Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023. RESULTS: 24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries. CONCLUSION: Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe.

Tuberculosis incidence in foreign-born people residing in European countries in 2020.

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.

The Bidirectional Relationship between Pulmonary Tuberculosis and Lung Cancer.

Lung cancer and pulmonary tuberculosis are two significant public health problems that continue to take millions of lives each year. They may have similar symptoms and, in some cases, are diagnosed simultaneously or may have a causal relationship. In tuberculosis disease, the chronic inflammation, different produced molecules, genomic changes, and fibrosis are believed to be important factors that may promote carcinogenesis. As a reverse reaction, the development of carcinogenesis and the treatment may induce the reactivation of latent tuberculosis infection. Moreover, the recently used checkpoint inhibitors are a debatable subject since they help treat lung cancer but may lead to the reactivation of pulmonary tuberculosis and checkpoint-induced pneumonitis. Pulmonary rehabilitation is an effective intervention in post-tuberculosis patients and lung cancer patients and should be recommended to improve outcomes in these pathologies.

Diagnostic performance of the AID line probe assay in the detection of Mycobacterium tuberculosis and drug resistance in Romanian patients with presumed TB.

BACKGROUND: The AID line probe assay has shown promising evaluation data on the detection of Mycobacterium tuberculosis as well as 1st- and 2nd-line drug resistance, using isolates and selected clinical samples in previous studies. METHODS: The diagnostic performance of three AID-modules (AID INH/RIF, AID FQ/EMB and AID AG) was analyzed in sputum samples from patients with presumed tuberculosis against culture methods and phenotypic drug resistance as reference standards. RESULTS: 59 patients had culture-confirmed tuberculosis. All AID modules showed moderate sensitivity (46/59, 78.0%, 65.3-87.7) and very good specificity (100%, 95.5%, 93.7%). There was a high proportion of invalid tests, resulting in 32.6%, 78.3% and 19.6% of 46 AID-positive tuberculosis cases, who could not be assessed for drug resistance by the AID INH/RIF-, AID FQ/EM- and AID AG-module, respectively. A small number of patients showed drug resistance by reference standards: Three MDR-TB cases plus three, one and one patients with resistance to streptomycin, fluoroquinolones and aminoglycosides, respectively. The AID-assay detected all MDR-TB cases, two of three streptomycin-resistant TB cases, one of one of fluoroquinolone-resistant and missed one aminoglycoside-resistant TB case. DISCUSSION: The high proportion of invalid results precludes the use of the AID-assay from direct sputum-based tuberculosis and drug-resistance testing.

Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model.

BACKGROUND: The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB. METHODS: Adult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points. RESULTS: 50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9-0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001). CONCLUSION: Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.

Drug Susceptibility Patterns in MDR-TB Patients: Challenges for Future Regimen Design. A Cross-Sectional Study.

Globally, there is substantial concern regarding the challenges of treating complex drug resistance patterns in multidrug resistant tuberculosis cases. Utilising data from three different settings (Estonia, Latvia, Romania) we sought to contrast drug susceptibility profiles for multidrug resistant tuberculosis cases, highlight the difficulties in designing universal regimen, and inform future regimen selection. Demographic and microbiological surveillance data for multidrug resistant tuberculosis cases from 2004-13 were analysed. High levels of additional resistance to currently recommended second line drugs were seen in all settings, with extensive variability between countries. Accurate drug susceptibility testing and drug susceptibility testing data are vital to inform the development of comprehensive, flexible, multidrug resistant tuberculosis guidance.

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.

[Tuberculosis continues to be a concern]. / Tuberculoza, în continuare în atentie.

Tuberculosis (TB) has not been eliminated from none of the world's regions up to now. Trends of TB endemic were constantly favorable in Romania in the recent years: number of new cases and relapses decreased with 13 235, incidence rate with 42%, incidence rate in children with 51% and mortality rate with 44%, from 2002 to 2011. The highest TB risk is being observed in men living in rural area and in those of 45-54 age group. The counties with the highest TB incidence rates are those in the South-West part of the country. The favorable trend of TB endemic in Romania has been achieved through a constant case detection rate over 70% and a treatment success rate over 80% in the recent years. The current major concerns in TB control in the country, as well as all over the world, are TB-HIV co-infection and micobacterial drug-resistance. Also, a negative aspect of TB endemic in Romania is that a number of severe forms of TB, TB-HIV, MDR-TB or deaths are still reported in children under 15 years old, each year. The response of health system to the TB problem consists in the development of the National TB Programme, which achieved many successes in the recent years, but in the same time is confronted with many challenges. However, the programatic control of the disease can be obtained by health services only in partnership with other services, institutions and organizations, which may offer economic and social support to the patients and their families.

