Candidate anti-tuberculosis medicines and regimens under clinical evaluation.

BACKGROUND: Tuberculosis (TB) is the leading cause of mortality by an infectious disease worldwide. Despite national and international efforts, the world is not on track to end TB by 2030. Antibiotic treatment of TB is longer than for most infectious diseases and is complicated by frequent adverse events. To counter emerging Mycobacterium tuberculosis drug resistance and provide effective, safe drug treatments of shorter duration, novel anti-TB medicines, and treatment regimens are needed. Through a joint global effort, more candidate medicines are in the clinical phases of drug development than ever before. OBJECTIVES: To review anti-TB medicines and treatment regimens under clinical evaluation for the future treatment of drug-susceptible and drug-resistant TB. SOURCES: Pre-clinical and clinical studies on novel anti-TB drugs. CONTENT: Description of novel protein synthesis inhibitors (oxazolidinones and oxaboroles), respiratory chain inhibitors (diarylquinolines and cytochrome bc1 complex inhibitor), cell wall inhibitors (decaprenylphosphoryl-ß-d-ribose 2'-epimerase, inhibitors, thioamides, and carbapenems), and cholesterol metabolism inhibitor currently evaluated in clinical trials and novel clinical trial platforms for the evaluation of treatment regimens, rather than single entities. IMPLICATIONS: A large number of potential anti-TB candidate medicines and innovations in clinical trial design for the evaluation of regimens, rather than single medicines, provide hope for improvements in the treatment of TB.

Rationale and Purpose: The FLUTE Study to Evaluate Fluorography Mass Screening for Tuberculosis and Other Diseases, as Conducted in Eastern Europe and Central Asia Countries.

In Belarus and several EECA countries, periodic population-based chest X-ray "fluorography programme" use as a mass screening tool for the diagnosis of tuberculosis (TB) has been used for decades. This mass screening has also often been justified for the early detection of lung cancer (LC), although no mortality benefits were demonstrated by screening with chest X-ray in international randomized trials. In Belarus, fluorography testing is mandatory every one to three years for all adults depending on age and the so-called "risk groups". The World Bank and WHO estimate that Belarus spends USD11 million annually on mass fluorography screening and advocate for more targeted screening approaches to increase diagnostic yield for TB and not to use it for screening for LC. The study is a retrospective review of medical records to assess the yield of fluorography to detect true cases of LC and/or TB in asymptomatic patients in two rural and two urban districts in Belarus for 2015-2017 with positive screening results for presumed of TB or LC. The study provided the rationale to implement the improved policy and practices regarding the role of fluorography in the early detection of LC and TB in Belarus and elsewhere.

Integrated use of laboratory services for multiple infectious diseases in the WHO European Region during the COVID-19 pandemic and beyond.

Technical advances in diagnostic techniques have permitted the possibility of multi-disease-based approaches for diagnosis and treatment monitoring of several infectious diseases, including tuberculosis (TB), human immunodeficiency virus (HIV), viral hepatitis and sexually transmitted infections (STI). However, in many countries, diagnosis and monitoring, as well as disease response programs, still operate as vertical systems, potentially causing delay in diagnosis and burden to patients and preventing the optimal use of available resources. With countries facing both human and financial resource constraints, during the COVID-19 pandemic even more than before, it is important that available resources are used as efficiently as possible, potential synergies are leveraged to maximise benefit for patients, continued provision of essential health services is ensured. For the infectious diseases, TB, HIV, hepatitis C (HCV) and STI, sharing devices and integrated services starting with rapid, quality-assured, and complete diagnostic services is beneficial for the continued development of adequate, efficient and effective treatment strategies. Here we explore the current and future potential (as well as some concerns), importance, implications and necessary implementation steps for the use of platforms for multi-disease testing for TB, HIV, HCV, STI and potentially other infectious diseases, including emerging pathogens, using the example of the COVID-19 pandemic.

Factors Associated with Unfavourable Treatment Outcomes in Patients with Tuberculosis: A 16-Year Cohort Study (2005-2020), Republic of Karakalpakstan, Uzbekistan.

Tuberculosis (TB) remains a public health burden in the Republic of Karakalpakstan, Uzbekistan. This region-wide retrospective cohort study reports the treatment outcomes of patients registered in the TB electronic register and treated with first-line drugs in the TB Programme of the Republic of Karakalpakstan from 2005-2020 and factors associated with unfavourable outcomes. Among 35,122 registered patients, 24,394 (69%) patients were adults, 2339 (7%) were children, 18,032 (51%) were male and 19,774 (68%) lived in rural areas. Of these patients, 29,130 (83%) had pulmonary TB and 7497 (>22%) had been previously treated. There were 7440 (21%) patients who had unfavourable treatment outcomes. Factors associated with unfavourable treatment outcomes included: increasing age, living in certain parts of the republic, disability, pensioner status, unemployment, being HIV-positive, having pulmonary TB, and receiving category II treatment. Factors associated with death included: being adult and elderly, living in certain parts of the republic, having a disability, pensioner status, being HIV-positive, and receiving category II treatment. Factors associated with failure included: being adolescent, female, having pulmonary TB. Factors associated with loss to follow-up included: being male, disability, pensioner status, unemployment, receiving category II treatment. In summary, there are sub-groups of patients who need special attention in order to decrease unfavourable treatment outcomes.

