S uc ce ss v s. D ea th ; S uc ce ss v s. Fa ilu re /R ec ur re nc e/ D ea th ; S uc ce ss v s. Al l U nf av or ab le ; A dv er se e ve nt s; SE TT IN G : Tr ea tm en t o f M D R- TB p at ie nt s w ith a dd iti on al fl uo ro qu in ol on e re sis ta nc e an d / o r M D R- TB p at ie nt s w ho a re tr ea tm en t i nt ol er an t o r w ho h ad n ot re sp on de d to p re vi ou s M D R- TB tr ea tm en t, us in g a sh or te r r eg im en c om po se d of b ed aq ui lin e, p re to m an id a nd li ne zo lid (B Pa L) o f 6 –9 m on th s du ra tio n in a c om bi na tio n of h os pi ta l a nd a m bu la to ry c ar e se tti ng s in S ou th A fri ca . T he d at a w er e de riv ed fr om th e N ix- TB s tu dy , w ith 1 08 p at ie nt s in clu de d fo r a na ly sis (t he w ho le s tu dy po pu la tio n w as 1 09 p at ie nt s, ho w ev er o ne p at ie nt w ith dr ew c on se nt a nd th is pe rs on w as n ot in clu de d in th e ef fic ac y an al ys es ) PE RS PE CT IV E: Pu bl ic he al th a nd h ea lth s ys te m s BA CK G RO UN D : Tr ea tm en t o f e xt en siv el y dr ug -r es ist an t f or m s of T B pr es en ts m ul tip le c ha lle ng es to c lin ici an s an d na tio na l T B pr og ra m m es b ot h du e to th e lim ite d ra ng e of m ed ici ne s av ai la bl e an d th e lif e- th re at en in g na tu re o f t he d ise as e. P at ie nt s w ith M D R/ RR -T B an d ad di tio na l f lu or oq ui no lo ne re sis ta nc e ha ve ty pi ca lly e xp er ie nc ed po or tr ea tm en t o ut co m es s in ce th e de sc rip tio n of X D R- TB w as fi rs t u se d in 2 00 6. 5 B as ed o n da ta re po rt ed b y M em be r S ta te s to W H O , f or th e co ho rt o f X D R- TB pa tie nt s w ho s ta rt ed tr ea tm en t i n 20 16 (a nd fo r w ho m tr ea tm en t o ut co m es w er e av ai la bl e in 2 01 8) , o nl y 39 % c om pl et ed tr ea tm en t s uc ce ss fu lly , w hi le 2 6% d ie d, tre at m en t f ai le d fo r 1 8% a nd a n ad di tio na l 1 8% w er e lo st to fo llo w u p or w er e no t e va lu at ed .6 Th e pr es sin g ne ed fo r m or e ef fe ct iv e tre at m en t r eg im en s fo r p at ie nt s w ith e xt en siv e dr ug re sis ta nc e, in clu di ng fl uo ro qu in ol on e re sis ta nc e an d m or e ex te ns iv e dr ug re sis ta nc e pr of ile s, ha s m ot iv at ed a n um be r o f s tu di es a nd in iti at iv es to te st m or e ef fe ct iv e an d no ve l t re at m en t r eg im en s, in clu siv e of n ew er a nd re pu rp os ed m ed ici ne s. O ne su ch st ud y is th e N ix- TB st ud y,7 c on du ct ed b y TB A llia nc e. T he N ix- TB st ud y w as a o ne a rm , p ha se th re e, o pe n la be l p ro sp ec tiv e co ho rt st ud y th at a ss es se d th e sa fe ty , e ffi ca cy , t ol er ab ilit y an d ph ar m ac ok in et ic pr op er tie s o f a 6 m on th tr ea tm en t r eg im en c om po se d of b ed aq ui lin e, p re to m an id 8 an d lin ez ol id (B Pa L) , e xt en da bl e to 9 m on th s f or th os e w ho m iss ed d os es o r f or p at ie nt s w ho re m ai ne d cu ltu re p os iti ve o r r ev er te d fro m c ul tu re n eg at ive to p os iti ve b et w ee n m on th s 4 to 6 o f tre at m en t. Th e st ud y w as c on du ct ed b et w ee n 20 14 a nd 2 01 9 at th re e st ud y sit es , a ll in S ou th A fri ca , w ith th e fir st p at ie nt e nr ol le d in A pr il 20 15 . E lig ib le p at ie nt s w er e ag ed 1 4 ye ar s a nd a bo ve , w ei gh ed ≥ 35 kg , h ad a d oc um en te d H IV re su lt an d ha d ba ct er io lo gi ca lly c on fir m ed sp ut um c ul tu re p os iti ve X D R- TB o r b ac te rio lo gi ca lly co nf irm ed M D R/ RR -T B bu t w ho w er e tre at m en t i nt ol er an t o r n on -r es po ns ive to p re vio us M D R/ RR -T B tre at m en t. A nu m be r o f o th er in clu sio n cr ite ria w er e ap pl ie d. Pa tie nt s w er e fo llo w ed u p fo r a p er io d of u p to 2 4 m on th s po st tr ea tm en t c om pl et io n. T he p rim ar y ou tc om e m ea su re w as th e in cid en ce o f b ac te rio lo gi c fa ilu re o r re la ps e or c lin ica l f ai lu re th ro ug h fo llo w u p un til 6 m on th s af te r t he e nd o f t re at m en t ( TB A llia nc e, N ix- TB s tu dy p ro to co l, av ai la bl e at : h ttp s:/ /c lin ica ltr ia ls. go v/ ct 2/ sh ow /N CT 02 33 37 99 ). Se co nd ar y ou tc om e m ea su re s co m pr ise d: 1. In cid en ce o f b ac te rio lo gi c fa ilu re o r r el ap se o r c lin ica l f ai lu re th ro ug h fo llo w u p un til 2 4 m on th s af te r t he e nd o f t re at m en t ( as a c on fir m at or y an al ys is) . 2. T im e to s pu tu m c ul tu re c on ve rs io n to n eg at iv e st at us th ro ug h th e tre at m en t p er io d. 3. T he p ro po rt io n of s ub je ct s w ith s pu tu m c ul tu re c on ve rs io n to n eg at iv e st at us a t 4 , 6 , 8 , 1 2, 1 6 an d 26 o r 3 9 w ee ks . 4. L in ez ol id d os in g (a ct ua l) an d ef fic ac y. 5. C ha ng e fro m b as el in e in T B sy m pt om s. 6. C ha ng e fro m b as el in e in P at ie nt R ep or te d H ea lth S ta tu s. 7. C ha ng e fro m b as el in e in w ei gh t ( TB A llia nc e, N ix- TB s tu dy p ro to co l, av ai la bl e at : h ttp s:/ /c lin ica ltr ia ls. go v/ ct 2/ sh ow /N CT 02 33 37 99 ). Th e N ix- TB s tu dy re gi m en c om pr ise d pr et om an id a dm in ist er ed a t 2 00 m g on ce d ai ly, b ed aq ui lin e ad m in ist er ed a t 4 00 m g on ce d ai ly fo r t he fi rs t t w o w ee ks o f tre at m en t ( da ys 1 to 1 4) a nd th en 2 00 m g th re e tim es a w ee k th er ea fte r, an d lin ez ol id c om m en ce d at 1 20 0m g pe r d ay (a dd iti on al in fo rm at io n on li ne zo lid d os in g is in clu de d un de r I m pl em en ta tio n co ns id er at io ns , b el ow ). Cl os e m icr ob io lo gi c, c lin ica l a nd a dv er se e ve nt m on ito rin g w er e fe at ur es o f t he N ix- TB s tu dy . 5 Em er ge nc e of X D R- TB [w eb sit e] . G en ev a, S w itz er la nd W or ld H ea lth O rg an iz at io n 20 06 (h ttp s:/ /w w w. w ho .in t/ m ed ia ce nt re /n ew s/ no te s/ 20 06 /n p2 3/ en , a cc es se d 28 F eb ru ar y 20 20 ). 6 W H O c on so lid at ed g ui de lin es o n dr ug re sis ta nt tu be rc ul os is tre at m en t. G en ev a, S w itz er la nd : W or ld H ea lth O rg an iz at io n; 2 01 9 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 31 13 89 /9 78 92 41 55 05 29 -e ng . pd f? ua =1 , a cc es se d 20 M ar ch 2 02 0) . 7 Th e N ix- TB s tu dy p ro to co l i s av ai la bl e at : h ttp s:/ /c lin ica ltr ia ls. go v/ ct 2/ sh ow /N CT 02 33 37 99 . A p ub lic at io n on th e re su lts o f t he s tu dy is a va ila bl e at : h ttp s:/ /w w w. ne jm .o rg /d oi /fu ll/ 10 .1 05 6/ N EJ M oa 19 01 81 4. 8 Pr et om an id is a n ew c he m ica l e nt ity a nd a m em be r o f a c la ss o f c om po un ds k no w n as n itr oi m id az o- ox az in es , w hi ch p os se ss s ig ni fic an t a nt i-T B ac tiv ity a nd a u ni qu e m ec ha ni sm o f a ct io n. WHO consolidated guidelines on tuberculosis: Online annexes98 Th e ev id en ce to in fo rm th is PI CO q ue st io n w as d er iv ed fr om th e N ix- TB s tu dy a nd in clu de d in fo rm at io n on 1 08 p at ie nt s. Th e to ta l s tu dy p op ul at io n w as 1 09 pa tie nt s; ho w ev er , o ne p at ie nt w ith dr ew in fo rm ed c on se nt to p ar tic ip at e in th e st ud y an d th is pe rs on w as in clu de d in s af et y an al ys es b ut n ot in th e an al ys es fo r ef fe ct iv en es s. Th es e da ta w er e co m pa re d to a s ub se t o f d at a fro m th e in di vi du al p at ie nt d at as et (I PD ) w hi ch o ve ra ll in clu de s 13 2 73 in di vi du al p at ie nt re co rd s fro m 55 d iff er en t s tu di es /c en tre s in 3 8 co un tri es . F or th e pr im ar y an al ys es , t he c om pa ra to r g ro up in clu de d pa tie nt s fro m th e IP D o n lo ng er tr ea tm en t r eg im en s (w ith a m ea n du ra tio n of tr ea tm en t o f 2 1. 0– 25 .5 m on th s) , w ho re ce iv ed b ot h be da qu ilin e an d lin ez ol id a s pa rt o f t he re gi m en (n o pa tie nt s re ce iv ed p re to m an id in th e IP D ). Th is co m pa ris on g ro up in clu de d 45 6 pa tie nt s w ho w er e tre at ed in B el ar us , I nd ia , F ra nc e, R us sia a nd in c ou nt rie s in A sia . T he in te rv en tio n an d co m pa ris on gr ou ps w er e m at ch ed e xa ct ly fo r X D R, M D R an d flu or oq ui no lo ne re sis ta nc e an d H IV s ta tu s, w ith p ro pe ns ity s co re m at ch in g fo r t he v ar ia bl es o f a ge , s ex , b as el in e cu ltu re re su lt, e xt en t o f d ise as e (d et er m in ed b y ba se lin e AF B sm ea r o r c he st x -r ay fi nd in gs o f c av ita tio n or b ila te ra l d ise as e if AF B sm ea r r es ul t w as m iss in g) a nd co un tr y in co m e le ve l ( W or ld B an k At la s m et ho d) . T re at m en t o ut co m es u se d in th es e an al ys es c om pr ise d th e in ve st ig at or d ef in ed o ut co m es fo r t he in te rv en tio n gr ou p (fo r t he N ix- TB s tu dy ) a nd tr ea tm en t o ut co m es la rg el y de fin ed a cc or di ng to W H O d ef in iti on s (L as er so n KF e t a l., 20 05 ; W or ld H ea lth O rg an iz at io n, 2 01 3: ht tp s:/ /w w w. w ho .in t/ tb /p ub lic at io ns /d ef in iti on s/ en /) fo r t he c om pa ra to r g ro up (f or th e pa tie nt s in clu de d in th e IP D ). In o rd er to a llo w a n eq ua l o pp or tu ni ty fo r tre at m en t o ut co m es to o cc ur fr om th e st ar t o f t re at m en t w he n co m pa rin g th e tw o gr ou ps , a ll ou tc om es w er e in clu de d fro m th e st ar t o f t re at m en t t o 24 m on th s po st tr ea tm en t s ta rt . T hi s m ea nt th at in th e in te rv en tio n gr ou p th es e ou tc om es o cc ur re d po st tr ea tm en t c om pl et io n an d fo r t he c om pa ra to r g ro up th e ou tc om es w er e en d of tr ea tm en t o ut co m es (a s pa tie nt s in th e IP D re ce iv ed a lo ng er re gi m en a nd w er e no t f ol lo w ed u p po st tr ea tm en t c om pl et io n) . T hr ee o th er c om pa ra to r gr ou ps fr om th e IP D in clu de d pa tie nt s on lo ng er tr ea tm en t r eg im en s w ho re ce iv ed a re gi m en w hi ch in clu de d be da qu ilin e, o r a re gi m en w hi ch in clu de d lin ez ol id , or a re gi m en w ith n ei th er b ed aq ui lin e or li ne zo lid in clu de d. T he in iti al in te nt io n of th e G D G w as to a ss es s th e in te rv en tio n re gi m en a ga in st a ll th re e co m pa ris on gr ou ps h ow ev er , d ur in g th ei r d el ib er at io ns th e pa ne l a gr ee d th at th e ju dg em en ts s ho ul d be b as ed o n th e co m pa ris on g ro up w ho re ce iv ed b ed aq ui lin e an d lin ez ol id a s pa rt o f t he ir re gi m en , a s th es e pa tie nt s m os t c lo se ly re se m bl e pa tie nt s w ho w ou ld re ce iv e cu rre nt ly re co m m en de d lo ng er re gi m en s co m po se d w ith m ed ici ne s fro m G ro up s A , B a nd C . H ow ev er , a d ire ct c om pa ris on o f B Pa L w ith a ll- or al lo ng er re gi m en s co ns tru ct ed a cc or di ng to th e m os t r ec en t W H O re co m m en da tio ns is su ed in M ay 2 01 9 w as n ot p os sib le a s th es e re gi m en s m ay h av e on ly b ee n in u se s in ce m id -2 01 9, a nd tr ea tm en t o ut co m es fo r t he se p at ie nt s ar e no t y et a va ila bl e. A dd iti on al d at a re vi ew ed b y th e G ui de lin e D ev el op m en t G ro up re le va nt to th is PI CO q ue st io n w er e a co st e ffe ct iv en es s an al ys is, a s tu dy on th e ac ce pt ab ilit y an d lik el ih oo d of im pl em en ta tio n of th e BP aL re gi m en , m od el le d ph ar m ac o- kin et ic da ta b as ed o n th e de ve lo pm en t o f a p ha rm ac o- kin et ic to xic od yn am ic m od el a nd a s um m ar y re vi ew o f p re cli ni ca l a nd e ar ly c lin ica l d at a on p re to m an id . T he c os t e ffe ct iv en es s an al ys is, a cc ep ta bi lit y st ud y an d m od el le d ph ar m ac ok in et ic st ud ie s w er e co nd uc te d as p ar t o f t he N ix- TB s tu dy a nd w er e sp on so re d by T B Al lia nc e. CO N FL IC T O F IN TE RE ST S: Su sa n AB D EL -R AH M AN , D an ie la C IR IL LO , A gn es G EB H AR D, A le na S KR AH IN A , A nd re w V ER N O N Annex 4: GRADE evidence-to-decision tables 99 A ss es sm en t Pr ob le m Is th e pr ob le m a p rio rit y? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ○ P ro ba bl y ye s ● Ye s ○ V ar ie s ○ D on ’t kn ow Tu be rc ul os is (T B) re m ai ns a th re at to g lo ba l p ub lic h ea lth a nd is th e to p in fe ct io us c au se o f d ea th in th e w or ld . I n 20 18 , a n es tim at ed 1 0 m illi on p eo pl e de ve lo pe d TB a nd 1 .4 m illi on d ie d fro m th e di se as e. A bo ut 5 00 0 00 n ew c as es o f m ul tid ru g- o r r ifa m pi cin -r es ist an t T B (M D R/ RR -T B) w er e es tim at ed to e m er ge in 20 18 . W hi le a ll of th es e w ou ld h av e be en e lig ib le fo r a s ec on d- lin e TB tr ea tm en t re gi m en , o nl y 15 6 07 1 en ro lm en ts o n tre at m en t w er e re po rt ed b y co un tri es in 2 01 8 – ab ou t 3 0% o f t he e st im at ed c as el oa d. In a dd iti on , t he a ve ra ge pr op or tio n of M D R- TB c as es w ith e xt en siv el y dr ug -r es ist an t T B (X D R- TB ) i s ap pr ox im at el y 6. 2% (9 5% c on fid en ce in te rv al [C I]: 4 .4 –8 .2 % ). D es pi te th is, sig ni fic an t i m pr ov em en ts in th e av ai la bi lit y of e nh an ce d di ag no st ics a nd m or e ef fe ct iv e m ed ici ne s ha s oc cu rre d in re ce nt y ea rs , a nd h as le d to e ar lie r d et ec tio n an d hi gh er s uc ce ss ra te s am on g pa tie nt s w ith M D R/ RR -T B in a n um be r o f na tio na l p ro gr am m es . H ow ev er , t he se s uc ce ss es h av e no t b ee n re pr od uc ed in th e re st o f t he w or ld , a nd th e ov er al l t re at m en t s uc ce ss ra te w or ld w id e re ac he d on ly 5 6% fo r M D R/ RR -T B pa tie nt s w ho s ta rt ed o n tre at m en t i n 20 16 , a nd o nl y 39 % fo r p at ie nt s w ith X D R- TB . WHO consolidated guidelines on tuberculosis: Online annexes100 D es ir ab le E ff ec ts H ow s ub st an tia l a re th e de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Tr iv ia l ○ S m al l ● M od er at e ○ L ar ge ○ V ar ie s ○ D on ’t kn ow O ut co m es W ith lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id in a dd iti on to ot he r a nt i- TB dr ug s W ith tr ea tm en t re gi m en la st in g 6– 9 m on th s co m po se d of be da qu ili ne , pr et om an id an d lin ez ol id D iff er en ce Re la tiv e ef fe ct (9 5% CI ) Su cc es s vs . F ai lu re / Re cu rre nc e fo llo w u p: m ea n 24 m on th s 92 p er 1 00 97 p er 1 00 (9 0 to 9 9) 6 m or e pe r 10 0 (2 fe w er to 8 m or e) O R 3. 3 (0 .8 to 13 .7 ) Su cc es s vs . D ea th fo llo w u p: m ea n 24 m on th s 92 p er 1 00 92 p er 1 00 (5 3 to 9 9) 0 fe w er pe r 10 0 (3 9 fe w er to 7 m or e) O R 1. 0 (0 .1 to 8. 2) Su cc es s vs . F ai lu re / Re cu rre nc e/ D ea th fo llo w u p: m ea n 24 m on th s 85 p er 1 00 91 p er 1 00 (8 0 to 9 6) 6 m or e pe r 10 0 (5 fe w er to 11 m or e) O R 1. 8 (0 .7 to 4. 4) Su cc es s vs . A ll Un fa vo ra bl e fo llo w u p: m ea n 24 m on th s 82 p er 1 00 85 p er 1 00 (7 0 to 9 3) 3 m or e pe r 10 0 (1 2 fe w er to 11 m or e) O R 1. 2 (0 .5 to 3. 1) Ad ve rs e ev en ts BP aL re gi m en : 1 (0 .9 % ) p at ie nt d ie d, 2 7 (2 5% ) p at ie nt s ex pe rie nc ed o th er s er io us a dv er se e ve nt s in clu di ng ho sp ita liz at io ns a nd li fe -t hr ea te ni ng e ve nt s, an d 53 (4 9% ) pa tie nt s ex pe rie nc ed a t l ea st o ne G ra de 3 –4 a dv er se e ve nt s. D ru g di sc on tin ua tio n fo r a dv er se e ve nt s: re la te d to a ll th re e dr ug s in 1 p at ie nt , a nd re la te d to li ne zo lid (i ni tia l d os e 12 00 m g/ da y) d isc on tin ue d in a no th er 3 5 (3 2% ) p at ie nt s. O nl y 20 (1 8% ) p at ie nt s co m pl et ed a fu ll co ur se o f 1 20 0 m g/ da y. In th e IP D s tu di es (9 0% re ce iv ed ≤ 60 0m g/ da y) , t he p oo le d ra te o f lin ez ol id p er m an en t d isc on tin ua tio n w as 1 7. 9% , a nd in th e En dT B st ud y (a ll pa tie nt s re ce iv ed 6 00 m g/ da y or le ss ), th e ra te o f l in ez ol id d isc on tin ua tio n w as 1 3. 1% . I n En dT B: 9 o ut of 1 09 4 pa rt ici pa nt s (0 .8 % ) d ie d of a p os sib ly o r p ro ba bl y dr ug re la te d ad ve rs e ev en t, in clu di ng tw o pa rt ici pa nt s w ith su dd en c ar di ac d ea th a nd Q T pr ol on ga tio n. Th e G D G p an el n ot ed th at th e ev id en ce w as u nc er ta in , r ef le ct ed in th e ce rt ai nt y ra tin g of “v er y lo w ”. Th ey a lso a ck no w le dg ed th e ov er al l h ig h su cc es s ra te s in th e N ix- TB s tu dy . Th e pa ne l v ot ed o n th e m ag ni tu de o f t he d es ira bl e ef fe ct s, w ith 1 7 vo tin g “s m al l” an d 7 vo tin g “tr iv ia l”. O ne a bs ta in ed , a nd 5 re po rt ed c on fli ct s of in te re st . Th e pa ne l t he n re -e va lu at ed th e di ffe re nt ia l d es ira bl e ef fe ct s of th e sh or te r re gi m en w ith re ga rd to b ur de n (w hi ch is a d es ira bl e ef fe ct if is re du ce d by th e in te rv en tio n) . T hi s re -e va lu at io n w as b ro ug ht u p w he n th e ba la nc e of th e ef fe ct s w as fo un d to b e in co ns ist en t w ith th e cr ite ria n ot ed u nd er d es ira bl e an d un de sir ab le e ffe ct s. Pa tie nt re pr es en ta tiv es ra ise d th e iss ue s of o th er c on se qu en ce s of a lo ng er du ra tio n of tr ea tm en t; th es e in clu de a la rg er p ill bu rd en a nd m ay in clu de de pr es sio n an d ot he r u nd es ira bl e ef fe ct s. Th e pa ne l n ot ed th at lo ss to fo llo w -u p do es n ot c ap tu re a ll of th e bu rd en o f d iff er in g M D R/ RR -T B re gi m en s on p at ie nt s. Af te r t he se a dd iti on al d isc us sio ns , t he G D G c am e to c on se ns us (t hr ou gh v ot in g) th at th e di ffe re nc e in th e de sir ab le e ffe ct s w er e m od er at e. T he v ot es w er e ta llie d as 5 fo r “ sm al l” an d 18 fo r “ m od er at e” . O ne m em be r a bs ta in ed a nd 5 m em be rs re po rt ed c on fli ct s of in te re st ; a no th er G D G m em be r w as n ot p re se nt a t t he m ee tin g by th is po in t. Ad di tio na l e vi de nc e pr es en te d in clu de d m od el le d ph ar m ac ok in et ic da ta b as ed on th e de ve lo pm en t o f a p ha rm ac ok in et ic– to xic od yn am ic m od el d es ig ne d to q ua nt ify th e re la tio ns hi p be tw ee n ph ar m ac ok in et ic an d to xic q ua lit ie s of lin ez ol id a s pa rt o f a 6 -m on th B Pa L re gi m en . T he se a na ly se s w er e sp on so re d by th e TB A llia nc e an d w er e ba se d on d at a fro m th e N ix- TB s tu dy . I nf or m at io n on m od el le d da ta fr om 8 8 pa tie nt s w ho re ce iv ed li ne zo lid in th e N ix- TB s tu dy w as p re se nt ed . T hi s pa tie nt p op ul at io n in clu de d in fo rm at io n on 7 p at ie nt s w ho h ad d ie d; 2 1 in di vi du al s fro m th e N ix- TB s tu dy w er e ex clu de d fro m th es e an al ys es b ec au se 1 6 ha d in co m pl et e do sin g hi st or ie s (i. e. th ey w er e re ce iv in g on go in g tre at m en t a t t he ti m e of a na ly sis ) a nd 5 h ad u nv er ifi ab le d os in g hi st or ie s. Am on g th e 10 9 pa tie nt s in th e N ix- TB s tu dy , a na em ia w as re po rt ed in 3 7% a nd p er ip he ra l s en so ry n eu ro pa th y w as re po rt ed in 6 9% . O n th e ba sis of th e m od el le d da ta , i t w as c on clu de d th at th e ph ar m ac ok in et ics re la te d to lin ez ol id a re n on lin ea r i n pa tie nt s w ith X D R- TB a nd th at in di vi du al li ne zo lid co nc en tra tio n tim es a re th e be st p re di ct or o f t ox ici ty. H ig he r t ox ici ty ra te s w er e ob se rv ed a t h ig he r t ot al d ai ly d os es , w ith c om pa ra bl e to xic ity ra te s fo r B ID a nd Q D d os in g sc he du le s. An ae m ia c an b e m an ag ed b y clo se ly m on ito rin g ch an ge s in h ae m og lo bi n ov er th e fir st 4 w ee ks o f t re at m en t ( in p ar tic ul ar , c ha ng es in ha em og lo bi n th at re pr es en t a > 10 % in cr ea se fr om b as el in e sh ou ld tr ig ge r a re du ct io n in th e do se o f l in ez ol id – h ae m og lo bi n le ve ls re co ve r w el l a fte r d os e re du ct io ns ). Pe rip he ra l n eu ro pa th y sh ou ld b e clo se ly m on ito re d; w he n it do es oc cu r, it is re ve rs ib le fo r m os t p at ie nt s w ith in 3 m on th s. Th ro m bo cy to pe ni a is po te nt ia lly n ot a m aj or c on ce rn w ith h ig h- do se li ne zo lid fo r p at ie nt s w ith XD R- TB . Annex 4: GRADE evidence-to-decision tables 101 D es ir ab le E ff ec ts H ow s ub st an tia l a re th e de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Tr iv ia l ○ S m al l ● M od er at e ○ L ar ge ○ V ar ie s ○ D on ’t kn ow O ut co m es W ith lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id in a dd iti on to ot he r a nt i- TB dr ug s W ith tr ea tm en t re gi m en la st in g 6– 9 m on th s co m po se d of be da qu ili ne , pr et om an id an d lin ez ol id D iff er en ce Re la tiv e ef fe ct (9 5% CI ) Su cc es s vs . F ai lu re / Re cu rre nc e fo llo w u p: m ea n 24 m on th s 92 p er 1 00 97 p er 1 00 (9 0 to 9 9) 6 m or e pe r 10 0 (2 fe w er to 8 m or e) O R 3. 3 (0 .8 to 13 .7 ) Su cc es s vs . D ea th fo llo w u p: m ea n 24 m on th s 92 p er 1 00 92 p er 1 00 (5 3 to 9 9) 0 fe w er pe r 10 0 (3 9 fe w er to 7 m or e) O R 1. 0 (0 .1 to 8. 2) Su cc es s vs . F ai lu re / Re cu rre nc e/ D ea th fo llo w u p: m ea n 24 m on th s 85 p er 1 00 91 p er 1 00 (8 0 to 9 6) 6 m or e pe r 10 0 (5 fe w er to 11 m or e) O R 1. 8 (0 .7 to 4. 4) Su cc es s vs . A ll Un fa vo ra bl e fo llo w u p: m ea n 24 m on th s 82 p er 1 00 85 p er 1 00 (7 0 to 9 3) 3 m or e pe r 10 0 (1 2 fe w er to 11 m or e) O R 1. 2 (0 .5 to 3. 1) Ad ve rs e ev en ts BP aL re gi m en : 1 (0 .9 % ) p at ie nt d ie d, 2 7 (2 5% ) p at ie nt s ex pe rie nc ed o th er s er io us a dv er se e ve nt s in clu di ng ho sp ita liz at io ns a nd li fe -t hr ea te ni ng e ve nt s, an d 53 (4 9% ) pa tie nt s ex pe rie nc ed a t l ea st o ne G ra de 3 –4 a dv er se e ve nt s. D ru g di sc on tin ua tio n fo r a dv er se e ve nt s: re la te d to a ll th re e dr ug s in 1 p at ie nt , a nd re la te d to li ne zo lid (i ni tia l d os e 12 00 m g/ da y) d isc on tin ue d in a no th er 3 5 (3 2% ) p at ie nt s. O nl y 20 (1 8% ) p at ie nt s co m pl et ed a fu ll co ur se o f 1 20 0 m g/ da y. In th e IP D s tu di es (9 0% re ce iv ed ≤ 60 0m g/ da y) , t he p oo le d ra te o f lin ez ol id p er m an en t d isc on tin ua tio n w as 1 7. 9% , a nd in th e En dT B st ud y (a ll pa tie nt s re ce iv ed 6 00 m g/ da y or le ss ), th e ra te o f l in ez ol id d isc on tin ua tio n w as 1 3. 1% . I n En dT B: 9 o ut of 1 09 4 pa rt ici pa nt s (0 .8 % ) d ie d of a p os sib ly o r p ro ba bl y dr ug re la te d ad ve rs e ev en t, in clu di ng tw o pa rt ici pa nt s w ith su dd en c ar di ac d ea th a nd Q T pr ol on ga tio n. Th e G D G p an el n ot ed th at th e ev id en ce w as u nc er ta in , r ef le ct ed in th e ce rt ai nt y ra tin g of “v er y lo w ”. Th ey a lso a ck no w le dg ed th e ov er al l h ig h su cc es s ra te s in th e N ix- TB s tu dy . Th e pa ne l v ot ed o n th e m ag ni tu de o f t he d es ira bl e ef fe ct s, w ith 1 7 vo tin g “s m al l” an d 7 vo tin g “tr iv ia l”. O ne a bs ta in ed , a nd 5 re po rt ed c on fli ct s of in te re st . Th e pa ne l t he n re -e va lu at ed th e di ffe re nt ia l d es ira bl e ef fe ct s of th e sh or te r re gi m en w ith re ga rd to b ur de n (w hi ch is a d es ira bl e ef fe ct if is re du ce d by th e in te rv en tio n) . T hi s re -e va lu at io n w as b ro ug ht u p w he n th e ba la nc e of th e ef fe ct s w as fo un d to b e in co ns ist en t w ith th e cr ite ria n ot ed u nd er d es ira bl e an d un de sir ab le e ffe ct s. Pa tie nt re pr es en ta tiv es ra ise d th e iss ue s of o th er c on se qu en ce s of a lo ng er du ra tio n of tr ea tm en t; th es e in clu de a la rg er p ill bu rd en a nd m ay in clu de de pr es sio n an d ot he r u nd es ira bl e ef fe ct s. Th e pa ne l n ot ed th at lo ss to fo llo w -u p do es n ot c ap tu re a ll of th e bu rd en o f d iff er in g M D R/ RR -T B re gi m en s on p at ie nt s. Af te r t he se a dd iti on al d isc us sio ns , t he G D G c am e to c on se ns us (t hr ou gh v ot in g) th at th e di ffe re nc e in th e de sir ab le e ffe ct s w er e m od er at e. T he v ot es w er e ta llie d as 5 fo r “ sm al l” an d 18 fo r “ m od er at e” . O ne m em be r a bs ta in ed a nd 5 m em be rs re po rt ed c on fli ct s of in te re st ; a no th er G D G m em be r w as n ot p re se nt a t t he m ee tin g by th is po in t. Ad di tio na l e vi de nc e pr es en te d in clu de d m od el le d ph ar m ac ok in et ic da ta b as ed on th e de ve lo pm en t o f a p ha rm ac ok in et ic– to xic od yn am ic m od el d es ig ne d to q ua nt ify th e re la tio ns hi p be tw ee n ph ar m ac ok in et ic an d to xic q ua lit ie s of lin ez ol id a s pa rt o f a 6 -m on th B Pa L re gi m en . T he se a na ly se s w er e sp on so re d by th e TB A llia nc e an d w er e ba se d on d at a fro m th e N ix- TB s tu dy . I nf or m at io n on m od el le d da ta fr om 8 8 pa tie nt s w ho re ce iv ed li ne zo lid in th e N ix- TB s tu dy w as p re se nt ed . T hi s pa tie nt p op ul at io n in clu de d in fo rm at io n on 7 p at ie nt s w ho h ad d ie d; 2 1 in di vi du al s fro m th e N ix- TB s tu dy w er e ex clu de d fro m th es e an al ys es b ec au se 1 6 ha d in co m pl et e do sin g hi st or ie s (i. e. th ey w er e re ce iv in g on go in g tre at m en t a t t he ti m e of a na ly sis ) a nd 5 h ad u nv er ifi ab le d os in g hi st or ie s. Am on g th e 10 9 pa tie nt s in th e N ix- TB s tu dy , a na em ia w as re po rt ed in 3 7% a nd p er ip he ra l s en so ry n eu ro pa th y w as re po rt ed in 6 9% . O n th e ba sis of th e m od el le d da ta , i t w as c on clu de d th at th e ph ar m ac ok in et ics re la te d to lin ez ol id a re n on lin ea r i n pa tie nt s w ith X D R- TB a nd th at in di vi du al li ne zo lid co nc en tra tio n tim es a re th e be st p re di ct or o f t ox ici ty. H ig he r t ox ici ty ra te s w er e ob se rv ed a t h ig he r t ot al d ai ly d os es , w ith c om pa ra bl e to xic ity ra te s fo r B ID a nd Q D d os in g sc he du le s. An ae m ia c an b e m an ag ed b y clo se ly m on ito rin g ch an ge s in h ae m og lo bi n ov er th e fir st 4 w ee ks o f t re at m en t ( in p ar tic ul ar , c ha ng es in ha em og lo bi n th at re pr es en t a > 10 % in cr ea se fr om b as el in e sh ou ld tr ig ge r a re du ct io n in th e do se o f l in ez ol id – h ae m og lo bi n le ve ls re co ve r w el l a fte r d os e re du ct io ns ). Pe rip he ra l n eu ro pa th y sh ou ld b e clo se ly m on ito re d; w he n it do es oc cu r, it is re ve rs ib le fo r m os t p at ie nt s w ith in 3 m on th s. Th ro m bo cy to pe ni a is po te nt ia lly n ot a m aj or c on ce rn w ith h ig h- do se li ne zo lid fo r p at ie nt s w ith XD R- TB . Th e G D G c on sid er ed th e de sir ab le e ffe ct o f t re at m en t s uc ce ss , w hi ch w as h ig he r in th e in te rv en tio n gr ou ps th an in th e co m pa ra to r g ro up s, fo r a ll fo ur tr ea tm en t ou tc om es th at w er e as se ss ed . O ve ra ll, w he n co m pa rin g tre at m en t s uc ce ss w ith fa ilu re /r ec ur re nc e, th e tre at m en t s uc ce ss ra te in th e N ix- TB s tu dy w as 9 7. 0% , co m pa re d w ith 9 1. 7% in th e co m pa ra to r g ro up (r es ul tin g in 6 m or e tre at m en t su cc es se s pe r 1 00 p at ie nt s) . F or tr ea tm en t s uc ce ss v er su s de at h, tr ea tm en t su cc es s w as 9 3. 2% in th e N ix- TB s tu dy c om pa re d w ith 9 1. 9% in th e co m pa ra to r gr ou p (re su lti ng in 1 m or e tre at m en t s uc ce ss p er 1 00 p at ie nt s) . T he G D G co ns id er ed ra te s of lo ss to fo llo w -u p to b e a de sir ab le e ffe ct ; t he p ro po rt io n of pa tie nt s w ho w er e lo st to fo llo w -u p w as lo w er in th e in te rv en tio n gr ou p (1 .8 % ) co m pa re d w ith th e co m pa ris on g ro up (3 .1 % ). Th e un ce rt ai nt y in th e ev id en ce w as a ck no w le dg ed b y th e pa ne l w he n m ak in g th ei r j ud ge m en t o n th e de sir ab le (a nd u nd es ira bl e) e ffe ct s. Th e BP aL re gi m en w as a ss oc ia te d w ith a h ig h ra te o f a dv er se e ve nt s, co ns id er ed to b e re la te d to th e st ud y dr ug s. Th is in clu de d th e de at h of 1 (0 .9 % ) p ar tic ip an t; ot he r s er io us a dv er se e ve nt s (in clu di ng h os pi ta liz at io ns a nd li fe -t hr ea te ni ng ev en ts ) i n 27 (2 5% ) p ar tic ip an ts a nd a t l ea st o ne G ra de 3 –4 a dv er se e ve nt in 5 3 (4 9% ) p ar tic ip an ts . T hi s le d to d isc on tin ua tio n of a ll th re e dr ug s fo r 1 p at ie nt , an d di sc on tin ua tio n of li ne zo lid (i ni tia l d os e 12 00 m g/ da y) fo r a no th er 3 5 (3 2% ) p at ie nt s. O nl y 18 (1 7% ) p at ie nt s co m pl et ed a fu ll co ur se o f l in ez ol id a t 12 00 m g/ da y. Th e G D G n ot ed th at it is d iff icu lt to c om pa re th es e ad ve rs e ev en t r at es w ith ot he r s tu di es b ec au se o f m aj or a nd im po rt an t d iff er en ce s in a dv er se e ve nt as ce rt ai nm en t, as se ss m en t, an d re po rt in g. H ow ev er , i n th e IP D s tu di es (w he re 90 % o f p at ie nt s re ce iv ed a li ne zo lid d os e of ≤ 60 0 m g/ da y) , t he p oo le d ra te of p er m an en t d isc on tin ua tio n of li ne zo lid w as 1 7. 9% , a nd in th e En dT B tri al (w he re a ll pa tie nt s re ce iv ed ≤ 60 0 m g/ da y of li ne zo lid ), th e ra te o f l in ez ol id di sc on tin ua tio n w as 1 3. 1% . I n bo th o f t he se s tu di es , > 80 % o f p at ie nt s re ce iv ed a st ar tin g do se o f l in ez ol id o f 6 00 m g/ da y. In th e En dT B st ud y, pr el im in ar y an al ys es su gg es te d th at 9 o f 1 09 4 pa rt ici pa nt s (0 .8 % ) d ie d of a p os sib ly o r p ro ba bl y dr ug -r el at ed a dv er se e ve nt , i nc lu di ng 2 p ar tic ip an ts w ith s ud de n ca rd ia c de at h WHO consolidated guidelines on tuberculosis: Online annexes102 U nd es ir ab le E ff ec ts H ow s ub st an tia l a re th e un de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge ● M od er at e ○ S m al l ○ Tr iv ia l ○ V ar ie s ○ D on ’t kn ow O ut co m es W ith lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id in a dd iti on to ot he r a nt i- TB dr ug s W ith tr ea tm en t re gi m en la st in g 6– 9 m on th s co m po se d of be da qu ili ne , pr et om an id an d lin ez ol id D iff er en ce Re la tiv e ef fe ct (9 5% CI ) Su cc es s vs . F ai lu re / Re cu rre nc e fo llo w u p: m ea n 24 m on th s 92 p er 1 00 97 p er 1 00 (9 0 to 9 9) 6 m or e pe r 10 0 (2 fe w er to 8 m or e) O R 3. 3 (0 .8 to 13 .7 ) Su cc es s vs . D ea th fo llo w u p: m ea n 24 m on th s 92 p er 1 00 92 p er 1 00 (5 3 to 9 9) 0 fe w er pe r 10 0 (3 9 fe w er to 7 m or e) O R 1. 0 (0 .1 to 8. 2) Su cc es s vs . F ai lu re / Re cu rre nc e/ D ea th fo llo w u p: m ea n 24 m on th s 85 p er 1 00 91 p er 1 00 (8 0 to 9 6) 6 m or e pe r 10 0 (5 fe w er to 11 m or e) O R 1. 8 (0 .7 to 4. 4) Su cc es s vs . A ll Un fa vo ra bl e fo llo w u p: m ea n 24 m on th s 82 p er 1 00 85 p er 1 00 (7 0 to 9 3) 3 m or e pe r 10 0 (1 2 fe w er to 11 m or e) O R 1. 2 (0 .5 to 3. 