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BACKGROUND: Anecdotal information suggests that clinical practice regarding the use of putative hepatoprotective agents in TB treatment varies across countries in the WHO European Region. METHODS: Between November 2023 and May 2024, we conducted a standardised questionnaire survey on the use of putative hepatoprotective agents in patients receiving TB treatment among Tuberculosis Network European Trials Group (TBnet) representatives in countries in the WHO European Region. RESULTS: We received valid responses from 37 of 53 countries (69.8%), with 16 (43.2%) reporting regular use of putative hepatoprotective agents during anti-TB treatment. Half of these countries (n = 8) are part of the former Soviet Union. In five countries, these agents are recommended by national guidelines. The most commonly used hepatoprotective agents were silibin/silymarin (n = 9, 56.3%), ursodeoxycholic acid (n = 5, 31.3%), and soy phospholipids (n = 4, 25.0%). Treatment duration varied, with 56.3% (n = 9) using them for less than 1 month, 18.8% (n = 3) for 1–3 months, and 18.8% (n = 3) for 4–6 months. CONCLUSIONS: Putative hepatoprotective agents are widely used as an adjunct to TB treatment in the WHO European Region, particularly in the countries of the former Soviet Union, some of which have included them in their national guidelines.

In 2022, the WHO European Region accounted for 15.1% of all incident rifampicin-resistant/multidrug-resistant TB (RR/MDR-TB) cases. Most occurred in 18 high-priority countries of eastern Europe and central Asia, many of which joined an initiative led by the WHO Regional Office for Europe. The aim was to introduce three, fully oral, 9-month modified shorter treatment regimens (mSTR) to treat RR/MDR-TB under operational research conditions. The three regimens were: 1) bedaquiline + linezolid + levofloxacin + clofazimine + cycloserine (BdqLzdLfxCfzCs); 2) BdqLzdLfxCfz + delamanid (Dlm) for children over 6 years of age and adults; and 3) DlmLzdLfxCfz for children under 6 years of age. The project aimed to enhance treatment success, facilitate mSTR implementation, promote quality of care and build research capacity, while also contributing to global knowledge on all-oral mSTR use. Between April 2020 and June 2022, >2,800 patients underwent mSTR treatment in the WHO European Region. This unique experience promoted further collaboration with national tuberculosis programmes, health authorities, experts and donors within and outside Europe, with a focus on implementing operational research and improving the quality of care in high TB burden countries of the region. In the hope of encouraging others to adopt this model, we have described the principles of the initiative, its strengths and weaknesses and next steps.

The World Health Organization (WHO) recommends countries introduce new anti-TB drugs in the treatment of multidrug-resistant tuberculosis.The aim of the study is to prospectively evaluate the effectiveness of bedaquiline (and/or delamanid)- containing regimens in a large cohort of consecutive TB patients treated globally.This observational, prospective study is based on data collected and provided by Global Tuberculosis Network (GTN) centres and analysed twice a year.All consecutive patients (including children/adolescents) treated with bedaquiline and/or delamanid were enrolled, and managed according to WHO and national guidelines.Overall, 52 centres from 29 countries/regions in all continents reported 883 patients as of January 31st 2021, 24/29 countries/regions providing data on 100% of their consecutive patients (10–80% in the remaining 5 countries).The drug-resistance pattern of the patients was severe (>30% with extensively drug-resistant -TB; median number of resistant drugs 5 (3−7) in the overall cohort and 6 (4−8) among patients with a final outcome).For the patients with a final outcome (477/883, 54.0%) the median (IQR) number of months of anti-TB treatment was 18 (13−23) (in days 553 (385–678)). The proportion of patients achieving sputum smear and culture conversion ranged from 93.4% and 92.8% respectively (whole cohort) to 89.3% and 88.8% respectively (patients with a final outcome), a median (IQR) time to sputum smear and culture conversion of 58 (30−90) days for the whole cohort and 60 (30−100) for patients with a final outcome and, respectively, of 55 (30−90) and 60 (30−90) days for culture conversion.Of 383 patients treated with bedaquiline but not delamanid, 284 (74.2%) achieved treatment success, while 25 (6.5%) died, 11 (2.9%) failed and 63 (16.5%) were lost to follow-up.