Operational Research to Inform Programmatic Approaches to the Management of Tuberculosis in Uzbekistan.

Globally, an estimated 10 million people fell ill with tuberculosis (TB) in 2019, a number that has been declining very slowly in recent years [...].

Tuberculosis Notification Trends and Treatment Outcomes in Penitentiary and Civilian Health Care Sectors in the WHO European Region.

SETTING: Tuberculosis (TB) morbidity in penitentiary sectors is one of the major barriers to ending TB in the World Health Organization (WHO) European Region. OBJECTIVES AND DESIGN: a comparative analysis of TB notification rates during 2014-2018 and of treatment outcomes in the civilian and penitentiary sectors in the WHO European Region, with an assessment of risks of developing TB among people experience incarceration. RESULTS: in the WHO European Region, incident TB rates in inmates were 4-24 times higher than in the civilian population. In 12 eastern Europe and central Asia (EECA) countries, inmates compared to civilians had higher relative risks of developing TB (RR = 25) than in the rest of the region (RR = 11), with the highest rates reported in inmates in Azerbaijan, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation, and Ukraine. The average annual change in TB notification rates between 2014 and 2018 was -7.0% in the civilian sector and -10.9% in the penitentiary sector. A total of 15 countries achieved treatment success rates of over 85% for new penitentiary sector TB patients, the target for the WHO European Region. In 10 countries, there were no significant differences in treatment outcomes between civilian and penitentiary sectors. CONCLUSION: 42 out of 53 (79%) WHO European Region countries reported TB data for the selected time periods. Most countries in the region achieved a substantial decline in TB burden in prisons, which indicates the effectiveness of recent interventions in correctional institutions. Nevertheless, people who experience incarceration remain an at-risk population for acquiring infection, developing active disease and unfavourable treatment outcomes. Therefore, TB prevention and care practices in inmates need to be improved.

Early COVID-19 pandemic's toll on tuberculosis services, WHO European Region, January to June 2020.

BackgroundEssential health services, including for tuberculosis (TB), are being affected by public health and social measures (PHSM) introduced to control COVID-19. In many settings, TB resources, facilities and equipment are being redirected towards COVID-19 response.AimWe sought to assess the COVID-19 pandemic's impact on TB services in the World Health Organization (WHO) European Region.MethodsThe fifty-three European Region Member States were asked to report qualitative and quantitative data in quarter one and two (Q1 and Q2) 2020. TB notifications were triangulated with the severity score on domestic movement restrictions to assess how they may have influenced TB detection.ResultsTwenty-nine countries reported monthly TB notifications for the first half of 2019 and 2020. TB notifications decreased by 35.5% during Q2 2020 compared with Q2 2019, which is six-fold more than the average annual decrease of 5.1% documented during 2015-2019. The number of patients enrolled in rifampicin-resistant/multidrug-resistant TB treatment also decreased dramatically in Q2 2020, by 33.5%. The highest movement restriction severity score was observed between April and May 2020, which coincided with the highest observed decrease in TB notifications.ConclusionA decrease in TB detection and enrolment to treatment may cause increases in TB burden and threatens the Region's ability to reach the TB targets of the 2030 Sustainable Development Goals, still this might be mitigated with rapid restoration of TB services and the implementation of targeted interventions during periods with severe PHSM in place, such as those introduced in response to the COVID-19 pandemic.

Operational research as an instrument to address the critical gaps for effective treatment of tuberculosis in eastern Europe and central Asia.

Editorial.

Factors associated with culture conversion among adults treated for pulmonary extensively drug-resistant tuberculosis during 2018-2019 in the Russian Federation: an observational cohort study.