1) Th e iss ue o f s er io us a dv er se e ve nt s, pa rt icu la rly th os e re la te d to li ne zo lid , a nd po te nt ia l s af et y sig na ls re la te d to m al e in fe rt ilit y ob se rv ed in a ni m al (m ur in e) m od el s, w er e of c on ce rn to th e pa ne l. Th e G D G h ig hl ig ht ed th e po te nt ia l di ffi cu lti es in m on ito rin g of in fe rt ilit y in a p ro gr am m at ic se tti ng . A dd iti on al hu m an s pe rm s tu di es re co m m en de d by th e US F oo d an d D ru g Ad m in ist ra tio n w ill be c ar rie d ou t b y th e TB A llia nc e; h ow ev er , t he se d at a w er e no t a va ila bl e fo r th e G D G to c on sid er a t t he ti m e of th e m ee tin g (a nd th ey w ill no t b e av ai la bl e fo r a fe w y ea rs ). Th e G D G d et er m in ed th at in fe rt ilit y is a se rio us is su e be ca us e it af fe ct s no t o nl y pa tie nt s bu t a lso th ei r f am ilie s. Th e G D G a lso a ck no w le dg ed th at , a t t he ti m e th e N ix- TB s tu dy s ta rt ed , t he re w er e fe w tr ea tm en t o pt io ns fo r pa tie nt s an d th er e w as a h ig h ca se fa ta lit y ra te , w hi ch m ea ns th at p at ie nt s m ig ht ha ve p la ce d a di ffe re nt v al ue o n po te nt ia l m al e in fe rt ilit y th an th ey m ig ht n ow . Ad di tio na l e vi de nc e pr es en te d in clu de d m od el le d ph ar m ac ok in et ic da ta b as ed on th e de ve lo pm en t o f a p ha rm ac ok in et ic– to xic od yn am ic m od el d es ig ne d to q ua nt ify th e be tw ee n ph ar m ac ok in et ics a nd to xic ity o f l in ez ol id a s pa rt o f a 6- m on th B Pa L re gi m en . T he se a na ly se s w er e sp on so re d by th e TB A llia nc e an d w er e ba se d on d at a fro m th e N ix- TB s tu dy . I nf or m at io n on m od el le d da ta fro m 8 8 pa rt ici pa nt s w ho re ce iv ed li ne zo lid in th e N ix- TB s tu dy w as p re se nt ed . Th e in fo rm at io n on th is po pu la tio n in clu de d da ta o n 7 pa tie nt s w ho h ad d ie d. Tw en ty -o ne in di vi du al s fro m th e N ix- TB s tu dy w er e ex clu de d fro m th es e an al ys es be ca us e 16 h ad in co m pl et e do sin g hi st or ie s (i. e. th ey w er e re ce iv in g on go in g tre at m en t a t t he ti m e of a na ly sis ) a nd 5 h ad u nv er ifi ab le d os in g hi st or ie s. Am on g th e 10 9 pa tie nt s in th e N ix- TB s tu dy , a na em ia w as re po rt ed in 3 7% of p at ie nt s an d pe rip he ra l s en so ry n eu ro pa th y w as re po rt ed in 6 9% . O n th e ba sis o f t he m od el le d da ta , i t w as c on clu de d th at th e ph ar m ac ok in et ics re la te d to li ne zo lid a re n on lin ea r i n pa tie nt s w ith X D R- TB a nd th at in di vi du al li ne zo lid co nc en tra tio n tim es a re th e be st p re di ct or o f t ox ici ty. H ig he r t ox ici ty ra te s w er e ob se rv ed a t h ig he r t ot al d ai ly d os es , w ith c om pa ra bl e to xic ity ra te s fo r B ID a nd Q D d os in g sc he du le s. An ae m ia c an b e m an ag ed b y clo se ly m on ito rin g ch an ge s in h ae m og lo bi n ov er th e fir st 4 w ee ks o f t re at m en t ( in p ar tic ul ar , i nc re as es in ha em og lo bi n of > 10 % o ve r b as el in e sh ou ld tr ig ge r a re du ct io n in th e do se o f lin ez ol id ; h ae m og lo bi n le ve ls re co ve r w el l a fte r d os e re du ct io ns ). Pe rip he ra l ne ur op at hy s ho ul d be c lo se ly m on ito re d; w he n it do es o cc ur , i t i s re ve rs ib le fo r m os t p at ie nt s w ith in 3 m on th s. Th ro m bo cy to pe ni a is po te nt ia lly n ot a m aj or co nc er n w ith h ig h- do se li ne zo lid fo r p at ie nt s w ith X D R- TB . Annex 4: GRADE evidence-to-decision tables 103 U nd es ir ab le E ff ec ts H ow s ub st an tia l a re th e un de si ra bl e an tic ip at ed e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge ● M od er at e ○ S m al l ○ Tr iv ia l ○ V ar ie s ○ D on ’t kn ow O ut co m es W ith lo ng er re gi m en s co nt ai ni ng be da qu ili ne an d lin ez ol id in a dd iti on to ot he r a nt i- TB dr ug s W ith tr ea tm en t re gi m en la st in g 6– 9 m on th s co m po se d of be da qu ili ne , pr et om an id an d lin ez ol id D iff er en ce Re la tiv e ef fe ct (9 5% CI ) Su cc es s vs . F ai lu re / Re cu rre nc e fo llo w u p: m ea n 24 m on th s 92 p er 1 00 97 p er 1 00 (9 0 to 9 9) 6 m or e pe r 10 0 (2 fe w er to 8 m or e) O R 3. 3 (0 .8 to 13 .7 ) Su cc es s vs . D ea th fo llo w u p: m ea n 24 m on th s 92 p er 1 00 92 p er 1 00 (5 3 to 9 9) 0 fe w er pe r 10 0 (3 9 fe w er to 7 m or e) O R 1. 0 (0 .1 to 8. 2) Su cc es s vs . F ai lu re / Re cu rre nc e/ D ea th fo llo w u p: m ea n 24 m on th s 85 p er 1 00 91 p er 1 00 (8 0 to 9 6) 6 m or e pe r 10 0 (5 fe w er to 11 m or e) O R 1. 8 (0 .7 to 4. 4) Su cc es s vs . A ll Un fa vo ra bl e fo llo w u p: m ea n 24 m on th s 82 p er 1 00 85 p er 1 00 (7 0 to 9 3) 3 m or e pe r 10 0 (1 2 fe w er to 11 m or e) O R 1. 2 (0 .5 to 3. 1) Th e iss ue o f s er io us a dv er se e ve nt s, pa rt icu la rly th os e re la te d to li ne zo lid , a nd po te nt ia l s af et y sig na ls re la te d to m al e in fe rt ilit y ob se rv ed in a ni m al (m ur in e) m od el s, w er e of c on ce rn to th e pa ne l. Th e G D G h ig hl ig ht ed th e po te nt ia l di ffi cu lti es in m on ito rin g of in fe rt ilit y in a p ro gr am m at ic se tti ng . A dd iti on al hu m an s pe rm s tu di es re co m m en de d by th e US F oo d an d D ru g Ad m in ist ra tio n w ill be c ar rie d ou t b y th e TB A llia nc e; h ow ev er , t he se d at a w er e no t a va ila bl e fo r th e G D G to c on sid er a t t he ti m e of th e m ee tin g (a nd th ey w ill no t b e av ai la bl e fo r a fe w y ea rs ). Th e G D G d et er m in ed th at in fe rt ilit y is a se rio us is su e be ca us e it af fe ct s no t o nl y pa tie nt s bu t a lso th ei r f am ilie s. Th e G D G a lso a ck no w le dg ed th at , a t t he ti m e th e N ix- TB s tu dy s ta rt ed , t he re w er e fe w tr ea tm en t o pt io ns fo r pa tie nt s an d th er e w as a h ig h ca se fa ta lit y ra te , w hi ch m ea ns th at p at ie nt s m ig ht ha ve p la ce d a di ffe re nt v al ue o n po te nt ia l m al e in fe rt ilit y th an th ey m ig ht n ow . Ad di tio na l e vi de nc e pr es en te d in clu de d m od el le d ph ar m ac ok in et ic da ta b as ed on th e de ve lo pm en t o f a p ha rm ac ok in et ic– to xic od yn am ic m od el d es ig ne d to q ua nt ify th e be tw ee n ph ar m ac ok in et ics a nd to xic ity o f l in ez ol id a s pa rt o f a 6- m on th B Pa L re gi m en . T he se a na ly se s w er e sp on so re d by th e TB A llia nc e an d w er e ba se d on d at a fro m th e N ix- TB s tu dy . I nf or m at io n on m od el le d da ta fro m 8 8 pa rt ici pa nt s w ho re ce iv ed li ne zo lid in th e N ix- TB s tu dy w as p re se nt ed . Th e in fo rm at io n on th is po pu la tio n in clu de d da ta o n 7 pa tie nt s w ho h ad d ie d. Tw en ty -o ne in di vi du al s fro m th e N ix- TB s tu dy w er e ex clu de d fro m th es e an al ys es be ca us e 16 h ad in co m pl et e do sin g hi st or ie s (i. e. th ey w er e re ce iv in g on go in g tre at m en t a t t he ti m e of a na ly sis ) a nd 5 h ad u nv er ifi ab le d os in g hi st or ie s. Am on g th e 10 9 pa tie nt s in th e N ix- TB s tu dy , a na em ia w as re po rt ed in 3 7% of p at ie nt s an d pe rip he ra l s en so ry n eu ro pa th y w as re po rt ed in 6 9% . O n th e ba sis o f t he m od el le d da ta , i t w as c on clu de d th at th e ph ar m ac ok in et ics re la te d to li ne zo lid a re n on lin ea r i n pa tie nt s w ith X D R- TB a nd th at in di vi du al li ne zo lid co nc en tra tio n tim es a re th e be st p re di ct or o f t ox ici ty. H ig he r t ox ici ty ra te s w er e ob se rv ed a t h ig he r t ot al d ai ly d os es , w ith c om pa ra bl e to xic ity ra te s fo r B ID a nd Q D d os in g sc he du le s. An ae m ia c an b e m an ag ed b y clo se ly m on ito rin g ch an ge s in h ae m og lo bi n ov er th e fir st 4 w ee ks o f t re at m en t ( in p ar tic ul ar , i nc re as es in ha em og lo bi n of > 10 % o ve r b as el in e sh ou ld tr ig ge r a re du ct io n in th e do se o f lin ez ol id ; h ae m og lo bi n le ve ls re co ve r w el l a fte r d os e re du ct io ns ). Pe rip he ra l ne ur op at hy s ho ul d be c lo se ly m on ito re d; w he n it do es o cc ur , i t i s re ve rs ib le fo r m os t p at ie nt s w ith in 3 m on th s. Th ro m bo cy to pe ni a is po te nt ia lly n ot a m aj or co nc er n w ith h ig h- do se li ne zo lid fo r p at ie nt s w ith X D R- TB . Ad ve rs e ev en ts BP aL re gi m en : 1 (0 .9 % ) p at ie nt d ie d, 2 7 (2 5% ) p at ie nt s ex pe rie nc ed o th er s er io us a dv er se e ve nt s in clu di ng ho sp ita liz at io ns a nd li fe -t hr ea te ni ng e ve nt s, an d 53 (4 9% ) pa tie nt s ex pe rie nc ed a t l ea st o ne G ra de 3 –4 a dv er se e ve nt s. D ru g di sc on tin ua tio n fo r a dv er se e ve nt s: re la te d to a ll th re e dr ug s in 1 p at ie nt , a nd re la te d to li ne zo lid (i ni tia l d os e 12 00 m g/ da y) d isc on tin ue d in a no th er 3 5 (3 2% ) p at ie nt s. O nl y 20 (1 8% ) p at ie nt s co m pl et ed a fu ll co ur se o f 1 20 0 m g/ da y. In th e IP D s tu di es (9 0% re ce iv ed 6 00 m g/ da y or le ss ), th e po ol ed ra te o f L ZD p er m an en t d isc on tin ua tio n w as 1 7. 9% , a nd in th e En dT B st ud y (a ll pa tie nt s re ce iv ed 6 00 m g/ da y or le ss ), th e ra te o f L ZD d isc on tin ua tio n w as 1 3. 1% . I n En dT B: 9 p er so ns ou t o f 1 09 4 (0 .8 % ) d ie d of a p os sib ly /p ro ba bl y dr ug re la te d AE , i nc lu di ng tw o pe rs on s w ith s ud de n ca rd ia c de at h an d Q T pr ol on ga tio n. An ot he r u nd es ira bl e ef fe ct th at th e G D G c on sid er ed w as th e in co ns ist en cy o f ev id en ce o n th e re ve rs ib ilit y of p er ip he ra l n eu ro pa th y; th e ev id en ce s ug ge st ed ei th er c om pl et e or in co m pl et e re ve rs ib ilit y of p er ip he ra l n eu ro pa th y. Bo th pa tie nt s an d cli ni cia ns w ho w er e pa ne l m em be rs d es cr ib ed th e po te nt ia lly de bi lit at in g ef fe ct s of ir re ve rs ib le p er ip he ra l n eu ro pa th y, w hi ch w er e of c on ce rn . G D G m em be rs a lso c on sid er ed th e fa ct th at lo ng er re gi m en s fo r M D R/ RR -T B ca rr y a su bs ta nt ia lly h ig he r p ill bu rd en , w hi ch m ay b e vi ew ed a s un de sir ab le fo r m an y pa tie nt s. Ri sk o f b ia s w ith re ga rd to th e co m pa ris on w as m en tio ne d by p an el m em be rs (m on ito rin g of a dv er se e ffe ct s w as m or e fre qu en t i n th e N ix- TB s tu dy th an in th e co m pa ris on g ro up , w hi ch in clu de s pr og ra m m at ic da ta ). Th is w as n ot n ec es sa ril y a pr ob le m w ith th e IP D c oh or ts , b ut p os ed a p ro bl em w ith th e la ck o f a c on tro l gr ou p in th e st ud y th at te st ed th e in te rv en tio n. Th e G D G c on sid er ed th e de sir ab le e ffe ct o f t re at m en t s uc ce ss , w hi ch w as h ig he r in th e in te rv en tio n gr ou ps th an in th e co m pa ra to r g ro up s, fo r a ll fo ur tr ea tm en t ou tc om es th at w er e as se ss ed . O ve ra ll, w he n co m pa rin g tre at m en t s uc ce ss w ith fa ilu re /r ec ur re nc e, th e tre at m en t s uc ce ss ra te in th e N ix- TB s tu dy w as 9 7. 0% , co m pa re d w ith 9 1. 7% in th e co m pa ra to r g ro up (r es ul tin g in 6 m or e tre at m en t su cc es se s pe r 1 00 p at ie nt s) . F or tr ea tm en t s uc ce ss v er su s de at h, tr ea tm en t su cc es s w as 9 3. 2% in th e N ix- TB s tu dy c om pa re d w ith 9 1. 9% in th e co m pa ra to r gr ou p (re su lti ng in 1 m or e tre at m en t s uc ce ss p er 1 00 p at ie nt s) . T he G D G co ns id er ed ra te s of lo ss to fo llo w -u p to b e a de sir ab le e ffe ct ; t he p ro po rt io n of pa tie nt s w ho w er e lo st to fo llo w -u p w as lo w er in th e in te rv en tio n gr ou p (1 .8 % ) co m pa re d w ith th e co m pa ris on g ro up (3 .1 % ). Th e un ce rt ai nt y in th e ev id en ce w as a ck no w le dg ed b y th e pa ne l w he n m ak in g th ei r j ud ge m en t o n th e de sir ab le (a nd u nd es ira bl e) e ffe ct s. Th e BP aL re gi m en w as a ss oc ia te d w ith a h ig h ra te o f a dv er se e ve nt s, co ns id er ed to b e re la te d to th e st ud y dr ug s. Th is in clu de d th e de at h of 1 (0 .9 % ) p ar tic ip an t; ot he r s er io us a dv er se e ve nt s (in clu di ng h os pi ta liz at io ns a nd li fe -t hr ea te ni ng ev en ts ) i n 27 (2 5% ) p ar tic ip an ts a nd a t l ea st o ne G ra de 3 –4 a dv er se e ve nt in 5 3 (4 9% ) p ar tic ip an ts . T hi s le d to d isc on tin ua tio n of a ll th re e dr ug s fo r 1 p at ie nt , an d di sc on tin ua tio n of li ne zo lid (i ni tia l d os e 12 00 m g/ da y) fo r a no th er 3 5 (3 2% ) p at ie nt s. O nl y 18 (1 7% ) p at ie nt s co m pl et ed a fu ll co ur se o f l in ez ol id a t 12 00 m g/ da y. Th e G D G n ot ed th at it is d iff icu lt to c om pa re th es e ad ve rs e ev en t r at es w ith ot he r s tu di es b ec au se o f m aj or a nd im po rt an t d iff er en ce s in a dv er se e ve nt as ce rt ai nm en t, as se ss m en t, an d re po rt in g. H ow ev er , i n th e IP D s tu di es (w he re 90 % o f p at ie nt s re ce iv ed a li ne zo lid d os e of ≤ 60 0 m g/ da y) , t he p oo le d ra te of p er m an en t d isc on tin ua tio n of li ne zo lid w as 1 7. 9% , a nd in th e En dT B tri al (w he re a ll pa tie nt s re ce iv ed ≤ 60 0 m g/ da y of li ne zo lid ), th e ra te o f l in ez ol id di sc on tin ua tio n w as 1 3. 1% . I n bo th o f t he se s tu di es , > 80 % o f p at ie nt s re ce iv ed a st ar tin g do se o f l in ez ol id o f 6 00 m g/ da y. In th e En dT B st ud y, pr el im in ar y an al ys es su gg es te d th at 9 o f 1 09 4 pa rt ici pa nt s (0 .8 % ) d ie d of a p os sib ly o r p ro ba bl y dr ug -r el at ed a dv er se e ve nt , i nc lu di ng 2 p ar tic ip an ts w ith s ud de n ca rd ia c de at h WHO consolidated guidelines on tuberculosis: Online annexes104 Ce rt ai nt y of e vi de nc e W ha t i s th e ov er al l c er ta in ty o f t he e vi de nc e of e ff ec ts ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ● Ve ry lo w ○ L ow ○ M od er at e ○ H ig h ○ N o in clu de d st ud ie s Th e pr im ar y so ur ce o f e vi de nc e fo r t hi s PI CO q ue st io n is th e N ix- TB s tu dy , w hi ch w as c om po se d of 1 09 p at ie nt s re cr ui te d in a o ne -a rm , p ha se II I, op en - la be l s tu dy th at a ss es se d th e sa fe ty , e ffi ca cy , t ol er ab ilit y, an d ph ar m ac ok in et ic pr op er tie s of a 6 -m on th tr ea tm en t r eg im en c om po se d of b ed aq ui lin e, pr et om an id a nd li ne zo lid (B Pa L) in S ou th A fri ca . T he e vi de nc e w as g en er at ed , in th e co nt ex t o f t ho ro ug h m on ito rin g an d fo llo w -u p, a t b as el in e, th ro ug ho ut tre at m en t, an d fo r 2 4 m on th s af te r t re at m en t c om pl et io n. T he re w er e 10 9 pa tie nt s in th e in te nt io n- to -t re at p op ul at io n an d 10 8 in th e m od ifi ed in te nt io n- to -t re at p op ul at io n. T he se d at a w er e co m pa re d w ith th e da ta fr om th e IP D be ca us e th e st ud y w as n ot a ra nd om iz ed , c on tro lle d tri al . O ve ra ll, th e ce rt ai nt y of th e ev id en ce w as c la ss ifi ed a s “v er y lo w ”. Th e ch ai r o f t he G D G p an el n ot ed th at c on fid en ce in te rv al s (C Is) a ro un d th e es tim at es o f e ffe ct h av e lim ite d ap pl ica tio n in th e co nt ex t o f v er y lo w e vi de nc e. Va lu es Is th er e im po rt an t u nc er ta in ty a bo ut o r v ar ia bi lit y in h ow m uc h pe op le v al ue th e m ai n ou tc om es ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ Im po rt an t un ce rt ai nt y or va ria bi lit y ● Po ss ib ly im po rt an t un ce rt ai nt y or va ria bi lit y ○ P ro ba bl y no im po rt an t un ce rt ai nt y or va ria bi lit y ○ N o im po rt an t un ce rt ai nt y or va ria bi lit y N o re se ar ch e vi de nc e w as id en tif ie d. Al th ou gh n o re se ar ch e vi de nc e w as id en tif ie d, th e pa ne l f el t t ha t t he re w as po ss ib ly im po rt an t u nc er ta in ty o r v ar ia bi lit y in h ow m uc h pe op le w ou ld v al ue th e m ai n ou tc om es . F er til ity w as ra ise d as a n ou tc om e fo r w hi ch th er e is le ss in fo rm at io n. T he p an el th ou gh t t ha t t hi s w ou ld in cr ea se th e co m pl ex ity o f t he ju dg em en t a bo ut h ow m uc h pe op le w ou ld v al ue th e ou tc om es . T he G D G de te rm in ed th at in fe rt ilit y is a se rio us is su e be ca us e it af fe ct s no t o nl y pa tie nt s bu t a lso th ei r f am ilie s. Th e pa ne l n ot ed th at th er e ar e ot he r s af et y ou tc om es (e .g . ot he r a dv er se e ve nt s, in clu di ng p er ip he ra l n eu ro pa th y) th at m ay v ar y an d th at pe op le m ay v al ue d iff er en tly . In di re ct e vi de nc e w as c on sid er ed b y th e pa ne l i n th e fo rm o f a s ep ar at e qu al ita tiv e st ud y co nd uc te d am on g 16 p at ie nt s w ith d ru g- re sis ta nt T B w ho w er e fro m h ig h TB b ur de n co un tri es (w hi ch in fo rm ed th e ju dg em en ts o n PI CO 1 ). Th e ai m o f t he s tu dy w as to d et er m in e th e m os t a cc ep ta bl e tre at m en t r eg im en fo r dr ug -r es ist an t T B. O n th e ba sis o f t he re su lts o f t hi s st ud y, th e pr ef er re d re gi m en w as s ho rt a nd in je ct io n- fre e w ith fe w to n o ph ys ica l o r m en ta l h ea lth s id e- ef fe ct s an d w ith a lo w p ill bu rd en . R an ke d pr ef er en ce s fo r t re at m en t o f d ru g- re sis ta nt T B in clu de d (1 ) a dv er se e ve nt s, (2 ) d ur at io n, (3 ) i nj ec tio n (fr ee ) a nd (4 ) p ill bu rd en . Annex 4: GRADE evidence-to-decision tables 105 Ba la nc e of e ff ec ts D oe s th e ba la nc e be tw ee n de si ra bl e an d un de si ra bl e ef fe ct s fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ● D oe s no t fa vo r e ith er th e in te rv en tio n or th e co m pa ris on ○ P ro ba bl y fa vo rs th e in te rv en tio n ○ F av or s th e in te rv en tio n ○ V ar ie s ○ D on ’t kn ow Th e pa ne l n ot ed th e m od er at e de sir ab le e ffe ct s an d th e m od er at e un de sir ab le ef fe ct s (a nd th e lo w c er ta in ty o f t he e vi de nc e ov er al l). a nd to ok th is in to a cc ou nt w he n m ak in g th ei r j ud ge m en t a bo ut th e ba la nc e of e ffe ct s, w hi ch w er e fe lt to no t f av ou r e ith er th e in te rv en tio n or th e co m pa ris on . Th e pa ne l c on sid er ed a t l en gt h th e de sir ab le a nd u nd es ira bl e ef fe ct s an d th e ba la nc e of th es e ef fe ct s, no tin g th e ve ry lo w c er ta in ty o f t he e vi de nc e an d ac kn ow le dg in g th e ef fo rt s to m at ch p at ie nt s in th e in te rv en tio n an d co m pa ra to r gr ou ps (t hr ou gh e xa ct a nd p ro pe ns ity s co re -b as ed m at ch in g) . T he G D G n ot ed th at ra nd om iz ed , c on tro lle d tri al s ar e ne ed ed in th e fu tu re , w hi ch m ay a llo w fo r a m or e clo se ly a lig ne d co m pa ris on g ro up w ith le ss p ot en tia l f or re sid ua l co nf ou nd in g. T hr ou gh a v ot in g pr oc es s, th e pa ne l c on clu de d th at th e ba la nc e of e ffe ct s do es n ot fa vo ur e ith er th e in te rv en tio n or th e co m pa ris on . F ift ee n pa ne l m em be rs v ot ed th at th e ba la nc e of e ffe ct s do es n ot fa vo ur e ith er th e in te rv en tio n or th e co m pa ris on , 5 v ot ed th at th e ba la nc e of e ffe ct s pr ob ab ly do es fa vo ur th e co m pa ris on a nd 4 v ot ed th at th ey d id n ot k no w. O ne m em be r ab st ai ne d, a nd 5 re po rt ed c on fli ct s of in te re st . WHO consolidated guidelines on tuberculosis: Online annexes106 Re so ur ce s re qu ir ed H ow la rg e ar e th e re so ur ce re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ L ar ge c os ts ○ M od er at e co st s ○ N eg lig ib le c os ts an d sa vi ng s ○ M od er at e sa vi ng s ● La rg e sa vi ng s ○ V ar ie s ○ D on ’t kn ow N o re se ar ch e vi de nc e w as id en tif ie d. Th e G D G c on sid er ed e vi de nc e fro m a c os t– ef fe ct iv en es s an al ys is st ud y w hi ch w as c on du ct ed b y st af f f ro m th e Lo nd on S ch oo l o f H yg ie ne & Tr op ica l M ed ici ne on b eh al f o f t he T B Al lia nc e. T he G D G n ot ed th at th e an al ys is w as n ot d on e fo r t hi s –e vi de nc e to d ec isi on fr am ew or k – th at is , u nd es ira bl e ef fe ct s w er e no t co ns id er ed a cc or di ng to th e G D G ’s ju dg em en ts . T hi s m ad e th e co st –e ffe ct iv en es s an al ys es in fo rm at iv e bu t n ot d ire ct ly b as ed o n th e ev id en ce th at th e G D G w as a ss es sin g. Th e an al ys es w er e ba se d on G eo rg ia , t he P hi lip pi ne s, an d So ut h Af ric a. T he ai m s of th e re se ar ch w er e to e st im at e th e co st –e ffe ct iv en es s of a n ew re gi m en co nt ai ni ng b ed aq ui lin e, p re to m an id , a nd li ne zo lid (B Pa L) c om pa re d w ith th e st an da rd o f c ar e at a g iv en p ric e, a nd to e st im at e th e m ax im um d ru g pr ice a t w hi ch th e BP aL re gi m en c ou ld b e co ns id er ed c os t-e ffe ct iv e or c os t-n eu tra l i n ea ch s et tin g. T he p er sp ec tiv e ta ke n w as a h ea lth s er vi ce o ne , a nd th e st ud y as su m ed B Pa L to b e ef fe ct iv e. W he n as se ss in g th e po te nt ia l c os t– ef fe ct iv en es s of B Pa L fo r t he tr ea tm en t o f X D R- TB , t he G D G o bs er ve d th at in a ll th re e se tti ng s th is re gi m en h as th e po te nt ia l t o be c os t-s av in g at a g iv en d ru g pr ice o f U S$ 3 64 pe r t re at m en t c ou rs e fo r p re to m an id . T he s tu dy fo un d th at c os t-s av in gs a re a fu nc tio n of th e co st o f c ar e an d th e m ag ni tu de o f X D R- TB b ur de n, a nd a re ab ou t U S$ 4 49 0 – no t i nc lu di ng a nt ire tro vi ra l t he ra py (A RT ) c os ts – in S ou th Af ric a; U S$ 4 06 0 in G eo rg ia a nd U S$ 3 86 0 in th e Ph ilip pi ne s. In h ig h H IV -T B pr ev al en ce s et tin gs s uc h as S ou th A fri ca , r el at ed fu tu re c os ts s uc h as th os e fro m th e H IV p ro gr am m e (A RT c os ts ) r ed uc e th e m ag ni tu de o f e xp ec te d co st s av in gs to U S$ 1 40 0 pe r p at ie nt . O ve ra ll, w he n BP aL is in tro du ce d to a la rg er p op ul at io n (in clu di ng th os e w ith M D R- TB tr ea tm en t f ai lu re a nd th os e w ith tr ea tm en t in to le ra nc e) , t he G D G o bs er ve d an in cr ea se in th e in cr em en ta l b en ef its , b ot h in te rm s of d ea th s an d di sa bi lit y ad ju st ed li fe -y ea rs a ve rt ed a nd in cr em en ta l c os ts . Fo od c os ts w er e no t i nc lu de d in th e co st –e ffe ct iv en es s an al ys is an d w ou ld n ee d to b e co ns id er ed w he n BP aL is im pl em en te d. D ur in g th e N ix- TB s tu dy , a ll st ud y m ed ica tio ns w er e ad m in ist er ed w ith fo od (b ec au se o f t he a dm in ist ra tio n of be da qu ilin e, w hi ch w ill al so n ow fe at ur e as a c or e m ed ici ne in lo ng er tr ea tm en t re gi m en s fo r M D R/ RR -T B) . T he c os t o f t he B Pa L re gi m en is U S$ 1 04 0 ac co rd in g to th e G lo ba l D ru g Fa cil ity (G FD ), ba se d on G D F- w ei gh te d av er ag e ta bl et p ric e. Ce rt ai nt y of e vi de nc e of r eq ui re d re so ur ce s W ha t i s th e ce rt ai nt y of th e ev id en ce o f r es ou rc e re qu ire m en ts (c os ts )? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ V er y lo w ○ L ow ○ M od er at e ○ H ig h ● N o in clu de d st ud ie s N o re se ar ch e vi de nc e w as id en tif ie d. Annex 4: GRADE evidence-to-decision tables 107 Co st e ff ec ti ve ne ss D oe s th e co st -e ff ec tiv en es s of th e in te rv en tio n fa vo r t he in te rv en tio n or th e co m pa ris on ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ F av or s th e co m pa ris on ○ P ro ba bl y fa vo rs th e co m pa ris on ○ D oe s no t fa vo r e ith er th e in te rv en tio n or th e co m pa ris on ○ P ro ba bl y fa vo rs th e in te rv en tio n ○ F av or s th e in te rv en tio n ○ V ar ie s ● N o in clu de d st ud ie s N o re se ar ch e vi de nc e w as id en tif ie d. Th e G D G c on sid er ed e vi de nc e fro m a c os t– ef fe ct iv en es s an al ys is st ud y th at w as co nd uc te d by s ta ff fro m th e Lo nd on S ch oo l o f H yg ie ne & Tr op ica l M ed ici ne o n be ha lf of th e TB A llia nc e. T he G D G n ot ed th at th e co st –e ffe ct iv en es s an al ys is w as no t d on e fo r t hi s ev id en ce to d ec isi on fr am ew or k – th at is , u nd es ira bl e ef fe ct s w er e no t c on sid er ed a cc or di ng to th e G D G ’s ju dg em en ts . T hi s m ad e th e co st – ef fe ct iv en es s an al ys es in fo rm at iv e bu t n ot d ire ct ly b as ed o n th e ev id en ce th at th e G D G w as a ss es sin g. Th e an al ys es w er e ba se d on G eo rg ia , t he P hi lip pi ne s, an d So ut h Af ric a. T he ai m s of th e re se ar ch w er e to e st im at e th e co st –e ffe ct iv en es s of a n ew re gi m en co nt ai ni ng b ed aq ui lin e, p re to m an id a nd li ne zo lid (B Pa L) c om pa re d w ith th e st an da rd o f c ar e at a g iv en p ric e, a nd to e st im at e th e m ax im um d ru g pr ice a t w hi ch th e BP aL re gi m en c ou ld b e co ns id er ed c os t-e ffe ct iv e or c os t-n eu tra l i n ea ch s et tin g. T he p er sp ec tiv e ta ke n w as a h ea lth s er vi ce o ne , a nd th e st ud y as su m ed B Pa L to b e ef fe ct iv e. W he n as se ss in g th e po te nt ia l c os t– ef fe ct iv en es s of B Pa L fo r t he tr ea tm en t o f X D R- TB , t he G D G o bs er ve d th at in a ll th re e se tti ng s, th is re gi m en h as th e po te nt ia l t o be c os t s av in g at a g iv en d ru g pr ice o f U S$ 3 64 pe r t re at m en t c ou rs e fo r p re to m an id . T he s tu dy fo un d th at c os t s av in gs a re a fu nc tio n of th e co st o f c ar e an d th e m ag ni tu de o f X D R- TB b ur de n, a nd a re ab ou t U S$ 4 49 0 – no t i nc lu di ng a nt ire tro vi ra l t he ra py (A RT ) c os ts – in S ou th Af ric a; U S$ 4 06 0 in G eo rg ia a nd U S$ 3 86 0 in th e Ph ilip pi ne s.. In h ig h H IV -T B pr ev al en ce s et tin gs , s uc h as S ou th A fri ca , r el at ed fu tu re c os ts s uc h as th os e fro m th e H IV p ro gr am m e (A RT c os ts ) r ed uc e th e m ag ni tu de o f e xp ec te d co st sa vi ng s to U S$ 1 40 0 pe r p at ie nt . O ve ra ll, w he n BP aL is in tro du ce d to a la rg er po pu la tio n (in clu di ng p at ie nt s w ith fa ilu re o f M D R- TB tr ea tm en t a nd th os e w ho ca nn ot to le ra te tr ea tm en t), th e G D G o bs er ve d an in cr ea se in th e in cr em en ta l be ne fit s, bo th in te rm s of d ea th s an d di sa bi lit y ad ju st ed li fe y ea rs a ve rt ed a nd in cr em en ta l c os ts . Fo od c os ts w er e no t i nc lu de d in th e co st –e ffe ct iv en es s an al ys is an d w ou ld n ee d to b e co ns id er ed w he n BP aL is im pl em en te d. D ur in g th e N ix- TB s tu dy , a ll st ud y m ed ica tio ns w er e ad m in ist er ed w ith fo od (b ec au se o f t he a dm in ist ra tio n of be da qu ilin e, w hi ch w ill al so n ow fe at ur e as a c or e m ed ici ne in lo ng er tr ea tm en t re gi m en s fo r M D R/ RR -T B) . WHO consolidated guidelines on tuberculosis: Online annexes108 Eq ui ty W ha t w ou ld b e th e im pa ct o n he al th e qu ity ? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ R ed uc ed ○ P ro ba bl y re du ce d ○ P ro ba bl y no im pa ct ● Pr ob ab ly in cr ea se d ○ In cr ea se d ○ V ar ie s ○ D on ’t kn ow N o re se ar ch e vi de nc e w as id en tif ie d. Al th ou gh n o re se ar ch e vi de nc e w as id en tif ie d, th e G D G p an el fe lt th at th e im pa ct o n he al th e qu ity w ou ld b e a pr ob ab le in cr ea se , g iv en th e op tio n of a sh or te r r eg im en th at c ou ld b e av ai la bl e gl ob al ly (i .e . a va ila bl e to a ll pa tie nt s) . Th e G D F ha s id en tif ie d a pr ice fo r p re to m an id a nd s ta te d th at it w ill m ak e th e BP aL re gi m en a va ila bl e to n at io na l T B pr og ra m m es , d ep en de nt u po n th e re co m m en da tio n fro m th e pa ne l. Th e G D F re pr es en ta tiv e no te d th at tw o bo ttl es o f b ed aq ui lin e w ill ne ed to b e or de re d fo r a ny on e w ho is re ce iv in g th e BP aL re gi m en . C hi ld re n an d pr eg na nt w om en w er e in el ig ib le fo r i nc lu sio n in th e N ix- TB s tu dy a nd th er ef or e w ill no t b e an e lig ib le p op ul at io n fo r B Pa L if it is re co m m en de d, w hi ch m ay b e an e qu ity is su e. Annex 4: GRADE evidence-to-decision tables 109 A cc ep ta bi lit y Is th e in te rv en tio n ac ce pt ab le to k ey s ta ke ho ld er s? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ● Pr ob ab ly y es ○ Y es ○ V ar ie s ○ D on ’t kn ow Th e G D G p an el th ou gh t t ha t t he ju dg em en t w as p ro ba bly ye s b ec au se th e co nc er ns re ga rd in g re pr od uc tiv e to xic iti es w er e no t d isc us se d as p ar t o f t he ac ce pt ab ilit y st ud y co nd uc te d by K N CV (b ec au se th is w as n ot k no w n to th e st ud y in ve st ig at or s at th e tim e) a nd th e co m pa ra to r u se d in th is st ud y w as n ot th e sa m e as th at fo r t he e vi de nc e th at w as a ss es se d. Th e G D G c on sid er ed e vi de nc e fro m a n ac ce pt ab ilit y an d fe as ib ilit y st ud y co nd uc te d by K N CV o n be ha lf of th e TB A llia nc e. T he o bj ec tiv es o f t he s tu dy w er e to a ss es s th e ac ce pt ab ilit y an d lik el ih oo d of im pl em en ta tio n of th e BP aL re gi m en a s an tic ip at ed b y ke y st ak eh ol de rs a nd b as ed o n a nu m be r o f c rit er ia (in clu di ng th e pe rc ei ve d be ne fit s an d ch al le ng es o f i m pl em en ta tio n of B Pa L an d lo ng er in di vi du al iz ed tr ea tm en t r eg im en s, an d ot he r p ra ct ica l r eq ui re m en ts o f im pl em en ta tio n) . T he s tu dy w as a m ixe d- m et ho ds , m ul tic ou nt ry , c ro ss -s ec tio na l in ve st ig at io n co nd uc te d in – 20 18 –2 01 9 am on g st ak eh ol de rs in In do ne sia , Ky rg ys ta n an d N ig er ia . V ie w s w er e of fe re d by a to ta l o f 1 88 p ar tic ip an ts , in clu di ng c ar eg iv er s, pr og ra m m at ic st ak eh ol de rs (i nc lu di ng n at io na l a nd in te rn at io na l p ro gr am m at ic st ak eh ol de rs a nd p at ie nt -a dv oc ac y gr ou ps ) a nd pu bl ic an d pr iv at e la bo ra to ry s ta ke ho ld er s. O n th e ba sis o f s ev en a ss es sm en t ca te go rie s (ra ng in g fro m p at ie nt fr ie nd lin es s to tr ea tm en t s af et y m on ito rin g) , th e ac ce pt ab ilit y of B Pa L w he n co m pa re d w ith a lo ng er tr ea tm en t r eg im en fo r M D R- TB w as h ig he r f or e ve ry c at eg or y. Ac ce pt ab ilit y w as h ig he r f or B Pa L th an fo r t he lo ng er M D R- TB re gi m en s in s ix of th e se ve n ca te go rie s as se ss ed , w ith th e ex ce pt io n of tr ea tm en t s af et y m on ito rin g, w he re th e di ffe re nc e w as n eg lig ib le . Th e m ai n dr iv er s of a cc ep ta bi lit y of B Pa L w er e th e sh or te r d ur at io n, a bs en ce o f in je ct ab le s, lo w er p ill bu rd en , a nt ici pa te d pa tie nt p re fe re nc es a nd lo w er fi na nc ia l bu rd en fo r p at ie nt s, an tic ip at ed h ig he r t re at m en t s uc ce ss , l ow er c os ts fo r t he he al th s ys te m , m in im al a dd iti on al re qu ire m en ts fo r d ia gn os tic p ro ce ss es , a nd a lo w er a nt ici pa te d pe r-p at ie nt b ur de n to th e TB la bo ra to ry fo r b ac te rio lo gi ca l tre at m en t m on ito rin g. In di re ct e vi de nc e w as c on sid er ed b y th e pa ne l i n th e fo rm of a s ep ar at e qu al ita tiv e st ud y co nd uc te d am on g 16 p at ie nt s w ith d ru g- re sis ta nt TB w ho w er e fro m h ig h bu rd en c ou nt rie s (w hi ch in fo rm ed th e ju dg em en ts o n PI CO 1 ). Th e ai m o f t he s tu dy w as to d et er m in e th e m os t a cc ep ta bl e tre at m en t re gi m en fo r d ru g- re sis ta nt T B. O n th e ba sis o f t he re su lts o f t hi s st ud y, th e pr ef er re d re gi m en w as s ho rt a nd in je ct io n- fre e w ith fe w to n o ph ys ica l o r m en ta l he al th s id e- ef fe ct s an d a lo w p ill bu rd en . R an ke d pr ef er en ce s fo r d ru g re sis ta nt TB tr ea tm en t w er e as fo llo w s: (1 ) a dv er se e ve nt s, (2 ) d ur at io n, (3 ) i nj ec tio n (fr ee ) an d (4 ) p ill bu rd en . WHO consolidated guidelines on tuberculosis: Online annexes110 Fe as ib ili ty Is th e in te rv en tio n fe as ib le to im pl em en t? JU D G EM EN T RE SE A RC H E VI D EN CE A D D IT IO N A L CO N SI D ER AT IO N S ○ N o ○ P ro ba bl y no ● Pr ob ab ly y es ○ Y es ○ V ar ie s ○ D on ’t kn ow Th e G D G c on sid er ed e vi de nc e fro m a n ac ce pt ab ilit y an d fe as ib ilit y st ud y co nd uc te d by K N CV o n be ha lf of th e TB A llia nc e. T he o bj ec tiv es o f t he s tu dy w er e to a ss es s th e ac ce pt ab ilit y an d lik el ih oo d of im pl em en ta tio n of th e BP aL re gi m en a s an tic ip at ed b y ke y st ak eh ol de rs a nd o n th e ba sis o f a n um be r o f cr ite ria , i nc lu di ng th e pe rc ei ve d be ne fit s an d ch al le ng es o f i m pl em en ta tio n of B Pa L an d lo ng er in di vi du al iz ed tr ea tm en t r eg im en s, an d ot he r p ra ct ica l re qu ire m en ts o f i m pl em en ta tio n. T he s tu dy w as a m ixe d- m et ho ds , m ul tic ou nt ry , cr os s- se ct io na l i nv es tig at io n co nd uc te d in 2 01 8– 20 19 a m on g st ak eh ol de rs in In do ne sia , K yr gy zs ta n an d N ig er ia . A to ta l o f 1 88 p ar tic ip an ts o ffe re d th ei r vi ew s, in clu di ng c ar eg iv er s, pr og ra m m at ic st ak eh ol de rs (i nc lu di ng n at io na l a nd in te rn at io na l p ro gr am m at ic st ak eh ol de rs a nd p at ie nt -a dv oc ac y gr ou ps ), an d pu bl ic an d pr iv at e la bo ra to ry s ta ke ho ld er s. O n th e ba sis o f s ev en a ss es sm en t ca te go rie s ( ra ng in g fro m fr ie nd lin es s f or p at ie nt s t o tre at m en t s af et y m on ito rin g) , th e ac ce pt ab ilit y of B Pa L w he n co m pa re d w ith a lo ng er tr ea tm en t r eg im en fo r M D R- TB w as h ig he r f or e ve ry c at eg or y. Ac ce pt ab ilit y w as h ig he r f or B Pa L th an fo r t he lo ng er M D R- TB re gi m en s in s ix of th e se ve n ca te go rie s as se ss ed , w ith th e ex ce pt io n of tr ea tm en t s af et y m on ito rin g, w he re th e di ffe re nc e w as n eg lig ib le . I n lin e w ith th e ov er al l h ig h ac ce pt ab ilit y of th e BP aL re gi m en , t he o ve ra ll lik el in es s of im pl em en tin g th e BP aL re gi m en a s a st an da rd o f c ar e fo r t he tr ea tm en t o f pa tie nt s w ith X D R- TB a nd M D R- TB tr ea tm en t f ai lu re /in to le ra nc e sc or ed a t 8 8; on ly 1 % o f t he 1 66 p ar tic ip an ts s co re d th at im pl em en ta tio n as “u nl ike ly,” a nd 11 % h ad a n eu tra l o pi ni on . T he li ke lin es s of im pl em en ta tio n w as s im ila r ( 84 % ) t o th at fo r t he B Pa L re gi m en a s a st an da rd o f c ar e fo r p at ie nt s w ith M D R- TB w ith flu or oq ui no lo ne re sis ta nc e, re ga rd le ss o f a dd iti on al re sis ta nc e to s ec on d- lin e in je ct ab le s. Th is in di ca te d th at th e re gi m en m ay b e fe as ib le to im pl em en t f ro m th e pe rs pe ct iv e of th os e in te rv ie w ed . Annex 4: GRADE evidence-to-decision tables 111 Su m m ar y of ju dg em en ts JU D G EM EN T PR O BL EM N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow D ES IR AB LE E FF EC TS Tr iv ia l Sm al l M od er at e La rg e Va rie s D on ’t kn ow UN D ES IR AB LE E FF EC TS La rg e M od er at e Sm al l Tr iv ia l Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s VA LU ES Im po rt an t un ce rt ai nt y or va ria bi lit y Po ss ib ly im po rt an t un ce rt ai nt y or va ria bi lit y Pr ob ab ly n o im po rt an t un ce rt ai nt y or va ria bi lit y N o im po rt an t un ce rt ai nt y or va ria bi lit y BA LA N CE O F EF FE CT S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s no t f av or ei th er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s D on ’t kn ow RE SO UR CE S RE Q UI RE D La rg e co st s M od er at e co st s N eg lig ib le c os ts a nd sa vi ng s M od er at e sa vi ng s La rg e sa vi ng s Va rie s D on ’t kn ow CE RT AI N TY O F EV ID EN CE O F RE Q UI RE D R ES O UR CE S Ve ry lo w Lo w M od er at e H ig h N o in clu de d st ud ie s CO ST E FF EC TI VE N ES S Fa vo rs th e co m pa ris on Pr ob ab ly fa vo rs th e co m pa ris on D oe s no t f av or e ith er th e in te rv en tio n or th e co m pa ris on Pr ob ab ly fa vo rs th e in te rv en tio n Fa vo rs th e in te rv en tio n Va rie s N o in cl ud ed st ud ie s EQ UI TY Re du ce d Pr ob ab ly re du ce d Pr ob ab ly n o im pa ct Pr ob ab ly in cr ea se d In cr ea se d Va rie s D on ’t kn ow AC CE PT AB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow FE AS IB IL IT Y N o Pr ob ab ly n o Pr ob ab ly y es Ye s Va rie s D on ’t kn ow Ty pe o f r ec om m en da tio n St ro ng re co m m en da tio n ag ai ns t th e in te rv en tio n ○ Co nd iti on al re co m m en da tio n ag ai ns t t he in te rv en tio n ○ Co nd iti on al re co m m en da tio n fo r e ith er th e in te rv en tio n or th e co m pa ris on ● Co nd iti on al re co m m en da tio n fo r th e in te rv en tio n ○ St ro ng re co m m en da tio n fo r t he in te rv en tio n ○ WHO consolidated guidelines on tuberculosis: Online annexes112 Co nc lu si on s Re co m m en da tio n A tre at m en t r eg im en la st in g 6– 9 m on th s co m po se d of b ed aq ui lin e, p re to m an id a nd li ne zo lid (B Pa L) m ay b e us ed u nd er o pe ra tio na l r es ea rc h co nd iti on s in M D R- TB p at ie nt s w ith T B th at is re sis ta nt to fl uo ro qu in ol on es w ho h av e ha d no p re vi ou s ex po su re to b ed aq ui lin e an d lin ez ol id fo r m or e th an tw o w ee ks (c on di tio na l r ec om m en da tio n, v er y lo w c er ta in ty in th e es tim at es o f e ffe ct ). Ju st ifi ca tio n Tr ea tm en t o f p at ie nt s w ith fo rm s of e xt en siv el y dr ug -r es ist an t T B (X D R- TB ) p re se nt s m ul tip le c ha lle ng es to c lin ici an s an d na tio na l T B pr og ra m m es , b ot h be ca us e of th e lim ite d ra ng e of m ed ici ne s av ai la bl e an d th e lif e- th re at en in g na tu re o f t he d ise as e. P at ie nt s w ith M D R/ RR -T B an d ad di tio na l f lu or oq ui no lo ne re sis ta nc e ha ve ty pi ca lly e xp er ie nc ed p oo r t re at m en t ou tc om es s in ce th e de sc rip tio n of X D R- TB w as fi rs t u se d in 2 00 6. 9 T he d at a re po rt ed b y m em be r s ta te s to W H O , f or th e co ho rt o f p at ie nt s w ith X D R- TB w ho s ta rt ed tr ea tm en t i n 20 16 (a nd fo r w ho m tr ea tm en t o ut co m es w er e av ai la bl e in 2 01 8) s ho w th at o nl y 39 % c om pl et ed tr ea tm en t s uc ce ss fu lly , w he re as 2 6% d ie d, 1 8% e xp er ie nc ed tr ea tm en t f ai lu re , a nd an a dd iti on al 1 8% w er e lo st to fo llo w -u p or w er e no t e va lu at ed .10 T he p re ss in g ne ed fo r m or e ef fe ct iv e tre at m en t r eg im en s fo r p at ie nt s w ith e xt en siv e dr ug re sis ta nc e, in clu di ng flu or oq ui no lo ne re sis ta nc e an d m or e ex te ns iv e dr ug re sis ta nc e pr of ile s, ha s m ot iv at ed a n um be r o f s tu di es a nd in iti at iv es to te st m or e ef fe ct iv e an d no ve l t re at m en t r eg im en s, in clu di ng ne w er a nd re pu rp os ed m ed ici ne s. O ne s uc h st ud y is th e N ix- TB s tu dy , c on du ct ed b y th e TB A llia nc e. T he N ix- TB s tu dy w as a o ne -a rm , p ha se II I, op en -la be l p ro sp ec tiv e co ho rt s tu dy th at a ss es se d th e sa fe ty , e ffi ca cy , to le ra bi lit y, an d ph ar m ac ok in et ic pr op er tie s of a 6 -m on th tr ea tm en t r eg im en c om po se d of b ed aq ui lin e, p re to m an id a nd li ne zo lid (B Pa L) , e xt en da bl e to 9 m on th s fo r t ho se w ho m iss ed do se s or fo r p at ie nt s w ho re m ai ne d cu ltu re p os iti ve o r r ev er te d fro m c ul tu re n eg at iv e to c ul tu re p os iti ve b et w ee n m on th s 4 an d 6 of tr ea tm en t. Th e st ud y w as c on du ct ed b et w ee n 20 14 an d 20 19 a t t hr ee s tu dy s ite s, al l i n So ut h Af ric a, w ith th e fir st p at ie nt e nr ol le d in A pr il 20 15 . E lig ib le p at ie nt s w er e ag ed 1 4 ye ar s or o ld er , w ei gh ed ≥ 35 k g, h ad a d oc um en te d H IV re su lt, an d ha d ba ct er io lo gi ca lly c on fir m ed s pu tu m c ul tu re p os iti ve X D R- TB o r b ac te rio lo gi ca lly c on fir m ed M D R/ RR -T B bu t c ou ld n ot to le ra te tr ea tm en t o r h ad d ise as e th at d id n ot re sp on d to pr ev io us M D R/ RR -T B tre at m en t. A nu m be r o f o th er in clu sio n cr ite ria w er e ap pl ie d. Pa tie nt s w er e fo llo w ed u p fo r a p er io d of u p to 2 4 m on th s af te r c om pl et io n of tr ea tm en t. Th e pr im ar y ou tc om e m ea su re w as th e in cid en ce o f b ac te rio lo gi ca l f ai lu re o r r el ap se o r c lin ica l fa ilu re th ro ug h fo llo w -u p un til 6 m on th s af te r t he e nd o f t re at m en t.1 1 S ec on da ry o ut co m e m ea su re s w er e as fo llo w s: 1. In cid en ce o f b ac te rio lo gi ca l f ai lu re o r r el ap se o r c lin ica l f ai lu re th ro ug h fo llo w u p un til 2 4 m on th s af te r t he e nd o f t re at m en t ( as a c on fir m at or y an al ys is) . 2. T im e to s pu tu m c ul tu re c on ve rs io n to n eg at iv e st at us th ro ug h th e tre at m en t p er io d. 3. P ro po rt io n of s ub je ct s w ith s pu tu m c ul tu re c on ve rs io n to n eg at iv e st at us a t 4 , 6 , 8 , 1 2, 1 6 an d 26 o r 3 9 w ee ks . 4. L in ez ol id d os in g (a ct ua l) an d ef fic ac y. 5. C ha ng e fro m b as el in e in T B sy m pt om s. 6. C ha ng e fro m b as el in e in p at ie nt re po rt ed h ea lth s ta tu s. 7. C ha ng e fro m b as el in e in w ei gh t ( TB A llia nc e, N ix- TB s tu dy p ro to co l, av ai la bl e at : h ttp s:/ /c lin ica ltr ia ls. go v/ ct 2/ sh ow /N CT 02 33 37 99 ). Th e N ix- TB s tu dy re gi m en c om pr ise d pr et om an id a dm in ist er ed a t 2 00 m g/ da y, be da qu ilin e ad m in ist er ed a t 4 00 m g/ da y fo r t he fi rs t 2 w ee ks o f t re at m en t ( da ys 1 –1 4) a nd 2 00 m g th re e tim es a w ee k th er ea fte r, an d lin ez ol id c om m en cin g at 1 20 0 m g/ da y (a dd iti on al in fo rm at io n on li ne zo lid d os in g is in clu de d un de r “ Im pl em en ta tio n co ns id er at io ns ”). C lo se m icr ob io lo gi c, cli ni ca l a nd a dv er se e ve nt m on ito rin g w er e fe at ur es o f t he N ix- TB s tu dy . 9 Em er ge nc e of X D R- TB . G en ev a, S w itz er la nd W or ld H ea lth O rg an iz at io n 20 06 (h ttp s:/ /w w w. w ho .in t/ m ed ia ce nt re /n ew s/ no te s/ 20 06 /n p2 3/ en , a cc es se d 28 F eb ru ar y 20 20 ). 10 G lo ba l t ub er cu lo sis re po rt 2 01 9 (W H O /C D S/ TB /2 01 9. 15 ). G en ev a, S w itz er la nd W or ld H ea lth O rg an iz at io n; 2 01 9 (h ttp s:/ /w w w. w ho .in t/ tb /p ub lic at io ns /g lo ba l_r ep or t/ en /, ac ce ss ed 2 9 M ay 2 02 0) . 11 Sa fe ty a nd e ffi ca cy o f v ar io us d os es a nd tr ea tm en t d ur at io ns o f l in ez ol id p lu s b ed aq ui lin e an d pr et om an id in p ar tic ip an ts w ith p ul m on ar y TB , X D R- TB , P re - X D R- TB o r n on -r es po ns iv e/ In to le ra nt M D R- TB (Z eN iX ) [w eb sit e] . M ar yl an d, U ni te d St at es o f A m er ica U .S . N at io na l L ib ra ry o f M ed ici ne ; 2 01 7 (h ttp s:/ /c lin ica ltr ia ls. go v/ ct 2/ sh ow /N CT 03 08 64 86 , a cc es se d 20 M ar ch 2 02 0) . Annex 4: GRADE evidence-to-decision tables 113 Th e ev id en ce to in fo rm th is PI CO q ue st io n w as d er ive d fro m th e N ix- TB st ud y an d in clu de d in fo rm at io n on 1 08 p at ie nt s. Th e to ta l s tu dy p op ul at io n w as 1 09 p at ie nt s; ho w ev er , 1 p at ie nt w ith dr ew in fo rm ed c on se nt to p ar tic ip at e in th e st ud y an d w as in clu de d in sa fe ty a na lys es b ut n ot in a na lys es fo r e ffe ct ive ne ss . T he se d at a w er e co m pa re d w ith a su bs et o f d at a fro m th e IP D, w hi ch o ve ra ll in clu de s 1 3 27 3 in di vid ua l p at ie nt re co rd s f ro m 5 5 di ffe re nt st ud ie s o r c en tre s i n 38 c ou nt rie s. Fo r t he p rim ar y an al ys es , t he c om pa ra to r g ro up in clu de d pa tie nt s f ro m th e IP D re ce ivi ng lo ng er tr ea tm en t r eg im en s ( w ith a m ea n du ra tio n of tr ea tm en t r an gi ng b et w ee n 21 .0 –2 5. 5 m on th s) , w ho re ce ive d bo th b ed aq ui lin e an d lin ez ol id a s p ar t o f t he re gi m en (n o pa tie nt s r ec ei ve d pr et om an id in th e IP D ). Th is co m pa ris on g ro up in clu de d 45 6 pa tie nt s w ho w er e tre at ed in B el ar us (R ep ub lic o f), F ra nc e, In di a, a nd R us sia , a nd in c ou nt rie s i n As ia . T he in te rv en tio n an d co m pa ris on g ro up s w er e m at ch ed e xa ct ly fo r X D R- TB st at us , M D R- TB st at us , f lu or oq ui no lo ne re sis ta nc e, a nd H IV st at us , w ith p ro pe ns ity sc or e m at ch in g fo r t he v ar ia bl es of a ge , s ex , b as el in e cu ltu re re su lt, e xt en t o f d ise as e (d et er m in ed b y ba se lin e AF B sm ea r o r c he st X -r ay fi nd in gs o f c av ita tio n or b y bi la te ra l d ise as e if AF B sm ea r r es ul t w as m iss in g) a nd co un tr y in co m e le ve l ( W or ld B an k At la s m et ho d) . T re at m en t o ut co m es u se d in th es e an al ys es c om pr ise d th e in ve st ig at or -d ef in ed o ut co m es fo r t he in te rv en tio n gr ou p (fo r t he N ix- TB st ud y) a nd tr ea tm en t o ut co m es la rg el y de fin ed a cc or di ng to W H O d ef in iti on s1 2 f or th e co m pa ra to r g ro up (f or th e pa tie nt s i nc lu de d in th e IP D ). To a llo w a n eq ua l o pp or tu ni ty fo r t re at m en t ou tc om es to o cc ur fr om th e st ar t o f t re at m en t w he n co m pa rin g th e tw o gr ou ps , a ll ou tc om es w er e in clu de d fro m th e st ar t o f t re at m en t t o 24 m on th s a fte r t he st ar t o f t re at m en t. Th is m ea nt th at , i n th e in te rv en tio n gr ou p, th es e ou tc om es o cc ur re d af te r c om pl et io n of tr ea tm en t, an d fo r t he c om pa ra to r g ro up , t he o ut co m es w er e en d- of -t re at m en t o ut co m es (b ec au se pa tie nt s i n th e IP D re ce ive d a lo ng er re gi m en a nd w er e no t m on ito re d af te r t re at m en t c om pl et io n) . T hr ee o th er c om pa ra to r g ro up s f ro m th e IP D in clu de d pa tie nt s r ec ei vin g lo ng er tre at m en t r eg im en s w hi ch in clu de d be da qu ilin e, o r a re gi m en w hi ch in clu de d lin ez ol id , o r a re gi m en w ith n ei th er b ed aq ui lin e or li ne zo lid in clu de d. T he in iti al in te nt io n of th e G D G w as to as se ss th e in te rv en tio n re gi m en a ga in st a ll th re e co m pa ris on g ro up s; ho w ev er , d ur in g th ei r d el ib er at io ns th e pa ne l a gr ee d th at th e ju dg em en ts sh ou ld b e ba se d on th e co m pa ris on g ro up w ho re ce ive d be da qu ilin e an d lin ez ol id a s p ar t o f t he ir re gi m en , b ec au se th es e pa tie nt s m os t c lo se ly re se m bl ed p at ie nt s w ho w ou ld re ce ive c ur re nt ly re co m m en de d lo ng er re gi m en s co m po se d of m ed ici ne s f ro m G ro up s A –C . H ow ev er , a d ire ct c om pa ris on o f B Pa L w ith a ll- or al lo ng er re gi m en s c on st ru ct ed a cc or di ng to th e m os t r ec en t W H O re co m m en da tio ns is su ed in M ay 2 01 9 w as n ot p os sib le , b ec au se th es e re gi m en s m ig ht h av e be en in u se o nl y sin ce m id -2 01 9, a nd tr ea tm en t o ut co m es fo r t he se p at ie nt s a re n ot y et a va ila bl e. Ad di tio na l d at a re vi ew ed b y th e G D G re le va nt to th is PI CO q ue st io n w er e a co st –e ffe ct iv en es s an al ys is, a s tu dy o n th e ac ce pt ab ilit y an d lik el ih oo d of im pl em en ta tio n of th e BP aL re gi m en , m od el le d ph ar m ac ok in et ic da ta b as ed o n th e de ve lo pm en t o f a p ha rm ac ok in et ic– to xic od yn am ic m od el , a nd a s um m ar y re vi ew o f p re cli ni ca l a nd e ar ly c lin ica l d at a on p re to m an id . T he co st –e ffe ct iv en es s an al ys is, a cc ep ta bi lit y st ud y, an d m od el le d ph ar m ac ok in et ic st ud ie s w er e co nd uc te d as p ar t o f t he N ix- TB s tu dy a nd w er e sp on so re d by th e TB A llia nc e. Th e G D G c on sid er ed th e de sir ab le e ffe ct o f t re at m en t s uc ce ss , w hi ch w as h ig he r i n th e in te rv en tio n gr ou p w he n co m pa re d w ith th e co m pa ra to r, fo r a ll fo ur tr ea tm en t o ut co m es th at w er e as se ss ed . O ve ra ll, w he n co m pa rin g tre at m en t s uc ce ss v er su s fa ilu re /r ec ur re nc e, th e tre at m en t s uc ce ss ra te in th e N ix- TB s tu dy w as 9 7. 0% c om pa re d w ith 9 1. 7% in th e co m pa ra to r gr ou p (re su lti ng in 6 m or e ou tc om es o f t re at m en t s uc ce ss p er 1 00 p at ie nt s) . F or th e co m pa ris on o f t re at m en t s uc ce ss v er su s de at h, tr ea tm en t s uc ce ss w as 9 3. 2% in th e N ix- TB s tu dy co m pa re d w ith 9 1. 9% in th e co m pa ra to r g ro up (r es ul tin g in 1 m or e ou tc om e of tr ea tm en t s uc ce ss p er 1 00 p at ie nt s) . F or th e co m pa ris on s of tr ea tm en t s uc ce ss v er su s fa ilu re /r ec ur re nc e/ de at h an d tre at m en t s uc ce ss v er su s al l u nf av ou ra bl e ou tc om es c om bi ne d (i. e. fa ilu re /r el ap se /d ea th a nd lo ss to fo llo w -u p) , t he p ro po rt io ns o f p at ie nt s w ith tr ea tm en t s uc ce ss in th e in te rv en tio n an d co m pa ra to r g ro up s w er e 90 .5 % v er su s 84 .8 % (6 m or e ou tc om es o f t re at m en t s uc ce ss p er 1 00 p at ie nt s) a nd 8 8. 9% v er su s 82 .2 % (2 m or e ou tc om es o f t re at m en t su cc es s pe r 1 00 p at ie nt s) , r es pe ct iv el y. O n th e ba sis o f t he se fi gu re s, th e pr im ar y an al ys is yi el de d ad ju st ed o dd s ra tio s (a O Rs ) o f 3 .3 fo r t re at m en t s uc ce ss (v er su s th e co m bi ne d ou tc om e of fa ilu re a nd re cu rre nc e; 9 5% C I: 0. 8– 13 .7 ), 1. 0 fo r s uc ce ss v er su s de at h (9 5% C I: 0. 1– 8. 2) , 1 .8 fo r s uc ce ss v er su s fa ilu re /r el ap se /d ea th (9 5% C I: 0. 7– 4. 4) , a nd 1 .2 fo r s uc ce ss v er su s al l u nf av ou ra bl e ou tc om es (9 5% C I: 0. 5– 3. 1) , w ith a m ea n du ra tio n of fo llo w -u p of 2 4 m on th s (ra ng e, 2 1– 25 .5 m on th s) , w he n BP aL w as c om pa re d w ith lo ng er re gi m en s co nt ai ni ng be da qu ilin e an d lin ez ol id . T he G D G c on sid er ed ra te s of lo ss to fo llo w -u p to b e a de sir ab le e ffe ct ; t he p ro po rt io n of p at ie nt s w ho w er e lo st to fo llo w -u p w as lo w er in th e in te rv en tio n (B Pa L) g ro up (1 .8 % ) t ha n in th e co m pa ris on g ro up (3 .1 % ); ho w ev er , t hi s di ffe re nc e w as n ot c on sid er ed b y th e pa ne l t o be la rg e. T he p an el a lso c on sid er ed a s ho rt en ed d ur at io n of tre at m en t a nd le ss d ru g ex po su re to b e de sir ab le e ffe ct s of th e in te rv en tio n, a nd n ot ed th at th es e w er e bo th c om po ne nt s of th e ov er al l b ur de n of a g iv en M D R/ RR -T B tre at m en t re gi m en , w hi ch m ay n ot b e w ho lly re fle ct ed in ra te s of lo ss to fo llo w -u p al on e. S pe cif ie d su bg ro up a na ly se s w er e un ab le to b e un de rt ak en b ec au se o f l im ita tio ns in th e sa m pl e siz e. 12 La se rs on K F, Th or pe L E, L ei m an e V, W ey er K , M itn ick C D, R ie ks tin a V et a l. Sp ea kin g th e sa m e la ng ua ge : t re at m en t o ut co m e de fin iti on s f or m ul tid ru g- re sis ta nt tu be rc ul os is. In t J Tu be rc L un g D is. 2 00 5; 9( 6) :6 40 –5 . an d D ef in iti on s an d re po rt in g fra m ew or k fo r t ub er cu lo sis – 2 01 3 re vi sio n (u pd at ed D ec em be r 2 01 4) [W H O /H TM /T B/ 20 13 .2 ]. G en ev a, S w itz er la nd : W or ld H ea lth O rg an iz at io n; 2 01 3 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 79 19 9/ 97 89 24 15 05 34 5_ en g. pd f? se qu en ce =1 , a cc es se d 20 M ar ch 2 02 0) . WHO consolidated guidelines on tuberculosis: Online annexes114 Th e BP aL re gi m en w as a lso a ss oc ia te d w ith a h ig h ra te o f a dv er se e ve nt s, co ns id er ed to b e re la te d to th e st ud y dr ug s, w hi ch w as a c on ce rn fo r G D G m em be rs . O f t he 1 09 p at ie nt s in th e N ix- TB s tu dy , 2 8 (2 5. 7% ) e xp er ie nc ed a t l ea st o ne s er io us a dv er se e ve nt . T hi s in clu de d 1 de at h (0 .9 % ) r el at ed to a cu te h ae m or rh ag ic pa nc re at iti s, 27 (2 5% ) o th er s er io us a dv er se ev en ts in clu di ng h os pi ta liz at io ns a nd li fe -t hr ea te ni ng e ve nt s, an d 2 (1 .8 % ) a dv er se e ve nt s th at re su lte d in p er sis te nt o r s ig ni fic an t d isa bi lit y or in ca pa cit y. Fi fty -t hr ee p ar tic ip an ts (4 9% ) ex pe rie nc ed a t l ea st o ne G ra de 3 –4 a dv er se e ve nt c on sid er ed to b e re la te d to th e st ud y dr ug s, co m pr isi ng 2 5 w ith p er ip he ra l n eu ro pa th y (re so lv ed in 1 1) , 1 6 w ith in cr ea se d he pa tic tra ns am in as es (r es ol ve d in 1 3) , 9 w ith h ae m at ol og ica l a dv er se e ve nt s (re so lv ed in a ll) , 8 w ho h ad in cr ea se d pa nc re at ic en zy m es (r es ol ve d in 7 ), an d 2 w ith o pt ic ne ur iti s (re so lv ed in b ot h) . T hi s le d to d ru g di sc on tin ua tio n of a ll th re e dr ug s fo r 1 p ar tic ip an t, an d lin ez ol id (i ni tia l d os e: 1 20 0 m g/ da y) w as d isc on tin ue d in a no th er 3 5 pa rt ici pa nt s (3 2% ). O nl y 18 pa rt ici pa nt s (1 7% ) c om pl et ed a fu ll co ur se o f l in ez ol id a t 1 20 0 m g/ da y. Th e G D G n ot ed th at it is d iff icu lt to c om pa re th es e ad ve rs e ev en t r at es w ith o th er s tu di es b ec au se o f m aj or a nd im po rt an t d iff er en ce s in a sc er ta in m en t, as se ss m en t, an d re po rt in g of a dv er se e ve nt s. H ow ev er , i n th e IP D s tu di es (w he re 9 0% o f p ar tic ip an ts re ce iv ed a li ne zo lid d os e of ≤ 60 0 m g/ da y) , th e po ol ed ra te o f p er m an en t d isc on tin ua tio n of li ne zo lid w as 1 7. 9% , a nd in th e En dT B ob se rv at io na l s tu dy (w he re a ll pa tie nt s re ce iv ed ≤ 60 0 m g/ da y of li ne zo lid ), th e ra te o f l in ez ol id di sc on tin ua tio n w as 1 3. 1% . I n bo th o f t he se s tu di es , > 80 % o f p ar tic ip an ts re ce iv ed a s ta rt in g do se o f l in ez ol id o f 6 00 m g/ da y. In p re lim in ar y an al ys es o f t he E nd TB o bs er va tio na l s tu dy , 9 of 1 09 4 pa rt ici pa nt s (0 .8 % ) d ie d of a p os sib ly o r p ro ba bl y dr ug -r el at ed a dv er se e ve nt , i nc lu di ng 2 p ar tic ip an ts w ith s ud de n ca rd ia c de at h; th es e pa tie nt s w er e re ce iv in g be da qu ilin e, clo fa zi m in e, c ap re om yc in , a nd p -a m in os al icy lic a cid (P AS ) a nd h ad h yp ok al ae m ia . In fo rm at io n pr es en te d fro m th e in de pe nd en t r ev ie w o f t he p re cli ni ca l d at a an d ea rly -p ha se c lin ica l d at a hi gh lig ht ed th at p re to m an id p os se ss es a ct iv ity a ga in st re pl ica tin g an d no nr ep lic at in g ba cil li th at is b ot h co nc en tra tio n an d do se d ep en de nt . A c om pr eh en siv e de sc rip tio n of th e sa fe ty s ig na ls w as re po rt ed , m an y of th es e sig na ls w er e ob se rv ed a t e xp os ur es th at a re h ig he r t ha n w ou ld b e us ed in h um an s; ho w ev er , s af et y sig na ls of n ot e in clu de li ve r t ox ici tie s (h yp er tro ph y of h ep at oc yt es , t ra ns am in as e el ev at io n, a nd in cr ea se d liv er w ei gh t, ob se rv ed a t h ig he r d os es in ro de nt s an d lo w er d os es in m on ke ys ) a nd re pr od uc tiv e to xic iti es in m al es o bs er ve d in a ni m al (m ur in e an d sim ia n) m od el s, w hi ch a pp ea r t o be b ot h tim e an d do se d ep en de nt . T he se o bs er va tio ns in m on ke ys m ig ht h av e be en a ttr ib ut ed to th e ge ne ra l d ec lin e of h ea lth in th es e an im al s; ho w ev er , t he s am e sig na ls w er e ob se rv ed in ro de nt m od el s w ith s om e ev id en ce th at th es e ef fe ct s m ig ht b e irr ev er sib le . I n m ou se m od el s, th es e ef fe ct s w er e ob se rv ed a t e xp os ur es th at w ou ld b e us ed in h um an s. Re pr od uc tiv e to xic iti es w er e al so o bs er ve d in fe m al es . Ad di tio na l i nf or m at io n on a dv er se e ve nt s pr es en te d to th e G D G in clu de d th e re su lts o f a p ha rm ac ok in et ic– to xic od yn am ic m od el (S av ic R, u np ub lis he d da ta , U ni ve rs ity o f C al ifo rn ia Sa n Fr an cis co , N ov em be r 2 01 9) . O n th e ba sis o f t he se d at a, it w as c on clu de d th at th e ph ar m ac ok in et ics re la te d to li ne zo lid a re n on lin ea r i n pa tie nt s w ith X D R- TB a nd th at in di vi du al lin ez ol id c on ce nt ra tio n tim es a re th e be st p re di ct or o f t ox ici ty. H ig he r t ox ici ty ra te s w er e ob se rv ed a t h ig he r t ot al d ai ly d os es , w ith c om pa ra bl e to xic ity ra te s fo r B ID a nd Q D d os in g sc he du le s. Th e re su lts o f t he m od el le d da ta h ig hl ig ht ed th at a na em ia c an b e m an ag ed b y clo se ly m on ito rin g ch an ge s in h ae m og lo bi n ov er th e fir st 4 w ee ks o f t re at m en t ( in p ar tic ul ar , ch an ge s in h ae m og lo bi n th at re pr es en t a > 10 % d ec re as e fro m b as el in e sh ou ld tr ig ge r a re du ct io n in th e do se o f l in ez ol id ; h ae m og lo bi n le ve ls re co ve r w el l a fte r d os e re du ct io ns ). Th ro m bo cy to pe ni a w as p ot en tia lly n ot a m aj or c on ce rn . T he s tu dy in ve st ig at or s re co m m en de d th at p er ip he ra l n eu ro pa th y be c lo se ly m on ito re d, a nd n ot ed th at th e m od el le d da ta sh ow ed th at , w he n it di d oc cu r, it w as re ve rs ib le fo r m os t p at ie nt s, w ith in 3 m on th s. Annex 4: GRADE evidence-to-decision tables 115 Su bg ro up c on si de ra tio ns Ch ild re n. C hi ld re n (a ge d 0– 13 y ea rs ) w er e ex clu de d fro m th e N ix- TB s tu dy ; t he re fo re , n o an al ys is sp ec ifi c to th is su bg ro up o f p at ie nt s co ul d be p er fo rm ed . I t i s re co m m en de d th at ch ild re n w ith p ul m on ar y M D R/ RR -T B w ith a dd iti on al re sis ta nc e to fl uo ro qu in ol on es b e gi ve n th e sa m e co ns id er at io n fo r l on ge r t re at m en t r eg im en s as a du lts , t o in clu de c om po ne nt s w ith a s af et y pr of ile th at is b et te r e st ab lis he d. B ed aq ui lin e is cu rre nt ly re co m m en de d on ly fo r c hi ld re n ag ed 6 y ea rs o r o ld er . I t i s ac kn ow le dg ed th at a dd iti on al d at a on th e us e of B Pa L in ch ild re n, w he n el ig ib le , w ou ld b e us ef ul ; t hi s m ay b e a fe at ur e of c ar ef ul ly p la nn ed a nd m on ito re d fu tu re re se ar ch . PL H IV : P LH IV re pr es en te d ha lf of th os e en ro lle d in th e N ix- TB s tu dy ; h ow ev er , i t w as im po ss ib le to p er fo rm a ny a dj us te d st ra tif ie d an al ys es fo r P LH IV b ec au se o f t he s am pl e siz e. PL H IV w er e el ig ib le to e nr ol in th e N ix- TB s tu dy if th ey h ad a C D 4 co un t o f > 50 c el ls/ µL a nd if th ey w er e us in g pe rm itt ed a nt ire tro vi ra l m ed ica tio ns .13 It is im po rt an t t o no te d ru g– dr ug in te ra ct io ns w he n ad m in ist er in g TB a nd H IV m ed ica tio ns in c om bi na tio n, in clu di ng th e do cu m en te d in te ra ct io ns b et w ee n be da qu ilin e an d ef av ire nz .14 E fa vi re nz a lso re du ce s pr et om an id ex po su re s sig ni fic an tly ; t he re fo re , a n al te rn at iv e an tir et ro vi ra l a ge nt s ho ul d be c on sid er ed if p re to m an id o r t he B Pa L re gi m en is to b e us ed .15 R eg im en s in clu di ng z id ov ud in e sh ou ld b e us ed w ith s pe cia l c au tio n be ca us e zi do vu di ne a nd li ne zo lid m ay b ot h ca us e pe rip he ra l n er ve to xic ity a nd a re k no w n to h av e m ye lo su pp re ss io n cr os s- to xic ity . Pr eg na nt a nd la ct at in g w om en w er e ex clu de d fro m th e N ix- TB s tu dy ; t he re fo re , n o an al ys is sp ec ifi c to th is su bg ro up o f p at ie nt s co ul d be p er fo rm ed . F or s uc h pa tie nt s, it is re co m m en de d th at a lo ng er re gi m en b e in di vi du al iz ed to in clu de c om po ne nt s w ith a s af et y pr of ile th at is b et te r e st ab lis he d. W he n th is is th e ca se , t he o ut co m es o f t re at m en t a nd pr eg na nc y (in clu di ng in fa nt c ha ra ct er ist ics ), an d po st pa rt um s ur ve illa nc e fo r c on ge ni ta l a no m al ie s, sh ou ld b e do cu m en te d to h el p in fo rm fu tu re re co m m en da tio ns fo r M D R- TB tr ea tm en t du rin g pr eg na nc y. Th e us e of b ed aq ui lin e in p re gn an cy h as b ee n sh ow n to b e as so cia te d w ith in fa nt s bo rn w ith a lo w er m ea n bi rt h w ei gh t, w he n co m pa re d w ith in fa nt s w ho se m ot he rs w ho d id n ot ta ke b ed aq ui lin e; h ow ev er , t hi s di d no t a pp ea r t o be a c lin ica lly s ig ni fic an t f in di ng w he n in fa nt s w er e fo llo w ed u p ov er ti m e. B re as tfe ed in g is no t r ec om m en de d fo r w om en ta kin g BP aL .16 Ex tr ap ul m on ar y TB : P ar tic ip an ts w ith e xt ra pu lm on ar y TB w er e ex clu de d fro m th e N ix- TB s tu dy ; t he re fo re , n o an al ys is sp ec ifi c to th is su bg ro up o f p at ie nt s co ul d be p er fo rm ed . T he W H O re co m m en da tio ns fo r l on ge r M D R- TB re gi m en s ap pl y to p at ie nt s w ith e xt ra pu lm on ar y di se as e, in clu di ng th os e w ith T B m en in gi tis . T he re a re fe w d at a on th e ce nt ra l n er vo us sy st em p en et ra tio n of b ed aq ui lin e or p re to m an id . Pa tie nt s w ith v er y lim ite d tr ea tm en t o pt io ns : I n so m e in st an ce s, pa tie nt s w ill ha ve e xt en siv e dr ug re sis ta nc e pr of ile s th at m ay m ak e it di ffi cu lt (o r i m po ss ib le ) t o co ns tru ct a re gi m en ba se d on e xis tin g W H O re co m m en da tio ns . I n su ch s itu at io ns , t he p at ie nt ’s lif e m ay b e en da ng er ed . T he re fo re , f or in di vi du al p at ie nt s fo r w ho m th e de sig n of a n ef fe ct iv e re gi m en ba se d on e xis tin g re co m m en da tio ns is n ot p os sib le ,17 th e BP aL re gi m en m ay b e co ns id er ed a la st re so rt u nd er p re va ilin g et hi ca l s ta nd ar ds . F or s uc h pa tie nt s, th e us e of B Pa L sh ou ld b e ac co m pa ni ed b y in di vi du al p at ie nt in fo rm ed c on se nt , a de qu at e co un se llin g on th e po te nt ia l b en ef its a nd h ar m s, an d ac tiv e m on ito rin g an d m an ag em en t o f a dv er se e ve nt s. Pa tie nt s sh ou ld a lso b e ad vi se d th at re pr od uc tiv e to xic iti es h av e be en o bs er ve d in a ni m al s tu di es , a nd th at th e po te nt ia l e ffe ct s on h um an m al e fe rt ilit y ha ve n ot b ee n ad eq ua te ly e va lu at ed a t th is tim e. 13 Th e pe rm itt ed a nt ire tro vir al tr ea tm en ts w er e as fo llo w s: (1 ) n ev ira pi ne in c om bi na tio n w ith a ny N RT Is; (2 ) l op in av ir/ rit on av ir in c om bi na tio n w ith a ny N RT Is; (3 ) t en of ov ir/ la m ivu di ne /a ba ca vir (i f n or m al re na l f un ct io n) ; (4 ) t rip le N RT I t he ra py c on sis tin g of z id ov ud in e, la m iv ud in e, a nd a ba ca vi r ( no tin g th e in cr ea se d ris k of p er ip he ra l n er ve to xic ity w ith z id ov ud in e an d lin ez ol id ); an d (5 ) r al te gr av ir in c om bi na tio n w ith N RT Is. 14 H IV d ru g in te ra ct io ns [w eb sit e] . L iv er po ol , U ni te d Ki ng do m U ni ve rs ity o f L iv er po ol 2 02 0 (h ttp s:/ /w w w. hi v- dr ug in te ra ct io ns .o rg /c he ck er , a cc es se d 11 M ar ch 2 02 0) . 