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts.The core published documents and guidelines have been reviewed, including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines.After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities. Keywords: MDR-TB, XDR-TB, Diagnosis, Treatment, Prevention, Rehabilitation of sequelae

Background: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population., Methods: We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230)., Findings: 1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success., Interpretation: Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens., Funding: Unitaid., Competing Interests: Declaration of interests AJG-P reports that his institution receives grant funding from the US National Institutes of Health (NIH) and Unitaid for paediatric studies of bedaquiline, delamanid, pretomanid, clofazimine, moxifloxacin, and levofloxacin. J-JY reports donations of linezolid (Zyvox) from Pfizer, Delamanid (Deltyba) from Otsuka Pharmaceutical, and Rifampicin (Rifampcin) from Yuhan for the for the clinical trials, in which he served as a principal investigator. JF reports grant funding form the Stop TB Partnership's Global Drug Facility. JRC reports grant funding to his institution from the Canadian Institutes of Health, Fonds de recherche du Quebec-Sante, the National Sanatorium Association, and WHO; and consulting fees from WHO, the World Bank, and the Saskatchewan Auditors Office. BSG reports grant funding from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain). GEV reports grant funding from the NIH, US Agency for International Development (USAID), Unitaid, Medecins Sans Frontiers, and Partners in Health; and consulting fees from the Gates Medical Research Institute. RS reports grant funding from the NIH, the Bill and Melinda Gates Foundation, USAID, and from UNITE4TB (Academia and Industry United Innovation and Treatment for Tuberculosis). AS reports participating at the Research Lead at UK Academics and Professionals to end Tuberculosis. All other authors declare no competing interests., (Copyright © 2025 World Health Organization. Published by Elsevier Ltd. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: In 2020, WHO guidelines prioritised the use of a standard fully oral short treatment regimen (STR) consisting of bedaquiline, levofloxacin or moxifloxacin, ethionamide, ethambutol, high-dose isoniazid, pyrazinamide, and clofazimine for the management of rifampicin-resistant tuberculosis. A high prevalence of resistance to constituent drugs precluded its widespread use by countries in the WHO European region. We evaluated three 9-month fully oral modified STRs (mSTRs) in which ethionamide, ethambutol, isoniazid, and pyrazinamide were replaced by linezolid, cycloserine, or delamanid (or a combination)., Methods: This multicountry, prospective, single-arm, cohort study examined the effectiveness and safety of mSTRs for fluoroquinolone-susceptible, rifampicin-resistant pulmonary tuberculosis in 13 countries in the WHO European region during 2020-23. We enrolled adults and children of all ages with bacteriologically confirmed rifampicin-resistant, fluoroquinolone-susceptible pulmonary tuberculosis, and children (aged 0-18 years) with clinically diagnosed disease and a confirmed contact with rifampicin-resistant, fluoroquinolone-susceptible tuberculosis. Participants aged 6 years or older received one of two regimens: bedaquiline, linezolid, levofloxacin, clofazimine, and cycloserine; or bedaquiline, linezolid, levofloxacin, clofazimine, and delamanid. Children younger than 6 years received delamanid, linezolid, levofloxacin, and clofazimine. Participants were followed up for 12 months after successful treatment completion to detect recurrence and death. The primary outcome was the cumulative probability of not having an unsuccessful study outcome (defined as treatment failure, on-treatment loss to follow-up, death, or recurrence) before 22 months of study follow-up. The primary safety outcome was the incidence of each adverse event of interest (peripheral neuropathy, optic neuritis, myelosuppression, hepatitis, prolonged QT interval, hypokalaemia, and acute kidney injury) of grade 3 or higher severity during the treatment course., Findings: Between Aug 28, 2020 and May 26, 2021, 7272 patients were screened and 2636 were included in the treatment cohort. 1966 (74·6%) were male, 670 (25·4%) were female, and median age was 43 years (IQR 33-53). Treatment success was recorded for 2181 (82·7%) participants. The cumulative probability of not having an unsuccessful study outcome 22 months after treatment initiation was 79% (95% CI 78-81). Increasing age (adjusted hazard ratio 2·61 [95% CI 1·70-4·04] for people aged >64 years vs 35-44 years), HIV-positive status (1·53 [1·16-2·01]), presence of bilateral cavities (1·68 [1·29-2·19]), smoking history (1·34 [1·05-1·71]), baseline anaemia (1·46 [1·15-1·86]), unemployment (1·37 [1·04-1·80]), elevated baseline liver enzymes (1·40 [1·13-1·73]), and excessive alcohol use (1·47 [1·14-1·89]) were positively associated with unsuccessful study outcomes. In the safety cohort of 2813 participants who received at least one dose, 301 adverse events of interest were recorded in 252 (9·0%) participants with the most frequent being myelosuppression (139 [4·9%] participants, 157 [52·2%] events)., Interpretation: The high treatment success and good safety results indicate considerable potential for the use of mSTRs in programmatic conditions, especially for individuals not eligible for the current WHO-recommended 6-month regimen and in settings with a need for alternative options., Funding: The Global Fund to Fight AIDS, Tuberculosis and Malaria; United States Agency for International Development; Government of Germany; and WHO., Translation: For the Russian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd. All rights reserved. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