Treatment outcomes for Multidrug/Rifampicin-Resistant Tuberculosis (MDR/RR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) remain poor across the globe and in the Russian Federation. Treatment of XDR-TB is challenging for programmes and patients often resulting in low success rates and onward transmission of drug-resistant strains. Analysis of factors affecting culture conversion rate among XDR-TB patients may serve as a basis for optimization of treatment regimens. We conducted a retrospective cohort study using health records from 54 patients with pulmonary XDR-TB treated at a tertiary level facility in the Russian Federation. The study population included adult patients with culture-positive pulmonary XDR-TB who started treatment between 1 January 2018-30 June 2019. Culture conversion was defined as two consecutive negative cultures, collected at least 30 days apart. The date of sputum culture conversion was taken from the first of two consecutive negative sputum cultures fulfilling these criteria. We measured time to culture conversion using cumulative incidence functions accounting for competing risks and applied binary cause-specific Cox regressions to assess associated factors. Sputum culture conversion was recorded for 43 (79.6%) patients. Median time to culture conversion adjusted for competing risk of loss to follow up was 4 months [95% confidence interval (CI): 2-5]. The number of patients who had culture converted by treatment months 2, 4, and 6 were 12 (22%), 29 (54%) and 38 (70%) respectively. In unadjusted analysis, positive baseline sputum smear microscopy [hazard ratio (HR): 0.34, 95% CI: 0.18-0.66; p=0.001), hepatitis C (HR: 0.35, 95% CI: 0.14-0.89; p=0.023], and human immunodeficiency virus (HR: 0.30 95%, CI: 0.09-0.97; p=0.045), and receipt of fewer than 4 effective drugs in the treatment regimen (HR: 0.13, 95% CI: 0.03-0.60; p=0.009) were associated with delayed culture conversion. When compared to their combined use, patients receiving regimens with bedaquiline only (HR: 0.12, 95% CI: 0.03-0.49; p=0.003) or linezolid only (HR: 0.21, 95% CI: 0.06-0.69; p=0.010) were less likely to achieve timely culture conversion. Factors delaying sputum culture conversion should be considered in the management of patients with XDR-TB and considered by clinicians for regimen design and treatment strategies. Our study outlines the importance of simultaneous inclusion of bedaquiline and linezolid in treatment regimens for patients with XDR-TB to reduce time to sputum conversion and increase treatment success.

Economic, Mental Health, HIV Prevention and HIV Treatment Impacts of COVID-19 and the COVID-19 Response on a Global Sample of Cisgender Gay Men and Other Men Who Have Sex with Men.

There is an urgent need to measure the impacts of COVID-19 among gay men and other men who have sex with men (MSM). We conducted a cross-sectional survey with a global sample of gay men and other MSM (n = 2732) from April 16, 2020 to May 4, 2020, through a social networking app. We characterized the economic, mental health, HIV prevention and HIV treatment impacts of COVID-19 and the COVID-19 response, and examined whether sub-groups of our study population are disproportionately impacted by COVID-19. Many gay men and other MSM not only reported economic and mental health consequences, but also interruptions to HIV prevention and testing, and HIV care and treatment services. These consequences were significantly greater among people living with HIV, racial/ethnic minorities, immigrants, sex workers, and socio-economically disadvantaged groups. These findings highlight the urgent need to mitigate the negative impacts of COVID-19 among gay men and other MSM.

RESUMEN: Existe una necesidad urgente para medir los impactos de COVID-19 entre hombres gay y otros hombres que tienen sexo con hombres (HSH). Hemos conducido una encuesta multifuncional con una prueba mundial de hombres gay y otros HSH (n = 2732) desde el 16 de Abril hasta el 4 de Mayo del 2020, a través de una aplicación de red social. Nosotros caracterizamos los impactos económicos, de salud mental, prevención del VIH y tratamiento del VIH e impactos a COVID-19 y la respuesta de COVID-19, y examinamos si subgrupos de nuestra población de estudio fueron impactados desproporcionadamente por COVID-19. Muchos hombres no tan solo reportaron consecuencias económicas y de salud mental, sino también interrupciones de prevención y de pruebas de VIH, y cuidado del VIH y servicios de tratamiento. Encontramos consecuencias más significantes entre personas viviendo con VIH, grupos raciales/etnicos, migrantes, sexo servidores, y groupos socioeconomicamente disfavorecidos. Los resultados subrayan la necesidad crucial de mitigar los impactos multifacéticos de COVID-19 entre los hombres homosexuales y otros HSH, especialmente para aquellos con vulnerabilidades entrelazadas.

Drug-resistant tuberculosis in eastern Europe and central Asia: a time-series analysis of routine surveillance data.