15 D ru g ap pr ov al p ac ka ge : P re to m an id [w eb sit e] . M ar yla nd , U ni te d St at es o f A m er ica : U .S . F oo d an d D ru g Ad m in ist ra tio n; 2 01 9 (h ttp s:/ /w w w. ac ce ss da ta .fd a. go v/ dr ug sa tfd a_ do cs /n da /2 01 9/ 21 28 62 O rig 1s 00 0T O C. cf m , a cc es se d 28 F eb ru ar y 20 20 ). 16 D ru g ap pr ov al p ac ka ge : P re to m an id [w eb sit e] . M ar yla nd , U ni te d St at es o f A m er ica : U .S . F oo d an d D ru g Ad m in ist ra tio n; 2 01 9 (h ttp s:/ /w w w. ac ce ss da ta .fd a. go v/ dr ug sa tfd a_ do cs /n da /2 01 9/ 21 28 62 O rig 1s 00 0T O C. cf m , a cc es se d 28 F eb ru ar y 20 20 ). 17 Us ua lly th is gr ou p of p at ie nt s w ou ld in clu de th os e w ith a n ex te ns iv e dr ug re sis ta nc e pr of ile w ho h av e ve ry li m ite d tre at m en t o pt io ns a s pa rt o f a lo ng er tr ea tm en t r eg im en . WHO consolidated guidelines on tuberculosis: Online annexes116 Im pl em en ta tio n co ns id er at io ns G iv en th e pa uc ity o f e vi de nc e on th e us e of B Pa L, a nd th e co nc er ns m en tio ne d ab ov e, m em be rs o f t he G D G s ug ge st ed th at it s us e sh ou ld b e co nd iti on al u po n im pl em en ta tio n in th e co nt ex t o f o pe ra tio na l r es ea rc h on ly. T he G D G e m ph as iz ed th at , d es pi te th e pr om isi ng tr ea tm en t s uc ce ss ra te s ob se rv ed in th e N ix- TB s tu dy , t he re gi m en m ay n ot b e co ns id er ed fo r p ro gr am m at ic us e w or ld w id e un til a dd iti on al e vi de nc e on e ffi ca cy a nd s af et y ha s be en g en er at ed . T he G D G m em be rs e m ph as iz ed th e ne ed fo r t hi s re se ar ch to ta ke th e fo rm o f ra nd om iz ed , c on tro lle d tri al s as w el l a s ob se rv at io na l s tu di es . G iv en th e co nd iti on al ity o f t hi s re co m m en da tio n in th e co nt ex t o f a dd iti on al re se ar ch , c er ta in s ta nd ar ds a nd p rin cip le s ar e pr er eq ui sit es fo r t he im pl em en ta tio n of B Pa L. F ur th er , t he G D G e m ph as iz ed th at in a ny o pe ra tio na l r es ea rc h st ud y in vo lv in g BP aL , t he p rin cip le s of g oo d cli ni ca l p ra ct ice s ho ul d ap pl y. O ve ra ll, to re pr od uc e th e tre at m en t s uc ce ss ra te s ob se rv ed in th e N ix- TB s tu dy , a ll ef fo rt s ne ed to b e m ad e to c ar ef ul ly s el ec t e lig ib le p at ie nt s an d th en , o nc e th ey a re e nr ol le d, to pr ov id e ef fe ct iv e pa tie nt s up po rt to e na bl e ad he re nc e to tr ea tm en t, as w el l a s clo se m on ito rin g fo r a dv er se e ve nt s, re sp on se to tr ea tm en t, an d em er gi ng d ru g re sis ta nc e. A ll ef fo rt s sh ou ld b e m ad e to d o th e fo llo w in g: • En su re p ro pe r p at ie nt in clu sio n (u se is n ot a dv ise d in p re gn an t a nd la ct at in g w om en a nd in c hi ld re n, n ot in g th e ot he r i nc lu sio n an d ex clu sio n cr ite ria o f t he N ix- TB s tu dy ). Al th ou gh D ST is a n im po rt an t c om po ne nt o f p at ie nt s el ec tio n fo r t he B Pa L re gi m en (d es cr ib ed b el ow ), an ot he r k ey im pl em en ta tio n co ns id er at io n is pr io r T B tre at m en t h ist or y. Pa tie nt s ar e el ig ib le fo r t he B Pa L re gi m en o nl y if th ey h av e no t r ec ei ve d be da qu ilin e or li ne zo lid fo r 2 w ee ks o r m or e pr ev io us ly, a nd th is w as a n el ig ib ilit y cr ite rio n of th e N ix- TB s tu dy . G iv en th at th e cu rre nt W H O re co m m en da tio n fo r l on ge r t re at m en t r eg im en s fo r M D R/ RR -T B in clu de s be da qu ilin e an d lin ez ol id a s pr io rit y m ed ici ne s in G ro up A , s om e pa tie nt s w ho ha ve p re vi ou sly s ta rt ed tr ea tm en t w ith a lo ng er M D R/ RR -T B re gi m en m ay in fa ct b e in el ig ib le fo r B Pa L sh ou ld th ey la te r d ev el op fl uo ro qu in ol on e re sis ta nc e. T hi s re af fir m s pr ev io us st at em en ts b y W H O o n th e ne ed to c ar ef ul ly s el ec t e lig ib le p at ie nt s fo r l on ge r o r s ho rt er M D R/ RR -T B tre at m en t r eg im en s, an d th en , o nc e pa tie nt s ar e re ce iv in g a re gi m en , t o en su re pa tie nt s up po rt a nd c lo se m on ito rin g an d fo llo w -u p, in clu di ng m on ito rin g fo r t re at m en t f ai lu re a nd re la ps e, a nd e m er gi ng d ru g re sis ta nc e, w ith D ST p er fo rm ed w he n in di ca te d. If re sis ta nc e is su sp ec te d du rin g tre at m en t a nd D ST is n ot a va ila bl e, th e st ra in s sh ou ld b e co ns er ve d an d re fe rre d to a W H O s up ra na tio na l T B re fe re nc e la bo ra to ry fo r f ur th er te st in g. Ea ch o pe ra tio na l r es ea rc h pr ot oc ol o n th e us e of B Pa L in a g iv en s et tin g w ill ne ed to in clu de d et ai le d in clu sio n an d ex clu sio n cr ite ria . • O bt ai n sig ne d pa tie nt in fo rm ed c on se nt a fte r d et ai le d ex pl an at io ns o n th e no ve l n at ur e of th e re gi m en a nd p re to m an id , i nc lu di ng th e ris ks a nd b en ef its o f t he re gi m en . T he G D G m em be rs th ou gh t t ha t a lth ou gh in di vi du al p at ie nt in fo rm ed c on se nt is n ec es sa ry , i t s ho ul d no t b e ov er ly b ur de ns om e fo r p at ie nt s; th er ef or e, c on se nt fo rm s sh ou ld b e ad ap te d, co nt ex tu al iz ed , s tre am lin ed a nd p ro vi de d in th e lo ca l l an gu ag e( s) s o th at th ey a re e as y fo r p at ie nt s to u nd er st an d. N ev er th el es s, th e G D G a lso n ot ed th at p at ie nt s sh ou ld b e fu lly in fo rm ed a bo ut th e re gi m en , g iv en th at it a lso in clu de s a ne w c om po un d, p re to m an id . A s pa rt o f t he in fo rm ed c on se nt p ro ce ss , p at ie nt s sh ou ld b e of fe re d su ffi cie nt in fo rm at io n on po te nt ia l a dv er se e ve nt s, in clu di ng lo w b lo od c el l c ou nt s (e .g . a na em ia , t hr om bo cy to pe ni a, n eu tro pe ni a) , l iv er to xic iti es , a nd p er ip he ra l a nd o pt ic ne ur op at hy . P at ie nt s sh ou ld a lso be a dv ise d th at re pr od uc tiv e to xic iti es h av e be en o bs er ve d in a ni m al s tu di es a nd th at th e po te nt ia l e ffe ct s on h um an m al e fe rt ilit y ha ve n ot b ee n ad eq ua te ly e va lu at ed a t t hi s tim e. Pa tie nt s sh ou ld a lso b e in fo rm ed th at p re to m an id is e xc re te d in b re as t m ilk , a nd it s sa fe ty in in fa nt s an d ch ild re n ha s no t b ee n ad eq ua te ly e va lu at ed .18 A m ed ica tio n gu id e is av ai la bl e as p ar t o f t he p re to m an id p ro du ct la be l t ha t m ay b e us ed w he n in fo rm in g pa tie nt s ab ou t t he B Pa L re gi m en a s pa rt o f a re se ar ch s tu dy . • Tr ea tm en t m us t b e ad m in ist er ed u nd er c lo se ly m on ito re d co nd iti on s, to e na bl e op tim al d ru g ef fe ct iv en es s an d sa fe ty , a nd to m on ito r f or th e ac qu isi tio n of e m er gi ng d ru g re sis ta nc e, s ho ul d it ar ise . G iv en th at th e re gi m en is s ho rt er , t ha t i t i nc lu de s a ne w c om po un d (p re to m an id ), an d th at it s im pl em en ta tio n is in th e co nt ex t o f r es ea rc h, it m ay b e es pe cia lly im po rt an t t ha t c lin ica l p ro gr es s is m on ito re d af te r c om pl et io n of tr ea tm en t, to e ns ur e re la ps e fre e cu re . O th er d es ig n fe at ur es o f t he N ix- TB s tu dy h av e im pl ica tio ns fo r i ts im pl em en ta tio n un de r o pe ra tio na l r es ea rc h co nd iti on s. In th e N ix- TB s tu dy , a ll m ed ica tio ns w er e ad m in ist er ed w ith fo od th ro ug ho ut , a nd s tu dy m ed ica tio ns w er e su pe rv ise d ac co rd in g to lo ca l s ite p ra ct ice s, as a fo rm o f p at ie nt s up po rt . P re ve nt in g tre at m en t i nt er ru pt io n is im po rt an t f or in cr ea sin g th e lik el ih oo d of tr ea tm en t s uc ce ss . M ea su re s to s up po rt p at ie nt ad he re nc e, e ith er b y fa cil ita tin g pa tie nt v isi ts to h ea lth c ar e fa cil iti es o r h om e vi sit s by h ea lth c ar e st af f, or b y us in g di gi ta l t ec hn ol og ie s fo r d ai ly c om m un ica tio n, m ay b e im po rt an t f or re te nt io n of p at ie nt s in tr ea tm en t, ev en th ou gh th e re gi m en is c om pa ra tiv el y sh or t.1 9 W H O re co m m en da tio ns o n th e ca re a nd s up po rt o f p at ie nt s w ith M D R/ RR -T B ar e pr ov id ed in th e W H O c on so lid at ed g ui de lin es o n dr ug -r es ist an t T B tre at m en t.2 0 • Ac tiv e ph ar m ac ov ig ila nc e an d pr op er m an ag em en t o f a dv er se d ru g re ac tio ns a nd p re ve nt io n of c om pl ica tio ns fr om d ru g– dr ug in te ra ct io ns . T he n at io na l T B pr og ra m m e sh ou ld a ct ive ly m on ito r d ru g sa fe ty to e ns ur e pr op er p at ie nt c ar e, to re po rt a ny a dv er se d ru g re ac tio ns to th e re sp on sib le d ru g sa fe ty a ut ho rit y in th e co un tr y, an d to in fo rm n at io na l a nd g lo ba l p ol icy . 18 D ru g ap pr ov al p ac ka ge : P re to m an id [w eb sit e] . M ar yla nd , U ni te d St at es o f A m er ica : U .S . F oo d an d D ru g Ad m in ist ra tio n; 2 01 9 (h ttp s:/ /w w w. ac ce ss da ta .fd a. go v/ dr ug sa tfd a_ do cs /n da /2 01 9/ 21 28 62 O rig 1s 00 0T O C. cf m , a cc es se d 28 F eb ru ar y 20 20 ). 19 G ui de lin es fo r t re at m en t o f d ru g- su sc ep tib le tu be rc ul os is an d pa tie nt c ar e, 2 01 7 up da te (W H O /H TM /T B/ 20 17 .0 5) . G en ev a, S w itz er la nd : W or ld H ea lth O rg an iz at io n; 2 01 7 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 25 50 52 /9 78 92 41 55 00 00 -e ng .p df ?s eq ue nc e= 1, a cc es se d 20 M ar ch 2 02 0) . 20 W H O c on so lid at ed g ui de lin es o n dr ug re sis ta nt tu be rc ul os is tre at m en t. G en ev a, S w itz er la nd : W or ld H ea lth O rg an iz at io n; 2 01 9 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 31 13 89 /9 78 92 41 55 05 29 -e ng . pd f? ua =1 , a cc es se d 20 M ar ch 2 02 0) . Annex 4: GRADE evidence-to-decision tables 117 Th e im pl em en ta tio n of th e BP aL re gi m en in th e co nt ex t o f o pe ra tio na l r es ea rc h im pl ie s th at : • a st ud y pr ot oc ol h as b ee n de ve lo pe d by a pp ro pr ia te ly s kil le d an d ex pe rie nc ed re se ar ch er s; • th is re se ar ch p ro to co l i s su bm itt ed to a n at io na l e th ics b oa rd o r o th er e th ica l a pp ro va l c om m itt ee s; • th er e ar e pr e- sp ec ifi ed in clu sio n an d ex clu sio n cr ite ria in p la ce (n ot in g th e cr ite ria u se d fo r t he N ix- TB s tu dy );2 1 • th er e is an a pp ro pr ia te s ch ed ul e of s af et y m on ito rin g an d re po rt in g in p la ce , i nc lu di ng a ct iv e dr ug s af et y m on ito rin g (a D SM ) – u su al ly o ve rs ee n by a d at a sa fe ty m on ito rin g bo ar d or sim ila r i nd ep en de nt re se ar ch g ov er na nc e co m m itt ee ); • th er e is a pr ed ef in ed s ch ed ul e of c lin ica l a nd m icr ob io lo gi ca l m on ito rin g in p la ce , p re fe ra bl y in clu di ng fo llo w -u p af te r c om pl et io n of tr ea tm en t; • in di vi du al p at ie nt in fo rm ed c on se nt is o bt ai ne d; • pa tie nt s up po rt is p ro vi de d; a nd • st an da rd iz ed re po rt in g an d re co rd in g is us ed , i nc lu di ng fo r a dv er se e ve nt s. Re vi ew o f t re at m en t a nd m an ag em en t p ro to co ls by a n in de pe nd en t g ro up o f e xp er ts in c lin ica l m an ag em en t a nd p ub lic h ea lth , s uc h as th e na tio na l M D R- TB a dv iso ry g ro up , is re co m m en de d. D ru g- su sc ep tib ili ty te st in g is an im po rt an t i m pl em en ta tio n co ns id er at io n th at w ill ne ed fu rt he r e nh an ce m en t i n m an y co un tri es , g iv en th e in cr ea sin g po te nt ia l u se o f b ed aq ui lin e an d lin ez ol id (e ve n fo r l on ge r r eg im en s fo r M D R/ RR -T B) a nd th e in clu sio n of n ew m ed ici ne s – su ch a s pr et om an id – in M D R- TB tr ea tm en t r eg im en s. Ba se lin e D ST w ill co nf irm e lig ib ilit y fo r th e BP aL re gi m en ; t he re fo re , t he e st ab lis hm en t a nd s tre ng th en in g of d ru g- su sc ep tib ilit y te st in g se rv ice s w ill be a v ita l i m pl em en ta tio n co ns id er at io n. In p at ie nt s w ith b ac te rio lo gi ca lly co nf irm ed M D R/ RR -T B, 22 th e M TB D Rs l a ss ay m ay b e us ed a s th e in iti al te st , i n pr ef er en ce to c ul tu re a nd p he no ty pi c D ST , t o de te ct re sis ta nc e to fl uo ro qu in ol on es (c on di tio na l re co m m en da tio n; c er ta in ty o f e vi de nc e fo r d ire ct te st in g of s pu tu m fr om lo w to m od er at e. 23 In s et tin gs in w hi ch la bo ra to ry c ap ac ity fo r D ST to fl uo ro qu in ol on es is n ot y et a va ila bl e, o r ca nn ot b e ac ce ss ed , i t w ill be d iff icu lt to c ar ry o ut o pe ra tio na l r es ea rc h on B Pa L. If te st in g fo r s us ce pt ib ilit y to b ed aq ui lin e or li ne zo lid is a va ila bl e, it is h ig hl y de sir ab le th at th is is al so ca rr ie d ou t a t b as el in e; h ow ev er , t hi s ne ed n ot b e a pr er eq ui sit e fo r t re at m en t i ni tia tio n, n or n ee d it be s o in th e ab se nc e of c ul tu re c on ve rs io n du rin g tre at m en t. D ST fo r p re to m an id is no t y et a va ila bl e. C ur re nt ly, th er e is lim ite d ca pa cit y gl ob al ly to c ar ry o ut D ST fo r b ed aq ui lin e an d lin ez ol id ; h ow ev er , l ab or at or y ca pa cit y sh ou ld b e st re ng th en ed in th is ar ea a s th es e m ed ici ne s an d re gi m en s be co m e m or e w id el y us ed . N at io na l a nd re fe re nc e la bo ra to rie s w ill ne ed to h av e th e m ed ici ne p ow de rs a va ila bl e to e na bl e D ST to b e ca rr ie d ou t a nd w ill ne ed d at a on th e m in im um in hi bi to ry c on ce nt ra tio n (M IC ) d ist rib ut io n of a ll M yc ob ac ter ium tu be rcu los is lin ea ge s th at a re c irc ul at in g gl ob al ly. If re sis ta nc e to a ny o f t he c om po ne nt m ed ici ne s in th e BP aL re gi m en is d et ec te d, th e pa tie nt s ho ul d co m m en ce tr ea tm en t w ith a lo ng er M D R- TB re gi m en . W H O S up ra na tio na l R ef er en ce L ab or at or y N et w or k is av ai la bl e to su pp or t n at io na l T B re fe re nc e la bo ra to rie s in p er fo rm in g qu al ity -a ss ur ed D ST . A W H O te ch ni ca l c on su lta tio n in 2 01 7 es ta bl ish ed c rit ica l c on ce nt ra tio ns fo r D ST fo r t he fl uo ro qu in ol on es , be da qu ilin e, d el am an id , c lo fa zi m in e an d lin ez ol id .24 M et ho ds fo r t es tin g pr et om an id s us ce pt ib ilit y ar e cu rre nt ly u nd er d ev el op m en t. 21 Th e pr ot oc ol fo r t he N ix- TB s tu dy is a va ila bl e at : h ttp s:/ /c lin ica ltr ia ls. go v/ ct 2/ sh ow /N CT 02 33 37 99 22 M D R/ RR -T B is us ua lly c on fir m ed b y ra pi d m ol ec ul ar te st s t ha t d et ec t r es ist an ce to ri fa m pi cin a nd M . tu be rcu los is. C ur re nt W H O re co m m en da tio ns st at e th at th e Xp er t M TB /R IF a ss ay sh ou ld b e us ed ra th er th an co nv en tio na l m icr os co py , c ul tu re , a nd D ST a s th e in iti al d ia gn os tic te st in a du lts s us pe ct ed o f h av in g M D R- TB o r H IV -a ss oc ia te d TB (s tro ng re co m m en da tio n; h ig h- qu al ity e vi de nc e) . T he X pe rt M TB /R IF a ss ay sh ou ld b e us ed r at he r th an c on ve nt io na l m icr os co py , c ul tu re , a nd D ST a s th e in iti al d ia gn os tic te st in c hi ld re n su sp ec te d of h av in g M D R- TB o r H IV -a ss oc ia te d TB (s tro ng re co m m en da tio n; v er y lo w -q ua lit y ev id en ce ) – A ut om at ed re al -t im e nu cle ic ac id a m pl ifi ca tio n te ch no lo gy fo r r ap id a nd s im ul ta ne ou s de te ct io n of tu be rc ul os is an d rif am pi cin re sis ta nc e: X pe rt M TB /R IF a ss ay fo r t he d ia gn os is of p ul m on ar y an d ex tra pu lm on ar y TB in a du lts a nd c hi ld re n (W H O /H TM /T B/ 20 13 .1 6) . G en ev a, S w itz er la nd : W or ld H ea lth O rg an iz at io n; 2 01 3 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 11 24 72 /9 78 92 41 50 63 35 _e ng . pd f? se qu en ce =1 , a cc es se d 20 M ar ch 2 02 0) . A re ce nt W H O ra pi d co m m un ica tio n re in fo rc ed th e hi gh d ia gn os tic a cc ur ac y an d im pr ov ed p at ie nt o ut co m es o f r ap id m ol ec ul ar d ia gn os tic te st s s uc h as X pe rt M TB / RI F, Xp er t M TB /R IF U ltr a, a nd T ru eN at – R ap id c om m un ica tio n: m ol ec ul ar a ss ay s as in iti al te st s fo r t he d ia gn os is of tu be rc ul os is an d rif am pi cin re sis ta nc e. G en ev a, S w itz er la nd W or ld H ea lth O rg an iz at io n 20 20 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 33 03 95 /9 78 92 40 00 03 39 -e ng .p df , a cc es se d 20 M ar ch 2 02 0) . 23 Th e us e of m ol ec ul ar li ne p ro be a ss ay s fo r t he d et ec tio n of re sis ta nc e to s ec on d- lin e an ti- tu be rc ul os is dr ug s: po lic y gu id an ce [W H O /H TM /T B/ 20 16 .0 7] . G en ev a, S w itz er la nd : W or ld H ea lth O rg an iz at io n; 2 01 6 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 24 61 31 /9 78 92 41 51 05 61 -e ng .p df ?s eq ue nc e= 1, a cc es se d 20 M ar ch 2 02 0) . 24 Au to m at ed re al -t im e nu cle ic ac id a m pl ifi ca tio n te ch no lo gy fo r r ap id a nd si m ul ta ne ou s d et ec tio n of tu be rc ul os is an d rif am pi cin re sis ta nc e: X pe rt M TB /R IF a ss ay fo r t he d ia gn os is of p ul m on ar y an d ex tra pu lm on ar y TB in a du lts a nd c hi ld re n (W H O /H TM /T B/ 20 13 .1 6) . G en ev a, S w itz er la nd : W or ld H ea lth O rg an iz at io n; 2 01 3 (h ttp s:/ /a pp s.w ho .in t/ iri s/ bi ts tre am /h an dl e/ 10 66 5/ 11 24 72 /9 78 92 41 50 63 35 _e ng .p df ?s eq ue nc e= 1, ac ce ss ed 2 0 M ar ch 2 02 0) . WHO consolidated guidelines on tuberculosis: Online annexes118 D os in g of li ne zo lid : T he li ne zo lid d os ag e us ed in th e N ix- TB s tu dy w as 1 20 0 m g/ da y. In iti al ly, a ll st ud y pa rt ici pa nt s re ce iv ed 6 00 m g of li ne zo lid B D b ec au se th at w as th e ap pr ov ed d os e us ed to tr ea t b ac te ria l i nf ec tio ns fo r u p to 2 8 da ys a t t he ti m e th e st ud y co m m en ce d. H ow ev er , i n M ay 2 01 8, th e pr ot oc ol w as c ha ng ed to a d os in g of 1 20 0 m g O D. A cc or di ng to th e pr ot oc ol , d os e re du ct io n to 6 00 m g da ily a nd fu rt he r t o 30 0 m g da ily o r t em po ra ry c es sa tio n of li ne zo lid w as p er m itt ed fo r u p to 3 5 co ns ec ut iv e da ys , f or a ny k no w n lin ez ol id a dv er se re ac tio ns o f m ye lo su pp re ss io n, p er ip he ra l n eu ro pa th y an d op tic n eu ro pa th y. If to xic ity p ro hi bi te d fu rt he r t re at m en t w ith li ne zo lid , t he n pa tie nt s co ul d co nt in ue to ta ke b ed aq ui lin e an d pr et om an id , p ro vi de d th at th ey h ad re ce iv ed th e 12 00 m g/ da y do se fo r a t l ea st th e fir st 4 c on se cu tiv e w ee ks , w er e sp ut um s m ea r-n eg at iv e an d w er e re sp on di ng to tr ea tm en t a s in di ca te d by c lin ica l m on ito rin g an d fo llo w -u p. M iss ed d os es o f l in ez ol id w er e no t m ad e up d ur in g th e N ix- TB s tu dy , a nd d os e m od ifi ca tio ns fo r b ed aq ui lin e an d pr et om an id w er e no t al lo w ed . O ve ra ll, 18 p at ie nt s (1 7. 3% ) i n th e N ix- TB s tu dy c om pl et ed a fu ll co ur se o f l in ez ol id a t t he 1 20 0- m g do se , 3 8 (3 6. 5% ) c om pl et ed w ith a 6 00 -m g do se , 1 6 (1 5. 4% ) c om pl et ed w ith a 30 0- m g do se , a nd 3 2 (3 0. 7% ) s to pp ed li ne zo lid e ar ly b ec au se o f a n ad ve rs e ev en t. In v ie w o f t he e xp er ie nc e of th e N ix- TB s tu dy , i t m ay b e ne ce ss ar y to m od ify th e do se o f l in ez ol id du rin g tre at m en t o n th e ba sis o f a dv er se e ve nt s, hi gh lig ht in g th e im po rt an ce o f c lo se m on ito rin g, p at ie nt fo llo w -u p an d aD SM . A dd iti on al s tu di es – s uc h as th e Ze N ix st ud y (T B Al lia nc e) – ar e un de rw ay to a ss es s th e op tim al d os in g an d du ra tio n of li ne zo lid fo r t he tr ea tm en t o f d ru g- re sis ta nt T B; h ow ev er , t he re su lts o f t he se s tu di es a re n ot y et a va ila bl e fo r r ev ie w. To da te , t he B Pa L re gi m en h as b ee n st ud ie d as a s ta nd ar di ze d co ur se o f t re at m en t. M od ifi ca tio n of th e re gi m en th ro ug h ea rly d isc on tin ua tio n or re pl ac em en t o f a ny o f t he c om po ne nt m ed ici ne s m ay re su lt in p oo r t re at m en t o ut co m es . T he p re to m an id p ro du ct la be l r ec om m en ds th at if e ith er b ed aq ui lin e or p re to m an id ta bl et s ar e di sc on tin ue d, th e en tir e BP aL re gi m en sh ou ld a lso b e di sc on tin ue d. If li ne zo lid is p er m an en tly d isc on tin ue d du rin g th e in iti al 4 c on se cu tiv e w ee ks o f t re at m en t, th en b ed aq ui lin e an d pr et om an id s ho ul d al so b e di sc on tin ue d. If lin ez ol id is d isc on tin ue d af te r t he in iti al 4 w ee ks o f c on se cu tiv e tre at m en t, cli ni cia ns s ho ul d co nt in ue a dm in ist er in g be da qu ilin e an d pr et om an id , c on sis te nt w ith th e N ix- TB s tu dy pr ot oc ol . I n th e N ix- TB s tu dy , i t w as n ec es sa ry fo r p at ie nt s to c om pl et e 6 m on th s of th e re gi m en (i .e . 2 6 w ee ks o f p re sc rib ed d os es ) w ith in 8 m on th s, an d fo r t ho se w ho h ad tr ea tm en t ex te nd ed , i t w as n ec es sa ry fo r p at ie nt s to c om pl et e 9 m on th s of tr ea tm en t ( i.e . 3 9 w ee ks o f p re sc rib ed d os es ) w ith in 1 2 m on th s. Pa tie nt s w ho re m ai ne d cu ltu re p os iti ve o r w ho re ve rt ed to b ei ng c ul tu re p os iti ve b et w ee n m on th s 4 an d 6, a nd w ho se c lin ica l c on di tio n su gg es te d th ey m ig ht h av e on go in g TB in fe ct io n, h ad tr ea tm en t e xt en de d to a to ta l o f 9 m on th s. M on ito rin g an d ev al ua tio n Pa tie nt s w ho re ce iv e BP aL (o r a ny s ho rt er re gi m en fo r t he tr ea tm en t o f M D R/ RR -T B) n ee d to b e te st ed a t b as el in e an d th en m on ito re d du rin g tre at m en t u sin g sc he du le s of re le va nt cli ni ca l a nd la bo ra to ry te st in g. A cc or di ng to th e pr od uc t l ab el fo r p re to m an id , b as el in e as se ss m en ts b ef or e in iti at io n of th e BP aL re gi m en in clu de a ss es sm en ts fo r s ym pt om s an d sig ns of li ve r d ise as e (e .g . f at ig ue , a no re xia , n au se a, ja un di ce , d ar k ur in e, li ve r t en de rn es s an d he pa to m eg al y) a nd th e co nd uc t o f l ab or at or y te st s (a la ni ne a m in ot ra ns fe ra se [A LT ], as pa rt at e am in ot ra ns fe ra se [A ST ], al ka lin e ph os ph at as e, a nd b ilir ub in , c om pl et e bl oo d co un t a nd s er um p ot as siu m , c al ciu m , a nd m ag ne siu m , w hi ch s ho ul d be c or re ct ed if a bn or m al ). Tr ea tin g cli ni cia ns s ho ul d al so o bt ai n an e le ct ro ca rd io gr am b ef or e in iti at io n of tr ea tm en t. Th e ba se lin e m on ito rin g sc he du le o f t he N ix- TB s tu dy w as m uc h m or e co m pr eh en siv e th an th is, a nd in clu de d a th or ou gh b as el in e cli ni ca l a ss es sm en t, fo llo w ed b y a sc he du le o f w ee kly p at ie nt m on ito rin g un til w ee k 20 a nd th en m on ito rin g ev er y 4 to 6 w ee ks th er ea fte r, pa rt ly d ep en de nt on w he th er th e pa tie nt h ad tr ea tm en t f or 6 m on th s in to ta l o r w he th er tr ea tm en t w as e xt en de d by a no th er 3 m on th s (to 9 m on th s in to ta l). G iv en th at th e BP aL re gi m en is n ew a nd is b ei ng im pl em en te d un de r o pe ra tio na l r es ea rc h co nd iti on s, it is al so im po rt an t t o fo llo w u p w ith p at ie nt s af te r t he c om pl et io n of tr ea tm en t f or po ss ib le re la ps e. In th e N ix- TB s tu dy , m on ito rin g af te r c om pl et io n of tr ea tm en t w as c ar rie d ou t m on th ly fo r m on th s 1 to 3 , a nd th en e ve ry 3 m on th s th er ea fte r. Fo llo w -u p af te r t re at m en t co m pl et io n w as fo r a to ta l o f 2 4 m on th s; ho w ev er , a t t he ti m e of d at a an al ys is, a bo ut h al f o f t he p at ie nt s ha d be en fo llo w ed u p fo r t hi s pe rio d. T he a na ly sis o f t he N ix- TB s tu dy d at a in di ca te d th at th er e w as tr ea tm en t f ai lu re o r r ec ur re nc e in 3 p at ie nt s (2 .8 % o f p at ie nt s ov er al l), ta kin g in to a cc ou nt th e pe rio d of p os t t re at m en t c om pl et io n fo llo w -u p. D et ai le d sc he du le s of b as el in e an d fo llo w -u p m on ito rin g, in clu di ng p os t t re at m en t c om pl et io n, s ho ul d be d ev el op ed fo r a ny B Pa L op er at io na l r es ea rc h pr ot oc ol , w ith s ta nd ar di ze d m ea su re s fo r r ec or di ng a dv er se e ve nt s. Th e W H O fr am ew or k fo r a D SM n ee ds to b e ap pl ie d to p at ie nt s re ce iv in g an y ty pe o f M D R- TB re gi m en , t o en su re a pp ro pr ia te a ct io n an d an ac ce pt ab le le ve l o f m on ito rin g fo r a nd p ro m pt re sp on se to a dv er se e ve nt s – al on gs id e m on ito rin g fo r t re at m en t o ut co m es , i nc lu di ng e ar ly m on ito rin g fo r t re at m en t f ai lu re . A dd iti on al ev id en ce g en er at ed o n ad ve rs e ev en ts w ill be im po rt an t f or b ui ld in g th e ev id en ce b as e on th e sa fe ty o f t he B Pa L re gi m en in v ar ie d se tti ng s. M on ito rin g of c ha ng es in d os in g an d du ra tio n of li ne zo lid in p ar tic ul ar (w he n ne ed ed ) w ill al so b e im po rt an t f or in fo rm in g th e fu tu re e vi de nc e ba se o n th e w id er u se o f t he B Pa L re gi m en a nd th e to le ra bi lit y of li ne zo lid in th is re gi m en . Annex 4: GRADE evidence-to-decision tables 119 Re se ar ch p rio rit ie s • Re se ar ch o n th e us e of B Pa L to c om pa re e ffi ca cy , s af et y an d to le ra bi lit y to o th er a ll- or al re gi m en s. • D at a fro m o th er re gi on s an d co un tri es (b ey on d So ut h Af ric a) . • D es cr ip tio n of th e m ec ha ni sm a nd m ol ec ul ar m ar ke rs o f p re to m an id re sis ta nc e. S ur ve illa nc e fo r t he d ev el op m en t o f r es ist an ce , w ith a de qu at e co ns id er at io n pa id to th e im pa ct o f se le ct ed m ut at io ns . • D oc um en tin g of th e fu ll ad ve rs e ef fe ct p ro fil e of p re to m an id , a nd th e fre qu en cy o f r el ev an t a dv er se e ffe ct s, w ith a fo cu s on h ep at ot ox ici ty a nd re pr od uc tiv e to xic ity in h um an s. Re pr od uc tiv e to xic iti es o f p re to m an id h av e be en s ig na lle d in a ni m al s tu di es b ut p ot en tia l e ffe ct s of th is m ed ici ne o n hu m an fe rt ilit y ha ve n ot b ee n ad eq ua te ly e va lu at ed a nd re qu ire ap pr op ria te re se ar ch . • Ex pl or in g th e re la tiv e ef fic ac y (a nd a dd ed v al ue in m ul tid ru g re gi m en s) o f p re to m an id a nd d el am an id . • Re se ar ch o n op tim al d os e an d du ra tio n of li ne zo lid u se in d ru g- re sis ta nt T B re gi m en s (Z eN ix st ud y) . AF B: a cid -f as t b ac illu s; AR T: a nt ire tro vi ra l t he ra py ; B ID : T w ice a d ay [d os in g] ; B Pa L: b ed aq ui lin e, p re to m an id a nd lin ez ol id ; C I: co nf id en ce in te rv al ; G D F: G lo ba l D ru g Fa cil ity ; G D G : G ui de lin e D ev el op m en t G ro up ; H IV : hu m an im m un od ef ici en cy v iru s; IP D : i nd iv id ua l p at ie nt d at a; K N CV : K N CV Tu be rc ul os is Fo un da tio n; M D R- TB : m ul tid ru g- re sis ta nt tu be rc ul os is; M D R/ RR -T B: m ul tid ru g- o r r ifa m pi cin -r es ist an t t ub er cu lo sis ; M D R- TB : m ul tid ru g- re sis ta nt tu be rc ul os is; M IC : m in im um in hi bi to ry c on ce nt ra tio n; N RT I: nu cle os id e re ve rs e- tra ns cr ip ta se in hi bi to rs ; P LH IV : p eo pl e liv in g w ith h um an im m un od ef ici en cy v iru s; PI CO : p at ie nt s, in te rv en tio n, co m pa ra to r a nd o ut co m es (q ue st io ns ); Q D : o nc e a da y (d os in g) ; T B: tu be rc ul os is; W H O : W or ld H ea lth O rg an iz at io n; X D R- TB : e xt en siv el y dr ug -r es ist an t t ub er cu lo sis . WHO consolidated guidelines on tuberculosis: Online annexes120 A4.2 WHO treatment guidelines for isoniazid- resistant tuberculosis, 2018 Refer to Annex 6: GRADE evidence-to-decision tables in the WHO treatment guidelines for isoniazid- resistant tuberculosis (https://www.who.int/tb/publications/2018/WHO_treatment_guidelines_ isoniazid_resistant_TB_Online_GRADE_tables_Annexes.pdf, accessed 2 March 2019). A4.3 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update Refer to Annex 9: GRADE evidence-to-decision tables in the WHO treatment guidelines for multidrug-and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/ drug-resistant-tb/ Annexes_8–10.pdf, accessed 2 March 2019). A4.4 Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update Refer to Annex 2: GRADE glossary and summary of evidence tables (questions 6 and 7) in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update (https:// apps.who. int/iris/bitstream/handle/10665/70677/WHO_HTM_TB_2011.6b_eng.pdf, accessed 2 March 2019), where the content of the evidence-to-decision process was summarized in the remarks relating to each recommendation. A4.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 update Refer to Annex 5: Evidence-to-decision tables (question 4) in the WHO treatment guidelines for drug- resistant tuberculosis, 2016 update (https://apps.who.int/iris/bitstream/handle/10665/250125/ 9789241549639-webannexes-eng.pdf, accessed 2 March 2019). A4.6 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update Refer to Annex 4: Evidence-to-decision tables (questions 10 and 11) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/ dstb_guidance_2017/en/, accessed 2 March 2019) Annex 5: Summaries of unpublished data 121 Annex 5: Summaries of unpublished data A5.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020 update A5.1.1: Summary review for the GDG of preclinical and early clinicl data on pretomanid for use in MDR and XDR-TB: CPMT Project No.: 19010 By Professor Susan M Abdel-Rahman Overview: Pretomanid (Pa) was granted approval by the U.S. FDA in August 2019 to be used as part of a bedaquiline, pretomanid, linezolid (BPaL) regimen. This document summarizes a broader report to WHO detailing background information on Pa including pre-clinical dat and early phase clinical safety and efficacy. Chemistry: Pa represents a class of nitroimidazopyrans arising from the naturally occurring nitroimidazole, azomycin, and its synthetic derivative metronidazole. It bears structural similarity to the nitroimidazooxazole, delamanid.[1–4] Putative mechanisms of action for Pa include; 1) reductive activation to reactive nitro radical anion intermediates, 2) nitric oxide release, 3) ketomycolic acid depletion, and 4) toxic methylglyoxal accumulation.