BackgroundEuropean-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.AimWe aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.MethodsThe Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.ResultsData on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.ConclusionsCountry of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

Introduction: Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls., Methods and Analysis: Patients aged 18 years or older with sputum smear and culture-positive pulmonary MDR-TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if >80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM., Ethics and Dissemination: Ethical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal., Trial Registration Number: ClinicalTrials.gov Registry (NCT03409315)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new ( i.e. bedaquiline, delamanid) and repurposed ( i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care., Competing Interests: Conflict of interest: S. Borisov has nothing to disclose. Conflict of interest: E. Danila has nothing to disclose. Conflict of interest: A. Maryandyshev has nothing to disclose. Conflict of interest: M. Dalcolmo has nothing to disclose. Conflict of interest: S. Miliauskas has nothing to disclose. Conflict of interest: L. Kuksa reports personal fees for trial participation from Otsuka and Tibotec, personal fees for lectures from Johnson and Johnson Services Inc., outside the submitted work. Conflict of interest: S. Manga has nothing to disclose. Conflict of interest: A. Skrahina has nothing to disclose. Conflict of interest: S. Diktanas reports personal fees for trial participation from Otsuka, grants for meeting attendance from Janssen (Sirturo), outside the submitted work. Conflict of interest: L.R. Codecasa has nothing to disclose. Conflict of interest: A. Aleksa has nothing to disclose. Conflict of interest: J. Bruchfeld has nothing to disclose. Conflict of interest: A. Koleva has nothing to disclose. Conflict of interest: A. Piubello has nothing to disclose. Conflict of interest: Z.F. Udwadia has nothing to disclose. Conflict of interest: O.W. Akkerman has nothing to disclose. Conflict of interest: E. Belilovski has nothing to disclose. Conflict of interest: E. Bernal has nothing to disclose. Conflict of interest: M.J. Boeree has nothing to disclose. Conflict of interest: J. Cadiñanos Loidi has nothing to disclose. Conflict of interest: Q. Cai has nothing to disclose. Conflict of interest: J.J. Cebrian Gallardo has nothing to disclose. Conflict of interest: M. Dara has nothing to disclose. Conflict of interest: E. Davidavičienė has nothing to disclose. Conflict of interest: L. Davies Forsman has nothing to disclose. Conflict of interest: J. De Los Rios has nothing to disclose. Conflict of interest: J. Denholm has nothing to disclose. Conflict of interest: J. Drakšienė has nothing to disclose. Conflict of interest: R. Duarte has nothing to disclose. Conflict of interest: S.E. Elamin has nothing to disclose. Conflict of interest: N. Escobar Salinas has nothing to disclose. Conflict of interest: M. Ferrarese has nothing to disclose. Conflict of interest: A. Filippov has nothing to disclose. Conflict of interest: A. Garcia has nothing to disclose. Conflict of interest: J.M. García-García has nothing to disclose. Conflict of interest: I. Gaudiesiute has nothing to disclose. Conflict of interest: B. Gavazova has nothing to disclose. Conflict of interest: R. Gayoso has nothing to disclose. Conflict of interest: R. Gomez Rosso has nothing to disclose. Conflict of interest: V. Gruslys has nothing to disclose. Conflict of interest: G. Gualano has nothing to disclose. Conflict of interest: W. Hoefsloot has nothing to disclose. Conflict of interest: J. Jonsson has nothing to disclose. Conflict of interest: E. Khimova has nothing to disclose. Conflict of interest: H. Kunst has nothing to disclose. Conflict of interest: R. Laniado-Laborín has nothing to disclose. Conflict of interest: Y. Li has nothing to disclose. Conflict of interest: C. Magis-Escurra has nothing to disclose. Conflict of interest: V. Manfrin has nothing to disclose. Conflict of interest: V. Marchese has nothing to disclose. Conflict of interest: E. Martínez Robles has nothing to disclose. Conflict of interest: A. Matteelli has nothing to disclose. Conflict of interest: J. Mazza-Stalder has nothing to disclose. Conflict of interest: C. Moschos has nothing to disclose. Conflict of interest: M. Muñoz-Torrico has nothing to disclose. Conflict of interest: H. Mustafa Hamdan has nothing to disclose. Conflict of interest: B. Nakčerienė has nothing to disclose. Conflict of interest: L. Nicod has nothing to disclose. Conflict of interest: M. Nieto Marcos has nothing to disclose. Conflict of interest: D.J. Palmero has nothing to disclose. Conflict of interest: F. Palmieri has nothing to disclose. Conflict of interest: A. Papavasileiou has nothing to disclose. Conflict of interest: M-C. Payen has nothing to disclose. Conflict of interest: A. Pontarelli has nothing to disclose. Conflict of interest: S. Quirós has nothing to disclose. Conflict of interest: A. Rendon has nothing to disclose. Conflict of interest: L. Saderi has nothing to disclose. Conflict of interest: A. Šmite has nothing to disclose. Conflict of interest: I. Solovic has nothing to disclose. Conflict of interest: M.B. Souleymane has nothing to disclose. Conflict of interest: M. Tadolini has nothing to disclose. Conflict of interest: M. van den Boom has nothing to disclose. Conflict of interest: M. Vescovo has nothing to disclose. Conflict of interest: P. Viggiani has nothing to disclose. Conflict of interest: A. Yedilbayev has nothing to disclose. Conflict of interest: R. Zablockis has nothing to disclose. Conflict of interest: D. Zhurkin has nothing to disclose. Conflict of interest: M. Zignol has nothing to disclose. Conflict of interest: D. Visca has nothing to disclose. Conflict of interest: A. Spanevello has nothing to disclose. Conflict of interest: J.A. Caminero has nothing to disclose. Conflict of interest: J-W. Alffenaar has nothing to disclose. Conflict of interest: S. Tiberi has nothing to disclose. Conflict of interest: R. Centis has nothing to disclose. Conflict of interest: L. D'Ambrosio has nothing to disclose. Conflict of interest: E. Pontali has nothing to disclose. Conflict of interest: G. Sotgiu has nothing to disclose. Conflict of interest: G.B. Migliori has nothing to disclose., (Copyright ©ERS 2019.)