BACKGROUND: Among all WHO regions, the WHO European Region has the highest proportion of drug-resistant tuberculosis among new and retreated cases. The 18 high-priority countries in eastern Europe and central Asia account for 85% of the tuberculosis incidence and more than 90% of drug-resistant tuberculosis cases emerging in the region. We aimed to analyse time-series trends in notification rates of drug-resistant tuberculosis among new tuberculosis cases in the 18 high-priority countries in the WHO European Region. METHODS: We used country data stored in WHO's global tuberculosis database. For each country, we calculated annual notification rates per 100 000 population of new tuberculosis cases and of drug-resistant tuberculosis among new cases reported from Jan 1, 2000, to Dec 31, 2017. We computed annual percentage changes of notification rates and identified time-points of significant change in trends using the joinpoint regression method. FINDINGS: All 17 countries with data (no data available from Turkmenistan) showed a significant decline in new tuberculosis notification rates in the most recent years since the last joinpoint if one was identified. Notification rates of drug-resistant tuberculosis showed diverse trends, with substantial year-to-year variation. In the most recent years, notification rates of drug-resistant tuberculosis among new tuberculosis cases were decreasing in two countries (Estonia and Latvia), increasing in eight countries (Azerbaijan, Kyrgyzstan, Moldova [Republic of Moldova], Romania, Russia [Russian Federation], Tajikistan, Ukraine, and Uzbekistan), and stable in seven countries (Armenia, Belarus, Bulgaria, Georgia, Kazakhstan, Lithuania, and Turkey). INTERPRETATION: Our findings suggest that countries in the WHO European Region are more successful in controlling drug-susceptible tuberculosis than drug-resistant forms, and as a result, the proportion of drug-resistant strains among newly notified patients with tuberculosis is increasing in many settings. Two countries showed that it is possible to decrease incidence of both drug-susceptible and drug-resistant tuberculosis. If no additional efforts are made in prevention and care of patients with drug-resistant tuberculosis, further decline of the tuberculosis burden will be halted. Further studies are needed to investigate the success stories and document the most effective interventions to reach the target to end tuberculosis by 2030. FUNDING: United States Agency for International Development.

Tuberculosis, HIV, and viral hepatitis diagnostics in eastern Europe and central Asia: high time for integrated and people-centred services.

Globally, high rates (and in the WHO European region an increasing prevalence) of co-infection with tuberculosis and HIV and HIV and hepatitis C virus exist. In eastern European and central Asian countries, the tuberculosis, HIV, and viral hepatitis programmes, including diagnostic services, are separate vertical structures. In this Personal View, we consider underlying reasons for the poor integration for these diseases, particularly in the WHO European region, and how to address this with an initial focus on diagnostic services. In part, this low integration has reflected different diagnostic development histories, global funding sources, and sample types used for diagnosis (eg, typically sputum for tuberculosis and blood for HIV and hepatitis C). Cooperation between services improved as patients with tuberculosis needed routine testing for HIV and vice versa, but financial, infection control, and logistical barriers remain. Multidisease diagnostic platforms exist, but to be used optimally, appropriate staff training and sensible understanding of different laboratory and infection control risks needs rapid implementation. Technically these ideas are all feasible. Poor coordination between these vertical systems remains unhelpful. There is a need to increase political and operational integration of diagnostic and treatment services and bring them closer to patients.

HIV among women in the WHO European Region - epidemiological trends and predictors of late diagnosis, 2009-2018.

Human immunodeficiency virus (HIV) transmission among women remains an issue in the WHO European Region, with nearly 50,000 women diagnosed in 2018 and over half (54%) diagnosed late. Although new HIV diagnoses declined between 2009 and 2018 in the West of the Region, they increased in the Centre and East. Understanding the characteristics of women diagnosed with HIV can inform gender-sensitive prevention services including pre-exposure prophylaxis and early testing and linkage to care.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.

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.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study.

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.

Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe.

Evidence-based guidance is needed on 1) how tuberculosis (TB) infectiousness evolves in response to effective treatment and 2) how the TB infection risk can be minimised to help countries to implement community-based, outpatient-based care.This document aims to 1) review the available evidence on how quickly TB infectiousness responds to effective treatment (and which factors can lower or boost infectiousness), 2) review policy options on the infectiousness of TB patients relevant to the World Health Organization European Region, 3) define limitations of the available evidence and 4) provide recommendations for further research.The consensus document aims to target all professionals dealing with TB (e.g TB specialists, pulmonologists, infectious disease specialists, primary healthcare professionals, and other clinical and public health professionals), as well as health staff working in settings where TB infection is prevalent.

Prioritising children and adolescents in the tuberculosis response of the WHO European Region.

In 2017, in recognition of the challenges faced by Member States in managing childhood and adolescent tuberculosis (TB) at a country level, the WHO Regional Office for Europe held a Regional Consultation. In total, 35 countries participated in the consultations representing both high- and low-incidence Member States. Here, we provide an overview of the existing World Health Organization (WHO) documents and guidelines on childhood and adolescent TB and describe the outcomes of this regional meeting. National childhood and adolescent TB guidelines are available in 25% of Member States, while 33% reported that no such guidelines are at hand. In the majority of countries (83%), childhood and adolescent TB is part of the National Strategic Plan. The most pressing challenges in managing paediatric TB comprise the lack of adequate drug formulations, the difficult diagnosis, and treatment of presumed latent TB infection. Investments into childhood and adolescent TB need to be further advocated to achieve the End TB goals set by WHO to eliminate TB by 2030.