[1, 5–7] The cofactor F420 mediated redox system is integral to the activity of Pa and sequence variations in MTb proteins that are involved with the synthesis, oxidation or reduction of this cofactor are linked to resistance. These include Ddn (Rv3547), Fgd (Rv0407), fbiA (Rv3261), fbiB (Rv3262), fbiC (Rv1173), and fbiD (Rv2983).[1, 8–14] With limited exception, these proteins are not required for the growth/survival of MTb and their disruption does not limit mycobacterial fitness. [15–19] The frequency of spontaneous Pa resistance in vitro (10–5 to 10–7) is influenced by the concentration to which the isolates are exposed and the starting mycobacterial inoculum. Estimates are greater than that of rifampin but comparable to other agents including isoniazid, ethambutol, and pyrazinamide. [20] Spontaneous resistance rates in vivo are variable (~10–3–10–5) and increase in direct proportion with dose; however, they drop in combination with INH.[13, 21–23] Cross resistance to other antimycobacterial agents is rare with the exception of delamanid for which it is common but incomplete.[24] Cross resistance has also been documented with the more recently discovered nitrofuranylamides and 5-nitrothiophenes which share structural features with Pa and delamanid.[25,26] WHO consolidated guidelines on tuberculosis: Online annexes122 Microbiology: MIC for Pa against drug-susceptible, monoresistant, MDR, and XDR isolates of MTb (0.005–0.48 μg/mL) suggest that resistance phenotype has limited impact on Pa activity.[24] MICs against MTb increase in low oxygen conditions and in the presence of human albumin/serum.[24, 27–28] Pa demonstrates activity against other species in the Mycobacterium tuberculosis complex including M. bovis, M. africanum, and M. pinnipedii (MIC range <0.0312 to 0.125 μg/mL);however, there is little to no activity in other mycobacterial and non-mycobacterial species.[24] In vitro, Pa appears to exhibit both concentration- and time-dependent bactericidal activity.[24] Intracellular potency appears comparable to INH and inferior to delamanid and rifampin, though intracellular to extracellular ratios vary by drug and incubation condition.[29–31] Murine models support a dose-response relationship for Pa with a minimum effective dose of 12.5 mg/kg and a minimum bactericidal dose of 100 mg/kg. At this dose, CFU reductions in the lung and spleen comparable to INH (25 mg/kg), gatifloxacin (100 mg/kg) and moxifloxacin (100 mg/kg).[1, 21, 32]. Monotherapy with Pa at 50 mg/kg fails to achieve a sterile cure, though combinations with bedaquiline and an oxazolidinone achieve CFU reductions that are a full order of magnitude lower than achieved with Pa alone.[26, 33–35] The combination PaMZ is similarly effective in the guinea pig model.[1, 36] Dose fractionation studies in these animal models suggest that %T>MIC demonstrates the strongest association with CFU count reduction.[37] In humans, 14-day single-dose studies suggest no appreciable increase in EBA above 200 mg.[38–39] When administered in combination, EBA observed in regimens containing Pa did not appear inferior to combinations without this agent. Pa-based regimens also outperformed standard HRZE treatment regimens in select studies, though none of the combinations tested reflect the FDA approved BPaL regimen.[40–43] Pharmacology/Toxicology: Information relevant to understanding the disposition of Pa and its drug-interaction potential derives largely from the CDER review [44] and are summarized as follows: • Absolute bioavailability in non-human primate is less than 50% • Protein binding ranges from 86.3 to 86.5% with a low potential for partitioning into red blood cells. • Pa undergoes biotransformation by multiple P450 and non-P450 pathways with CYP3A4 the only relevant P450 accounting for up to 20% the drugs metabolism. • In vitro studies demonstrate the potential for Pa to inhibit CYP3A4/5, though at concentrations in excess of those observed with routine dosing. Recorded IC50 values suggest DDI mediated via other P450 isoforms is unlikely. • The potential for pretomanid to induce CYP3A4 appears to be negligible. • Pa does not appear to be a substrate for transporters evaluated to date; however, it does inhibit the renal tubular uptake transporter OAT3 at clinically relevant concentrations. • Clinically relevant in vivo DDI observed in humans are limited to a drop in Pa exposure when co-administered with CYP3A inducers (e.g. rifampin, efavirenz, lopinavir/ritonavir).[45–48] • Pa does appear to increase in moxifloxacin exposures in rats; however, the mechanism and relevance to humans is unclear. • Drug-food interactions are marked by an increase in Pa exposures (Cmax and AUC) when co-administered with a high-fat meal. The relative increase in bioavailability gets disproportionately larger with increasing dose.[49] • Cardiac toxicity mediated by hERG inhibition (IC50 was 17.3 μM) is not likely to be relevant at labeled doses. • Carcinogenicity and mutagenicity risk also appear low.[24, 44] However, safety signals in animals have been observed in various organ systems the most relevant of which is hepatotoxicity at labeled Annex 5: Summaries of unpublished data 123 doses.[24, 44] Testicular toxicity has also been observed at lower exposures and the uncertain human implications have lead the FDA to require additional post-marketing studies. Clinical Pharmacokinetics: In healthy volunteers, Pa concentrations peak between 4–5 hours post-dose with a less-than proportional relationship between dose and exposure through 600 to 1000 mg after which point increasing dose produces no corresponding increase in exposure.[50–51] Mean Pa half-life ranges from 15–20 hours explaining a doubling in the extent of exposure at steady state.[50] Efficacy/Safety: Nix-TB [24]: This non-comparative study of BPaL in 109 individuals reported favorable outcomes in 89%, 91% and 92% of their ITT, MITT, and PP populations respectively. No appreciable differences in response were observed as a function of HIV status, linezolid regimen (BID vs. QD), age, gender, race, cavitation, or time to positivity at baseline. All participants (100%) experienced at least 1 treatment emergent adverse event (TEAE), 99% of which were considered related to study regimen. The most frequently reported AE can be identified in the clinicaltrials.gov URL referenced above. Those most likely associated with Pa based on preclinical data include: dermatitis/eczema (53.2%), non-infective gastrointestinal upset (48.6%), hepatic disorder (38.5%), headache (29.4%), lens disorder (13.8%), severe cutaneous reaction (6.4%), and convulsions (1.8%). There were 8 deaths in the trial 7 of which led to premature discontinuation of the study and TEAE in an additional 5 patients that led to treatment discontinuation. STAND [52]: In this trial of PaMZ, the rate of unfavorable outcomes for the primary measure exceeded those of the standard HRZE treatment group. At the point of analysis, the Pa containing regimens failed non-inferiority criterion prompting early discontinuation of the trial. Note that this was preceded by a clinical hold from the FDA owing to 3 hepatotoxicity associated deaths. TEAE rates ranged from 87–94% in the Pa containing arms compared with 91% in standard treatment arm. The only SAE observed in more than 1 individual across all pretomanid containing regimens include increases in ALT/ AST and seizures. Additional AE observed with more than a 2-fold higher rate in the Pa groups (vs. HRZE) were gastrointestinal (nausea, vomiting, diarrhea) and pulmonary (pleuritic pain, hemoptysis, URI). ZeNix [53]: In this ongoing trial of BPaL, 83.6% of 61 participants have experienced at least one TEAE, 55.7% of which were considered related to study drug. The most frequently reported AE parallel those reported in Nix-TB. To date, TEAE have led to permanent discontinuation in 2 participants. Early Clinical Trials [38–43]: In the 14-day EBA monotherapy studies, reported SAE were restricted to complications of the underlying disease (pneumonia, pneumothorax, hemoptysis). The only non- serious AE experienced by more than one individual across all treatment arms was nausea, vomiting, headache, pruritis, rash, and iron deficiency anemia. In the 8-week BA studies, TEAE rates approximated those of the efficacy studies described above. When the regimens are broadly combined, and non- serious AE are evaluated against the standard HRZE regimen, neurologic and hepatic disturbances appeared to be more prevalent in the Pa containing regimens. Early clinical studies also identified a relationship between trough Pa concentrations and an increase in circulating serum creatinine levels which resolved after discontinuation of the drug.[50] Subsequent exploratory studies suggests that these changes are likely the result of inhibition of creatinine secretion at the level of the renal proximal tubule.[51] References: 1. Stover CK, et al. Nature. 2000 Jun 22; 405(6789): 962–6. 2. Thompson AM, et al. ACS Med Chem Lett. 2017 Nov 13;8(12):1275–1280. 3. Bahuguna A, et al. Med Res Rev. 2019 Jun 28. [Epub ahead of print] WHO consolidated guidelines on tuberculosis: Online annexes124 4. Zhang J, et al. Eur J Med Chem. 2019 Oct 1;179:376–388. 5. Moreno SN, et al. Environ Health Perspect. 1985 Dec;64:199–208. 6. Yuan Y, et al. Proceedings of the National Academy of Sciences Nov 1996, 93 (23) 12828–12833 7. Baptista R, et al. Sci Rep. 2018 Mar 23;8(1):5084. 8. Singh R, et al. Science. 2008 Nov 28;322(5906):1392–5. 9. Purwantini E, et al. PLoS One. 2013 Dec 11;8(12):e81985. 10. Haver HL, et al. Antimicrob Agents Chemother. 2015 Sep;59(9): 5316–23. 11. Manjunatha UH, et al. Proc Natl Acad Sci U S A. 2006 Jan 10; 103(2): 431–6. 12. Wen S, et al. Eur J Clin Microbiol Infect Dis. 2019 Jul;38(7):1293–1296 13. Rifat D, et al. bioRxiv 457754; Posted October 31, 2018. doi: https://doi.org/10.1101/457754 14. Bashiri G, et al. Nat Commun. 2019 Apr 5;10(1):1558. 15. Sassetti CM, et al. Mol Microbiol. 2003 Apr;48(1):77–84. 16. Sassetti CM, et al. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12989–94. 17. Rengarajan J, et al. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8327–32. 18. Dutta NK, et al. J Infect Dis. 2010 Jun 1;201(11):1743–52. 19. Zhang YJ, et al. PLoS Pathog. 2012 Sep;8(9):e1002946. 20. McGrath M, et al, J Antimicrob Chemother. 2014 Feb;69(2): 292–302. 21. Tyagi S, et al. Antimicrob Agents Chemother. 2005 Jun; 49(6): 2289–93. 22. Harper J, et al. J Infect Dis. 2012 Feb 15;205(4):595–602. 23. Li SY, et al. Antimicrob Agents Chemother. 2017 Aug 24;61(9). 24. Data on File, TB Alliance. 25. Hurdle JG, et al. J Antimicrob Chemother. 2008 Nov;62(5):1037–45. 26. Hartkoorn RC, et al. Antimicrob Agents Chemother. 2014 May;58(5): 2944–7. 27. Franzblau SG, et al. Tuberculosis (Edinb). 2012 Nov;92(6):453–88. 28. Upton AM, et al. Antimicrob Agents Chemother. 2015 Jan;59(1):136–44. 29. Matsumoto M, et al. PLoS Med. 2006 Nov;3(11):e466. 30. Stott KE, eta al. J Antimicrob Chemother. 2018 Sep 1;73(9):2305–2313. 31. Daskapan A, et al. Clin Pharmacokinet. 2019 Jun;58(6):747–766. 32. Lenaerts AJ, et al. Antimicrob Agents Chemother. 2005 Jun;49(6):2294–301 33. Dutta NK, et al. Int J Antimicrob Agents. 2014 Dec;44(6):564–6 34. Lanoix JP, et al. Antimicrob Agents Chemother. 2014;58(4):2316–21. 35. Tasneen R, et al. Antimicrob Agents Chemother. 2015 Oct 26;60(1):270–7. 36. Dutta NK, et al. Antimicrob Agents Chemother. 2013 Aug;57(8):3910–6. 37. Ahmad Z, et al. Antimicrob Agents Chemother. 2011 Jan;55(1):239–45. 38. NCT00944021 (https://clinicaltrials.gov/ct2/show/NCT00944021?term=NCT00944021&draw=2&rank=1) 39. NCT00567840 (https://clinicaltrials.gov/ct2/show/NCT00567840?term=NCT00567840&draw=2&rank=1) 40. NCT01215851 (https://clinicaltrials.gov/ct2/show/NCT01215851?term=NCT01215851&draw=2&rank=1) 41. NCT01691534 (https://clinicaltrials.gov/ct2/show/NCT01691534?term=NCT01691534&draw=2&rank=1) 42. NCT01498419 (https://clinicaltrials.gov/ct2/show/NCT01498419?term=NCT01498419&draw=2&rank=1) 43. NCT02193776 (https://clinicaltrials.gov/ct2/show/NCT02193776?term=NCT02193776&draw=2&rank=1) 44. CDER. 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NCT03086486 (https://clinicaltrials.gov/ct2/show/NCT03086486?term=NCT03086486&draw=2&rank=1) A5.1.2: Model-based projections of costs and cost effectiveness of changes in MDR/RR-TB regimens By Dr Emily A Kendall, MD PhD Background: Changes in recommended MDR/RR-TB treatment are likely to have economic consequences, through their effects on drug costs, drug delivery (for example, injections), safety monitoring requirements, numbers of follow-up visits, or (via changes in treatment outcomes) the number of TB patients who will require treatment in the future. Changes to recommended regimens might be cost-saving under common conditions, or might result in cost increases and potential access concerns that need to be weighed against clinical advantages. We developed a model to estimate the costs and cost- effectiveness of three potential changes to recommended treatments for MDR/RR TB. Methods: A single decision analytic modeling framework was developed to evaluate multiple regimen comparisons that were under consideration by the Guidelines Development Group (GDG). For PICO question 1, the costs and effectiveness of a shorter (9–12 month), all-oral, bedaquiline-containing regimen (modeled as based on South African guidelines) were compared to two types of currently recommended MDR/ RR-TB regimens: (a) a longer (18–20 month), bedaquiline-containing oral regimen (modeled as consisting of WHO class A and B drugs bedaquiline, linezolid, levofloxacin, clofazimine, and terizidone), or (b) a 9–12 month, injectable-containing regimen (modeled as evaluated in STREAM). For PICO 3 (use of bedaquiline for longer than 6 months in longer oral regimens), use of bedaquiline for 6 months in the 18–20 month regimen described above was compared to use for the duration of treatment. For PICO 4 (concurrent use of delamanid and bedaquiline), use of delamanid was modeled in two ways: (a) as an addition to the 18–20 month oral regimen (thus potentially increasing efficacy while adding cost) or (b) as a replacement for linezolid (with main goal to reduce toxicity). Each pair of regimens was compared in a population of adult patients with MDR/RR (not pre-XDR/ XDR) pulmonary TB. Modeled differences in TB outcomes between regimens (differences in relapse/ failure, mortality, and loss to follow up) were based on the statistical analyses of individual patient data performed for the GDG by Drs. J Campbell and R Menzies. Differences in cost, in 2019 US dollars, were evaluated from a health system perspective, accounting for resources required to manage current and future TB (including drugs, office visits and hospitalizations, safety monitoring, recurrences and secondary cases) and adverse events. Future non-TB health care costs (e.g. of ART) incurred as a result of preventing deaths were excluded. Serious adverse event risks were estimated per drug-month using data from a global surveillance project. Differences in effectiveness, in disability-adjusted life years (DALYs) averted, accounted for estimated morbidity and mortality during and after treatment (with disability weights13 for TB disease, drug side effects, treatment burden, and health status, and with 3%/year discounting of DALYs and costs). Primary analyses were based in South Africa, and sensitivity analyses explored the range of health care costs, drug costs, and HIV co-prevalence expected across low- and middle-income countries. WHO consolidated guidelines on tuberculosis: Online annexes126 Results: PICO 1: A shorter, all-oral, bedaquiline-containing regimen was projected to be cost-saving relative to either comparator regimen: by nearly $3,000 per patient when compared to a longer, all-oral regimen, and by $1,000 per patient when compared to a short, injectable-containing regimen (both in South Africa). Compared to the longer oral regimen, the majority of the resource savings associated with the shorter all-oral regimen were due to reduced costs of drugs, but savings were also projected in costs of health care delivery, adverse events, and future retreatments and secondary cases. Compared to the short, injectable-containing regimen, the shorter all-oral regimen did not reduce drug costs, but it provided similar projected resources savings in other categories. The shorter all-oral regimen was also projected to be more effective than either comparator. In sensitivity analyses, the resource savings of the shorter all-oral regimen relative to a longer all-oral regimen appeared extremely robust to country setting and underlying assumptions. The greatest variations in (cost savings) were seen with a two-fold decrease or increase in drug costs (cost savings $2000 and $4600, respectively) and with a two-fold decrease or increase in all non-drug healthcare costs (cost savings $2300 and $4000). The resource savings of the shorter all-oral regimen relative to the shorter injectable-containing regimen were nearly as robust, with the shorter all-oral regimen ceasing to be cost-saving (but remaining cost-effective, at < $400 per DALY averted) only when we assumed a large (four-fold) isolated increase in the cost of the drug bedaquiline. PICO 3: Extending the duration of bedaquiline treatment, from six months to the full 18–20 month duration of a longer all-oral regimen, was expected to add approximately $500 per patient to health system costs (at current drug prices). Cost-effectiveness depended heavily on the magnitude of the clinical benefit of extending treatment, and a sufficiently large benefit to achieve cost-effectiveness when used for all patients could not be observed in available data. If patients could be identified who would derive a clinically meaningful efficacy benefit (e.g. odds ratio of 0.6 for treatment success), then extending the duration of bedaquiline might be cost effective for those patients, at an estimated incremental cost effectiveness ratio in South Africa of $1,200 per DALY averted. PICO 4: Current high delamanid prices made cost-effectiveness difficult to achieve, whether delamanid was considered for inclusion in MDR/RR-TB treatment regimens in order to enhance efficacy (analysis a) or to prevent toxicity from another drug through substitution (assuming no significant loss of efficacy, analysis b). When adding delamanid to an otherwise-optimized longer all-oral regimen that already contained bedaquiline, the best-case incremental cost effectiveness ratio was $2,000 per DALY averted in South Africa, at the most optimistic data-consistent estimate of the efficacy benefit that delamanid might provide to patients. Data also supported an outcome of additional cost with no benefit, if true efficacy gains were minimal. When delamanid replaced a more toxic drug (e.g. linezolid) without changing regimen efficacy, then at current drug prices, the most optimistic incremental cost effectiveness ratio achievable in sensitivity analyses was $16,000 per DALY averted; this required assuming a serious adverse event rate of 0.7%/month for the drug that was replaced by delamanid (at the high end of the uncertainty range supported by data for linezolid), and high acute DALY impact per serious adverse event (0.4 DALYs each, similar to one full year with symptomatic active TB), and a high management cost of $17,000 per averted serious adverse event. Conclusions: A 9–12 all-oral regimen was projected to be both cost-saving and effective, relative to either a longer all-oral regimen or a shorter injectable-containing regimen, and cost savings were robust to setting- dependent variables and parameter uncertainty. On the other hand, extending the duration of bedaquiline or adding delamanid within longer MDR/ RR-TB regimens added substantial cost, and these changes were unlikely to be cost-effective at current prices when implemented for all patients, because of the relatively small effectiveness benefits Annex 5: Summaries of unpublished data 127 expected. However, moderate cost effectiveness was possible when used for select patients for whom effective regimens could not otherwise be composed. A5.1.3: Patient perspectives on DR-TB treatment: a summary report prepared for the November 2019 WHO GDG Meeting Introduction Patient values and preferences for treatment, and perspectives on treatment acceptability, feasibility and equity are key to the World Health Organization’s Evidence to Decision framework for drug- resistant tuberculosis (DR-TB) treatment interventions. A qualitative study was undertaken to illuminate patient perspectives and inform discussions for a November 2019 Guidelines Development Group (GDG) meeting for updated DR-TB treatment guidelines. A summary of the study is provided here. Methods Private in-depth interviews were held with persons who had received M/XDR-TB treatment in or after 2012, and were at least 18 years old and not receiving any form of TB treatment at the time of the study. They were recruited by referral from non-governmental organizations, as well as former patients with public profiles, from high DR-TB burden countries. Representation was sought from women, men, and people who had received newer or repurposed drugs for DR-TB. Interviews were conducted by phone in English, Russian, Mandarin or Spanish, and audio-recorded. Interview topics included: experiences with DR-TB treatment; preferences for treatment regimens; and the real or perceived acceptability of newer regimens, including perspectives on access and delivery. Recordings were transcribed, translated and identifiers removed. Data were thematically analyzed using OneNote to develop insights on patient values and preferences (characteristics, concerns and expectations of treatment that are considered to be most important); acceptability (appropriateness of treatment based on anticipated or experienced physical, cognitive and emotional effects); feasibility (practical considerations related to taking treatment); and equity (perceived or potential impacts on health and social inequalities). Ethics approval was granted by the Office of Research Ethics, York University, Canada. Findings Sixteen participants (44% female) of median age 29.5 years (range 22–64) were interviewed over two weeks in Oct 2019, from Africa (4), Asia (5), Eastern Europe (5) and South America (2). Nine (56%) participants began treatment for MDR-TB and 7 (44%) for pre-XDR or XDR-TB between 2011 to 2017. All had received longer regimens, from 1.5 up to 3 years. Most (96%) participants had experience with a second-line injectable and 40% with at least one of the new or repurposed drugs. One participant received bedaquiline as first-line therapy. Two participants were treated when they were adolescents. Few participants reported a co-morbidity: HIV (1), diabetes (2), chronic kidney illness (1). Participants’ acceptability and preferences for DR-TB treatment were rooted in the following core values: minimal disruption to normal life and independence during treatment, and full physical and mental recovery post treatment. A short, injection-free regimen with few to no side effects and a low pill burden was considered to be the most acceptable treatment for DR-TB. Barring the fulfillment of all these characteristics, a regimen with least side effects was prioritized, as side effects were considered to be the most disruptive aspect of treatment. This was followed by a shorter regimen, no injections, and fewer pills, in that order. Side effects that tended to resolve themselves over the course of a day or over the course of treatment (nausea, mild vomiting, body aches and pains, fatigue, and ringing in the ears) were disliked but tolerated. By contrast, severe and persistent vomiting, intense mental health effects ( severe depression including suicidal ideation, and severe anxiety including delusional thoughts), and any side effect that WHO consolidated guidelines on tuberculosis: Online annexes128 could result in organ or sensory damage (hearing or vision loss, major damage to organs such as the kidney or heart, jaundice, and severe neuropathy or burning) were all considered unacceptable, even if they were short-term and reversible. Severe mental health problems and any loss of hearing and vision were described as the worst side effects. Skin pigmentation and injection pain were highly undesirable; they were accepted in the short-term only if there was no other treatment choice. There were caveats and nuances to participants’ priorities, as well as important differences in acceptability, based on personal experiences with treatment, and the environment and context in which DR-TB care was received. Consequently, informed patient choice was considered a highly valuable component of the treatment decision-making process. Other elements valued by participants and considered crucial to acceptability of DR-TB treatment regimens were tight monitoring of serious adverse events, mental health counselling and support, ability to receive treatment in one’s own community (e.g., decentralized care), and universal access to new drugs and regimens. These values and preferences have implications for the feasibility of new DR-TB treatment interventions. Some patient values may conflict due to feasibility challenges, for example if treatment monitoring cannot be reasonably provided in the community. Feasibility issues give way to equity considerations if patient preferences are not upheld across all communities, or place certain populations at a disadvantage, such as those living in remote or rural locations where provision of new drugs or treatment monitoring may be difficult. Study attributes and limitations Open ended in-depth inquiry was key to uncovering the dynamic subjectivity of patient values and preferences. Saturation was likely not achieved with regards to the perspective of people with co-morbidities, permanent clinical sequalae, and experience with shorter, non-injectable regimens as first-line treatment. The sample was enriched by the voices of several participants who were TB peer educators and patient advocates and brought the experience of current patients into their narratives. Conclusion The study, rooted in the recent lived experience of people who were treated for DR-TB in a number of high burden countries, illuminates novel insights into patients’ core values, ranked preferences, and comparative risk perceptions and acceptability related to DR-TB treatment. Insights gained may inform patient-centred treatment guidelines for DR-TB. Acknowledgements The study was conducted by Amrita Daftary and Stephanie Law in preparation for the WHO GDG for updated DR-TB treatment in November 2019. AD is based at the School of Global Health & Dahdaleh Institute of Global Health Research, York University, Canada, and appointed to the Centre for the AIDS Programme of Research in South Africa (CAPRISA). SL is postdoctoral fellow at the Department of Global Health and Social Medicine, Harvard Medical School, Boston, USA. The researchers wish to acknowledge and sincerely thank the people who participated in this study, as well as referring organizations and persons. Annex 6: Statistical analysis plans 129 Annex 6: Statistical analysis plans A6.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020 update A6.1.1: PICO question 1: In MDR/RR-TB patients, does an all-oral treatment regimen lasting 9-12 months safely improve outcomes when compared with other regimens conforming to WHO guidelines? Effectiveness of an all-oral MDR/RR-TB regimen lasting 9–12 months in South Africa: Statistical Analysis Plan (draft) Prepared by Jonathon Campbell & Dick Menzies, McGill University: April 15, 2020 Overarching PICO Question (PICO 1) In MDR/RR-TB patients, does an all-oral, bedaquiline-containing regimen lasting 9–12 months safely improve outcomes when compared with other regimens conforming to current WHO guidelines? Population Intervention Comparator Outcomes MDR/RR-TB patients a. without additional drug resistance b. with additional drug resistance patterns (for FLDs and/or SLDs; if specific mutation data is available in dataset). c. with FQ resistance d. with severe disease (i.e. cavitary disease on radiography or SS+) e. previously treated with 2nd line drugs or not f. children (0–14y) / adults (adolescents 10–19y if available) g. persons with HIV (+/- ARVs) h. pregnant women i. with extrapulmonary disease j. with comorbidities (e.g. diabetes mellitus; malnutrition; mental disorders) – An all-oral shorter regimen of 9–12 months duration including bedaquiline 1. Shorter regimen recommended by WHO 2. Old longer regimens without new drugs in the IPD dataset 3. Longer regimens with new TB drugs from the IPD dataset 4. Longer regimens with use of new drugs from the EndTB dataset. • Successful completion of treatment (or lack of successful completion) • Bacteriological cure by end of treatment • Adherence to treatment (or treatment interruption due to non-adherence) • Treatment failure or relapse • Survival (or death) • Adverse reactions from anti-TB medicines • Acquisition (amplification) of drug resistance • Relapse free cure WHO consolidated guidelines on tuberculosis: Online annexes130 Research Questions Primary – intervention and comparator populations from South Africa data 1. Relative to the WHO recommended short-regimen lasting 9–12 months, does a bedaquiline- containing all-oral regimen lasting 9–12 months have the same or better outcomes? 2. Relative to a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all- oral regimen lasting 9–12 months have the same or better outcomes? 3. Relative to a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Secondary – intervention population from South Africa data, and comparator populations are from IPDinMDR – 2019 or the EndTB observational study 1. Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? 2. Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? 3. Relative to people in the EndTB data set receiving a regimen lasting ≥18 months with bedaquiline and/or delamanid (for a maximum of 6-months), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Background and Rationale The use of shorter (9–12 months) regimens, in particular the new all-oral regimens for MDR/RR-TB, is presumed to have more benefits as compared to longer regimens lasting ≥18 months; as well as to other shorter injectable-containing regimens. Primarily, the shorter duration puts a lower burden on patients and reduces the direct and indirect costs (both to the patient and the healthcare system) associated with treatment since MDR/RR-TB treatment is usually delivered through directly observed therapy. Secondly, injectable-agents are among the most toxic drugs used for MDR/RR-TB, have poor efficacy against TB and can lead to irreversible adverse events. While treatment & care delivery for TB25, including patients with drug-resistant TB can be community-based, usually injection-containing regimens must be administered at health facilities, adding travel and waiting time to the discomfort and inconvenience, and potentially contributing to poor treatment adherence in some cases. Thus, there are several advantages to a shorter all-oral regimen if they are as effective as regimens that (a) last longer and/or (b) contain an injectable. To date, shorter regimens have only been recommended for individuals who have not been exposed to second-line TB drugs (i.e. are new patients or have only received first-line TB drugs) and whose TB isolates have proven susceptibility to fluoroquinolones and second-line injectables. Given the nature of programmatic data, this latter criterion often simplifies to “not proven resistant” – i.e., their drug susceptibility test result is ‘susceptible’ or ‘not performed’ for these two classes of drugs, although in ideal settings, drug susceptibility results would be available. However, generally this means that patients with MDR/RR-TB that qualify for a shorter regimen are much less “complex”, than patients with MDR -TB with additional resistance patterns26 and XDR-TB, or that have been previously treated with second-line TB drugs. This makes comparisons of treatment of these two groups at very high-risk 25 Treatment & care delivery for TB is used in this context to refer to the administration of “Directly Observed Therapy [DOT]”. 