The World Health Organization (WHO) defines palliative care as the prevention and relief of the physical, psychological, social and spiritual suffering of adults and children with life-threatening illnesses and psycho-social support for their families. Palliative care and symptom relief (PCSR) also addresses suffering in nonlife-threatening situations such as after cure. PCSR should never be considered a substitute for tuberculosis (TB) prevention and treatment, but should be accessible by everyone in need. PCSR can reduce suffering and improve quality of life of patients with end-stage chronic illnesses while reducing costs for health care systems and providing financial risk protection for patients' families. It also may help enable patients to adhere to long and noxious treatments and thereby reduce mortality and help protect public health. Basic PCSR can be taught easily to TB specialists as well as primary care clinicians and delivered in hospitals, clinics or patients' homes combined with infection control. For these reasons, integration of PCSR into multidrug-resistant (MDR) and extensively drug-resistant TB (XDR-TB) treatment programs is medically and morally imperative. We propose an essential package of PCSR for people with M/XDR-TB that includes a set of safe, effective and inexpensive medicines and equipment, social supports for patients and caregivers living in extreme poverty, and necessary human resources. The package aligns with WHO guidance on programmatic management of drug-resistant (DR) TB and should be universally accessible by people affected by M/XDR-TB. We also describe the ethical practice of PCSR for people with M/XDR-TB and identify needed areas of research in PCSR for people with M/XDR-TB.