26 MDR -TB with additional resistance patterns refers to MDR-TB cases which present MDR-TB plus resistance to fluoroquinolones (MDR- TB+FQ) or additional resistance to injectable agents (MDR-TB+SLI). This term does NOT mean MDR with resistance to PZA, EMB, Ethionamide Cycloserine or other similar and commonly used second-line drugs. Annex 6: Statistical analysis plans 131 of bias. Thus, for the purposes of this PICO question, we will exclude patients from all data sources (detailed below in Section 3.1) who have been exposed to second line drugs previously or who are MDR-TB with additional resistance to a second-line injectable and/or a fluoroquinolone. The number of patients excluded will be quantified, but are expected to be minimal, with only 4% and 1.5% of patients treated with a short regimen in South Africa previously receiving second-line drugs and having MDR -TB with additional resistance patterns or XDR, respectively, in a prior analysis of 2014–2015 data. Within South Africa, over 10,000 people initiate MDR/RR-TB treatment each year. Both shorter (9–12 months) and longer (≥18 months) regimens have been used and, over the last 2–3 years, there has been a transition from the WHO recommended short, injectable-containing regimen, to one that has replaced the injectable with bedaquiline. Thus, the data from South Africa presents a unique opportunity to compare patient important outcomes with four different types of regimens27 delivered concurrently in the same settings, by the same providers, faced with the same health system resources and constraints. The comparisons within the South Africa data set are thus considered the primary analysis. In addition to comparison within South Africa, use of patients from the IPDinMDR – 2019 database and/or from the EndTB observational study allow comparisons between settings and patients with different characteristics. If findings are similar, we can be more confident in their generalizability. Due to many potentially confounding differences between health systems and patients with MDR/RR-TB, within South Africa, and other settings, the comparisons between South African cohorts and other cohorts will be considered secondary. Data Sources South Africa All data for MDR/RR-TB patients who initiated treatment within South Africa is housed within the Electronic Drug Resistant TB register (EDRWeb). This register includes information such as age, sex, facility of treatment, previous treatment history, HIV co-infection, ART use, every drug received during treatment, individual culture and smear results during treatment, drug-resistance testing (both genotypic and phenotypic), regimen type (short or long), and end-of-treatment outcomes. We plan to use data from every individual in South Africa who initiated any short-regimen between Jan 1 and Dec 31, 2017 (N=3772) and data from every individual in South Africa who initiated a “long”-regimen in Q1 and Q2 2017 (Jan 1 to June 30, 2017) (N=3722). We selected the year 2017 for the short, injectable-free regimen as this was the first year this short-regimen had been widely used throughout the country. As well, regardless of the date a person started treatment that year, every individual should have at least 6 months of post treatment follow-up for possible relapse (data extraction for relapse is being performed in August 2019). We selected the first two quarters of 2017 (1 January to 30 June) for the long regimen as these patients would be receiving treatment concurrently with the short regimen patients and 95% of patients initiating therapy within this interval should have had an end of treatment outcome by 31 December 2018, allowing at least 6 months of follow-up for possible relapse. There may be concerns regarding selection of individuals to a short or long regimen when both were systematically offered in 2017. To examine this, we will also compare outcomes with the BDQ short regimen received in 2017 with outcomes among patients who received the conventional (long) regimen in 2016 for a second comparison. In 2016 only 213 of 13,193 (1.6%) persons starting RR/MDR-TB treatment received a short regimen, suggesting that selection bias should have been minimal in 2016, compared to 2017. As many of the regimens being compared are significantly different in duration, accounting for relapse and death non-differentially presents a challenge. For example deaths during treatment may occur up to 18 or even 24 months after initiation of a conventional ‘long’ regimen, but only up to 12 months with 27 All-oral 9–12 month regimen; WHO recommended 9–12 month regimen; Longer regimen without new drugs; Longer regimen with new drugs. WHO consolidated guidelines on tuberculosis: Online annexes132 the short regimen. Therefore, death in Months 12–24 will be counted as ‘deaths during TB treatment’ with the long regimen, even if unrelated to TB, whereas they would not be classified as such with the short regimen. Similarly, a patient could have culture reversion at month 15 of a long regimen and be classified as a treatment failure, but such a late reversion would not detected with the short regimen (unless relapse was carefully measured). In both situations, knowledge of post-treatment relapse and death outcomes is crucial to minimize differential outcome ascertainment. We plan to detect relapses within EDRWeb by cross-matching all names of those treated in 2016 and 2017 with EDRWeb to ascertain if any patients who are classified as treatment success are subsequently restarted on MDR/ RR treatment. We will detect these relapses by probabilistically matching patients within EDRWeb. However, as deaths following treatment completion are not recorded with EDRWeb (treatment must be initiated to be entered in this system), we will link all patients who started treatment in Jan 1 to June 30 2017, and those who started the short regimen from July 1 to Dec 31 2017 and successfully completed treatment with the South African MRC using their South Africa ID number to see if death occurred after treatment completion. Information about the South Africa ID within EDRWeb is ~90% complete, so we expect this should result in a fairly complete capture of deaths post-treatment. IPDinMDR – 2019 In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for more than 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 itself was based on an IPD data set assembled in 2016– 17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018. This database contains records of~150 patients from the EndTB study, who will be removed and updated with the more complete data set (see below). Further, the IPD-2018 contains about 3,500 records from South Africa, which we will exclude for the purposes of the secondary analyses. Within this iteration of the IPD – 2019, we anticipate adding data from a public call executed by the WHO, however at the time of writing we are unsure of the type, number, and treatment regimens of patients who might be added. EndTB Observational Study The EndTB observational study includes 1094 patients with MDR-TB who were treated with bedaquiline- and/or delamanid-containing long regimens between 1 April 2015 and 31 March 2017 in 17 countries28. They were followed as part of an observational study – executed by three institutions – PIH, MSF and IRD. There is comprehensive data capture on all important variables within the data set, including detailed information on treatment associated adverse events. Considerations for the IPDinMDR – 2019 and EndTB Observational Study Data Sets Within the IPDinMDR – 2019 and EndTB data sets, there are important differences when compared to the South Africa cohorts from 2016 and 2017 that willl be analyzed. Firstly, these data sets contain patients treated from 2000–2017. We will only include patients initiating treatment from 1 January 2013 onwards to ensure comparability with the patients treated in 2016 and 2017 in South Africa. Further, it is important to compare patients treated in similar resource settings. The primary analysis will include patients treated in all settings, and in sensitivity analyses we will restrict the comparators to patients treated in other World Bank classified upper-middle-income countries, as is this is the category South Africa belongs to. We will quantify how many patients this represents and compare them to those we included from both studies. 28 Armenia, Bangladesh, Belarus, Democratic People’s Republic of Korea (DPRK), Ethiopia, Georgia, Haiti, Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Lesotho, Myanmar, Pakistan, Peru, South Africa and Vietnam; (http://endtb.org/about) Annex 6: Statistical analysis plans 133 Defining Regimens As the treatment trajectory of MDR/RR-TB represents the complex interaction of patient, provider and health system capacities and constraints, there may be deviations from intended durations of therapy and number of drugs used. We will examine descriptively the distribution of treatment duration for all persons who received long or short regimens, as well as the distribution of treatment duration for persons with successful treatment who received a long or a short regimen. Based on these descriptive analyses, we will select cut-points (ideally using inter-modal points) that appear to best define the duration of treatment that can be called ‘short’ and ‘long’ (e.g. how far before or after the ‘planned’ duration of ‘short’ treatment do we accept as still meeting the definition of a short regimen to include in this analysis?). Therefore, we propose to establish criteria to classify people within regimen types. For data from South Africa, we plan to classify people who received a long-regimen as those who: (i) were classified as receiving a long-regimen within EDRWeb; (ii) had treatment duration not exceeding 24 months; (iii) received ≥4 TB drugs (any drugs, regardless of susceptibility for this definition) during treatment, regardless of whether they were effective and; (iv) if given an outcome of cure or complete, had a treatment duration ≥17.5 months. For data from IPDinMDR – 2019 and the EndTB data set, all patients received a long regimen, therefore we will include people conforming to criteria (ii), (iii), and (iv). We plan to classify people who received a short-regimen as those who: (i) were classified as received a short-regimen within EDRWeb; (ii) had a treatment duration not exceeding 12 months; (iii) received ≥6 drugs during treatment and; (iv) if given an outcome of cure or complete, had a treatment duration ≥8.5 months. These duration cut-points are subject to change pending the distribution of treatment durations we find. The short regimen target duration is 9 months, but a 3-month (33%) extension is permissible by PICO definition, similarly, a long regimen target duration is 18 months, so the equivalent extension permissible is 24 months. Further, for the minimum treatment durations for success in the 2018 MDR Guideline Update, the 17.5 month cut-point for the long-regimen was used. A similar two-week period should be used for the short-regimen, which may reflect simply differences in dispensation of prescriptions (e.g. 36 weeks of meds vs. 270 days) or deviations in timing of visits and pills dispensed. We will describe any patients excluded because their treatment duration does not fall within these limits. Regimen Classifications Intervention Regimen All-Oral Short Bedaquiline-Containing Regimen: The intervention in each analysis will be individuals who receive a short regimen (lasting 9–12 months) who did not receive any injectable during treatment and received bedaquiline. Comparator Regimens 1. WHO Recommended Short-Regimen: The first comparator is the WHO recommended short- regimen, which consists of pyrazinamide, ethambutol, moxifloxacin/levofloxacin, and clofazimine given for 9–11 months with high-dose isoniazid, amikacin (if given kanamycin or capreomycin – these will be included), and ethionamide or prothionamide given in the first 4–6 months of treatment. 2. Long Regimen Without New TB Drugs: The second comparator is a long regimen given for a duration of 18–20 months, which does not contain one of the new TB drugs: bedaquiline, delamanid, linezolid, clofazimine, or carbapenems. The target duration of the regimen may not be reached due to treatment non-response, death, or loss to follow-up. Hence, we refer to long regimens as those intended to be given for ≥18 months in our analysis plan. 3. Long Regimen Containing New TB Drugs: The third comparator is a long regimen given for a duration of 18–20 months, which contains at least one of the new TB drugs: bedaquiline, WHO consolidated guidelines on tuberculosis: Online annexes134 delamanid, linezolid, clofazimine, or carbapenems. The target duration of the regimen may not be reached due to treatment non-response, death, or loss to follow-up. Hence, we refer to long regimens as those intended to be given for ≥18 months in our analysis plan. Regimens Excluded from Analysis a. Short-Regimen without Bedaquiline and Not Conforming to WHO Recommendations: It is possible patients are treated with a regimen lasting 9–12 months that does not conform to the WHO recommended regimen and does not contain bedaquiline. Individuals receiving a regimen falling into this category will be classified uniquely. We will compare characteristics and outcomes of these patients to others receiving a short regimen descriptively, but they will be excluded from analysis. b. Short-Regimen with Bedaquiline and an Injectable: It is possible patients began a short-regimen with an injectable, only to have it stopped and replaced with bedaquiline. Individuals receiving a regimen falling into this category will be classified uniquely. We will compare characteristics and outcomes of these patients to others receiving a short regimen descriptively, but they will be excluded from analysis. Analysis of Outcomes The PICO lists eight distinct outcomes: (i) Successful completion of treatment, (ii) Bacteriological cure by end of treatment, (iii) Adherence to treatment (or treatment interruption due to non-adherence)29; (iv) Treatment failure or relapse, (v) Death during treatment, (vi) Adverse reactions from anti-TB medicines, (vii) Acquisition (amplification) of drug resistance, and (viii) Sustained bacteriological cure at least 6 months after successful treatment We will combine failure and relapse, and also combine completion and cure as success. We will estimate odds of relapse free treatment success vs several combinations of poor outcomes, and also examine loss to follow-up (LTFU) vs other outcomes – as summarized below. Adverse reactions from anti-TB medicines, and acquisition of drug resistance during treatment can NOT be analyzed using South Africa data as this information is not routinely captured in South Africa’s EDRWeb. Comparisons analyzed: 1. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. failure/relapse 2. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. failure/relapse and death during treatment. 3. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. all other outcomes (fail/relapse, death, and loss to FU). 4. Lost to follow-up during treatment vs. all other outcomes. * The follow-up periods were selected as this will give follow-up times that are comparable for both regimens. A key consideration is that the first patient in our analysis initiates treatment in January 2017 and follow-up ends in June 2019 (30 months elapsing from the time of the first patient recruited until follow-up ends). This time elapsed necessarily shrinks as the year progresses. Thus, setting a limit of 24 months post-treatment initiation for follow-up, and censoring events occurring beyond this period, maximizes the study population for comparison. As this limitation necessarily excludes all patients initiating treatment beyond June 2017, we will conduct sensitivity analyses, examining outcomes 18-months post treatment initiation and 21-months post treatment initiation. Therefore, we will have three comparisons described in the table below: 29 This correlates with loss to follow-up Annex 6: Statistical analysis plans 135 Months of Follow-up Post- Treatment Initiation Dates of Patients Included Receiving Short Regimen Dates of Patients Included Receiving Long Regimen 18 months January to December 2017 January to June 2017 21 months January to September 2017 January to June 2017 24 months January to June 2017 January to June 2017 Outcomes are clinician defined within South Africa and from our experience largely reflect Laserson (WHO 2005) criteria; this is how the majority of outcomes have been defined in IPDinMDR – 2019 (44/53 studies). Within EndTB, outcomes are coded as per WHO 2013 outcomes, however we will also create outcomes based on microbiologic data to align with WHO 2005 for comparability. Summary of Approach for Each Research Question We will conduct all main analyses described in sections 5.1.1, 5.2.1, and 5.3.1 using the concurrent long regimen controls (from Q1 and Q2 2017) and the historical long regimen controls (from all of 2016). These estimates will be shown separately. We will only conduct sensitivity analyses in these sections on the concurrent long regimen controls. For the outcomes described in section 4.0, we will conduct sensitivity analyses examining outcomes up to 18-months and 21-months post-treatment initiation in addition to those at 24 months post-treatment initiation. Overall Descriptive Analysis Before analysis of each research question, we will conduct a descriptive analysis for each of the reference and exposure group (detailed below), looking at key characteristics including: age (continuous and 0–14 vs. 14+ and 10–19 vs. 19+), sex, previous treatment history (drugs received and outcome), baseline acid-fast bacilli smear result, number of drugs received during treatment, total number and type of drugs resistant to (not double-counting ‘similar ’ drugs of ethionamide/prothionamide and cycloserine/terizidone, for example), presence of specific drugs in the regimens (e.g. bedaquiline, linezolid, clofazimine, moxifloxacin/levofloxacin, delamanid), and province of treatment. This will help clarify if there are systematic differences between the people who received each regimen, possible differences in where each regimen was used, and provincial differences in overall treatment outcomes. The information elicited from this analysis will be used to inform further variables for matching and/or adjustment described below – for example, addition of a random-effect for province of treatment (or exact matching within the province). Thus, within the approach for each question, the listed variables are an a priori list for inclusion, but may be modified based on data completeness and availability, and further sensitivity analyses including/excluding other variables may be developed based on the results of the descriptive analyses. The descriptive analysis is also intended to determine how many individuals would be excluded due to regimen composition. We will see if there are any important differences between those included and excluded from analysis. Primary Analysis (within South Africa only) Primary Analysis Question 1 Relative to the WHO recommended short-regimen lasting 9–12 months, does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: WHO Recommended Short-Regimen WHO consolidated guidelines on tuberculosis: Online annexes136 Approach Our approach will be to use a combination of exact matching and propensity score-based matching on several covariates to create two groups that are as comparable as possible, and thereby minimize bias and confounding. Between the intervention and comparator groups, we will perform exact matching on HIV co-infection/ART-use, previous TB treatment history (a 2 level variable – never and prior 1st line [recall, all people who previously received 2nd line TB treatment will be excluded]), and total number of drugs the strain was resistant to – this latter covariate is key to ensure the groups are comparable with regard to the full resistance patterns. We will further perform propensity score- based matching on age, sex, and baseline sputum AFB smear result. This matching process will be conducted with replacement using a caliper distance of 0.02 during the propensity score-based matching. We will examine the distribution of the matched covariates within the intervention and comparator groups to assess the fidelity of the matching process. For each outcome described in section 4.0, within our ‘matched’ population we will conduct logistic regression using mixed-models including random-intercepts for each matched ‘pair ’ and, depending on what we find for the descriptive analysis, for province of treatment. We will not include random-slopes as our experience is that there are significant model convergence issues when these random-effects are included. The logistic regression analysis will calculate adjusted odds ratios and associated 95% confidence intervals. We will further conduct binomial regression, using only fixed effects, on the matched population to calculate adjusted risk differences and their associated 95% confidence intervals. Primary Analysis Question 2 Relative to a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Without New TB Drugs Approach We will utilize the same approach described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Primary Analysis Question 3 Relative to a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Containing New TB Drugs Approach We will utilize the same approach described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. If there are enough patients, we will conduct sensitivity analyses within sub-groups defined by use of specific drugs, or combinations of drugs. For example, the sub-group of patients who received, or did not receive linezolid, or delamanid, or bedaquiline, or carbapenems, as part of a long regimen. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses. We will further conduct a sensitivity analysis repeating the approach in section 5.1.1 for other new or repurposed drugs: delamanid, linezolid, and carbapenems. Annex 6: Statistical analysis plans 137 Secondary Analysis (Comparing to IPDinMDR – 2019 or EndTB Data Sets) Secondary Analysis Question 1 Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Without New TB Drugs Approach We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the IPDinMDR – 2019 data set who began treatment from the year 2013 onward and who were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes. Secondary Analysis Question 2 Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Containing New TB Drugs Approach We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the IPDinMDR – 2019 data set who began treatment from the year 2013 onward and who were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes. If there are enough patients, we will conduct further sensitivity analyses within sub-groups defined by use of specific drugs, or combinations of drugs. For example, the sub-group of patients who received, or did not receive linezolid, or clofazimine, or delamanid, or bedaquiline, or carbapenems, as part of a long regimen. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses. We will further conduct a sensitivity analysis repeating the approach in section 5.1.1 for other new or repurposed drugs: delamanid, linezolid, and carbapenems. Secondary Analysis Question 3 Relative to people in the EndTB data set receiving a regimen lasting ≥18 months with bedaquiline and/or delamanid (for a maximum of 6-months), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes? Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Containing New TB Drugs Approach We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the EndTB observational study data set who began treatment from the year 2013 onward and who WHO consolidated guidelines on tuberculosis: Online annexes138 were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes. As all patients in EndTB observational study data set received bedaquiline and/or delamanid, we will conduct further sensitivity analyses within sub-groups defined by use of these specific drugs. These will include patients who received, or did not receive, bedaquiline, or delamanid, or both bedaquiline and delamanid. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses. Limitations Within the South Africa cohorts, drug resistance testing is reflexive and generally relies solely on genotypic drug resistance tests: Xpert MTB/RIF for rifampicin and line probe assays for isoniazid and rifampicin (GenoType MTBDRplus) and fluoroquinolones and second-line injectables (GenoType MTBDRsl). Because of this, resistance to drugs commonly used in short regimens (pyrazinamide, clofazimine, ethambutol, and ethionamide/prothionamide) is likely not available for most patients. As we are matching patients exactly on previous treatment history and pre-XDR/XDR phenotypes are excluded (as they would not be eligible for a short-regimen), we expect these unknown resistances to be similar between the groups being compared. We do not have chest radiographic results at baseline which may have influenced a clinician’s decision to treat patient with a short or long regimen. Hence this must be considered an unmeasured confounder. Adverse events and acquisition (or amplification) of drug resistance are not reported in the South Africa cohorts, so analyses of these important outcomes are not possible. Co-morbidities of diabetes, mental health disorders, and others are not routinely captured within EDRWeb, so the potential impact of these disorders on treatment outcomes cannot be analyzed. Extrapulmonary TB is not included in the IPDinMDR – 2019 data set and represents only 2% of patients receiving a short regimen in a previous extract of EDRWeb, so they cannot be analyzed as a subgroup as well. However bacteriologic confirmation of cure or failure/relapse is rarely obtained, which makes analysis of these outcomes more subject to observer bias. And, in drug sensitive TB results of RCT in pulmonary TB have been successfully applied to treatment of extra-pulmonary TB. Annex 6: Statistical analysis plans 139 A6.1.2: PICO question 2: In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6-9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to WHO guidelines? Comparative analysis of outcomes and safety between current XDR- TB treatments and a new regimen of bedaquiline, pretomanid, and linezolid. Statistical Analysis Plan, Draft. Prepared by Dick Menzies, Nicholas Winters and Jonathon Campbell, McGill University. PICO Question (WHO): In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6–9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to current WHO guidelines? Population Intervention Comparator Outcomes XDR/TB patients or and/ or those who are treatment intolerant or with non- responsive MDR-TB: a. with additional drug resistance patterns b. with severe disease (i.e. cavitary disease on radiography or SS+) c. previously treated with 2nd line drugs or not persons with HIV (+/- ARVs) d. adults (adolescents 10–19y if available) e. With comorbidities (e.g. diabetes mellitus; malnutrition; mental disorders) – Nix-TB trial regimen containing bedaquiline, pretomanid and linezolid given for 6 to 9 months – Using matched controls from the individual patient dataset (*current WHO recommendations)[1] • Successful completion of treatment (or lack of successful completion) • Bacteriological cure by end of treatment • Adherence to treatment (or treatment interruption due to non-adherence) • Treatment failure or relapse • Survival (or death) • Adverse reactions from anti-TB medicines • Acquisition (amplification) of drug resistance Research Questions: 1. Do patients receiving BPaL have the same or better outcomes 24 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD, with total duration of treatment of 24 months (within an allowed range of 22.5 to 25.5 months) 2. Do patients receiving BPaL have the same or better outcomes 18 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD for with total duration of treatment of 18 months (within an allowed range of 17 to 19 months – see Page 6) WHO consolidated guidelines on tuberculosis: Online annexes140 3. What is the occurrence of Grade 3–5 adverse events (AE), serious AE, and AE resulting in permanent discontinuation of at least one of the three component drugs of the Nix-TB regimen. (This is descriptive only, and ideally these rates of AE would be compared to rates with a WHO recommended BDQ/LZD containing regimen, but the comparator would have to come from a data set with equally careful and thorough ascertainment of treatment associated AEs.) Rationale: Despite global advances in controlling Tuberculosis (TB), this remains one of the most important communicable diseases in the world, accounting for an estimated 10 million cases and 1.6 million deaths in 2017 [WHO TB Report 2018]. Treatment of drug sensitive TB is highly effective in randomized controlled trials, however, treatment is much less effective for drug resistant strains of TB, particularly multidrug resistant TB (MDR-TB), defined as TB that is resistant to both rifampicin (Rif ) and Isoniazid (INH). As TB strains become more resistant, the treatment is increasingly difficult. MDR-TB patients with additional resistance to at least one fluoroquinolone and one second-line injectable, termed extensively drug resistant TB (XDR-TB), are an increasing public health concern. There were an estimated 600,000 cases of MDR-TB in 2016, of which approximately 6.2% were XDR-TB [WHO TB report 2018]. Currently, for treatment of XDR-TB the WHO recommends the use of at least five drugs in the intensive phase and four in the continuation phase, with durations ranging from 18–24 months. In the XDR-TB patients notified to the WHO in 2015, only 34% completed treatment and 26% died. These poor outcomes are in large part due to a lack of novel drugs, as well as lengthy treatment duration and frequent drug toxicity that result in low adherence. In order to combat XDR-TB and prevent possible devastating epidemics, new drugs as well as shorter regimens that increase the likelihood of adherence are needed. A novel, all-oral, treatment regimen consisting of bedaquiline, pretomanid and linezolid (BPaL) for 6 months has been assessed in an open-label trial. However, the trial had no comparison group. To adequately assess the efficacy and safety of this new regimen in the context of current XDR-TB treatment, it is essential to compare outcomes in NIX-TB trial patients with similar patients who received different regimens. To do this we plan to use an individual patient dataset, contributed over the past 3 years by more than 55 centres. This data now includes more than 13,000 patients with MDR and more than 3,000 patients with pre-XDR and XDR TB. Data Sources: Intervention group: the Nix-TB study was a one arm, phase 3, open labeled trial assessing the safety and efficacy of BPaL in patients > 14 years of age with confirmed sputum culture-positive XDR-TB or treatment intolerant/non-responsive MDR-TB. The trial was conducted between 2014 and 2019 in South Africa. The data from this trial that will be used in our analyses includes, but is not limited to: age, sex, race, medical history (BMI, diabetes, alcohol), TB treatment history, AFB smear microscopy results, Gene Xpert results, HIV and ART use, chest x-ray results, sputum culture result, patient reported severity of TB symptoms and health status, hematology/CBC/FBC, clinical chemistry, urinalysis, DST results (phenotypic), adverse events (AE) and serious AE based on DMID severity scale. Control or comparison group: Patients included in an individual patient data meta-analysis (IPD-MA) study, that included MDR/XDR-TB patients from 53 studies/centres in 40 countries. The included patients began treatment between 1993 and 2016, but we will select patients treated after BDQ was approved for treatment of MDR-TB in 2013 (of the XDR or pre-XDR patients there were 1007 on Bdq and 956 on Lzd). These patients will be matched to patients in the Nix-TB trial, on the basis of patients’ characteristics, DST, drugs used, and other factors that will affect treatment propensity (described in detail below). Annex 6: Statistical analysis plans 141 Regimens: Intervention: The Nix-TB regimen consists of bedaquiline (Bdq, at a 400 mg once daily for 2 weeks then 200 mg 3 times per week), pretomanid (200 mg once daily) and linezolid (Lzd, at a daily dose of 1200 mg/day) for 6–9 months (9 months if sputum culture positive at 4 months). These patients were followed for up to 24 months after treatment end. Comparison (control): 4 comparator regimens will be assessed. Patients receiving regimens for up to 25.5 months (Q1) or 19.0 months (Q2) that contained: Bdq plus Lzd plus other anti-TB drugs, Bdq plus others, Lzd plus others, Neither Bdq nor Lzd, but other drugs. No patients in the IPD received pretomanid. In the Nix-TB trial there are treatment start and stop dates, and in the MDR IPD we have precise total/planned treatment duration until outcome. Thus, analyses will be conducted comparing patients in both regimens from time of treatment start to outcome or end of the specified analytical duration. The regimens used in the IPD-MA for XDR-TB are significantly longer than the 6–9mo BPaL regimen in the Nix-TB study. This will present difficulties in comparing end-of-treatment outcomes, particularly failure and death. Patients treated with the conventional longer regimens have a much longer time during which they could die (of TB or other causes) or fail. Patients treated with conventional 18 or 24 months regimens may have sputum culture conversion at 6 months, but later revert to culture positivity. If treatment had been only 6 months, they would have been considered a ‘cure’, and then a relapse. Similarly, if a patient dies in the 15th month of conventional XDR treatment, that is, by definition a ‘death during treatment’ whereas if the regimen had been only 6 or 9 months, this would not have been a death during treatment. It is therefore necessary to assess outcomes from treatment start to a specified duration of time where after any events that occur in the comparator groups are censored, as diagramed below (Tx = treatment). Therefore in our analyses of treatment outcomes, all relapses or deaths (regardless of cause) occurring post-treatment in NIX-TB patients, up to 25.5 months (Question 1) or up to 19.0 months (Question 2) post treatment start, will be considered to have the outcomes of failure/relapse, or death and considered equivalent to “during treatment” failure or deaths with conventional regimens. Tx start Comparator Tx end 6months 18months 24months BPaL Tx end Duration used in analysis Question 1 BPaL Comparator BPaL Comparator Tx start Comparator Tx end 6months 18months 24months BPaL Tx end Duration used in analysis Question 2 Censored (excluded) WHO consolidated guidelines on tuberculosis: Online annexes142 Outcome Definitions: The PICO lists seven distinct outcomes: (i) Successful completion of treatment, (ii) Bacteriological cure by end of treatment, (iii) Adherence to treatment (or treatment interruption due to non-adherence); (iv) Treatment failure or relapse, (v) Death during treatment, (vi) Adverse reactions from anti-TB medicines, and, (vii) Acquisition (amplification) of drug resistance In the analyses, we will combine failure and relapse, and also combine completion and cure as success. We will estimate odds of relapse free treatment success vs several combinations of poor outcomes, and also examine LTFU vs other outcomes – as summarized below. Adverse reactions from anti-TB medicines, and Acquisition of drug resistance during treatment can NOT be analyzed using the IPD data as this information is not routinely captured in many data sets. These two outcomes were measured in the NixTB study carefully, so can be described. As discussed below a different source of comparator data would be ideal. This has been discussed and agreed upon in principle by investigators with the EndTB and the Alliance, and is now described briefly in the sensitivity analyses. The outcomes are defined in the Nix-TB protocol as follows: Bacteriologic failure: during the treatment period = failure to attain culture conversion to negative; bacteriologic relapse: during the follow-up period = failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline; Clinical failure: a change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death. In the IPD cohorts treatment outcomes were defined according to the WHO guidelines, summarized below: WHO 2005 (Laserson) Outcome Definitions (44/53 studies in our IPD used these definitions or definitions based on bacteriologic criteria) Outcome Definition Cure Completed treatment according to program protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatment. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative cultures taken at least 30 days apart. Complete Completed treatment according to program protocol but does not meet the definition for cure because of lack of bacteriological results (i.e. fewer than five cultures were performed in the final 12 months of treatment). Failure Treatment will be considered to have failed if two or more of the five cultures recorded in the final 12 months of therapy are positive, or if any one of the final three cultures is positive. (Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment early because of poor clinical or radiological response or adverse events). Death A patient who dies for any reason during the course of MDR/RR-TB treatment Lost to Follow-up A patient whose treatment was interrupted for two or more consecutive months for any reason without medical approval. Annex 6: Statistical analysis plans 143 WHO 2013 Outcome Definitions: 9/53 studies in our IPD used these definitions Outcome Definition Cure Treatment completed as recommended by the national policy without evidence of failure AND three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase (or Month 8 if no intensive phase). Complete Treatment completed as recommended by the national policy without evidence of failure BUT no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase (or Month 8 if no intensive phase). Failure Treatment terminated or need for permanent regimen change of at least two anti-TB drugs because of: (1) lack of conversion by the end of the intensive phase, or (2) bacteriological reversion in the continuation phase after conversion to negative, or (3) evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs, or (4) adverse drug reactions. Death A patient who dies for any reason during the course of treatment Lost to Follow-up A patient whose treatment was interrupted for 2 consecutive months or more. For our analysis, we will use different outcome definitions for patients in the Nix-TB trial from patients in the IPD-2019. For Nix-TB, the detailed clinical and microbiologic data will be used to verify the investigator defined end-of-treatment outcomes. Assuming they match their definition outlined in their protocol, we will use their investigator defined end-of-treatment outcomes, plus account for relapse during up to 18 months of post-treatment follow-up. For the EOT outcomes in the IPD-2019, we will use the investigator defined outcomes as well. In the data set we have now, 44/53 data sets used 2005 WHO guidelines to define these outcomes, and 9/53 stated they used WHO2013, but all data sets contained sufficient information to verify that almost all patients met microbiologic outcome definitions (ie fit WHO2005). Therefore we have already redefined the outcomes of the nine studies that used the 2013 guidelines to conform to the 2005 WHO criteria. In summary, within the IPD-2019 data set, we will verify investigator defined outcomes, reclassify if applicable to meet microbiologic criteria (WHO 2005 criteria) and compare these end-of treatment outcomes in the analysis to the NixTB investigator defined outcomes (including relapse as above). The coding of all information from the Nix-TB study will be verified with Alliance staff, and all discordant outcomes will also be verified manually (ie if a specific patient is classified as having treatment success in the original data set but does not meet that definition using the data we have – this will be manually checked) Analytic approach: Descriptive statistics: Treatment outcomes: as described above, the treatment outcomes assigned to patients in the NixTB trial will be reclassified (potentially) according to WHO 2005 definitions, using the detailed clinical and microbiological information available from the Alliance. The concordance of these outcome swill be verified as a first step. Any discordance will be verified manually and the data and programming may also be verified with the Alliance. Duration: As the treatment trajectory of MDR/RR-TB represents the complex interaction of patient, provider and health system capacities and constraints, there may be deviations from intended durations of therapy and number of drugs used. In the IPD data, we will examine descriptively the WHO consolidated guidelines on tuberculosis: Online annexes144 distribution of treatment duration for persons with successful treatment who received one of the four comparator regimens. Based on these descriptive analyses, we will select cut-points (ideally using inter- modal points) that appear to best define the duration of treatment that can be called ‘18 months’ and ’24 months’ (e.g. how far before or after the exact duration of 18 or 24 months do we accept as still meeting the definition of a regimen of 18 or 24 months to include in this analysis?). A second issue is the planned duration in persons who die, or are lost to follow-up (‘default’), or fail and therapy is stopped early. These patients will not have an actual treatment duration of 18 or 24 months, but of course must be included in the analyses to avoid bias. To identify persons with these outcomes we will use the planned duration (listed in many data sets). In some data sets planned duration is not given. In these we will examine the frequency distribution of duration in those patients treated successfully at the same centres. If this is unimodal, then the mode will be considered the planned duration. If this is a more complex distribution then we will predict the duration based on key predictors of duration (age, extent of resistance, extent of disease and specific drugs used) at that centre. Patient populations Before analysis of each research question, we will conduct a descriptive analysis for the BPal and four comparator groups (detailed below), looking at key characteristics including: age (continuous and 0–14 vs. 14+ and 10–19 vs. 19+), sex, previous treatment history (drugs received and outcome), baseline acid-fast bacilli smear result, number of drugs received during treatment, total number and type of drugs resistant to (not double-counting ‘similar ’ drugs of ethionamide/ prothionamide and cycloserine/terizidone, for example), presence of specific drugs in the regimens (e.g. bedaquiline, linezolid, clofazimine, moxifloxacin/levofloxacin, delamanid), and country of treatment. This will help clarify if there are systematic differences between the people who received each regimen, and possible differences in characteristics and outcomes where each regimen was used. The information elicited from this analysis will be used to inform further variables for matching and/or adjustment described below, and addition of a random-effect for country of treatment (or exact matching by country). Thus, within the approach for each question, the listed variables are an a priori list for inclusion, but may be modified based on data completeness and availability, and further sensitivity analyses including/excluding other variables may be developed based on the results of the descriptive analyses. The descriptive analysis is also intended to determine how many individuals would be included, and excluded due to regimen composition. In addition, for non-Nix-TB patients we will include the number of drugs received during treatment and presence of specific drugs in the regimens (e.g. Bdq, Lzd, clofazimine, moxifloxacin/levofloxacin, delamanid). Comparing efficacy of regimens:: Q1: Do patients receiving BPaL have the same or better outcomes 24 months post treatment start compared to patients receiving one of 4 comparator non-pretomanid containing regimens, with total duration of treatment of 24 months (within an allowed range of 22.5 to 25.5 months). These four comparators are: (1) Bdq+Lzd+others, (2) Bdq+others, (3) Lzd+others, and (4) neither Bdq or Lzd containing regimens. Comparisons: 1. Relapse free treatment success (defined as cure or treatment completion) vs. bacteriological/clinical failure or relapse. 2. Relapse free treatment success vs. death 3. Relapse free treatment success vs. clinical/bacteriological failure or relapse, or death. 4. Relapse free treatment success vs. clinical/bacteriological failure or death or relapse or lost to follow-up/default. Our approach will use a combination of exact matching and propensity score-based matching on several covariates to select comparator groups from the IPD-MA that are as comparable as possible to the patients who received BPal, and thereby minimize bias and confounding. All patient matching Annex 6: Statistical analysis plans 145 will be performed by an algorithm in our statistical software that will randomly select from the best patient matches. This algorithm will not include outcome. The variables used for exact matching will depend on the distribution of characteristics in the Nix-TB data and will be finalized once we are able to explore this in detail. For exact matching, we anticipate matching on two variables we consider critical: (1) XDR vs non-responsive/intolerant MDR-TB; and, (2) HIV infection and ART-use. Once we have matched on these two critical variables, we intend to further match exactly, if possible, based on the following important variables: (3) number of drugs to which the patient’s isolate is resistant, and, (4) previous FLD/SLD use, and if the data allows, also (5) disease severity (indicated by one of: AFB smear, cavitary and/or Bilateral disease),. These variables will ensure that patients with clinical profiles which predict their treatment outcomes will be compared. There may be issues with identifying patients in the IPD cohort who have non-responsive/intolerant MDR-TB. If so, we will select IPD patients who have previous SLD use. In addition, we will match patients based on PS, calculated using age, sex, and remaining variables of the three important variables listed above which could not be used for exact matching (AFB smear, Cavitation, number of drugs resistant to, etc). We will allow a calliper distance equal to 0.2 of the standard deviation of the logit of the propensity score. Matching will be done with replacement. If no potential matches fall within the calliper distance, the next closest match to 0.2 of the standard deviation will be selected. We will assess the success of matching by assessing the balance of confounders between the two groups. Additionally, we will determine how many patients were matched more than once to different patients in Nix-TB. This will indicate the need for consideration of methods to control for the effects of independence and increased variance on model fit, from having multiple matches. The power of this analysis is limited by the small number of patients in the NixTB study. To enhance power, we will match up to 4 controls from the IPD to each Nix-TB patient, depending on whether there are sufficient numbers of suitable matches to each NixTB patient (Four is considered the optimal number to enhance power, after which little added power is gained by matching further controls). For each outcome, we will conduct logistic regression using mixed-models including random- intercepts for each matched ‘pair ’ and, depending on what we find for the descriptive analysis, for country of treatment. We will not include random-slopes as our experience is that there are significant convergence issues when these random-effects are also included. Outcomes will be dichotomous (i.e. the outcome occurred during the specified analysis duration = 1 vs. the outcome not occurring = 0). The logistic regression analysis will calculate adjusted odds ratios and associated 95% confidence intervals. We will further conduct binomial regression, using fixed effects, on the ‘matched’ group to calculate adjusted risk differences and their associated 95% confidence intervals. For post-treatment relapse, we will first determine in which data sets of IPD-2019 this outcome was assessed. Then we will obtain information from the study authors on the methods of ascertainment, the intensity of follow-up visits, and the duration of follow-up. This will give us an idea of the comparability of this outcome with that of the NixTB study. In addition duration of follow-up and timimg of relapse may not be available for all individuals or centres. Therefore we will present cumulative incidence of relapse in each study as the proportion of patients relapsing out of the total number of patients that succssfully completed treatment. This analysis will be repeated for each of the four comparisons listed above. Q2: Do patients receiving BPaL have the same or better outcomes 18 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD for with total duration of treatment of 18 months (within an allowed range of 17 to 19 months) We will use the same methods outlined in Q1, except that duration used in the analyses will be 18 months, and any event occurring in post treatment follow-up of the BPal group after this period will be censored. WHO consolidated guidelines on tuberculosis: Online annexes146 Q3: Descriptive analysis of the occurrence of Grade 3–5 adverse events (AE), serious AE, and AE resulting in permanent discontinuation of at least one of the three component drugs of the Nix-TB regimen. Three separate but related outcomes. We will describe the occurrence of any of the secondary outcomes listed above to present results on the safety related measures recorded in the Nix-TB data. Permanent discontinuation of each component drug of the BPaL regimen will be analysed, and the stoppage of one drug but continuation of the others will be considered a drug associated AE for the drug that was stopped. In addition, we will also investigate the effects of dose reduction. We will use proportions or mean (standard deviations) where appropriate. This will not be compared to any of the comparator groups in our IPD listed above. Comparator: As noted earlier, this safety analysis is limited by the lack of an adequate comparator population, as AE’s were not ascertained with the same methods in the IPD-MA studies. Ideally these rates of AE would be compared to rates with a WHO recommended BDQ/LZD containing regimen, but the comparator would have to come from a data set with equally careful and thorough ascertainment of treatment associated AEs. The only data set to which we have access with comparable methods of systematically assessing AEs is the EndTB data set. We suggest that the AEs’ reported – in patients who received one of the 4 types of regimens listed above in the EndTb study, would be compared with the AEs reported in NixTB. Note that this suggestion would require the agreement of the EndTB investigators as well as the Alliance) Sensitivity analyses: We will conduct the same analyses outlined in Q1 and 2 using different subpopulations of patients to select comparators: (1) Match patients in the Nix-TB trial to patients in IPD-2019, using ONLY South African cohorts. By limiting to South African cohorts, we will match to patients from the same region, which may account for unique characteristics of the patient populations. (2) Match patients in the Nix-TB trial to patients who received treatment ONLY in high income countries. This may result in a better match on the basis of resources available for follow-up. (3) Limit comparisons to patients from studies where relapse was ascertained for at least 6 months of follow-up post treatment end. We will contact authors from these studies to obtain any additional information re definition and methods for ascertainment for relapse. (4) to compare AE between Nix-TB and a suitable comparator group, we need to ensure we have patient populations that are comparable, but also that AE are ascertained in a similar way. In the IPD-2019 we did not have systematic methods to detect, define, investigate manage or report AEs. Thus, we will match patients in the Nix-TB trial to those from the EndTB data, as AE were collected and documented with similar intensity of monitoring to Nix-TB. Limitations: There may have been substantial selection bias into the Nix-TB trial, as there was no randomization. Hence participation could have been influenced by physician selection of patients judged better able to tolerate the regimen, or that were sicker, with fewer treatment options (i.e. selection bias could go either way). There is also the potential for bias in the comparison of patients in NixTB with the IPD patients due to differences in loss to follow up. We can lessen, but not eliminate the impact of these biases, by exact and propensity score matching patients in the Nix-TB study to patients in the MDR IPD. This matching should result in patient groups that are balanced with respect to measured confounding factors, which should enhance clinical utility of the results. There may also be limitations in achieving four exact matches on all variables for each NixTB patient. This is why we have listed variables in order of their importance, and PS matching on the same variables will be used if exact Annex 6: Statistical analysis plans 147 matching cannot be achieved. In addition, we will use PS matching with a wider caliper distance to achieve matching, if necessary. Additionally, as noted above, the data on safety is limited in our IPD, and so we will be unable to compare the secondary safety outcomes between patients in NixTB and the IPD. Relapse was not measured systematically in most studies included in the IPD-2019. Hence this may have been under-estimated. As well for patients treated for 24 months, they finish treatment at the same time as post treatment follow-up ends for the NIXTB patients. So to include post-treatment follow-up will bias results as different lengths of Follow-up can lead to differences in outcomes due to other events. Relapse can be measured for 6 months if treatment is only 18 months, but early relapse rates tend to be highest – so this may overestimate cumulative relapse rates. Sept 6, 2019 WHO consolidated guidelines on tuberculosis: Online annexes148 A6.1.3: PICO questions 3: In MDR/RR-TB patients, does a treatment regimen containing bedaquiline for more than six months safely improve outcomes when compared with bedaquiline for up to six months as part of longer regimens otherwise conforming to WHO guidelines? and 4: In MDR/RR-TB patients, does concurrent use of bedaquiline and delamanid safely improve outcomes when compared with other treatment regimen options otherwise conforming to WHO guidelines? Statistical Analysis Plan (draft) for PICO 3 & 4 using the EndTB observational study and the IPD2019 data: prepared by Dick Menzies & Jonathon Campbell, McGill University: Sept. 6, 2019 WHO Guidelines group – PICO questions Question 3. In MDR/RR-TB patients, does treatment with bedaquiline for more than six months safely improve outcomes when compared with treatment up to six months as part of regimens otherwise conforming to current WHO guidelines? Population Intervention Comparator Outcome MDR/RR-TB patients: a. Simple MDR-TB (no additional resistance, risk factors)- b. with additional drug resistance patterns, but not XDR c. with XDR-TB d. with severe disease (i.e. cavitary disease on radiography or SS+) e. previously treated with 2nd line drugs or not f. children (0–14y) / adults (adolescents 10–19y if available) g. persons with HIV (+/- ARVs) h. pregnant women i. people with diabetes mellitus j. extrapulmonary disease k. malnutrition - Use of bedaquiline as part of the treatment regimen beyond six months of treatment - A regimen containing bedaquiline for six months of treatment only • Successful completion of treatment (or lack of successful completion) • Bacteriological cure by end of treatment • Adherence to treatment (or treatment interruption due to non-adherence) • Treatment failure or relapse • Survival (or death) • Adverse events with anti-TB medicines • Acquisition (amplification) of drug resistance Annex 6: Statistical analysis plans 149 (PICO 3) Effectiveness of prolongation of bedaquiline beyond 24 weeks: Three specific questions – related to use of different information sources 1. Relative to bedaquiline (BDQ) use for 24 weeks (6 months), does prolongation of bedaquiline beyond 24 weeks (within properly designed regimens) result in improved treatment outcomes for patients with RR-TB in the EndTB observational study? 2. In the IPD-2019 data set, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to BDQ for 6 months, and to no BDQ? 3. In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to BDQ for 6 months, and to no BDQ? Five Outcomes of interest for the Proposed Analyses: End of treatment: 1. Relapse free treatment success (or simply success, if relapse not assessed) vs fail/relapse 2. Relapse free treatment success (or simply success if relapse not assessed) vs fail/relapse/death 3. Relapse free treatment success (or simply success if relapse not assessed) vs death alone 4. Relapse free treatment success (or simply success if relapse not assessed) vs fail/relapse/death/ LTFU (i.e. good vs all bad combined) During therapy: 5. Adverse events (AE) – defined as serious AEs that resulted in permanent discontinuation of that medication. • This information is available in considerable detail in the EndTB data following the MSF severity scale – definitions provided at the end of the document. It is less consistently available [~8000 patients in 30 datasets] and defined as grade 3–5 or serious AE that resulted in permanent discontinuation of that medication and may be differentially ascertained in the IPD2019. This may confound comparisons of AE rates – particularly for drugs that are used more, or less in the two datasets. • If permission granted from all parties, we will also compare AE in EndTB data set with AE detected in NixTB study. These two studies had more comparable intensity of AE detection, although different definitions, and methods for AE. N.B. Adherence (as % doses taken or other measure) is available in the EndTB data set, but not the IPD2019. Thus, this will only be described for the EndTB data set. DATA SETS to be used in PICO 3 analyses: IPD2019 In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 was itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018. Hence the IPD-2019 represents an update of the IPD-2018. We anticipate adding data from one national surveillance programs – in South Africa. We will delete the previous records of patients treated in the EndTB observational study, that were included in the IPD-2018, to avoid duplication and overlap with the new data set from EndTB. We may also add two other data sets – provided in response to a public call for data contributions. WHO consolidated guidelines on tuberculosis: Online annexes150 EndTB: 1094 patients with MDR-TB were treated with bedaquiline- and/or delamanid-containing regimens between 1 April 2015 and 31 March 2017. They were followed as part of an observational study – executed by three NGO’s – PIH, MSF and IRD. Rationale Why the question of optimal duration of BDQ is challenging. There are several important potential sources of bias in analysis of duration of therapy in observational studies. We note 2 examples here: i) Patients who live longer on RR-TB treatment can be treated longer with bedaquiline. Simply comparing the outcomes among people who survive to receive the longer treatment to those who didn’t receive the longer treatment can result in an overestimate of the benefits of the longer treatment. This bias is called “immortal time bias”. ii) Bedaquiline prolongation varied by patient factors and by country and time. Bedaquiline was prolonged most often in patients with baseline and on-treatment risk factors for poor outcome, i.e., patients whose initial response to treatment was poor, whose regimens without bedaquiline were considered weak, or whose resistance profile or treatment-emergent toxicities limited treatment options. Simply comparing the outcomes among people who got prolonged bedaquiline to those who did not could underestimate the benefits of prolonged bedaquiline. This bias is called (time- varying) confounding by indication. In the EndTB study, across countries and over time, the use of prolonged bedaquiline varied. Some countries prolonged bedaquiline in nearly all patients, while in other countries, bedaquiline prolongation was not permitted by national guidance. At other sites, bedaquiline prolongation became more common over time as clinicians became more comfortable with the drug. It’s important to acknowledge the focus on bedaquiline (and delamanid) duration is exceptional, as other drugs (i.e. linezolid) have analogous issues in that people can receive them longer if they don’t experience treatment-limiting toxicity, which in linezolid’s case is ~1 in 5 people. Thus, while the analysis approach that we propose attempts to minimize many sources of bias, we acknowledge it may not be possible to manage all biases. Defining ‘margins’ in duration analyses: Since start dates and end-dates of specific drugs are available in the EndTB dataset the duration can be defined to the precise number of days. But, in reality, the precise duration depends on timing of visits, and events