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis., Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration., Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I 2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses., Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition., Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Few studies have examined whether the Xpert MTB/RIF test improves time to treatment initiation for persons with multidrug-resistant tuberculosis (MDR TB). We determined the impact of this test in Latvia, where it was introduced in 2010. After descriptive analyses of pulmonary MDR TB patients in Latvia during 2009-2012, time to treatment initiation was calculated, and univariate and multivariable accelerated failure time models were constructed. Univariate results showed strong evidence of an association between having rifampin-resistant TB detected by Xpert MTB/RIF and reduced time to treatment initiation versus the test not being used. A multivariable model stratifying by previous TB showed similar results. Our finding that in Latvia, time to treatment initiation was decreased for MDR TB cases that were rifampin-resistant TB by XpertMTB/RIF has implications for the use of this test in other settings with a high burden of MDR TB in which rifampin resistance is highly predictive of MDR TB.

Background: Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined., Methods: Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens., Results: Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from ≤1 to ≥5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome., Conclusions: Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance., (Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Setting: Drug-resistant tuberculosis (TB) is an important public health problem in Latvia., Objective: To document trends, characteristics and treatment outcomes of registered patients with multi-drug-resistant (MDR-) and extensively drug-resistant (XDR-) TB in Latvia from 2000 to 2010., Design: A retrospective national cohort study., Results: Of 1779 patients, 1646 (92%) had MDR- and 133 (8%) XDR-TB. Over 11 years, the proportion of XDR-TB among MDR-TB patients increased from 2% to 18%. Compared to MDR-TB patients, those with XDR-TB were significantly more likely to have failed MDR-TB treatment (OR 8.4, 95%CI 4.3-16.2), have human immunodeficiency virus infection (OR 3.2, 95%CI 1.8-5.7), be illegal drug users (OR 5.7, 95%CI 2.6-11.6) or have had contact with MDR-TB patients (OR 1.9, 95%CI 1.3-2.8). Cure rates for XDR-TB were 50%. Compared with MDR-TB patients, those with XDR-TB had a higher risk of treatment failure (29% vs. 8%, respectively, P < 0.001). Unfavourable treatment outcomes were significantly associated with being male; having smear-positive disease; pulmonary cavities; failure, default or relapse after previous MDR-TB treatment; and a history of incarceration., Conclusion: More MDR-TB in Latvia is now also XDR-TB. This study identified several risk factors for XDR-TB and, for unfavourable treatment outcomes, highlighting the importance of early diagnosis and appropriate management of MDR-/XDR-TB.

Background: Increasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance., Methods: To assess the GLC's impact, we followed adults with pulmonary MDR tuberculosis from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLDs) in 9 countries that volunteered to participate, 5 countries that met GLC criteria, and 4 countries that did not apply to the GLC., Results: In total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLIs). The relative risk (95% confidence interval [CI]) of acquired resistance was lower at GLC-approved sites: 0.27 (.16-.47) for XDR tuberculosis, 0.28 (.17-.45) for FQ, and 0.15 (.06-.39) to 0.60 (.34-1.05) for 3 different SLIs. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios (95% CIs) were 0.21 (.07-.62) for acquired XDR tuberculosis and 0.23 (.09-.59) for acquired FQ resistance., Conclusions: Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries., Methods: From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis., Findings: Among 1278 patients, 43·7% showed resistance to at least one second-line drug, 20·0% to at least one second-line injectable drug, and 12·9% to at least one fluoroquinolone. 6·7% of patients had XDR tuberculosis (range across study sites 0·8-15·2%). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries., Interpretation: Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies., Funding: US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Setting: Latvia has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) globally. Clinical management of MDR-TB requires lengthy multidrug regimens that often cause adverse events., Design: We retrospectively reviewed records of patients who began MDR-TB treatment between 2000 and 2004. Treatment-related adverse events and factors associated with experiencing adverse events were evaluated. We also examined the frequency of and reasons for changing drug regimens., Results: Among 1027 cases, 807 (79%) experienced at least one adverse event, with a median of three events per case. The most commonly reported events were nausea (58%), vomiting (39%) and abdominal pain (24%). More serious events, such as psychiatric episodes (13%), hepatitis (9%) and renal failure (4%), were relatively frequent. A change in drug dose due to an adverse event occurred in 201 (20%) cases, while 661 (64%) had at least one drug discontinued temporarily or permanently. Being older, female, having bilateral lung cavities and a greater number of TB symptoms at baseline were associated with an increased number of events., Conclusion: Adverse events were prevalent among MDR-TB cases treated in Latvia, with over two thirds requiring discontinuation of at least one drug. MDR-TB patients who are female, older or have severe TB disease should be closely monitored for treatment-related adverse events.