such as missed visits, cancelled clinics, holidays or even just bad weather can result in variation of up to a month around the time when a specific drug is stopped. Hence we will first define a frequency distribution of duration for BDQ, in order to define the optimal cut-points for each duration. As an example, from recent analysis of one data set – the frequency of actual duration in days of one drug is plotted (see Annex 1). This plot shows a large number of persons with duration centred around 6 months, but we would conclude that for our purposes “6 months” duration should include patients with duration of 150 to 200 days. Therefore, in this SAP when we refer to duration of “24 weeks”, or “36 weeks”, or “52 weeks” we mean N weeks + NN weeks, with the value of NN to be determined from the initial descriptive analysis. Challenges in comparing results using the EndTB data, and the IPD2019 data: There are several important potential differences between the patient populations, treatment, and other factors between these two sources of individual patient data. Annex 6: Statistical analysis plans 151 i) The EndTB study was conducted by agencies and at centres with different patient populations, as well as resources and clinical expertise, from those in the IPD-2019. The IPD-2019 contains data from a greater variety of settings including samples of patients included in national MDR surveillance systems. Hence outcomes may be different in the IPD data-set – independent of measured clinical and treatment characteristics due to unmeasured confounding. While for some datasets in the IPD there may also be differences in outcomes, we will quantify differences between the IPD and EndTB descriptively. As we have done in the past, mixed models will be used to account for heterogeneity between datasets. ii) There is a perception that the EndTB sites have more complicated patients who have comorbidities and other challenges (homelessness, hx of incarceration, IV drug and alcohol use) that make developing an effective regimen especially difficult; iii) the extent and quality of data, particularly on-treatment, longitudinal observations; follow-up for recurrent disease (ie for relapse); iv) methods for collection and reporting of safety data; v) extent of prolongation of Bdq; vi) In the EndTB data set all patients received DLM or BDQ or both. But none got neither of these drugs – in contrast to large numbers of patients in the IPD data set who received neither. If DLM is very effective, this could substantially affect comparisons of the no BDQ group in the IPD2019 cohort to the no BDQ group in the EndTB data set since all these patients received DLM. We will, therefore, control for exposure to DLM in all analyses. vii) overall willingness to use Bdq/Dlm; viii) outcome classification. Some of these differences are sources of variability within the IPD as well (e.g., bdq use, outcome classification, safety, etc). However, the IPD2019 data set includes data from over 13,000 patients, treated in 53 studies in 40 countries/regions. The diversity of patients, disease, providers, and treatments provides an excellent opportunity to compare and contrast treatment related covariates in very different settings and should result in more generalizable findings. The results from Questions 1 and 2 will see if the effect of bedaquiline use beyond six-months is similar in EndTB and the IPD, after accounting for numerous possible confounders. Any confounding effect of DLM will be managed by controlling for delamanid in all analyses. The analysis for Question 3 will analyze the benefit of BDQ for 6 months, vs longer vs a group that did not receive BDQ while adjusting for use of delamanid as well as the data source or study (ie EndTB or IPD2019) and other covariates. In other words, in this analysis the reference group (comparator) will be the group who received BDQ for 6 months. While the IPD2019 data set has important limitations, compared to the EndTB data set, we believe there are important advantages of conducting the analyses of BDQ duration using both the IPD2019 data set and the EndTB dataset. These advantages include the greater diversity of settings and patients in which this question can be addressed – enhancing the generalizability of results. As well the diversity of settings increases the likelihood of diversity in patients receiving longer duration of BDQ – potentially reducing unmeasured confounding relative to actual differences in detectable treatment benefits. Finally, this should increase the number of patients who received any single regimen/combination of medications/duration of BDQ, so simply enhancing power. WHO consolidated guidelines on tuberculosis: Online annexes152 Overview of the analyses for the three specific Questions (end of treatment outcomes) Q1: Relative to bedaquiline (BDQ) cessation at 24 weeks, does prolongation of bedaquiline result in improved treatment outcomes for patients with RR-TB in the EndTB observational study? Comparator: use of bedaquiline for 24 weeks in EndTB Intervention: use of bedaquiline for >24 weeks in EndTB Sensitivity analysis comparator: use of bedaquiline for 24–36 weeks in EndTB Sensitivity analysis Intervention: use of bedaquiline for >36 weeks in EndTB Defining a Time Cut-Off for Bedaquiline Use As discussed above, it seems likely that BDQ use will not be precisely 24 weeks in many patients, due to the vagaries of dates of visits, drug supply, delays in starting, or stopping, or missed doses. We want to know, as best as we can, if 6 months, or 9 months is planned – what, in reality is the duration? If we restricted analysis to those who got exactly 180 or 270 days – we would have about 20 people. So, we need to account for some variation in actual duration. Hence, we propose to examine the frequency distribution of duration of BDQ to attempt to find ‘inter-modal’ cut-points that best discriminate patients treated with BDQ for ’24 weeks’, or 36 weeks, or 52 weeks. ONLY TO DEFINE THIS CUT-POINT, we will exclude patients who died or were lost to follow-up to ensure that the population assessed are only those who could have received the drug to this point. This will also be done for the sensitivity analysis population. It should be recognized that any selected timepoint will necessarily dichotomize some patients who received only a few days difference of bedaquiline treatment, however by selecting the inter-modal points, this problem should be minimized. The rest of this plan below is written assuming 24 weeks is selected but will be adjusted based on our findings here and may represent a range (e.g., 20–26 weeks of bedaquiline). Step 1: Descriptive Analysis of the Population Subgroups We will then undertake descriptive analysis to characterize those who did not receive BDQ, those who received BDQ for at least one month, but <6 months, and those who received at least 24 weeks – divided into two groups: (BDQ for 24 weeks; and BDQ for >24 weeks). We will also sub-divide the group with BDQ for >24 weeks into persons who were treated with BDQ for 24–36 weeks, and those who received BDQ for >36 weeks. The description will include: site where treated, baseline/pre- treatment characteristics: sex, age, HIV and ART treatment, other comorbidities, prior TB treatment, AFB smear, CXR results, DST results (both in terms of resistance patterns and total number of drugs resistant to), year of starting treatment, and number of likely effective drugs used initially. Consideration of the total number of drugs resistant warrants further explanation. It is possible that for drugs with DST that is perceived to be unreliable (e.g. cycloserine, PAS), in the event they were found susceptible, they were reinforced, or in the event they were found resistant, the drug was used anyways. Likewise, there may be reasons some drugs had DST done on them, perhaps due to previous exposure or a regimen was failing. Thus, for these reasons it is important to consider the total number of drugs a patient is resistant to, as well, the more drugs a person is resistant to, the more limited treatment options are, and the more probable it is that bedaquiline is extended. So, we plan to adjust for this covariate in statistical analysis. Because of this, we propose to count the number of drugs individuals are resistant to drugs other than fluoroquinolones and second-line injectables (which will be accounted for in the composite resistance pattern of MDR, pre-XDR, and XDR) – we will assume cross-resistance to similar drugs (e.g. ethionamide and prothionamide or cycloserine and terizidone, or amikacin and kanamycin – unless there is DST for both drugs). There are also sensitivity analyses surrounding this, detailed in the appropriate section below. We are also interested in events during treatment that would affect clinical decisions at the time points of interest – meaning at 6, 9 and 12 months. These would include: culture and DST results indicating any newly detected drug resistance from cultures Annex 6: Statistical analysis plans 153 of samples collected prior to the end of week 16 (we assume that at the time of the 6-months evaluation, that cultures and DST would be available only for samples collected prior to weeks 16 and 12 respectively. We would examine AFB smear and CXR results from 24 weeks, as well as number of drugs permanently stopped due to intolerance / AEs up to 24 weeks – all of which information would be available at the 6-month evaluation and could be indications for extension of BDQ. This descriptive analysis will be further stratified by site to determine if there are unique site characteristics. We will further describe exact resistance patterns of all drugs (Resistant, Susceptible, Not Done/Unknown) to see how common testing was and prevalent resistances were when testing was done. We will repeat the descriptive analysis using appropriate time-points for the proposed sensitivity analysis. Step 2: Exploring the use of delamanid – descriptively In the same way as bedaquiline, we will descriptively examine the characteristics of people who received delamanid (no BDQ) or did not receive delamanid, and compare those to patients who received DLM and BDQ and to patients who received BDQ alone. One issue that will be explored is whether delamanid was used from the start, or introduced after, since many patients received DLM after several months of therapy. This raises the possibility of indication bias, since those who had DLM added are likely to have been responding poorly, but on the other hand, also immortal time bias since patients had to survive longer to have a chance of later introduction of delamanid. (This is where separate analyses of failure, and death may be especially helpful). Thus we will describe median (IQR) time of delamanid start after treatment start and also how many started within 0–3 months, 4–6 months, 7–9 months, or 9+ months after treatment start. We will also look at these characteristics by site, as policies regarding use may vary between sites, and could be an important potential determinant of use. We will examine whether characteristics of patients was ‘balanced’ between the treatment groups as defined above. Even if there is no evidence of substantial confounding of patient characteristics with DLM use, we will consider delamanid as a unique drug given and adjust for its use in the multivariable analyses described below (like LZD or later generation FQN, for example). Step 3: Analysis of duration of BDQ To assess the benefit of bedaquiline extension beyond 24 weeks, we plan two analytical methods and will compare the results. We will do this for each of the four outcomes defined above each method will be repeated for sensitivity analysis. Method 1: Exact and Propensity score matching. Patient characteristics at baseline that are missing will be imputed using multivariate imputation via chained equations. Note – exposure and outcome data will never be imputed. We will match persons who received bedaquiline for 24 weeks to those who received it longer using a combination of exact and propensity score based matching for covariates that are likely to influence treatment extension at week 24. These covariates include: Baseline characteristics: Resistance to FQ or SLI, total Number of drugs resistant to, AFB smear, Cavitation on CXR, HIV-coinfection and ART use, previous treatment history (first-line drugs only or also second-line), age and sex. During-treatment characteristics: culture status at 12 and 16 weeks (ie culture conversion or non-conversion), number of acquired/new resistances at 16 weeks (0, 1, or 2+), cumulative number of drugs stopped due to adverse events at week 24 (0,1 or 2+), radiologic findings at week 24, treatment at Week 24 including use of receipt of fluoroquinolone, linezolid, and delamanid and number of other likely effective medications. As we have done in past analyses, we attempt to match exactly on as many covariates as possible (recognizing that within the EndTB data set this may be challenging), and propensity score match on the remainder. The covariates selected for exact matching are those with strongest association with the outcomes of interest for that analysis. We will propensity score match on the remaining covariates listed above. We again will consider clustering by site and further adjustment by year of treatment start and/or country level income. We will estimate adjusted odds ratios and associated 95% CI. For each analysis, the matched groups will be examined in standard reports looking at the improvement (or not) in balance of characteristics between the two groups from the matching algorithm. WHO consolidated guidelines on tuberculosis: Online annexes154 Method 2: Survival Analysis using inverse probability of treatment weighting (IPTW) and inverse probability of censor weighting (IPCW). The survival analysis will begin with everyone included in the analysis population who received treatment with bedaquiline for at least six months (i.e., baseline=month 6). We will examine exposure in two ways. (1) Dichotomous: received only six-months of BDQ vs. received more than six-months of BDQ; (2) Continuous: treating months of BDQ beyond six as a continuous variable. The outcome of interest will be failure/relapse/death (composite). We will treat loss to follow-up as a censoring event. We will include patient time until the end of follow-up for relapse. We will construct a baseline patient profile based on what would be clinically known at month 6, including time-fixed covariates of age, sex, previous treatment history, etc. From here, we will update information each month for patients that is time-varying: receipt of concomitant drugs (type and number), number of AE requiring drugs to be stopped, culture status, radiologic findings. Using these time-fixed and time-varying covariates, we will estimate the IPCW for the population (i.e., for LTFU). We will also estimate the IPTW based on timing of BDQ stop (i.e, for people stopping BDQ at month 6, IPTW will be estimated for all time points; for people continuing to receive BDQ beyond month 6, IPTW will be estimated until the time of BDQ stop, then considered constant). We will then run a survival analysis, clustering by patients and centre and incorporating the calculated IPCW and IPTW weights. This analysis will be run for both dichotomous and continuous outcome. For the continuous outcome, please see sensitivity analyses where we consider the benefit of bedaquiline to be non-linear and we describe alternate analytic methods to be explored (e.g. g-formula). Q2: In IPD-2019 data set, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to no BDQ and BDQ for 6 months? Exposure 1: No use of Bedaquiline (defined as <30 days) in IPD2019 Reference (comparator) 1: Use of bedaquiline for 24 weeks in IPD2019 (exact duration based on descriptive analysis as in Q1). Exposure 2: Use of bedaquiline for >24 weeks in IPD2019 (exact duration based on descriptive analysis as in Q1). We propose three analyses: No BDQ to 24 weeks, and 24 weeks to BDQ to >24 weeks, plus a combined – where BDQ use is a 3-level categorical variable (none, 24 weeks, and >24 weeks). Since this is all within IPD2019 – We propose to match patients exactly on the baseline characteristics of fluoroquinolone and second line injectable resistance, HIV co-infection and ART use, and country- level income (using World Bank categories). We will match patients further using propensity score matching on age, sex, previous TB treatment (first line and second line drugs), extent of disease (AFB smear and/or cavitation on CXR), use of linezolid, use of fluoroquinolones, use of delamanid, BMI (dichotomized as underweight or not), and number of other effective drugs used in the initial regimen. Because of limitations of lack of detailed information about changes and events during therapy, we cannot include these variables in this analysis. Q3: In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to no BDQ and BDQ for 6 months? Exposure 1: No use of Bedaquiline (defined as <30 days) in IPD2019 Reference (comparator) 1: Use of bedaquiline for 24 weeks in IPD2019 (exact duration considered 24 weeks based on descriptive analysis as in Q1). Exposure 2: Use of bedaquiline for >24 weeks EndTB and in IPD2019 In the analysis strategy deployed, the “exposure” will be BDQ use for 24 weeks or >24 weeks, as treatment in the combined data set of EndTB and IPD2019. The comparator will be BDQ use for <30 Annex 6: Statistical analysis plans 155 days in IPD2019. Our analytic approach will follow the same approach as described in Q2 comparing the reference to exposure 1 and exposure 2, and when comparing exposure 1 to exposure 2. Outcome 5: Analysis of adverse events: The analysis plan for adverse events is made somewhat difficult by the fact that we are not yet certain of the data available from the EndTB study. In the IPD2019 we have information on type of adverse events, and the drug considered responsible by the treating team, as well as whether that drug was permanently stopped – in 30 studies with >8000 patients. We did not have much information on the severity of the AE (i.e. few studies provided information on the Grade), so the analysis was simply the cumulative percent of patients who received at least 1 month of the drug, and the drug was stopped permanently because of an AE, as well as type of AE in most of these studies. Using this we calculated a proportion stopping each drug in each study. We propose to try three approaches to analyze the occurrence of AE. First, we will perform standard aggregate data meta-analysis for proportions. The estimated proportion of patients within each cohort in whom each specific drug was stopped permanently (out of all patients in the cohort receiving that drug) because of an AE ( AE incidence) . Then AE proportion for each drug from each cohort will be estimated using generalized linear mixed model with random effects at cohort level using the “metaprop” function within R package “meta”, then pooled using standard aggregate data random effects meta-analysis. To address the PICO question, we will sub-divide each cohort into ‘comparator = 6 months BDQ’ and ‘intervention = BDQ longer’. This analysis will be conducted without adjustment for confounders, then we will assess the relationship of covariates (especially age, sex, HIV status, and extent of disease indicators) to AE, and repeat the analysis with adjustment for these confounders. Second, we can perform an arm-based network meta-analysis using the “nma.ab.bin” function within R package “pcnetmeta” (ref ). In this approach, drugs not used in a study or cohort will be considered as missing at random. The use of a multivariate Bayesian mixed model allows estimation of the population averaged treatment specific event proportions. This model will account for the correlation between different treatments within each cohort as compared to the above approach that estimated drug-specific event proportions based solely on cohorts that used the particular drug. Absolute risk of AE for each drug will be estimated using a random effects model within the Bayesian framework, and the median value with 95% credible interval and mean value with standard deviation reported. A third approach is to use a ranking-based non-parametric method, as this should more accurately assess the relative toxicity of shorter and longer BDQ vs other drugs in different studies (i.e. if comparing AE in IPD2019 and EndTB. In the first step, within each cohort the drugs used were ranked in the order of observed AE incidence of each drug, from one to N (representing the total number of distinct drugs prescribed). If more than one drug was stopped, they received a proportion of a point (e.g. if two drugs stopped 0.5, if three drugs stopped 0.33, etc.) Note that ‘incidence’ refers to cumulative incidence in the IPD2019 – as we may not have adequate information on drug duration, so we have used the proportion who stopped among those who received the drug for at least 1 month. If two or more drugs had the same AE incidence in a study, the drugs were assigned tied ranks. Next, the raw ranks were adjusted by the maximum distinct number of drugs of all cohorts. In a third step, the unweighted average rank for each drug was calculated across all cohorts using the drug, with equal weight ascribed to each cohort. The weighted average rank for each drug will be estimated in the same way except a weight will be assigned for each cohort based on the number of patients using the drug in that cohort; however, cohorts with large sample size will have a dominant influence on the average ranks; therefore, the unweighted ranking will be considered the primary approach. For this PICO, we will assess the ranking of BDQ in those who received BDQ for 6 months (reference or comparator), vs more than 6 months. A change in ranking would imply greater or lesser AE in the intervention group. An improved AE ranking might suggest selection – since those who tolerate a drug are more likely to continue it. WHO consolidated guidelines on tuberculosis: Online annexes156 Limitations (PICO 3 analysis) As noted above, patients may receive prolonged bedaquiline, because they were sicker, or had fewer treatment options (AE, or more resistance ). Indeed, information from the investigators indicates that all EndTB countries initiated BDQ use in the patients with the worst MDRTB and the least treatment options – many after prior treatment failures. Early in the EndTB project, countries were very conservative to use BDQ therefore it was included only when cases were desperate and late in the treatment. Second, across countries and over time, the use of prolonged bedaquiline may have varied. However, this is in fact an advantage, as some differences in bedaquiline prescription and duration may have had less to do with patient characteristics, and more to do with local policy, physicians’ beliefs, and BDQ availability – creating a quasi-experimental situation – with less confounding due to patient characteristics. We will use two methods to control for confounding; however, we will not be able to completely control all possible confounding, especially unmeasured confounding. But we expect that if unmeasured confounding is related to indication, then this will act to underestimate the benefit of bedaquiline if sicker patients or those with fewer effective drugs are more likely to receive prolonged bedaquiline. Potential Sensitivity analyses 1. Analyses repeated but accounting for missed doses (due to non-adherence) from the 24 weeks of initial bedaquiline exposure in EndTB. 2. Assess time to loss-to FU/dropout/default, inpatients who take no BDQ, 6 months BDQ and >6 months BDQ. Compare time to LTFU in EndTB and IPD2019 in same sub-groups based on BDQ duration. 3. Examine whether the effect of prolongation depends on specific other drugs used in the treatment regimen (eg, Dlm, clofazimine, PZA or cycloserine). 4. Assess whether Bdq prolongation is more effective than no Bdq prolongation in patients with an indication for prolongation, i.e., patients whose regimen would be compromised if Bdq were withdrawn (resistance, toxicity, culture positivity, etc). It’s very possible that Bdq prolongation is not helpful in patients who don’t need it after 6 months. Including these patients in an analysis of effectiveness of Bdq prolongation could underestimate the contribution of prolongation. To analyze the effect of prolongation in those who need prolongation would require establishing the risk group based on patient characteristics after 6 months of Bdq, not only those at baseline. 5. For Question 1, Method 2: We will consider modelling time non-linearly using a spline or by including a second quadratic term for duration. Further, we will also use g-formula to calculate the expected probabilities of our outcome, which would reduce biases introduced due to people surviving longer can receive bedaquiline longer. Finally, we will consider LTFU an outcome, and not a censoring event, since LTFU may be due to undetected, clinically important reasons of long duration and/or toxicity. 6. For Question 1: We will not consider the number of drugs a person is resistant to, but instead consider drugs with perceived unreliable DST (notably E, Z, PAS, Eto/Pto, Cs/Trd) as (a) susceptible regardless of result and (b) resistant regardless of result. 7. For AE: Compare frequency of specific drug related AE in EndTB and NixTB studies. Adverse Event Definitions in EndTB EndTB AEs are classified using severity grades 1–5 according to the MSF severity scale. They use the commonly-accepted (ICH-GCP among others) criteria to classify events as serious: results in death; is life-threatening (places the subject at immediate risk of death from the event as it occurred); results in inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; or is otherwise medically significant: based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. Annex 6: Statistical analysis plans 157 Question 4. In MDR/RR-TB patients, does concomitant use of bedaquiline and delamanid safely improve outcomes when compared with other treatment options in regimens otherwise conforming to current WHO guidelines? Population Intervention Comparator Outcomes MDR/RR-TB patients a. with additional drug resistance patterns b. with XDR-TB c. with severe disease (i.e. cavitary disease on radiography or SS+) d. previously treated with 2nd line drugs or not e. children (0–14y) / adults (adolescents 10–19y if available) f. persons with HIV (+/- ARVs) g. pregnant women h. people with diabetes mellitus i. extrapulmonary disease j. malnutrition – Concomitant use of bedaquiline and delamanid, given for six months of treatment – A regimen without concomitant use of bedaquiline and delamanid for six months of treatment • Successful completion of treatment (or lack of successful completion) • Bacteriological cure by end of treatment • Adherence to treatment (or treatment interruption due to non-adherence) • Treatment failure or relapse • Survival (or death) • Adverse events with anti-TB medicines • Acquisition (amplification) of drug resistance (PICO 4) Adding Delamanid to bedaquiline: specific questions 1. In the EndTB data set are treatment outcomes improved with concomitant use of BDQ and DLM compared to use of BDQ without DLM (in addition to other components of an adequate MDR regimen)? 2. In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved with concomitant use of BDQ and DLM compared to use of other treatment options? Challenges in this analysis: In the EndTB study, DLM use varied between sites, and may have been started at beginning, or given later in therapy, even given as ‘salvage therapy’. If added later, DLM may have been added because of local or individual preference/protocol, or based on response to therapy to that point. Hence, we will begin this analysis with a careful descriptive analysis (as described above as Step 2 for PICO 3) – comparing those who received DLM to those who did not – separately within the EndTB data set. We will also perform the same descriptive analyses for the IPD2019 (where same problems likely applied). This will include an assessment of timing of DLM start, and duration of use. Study population/data sources (PICO 4): IPD-2019. In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 was itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018. WHO consolidated guidelines on tuberculosis: Online annexes158 Hence the IPD-2019 represents an update of the IPD-2018. We anticipate adding data from one national surveillance programs – in South Africa. We will delete the previous records of patients treated in the EndTB observational study, that were included in the IPD-2018, to avoid duplication and overlap with the new data set from EndTB. We may also add two other data sets – provided in response to a public call for data contributions. EndTB: 1094 patients with MDR-TB were treated with bedaquiline- and/or delamanid-containing regimens between 1 April 2015 and 31 March 2017. They were followed as part of an observational study – executed by three NGO’s – PIH, MSF and IRD. Approach As with PICO 3, the approach here will have the same outcomes. We will again observe the distribution of ‘duration’ for people receiving BDQ and DLM to define cut-points to call the duration six-months. We will perform the same descriptive analyses described in Question 1 of PICO 3 for the intervention population receiving BDQ and DLM to six months and perform the same statistical analyses comparing it to the comparator populations of (1) people who received only Bdq; (2) people who received only Dlm; (3) people who received BDQ and Dlm for <6 months and; (4) people who received BDQ and Dlm for more than 6 months. We will limit analyses within EndTB as this data set is the only one with enough detail to adequate control for the numerous time-varying confounders that may influence which patients fell into the intervention group or one of the four comparator groups. Limitations – PICO 4 Many of the same limitations apply to PICO 4 as PICO 3, except that in addition there were fewer patients treated – in IPD2019 or end-TB data sets – limiting ability to match on key confounding covariates and limiting power as well to detect small benefits (or harms). In addition, there may have been even greater selection biases (and immortal time bias) affecting estimates of effect of DLM on outcomes. A6.2 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update Refer to Annex 10: Summaries of unpublished data and analysis plans used for the recommendations in the WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/Annexes_8-10.pdf, accessed 2 March 2019). A6.3 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update Refer to Annex 5: Reports of the systematic reviews (reports on systematic reviews for: adherence interventions in tuberculosis treatment and decentralized treatment and care for multidrug-resistant tuberculosis patients) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/dstb_guidance_2017/en/, accessed 2 March 2019). The systematic reviews have subsequently been published (37,38)
Всемирная организация здравоохранения (ВОЗ / WHO) · Publications
WHO consolidated guidelines on tuberculosis: module 4: treatment: drug-resistant tuberculosis treatment: online annexes
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