[Tuberculosis in Romania. Problems and solutions]. / Tuberculoza in România. Probleme si solutii.

UNLABELLED: The analysis of the Management Unit of the National TB Programme (NTP) database, together with the reports of the TB county managers, allowed to the authors to identify some weaknesses of TB control in Romania in the recent years and to propose the appropriate measures. PROBLEMS: The marked decrease in the reduction of TB cases reported annually from 2,761 in 2005-2006, to 145 in 2007-2008 and the stagnation of mortality rate: 7.5 per ten thousand in 2007 and 7.6 per ten thousand in 2008. Deficiencies in data recording and reporting through informatic system of the NTP. Lack of financial resources for system maintenance and upgrade. Deficiencies in monitoring and control of mycobacterium resistance to antituberculous drugs phenomenon at national level. Sensitivity testing only for a small percentage of culture confirmed new TB cases (21%). Higher percentage of MDR in new TB cases compared to the results of national survey of mycobacterium drug resistance 2003-2004. Lack of personnel: 16 TB dispensaries without any pulmonologist, vacancies for 259 doctors, 436 nurses and 433 auxiliary personnel. Important deficiencies in the NTP network's infrastructure and logistics countrywide. Discontinuities in the supply with first and second line antituberculous drugs resulting in interruption of treatments. Lack of an officially endorsed protocol for the diagnosis, treatment and monitoring of cases with TB/HIV co-infection. Solutions: Revitalization of monitoring-supervision activities of the NTP running countrywide, provision with necessary financial resources to perform the scheduled visits in counties. Providing maintenance and upgrade of the informatic system for data collection. Implementation of the necessary measures in order to attract and maintain the personnel in the NTP network. Conduct the national survey of mycobacterium susceptibility to first and second line antituberculous drugs and drug susceptibility testing of the most culture confirmed TB cases. Restore the centralized procurement of TB drugs. Finalization and official endorsement of the protocol for TB/HIV co-infection initiated in 2004.

[National Program for TB Control (NPTC): report of 2005 activities, evolution of endemic disease, challenges, priorities]. / Programul national de control al tuberculozei (PNCT): raportul activitatilor desfasurate în anul 2005, evolutia endemiei, probleme, prioritati.

The authors analyze the current status of anti-TB activity in Romania, in which several factors are involved: the pneumo-phthisiology network, the central unit (M. Nasta Institute of Pneumology), the Health Insurance, Health Ministry as well as international funding and technical assistance units (Global Fund, World Health Organisation). Current TB incidence data are reviewed, as well as the events in NPTC during 2005: training of the personnel involved in TB care (pneumologists and general practitioners, nurses, laboratory staff), improving TB care in risk groups (children, inmates, HIV positives, gypsies), improving the functionality of bK laboratory network, improving access of multidrug resistant TB patients to good quality services, improving the system for acquiring and distributing medication, developing a functional system for monitoring the NPTC, integrating TB in the national system for transmissible diseases survey, elaborating guidelines on different aspects of TB care. In 2005, WHO performed an evaluation mission in Romania, finally proposing solutions for current issues: the Government Decision of the NPTC actions, establishing the status of the county NPTC managers, using incentives for patients, improving drug management by application to international organisms, increasing the personnel numbers in national reference laboratories, improving the informational circuits between factors involved in NPTC.

[The tuberculosis endemy in Bucharest, Romania, in 2005]. / Aspecte ale endemiei de tuberculoza în municipiul Bucuresti în anul 2005.

In Bucharest, TB incidence (new cases + relapses) was 65.9 per thousand in 1985. After that, it increased every year, reaching 154.1 per thousand in 2001. In the last 4 years the incidence decreased to 120 per thousand, meaning a decrease rate of 22% in this interval. In 2005, incidence ranged between 91 per thousand in Sector 1, and 138.7 per thousand in Sector 5. Among all patients registered in 2005, 86.1% were new cases and 13.9% relapses. One noted also a decrease of TB incidence in children, from 65.2 per thousand in 2002 to 27.8 per thousand in 2005. Progressive extension of DOTS in the whole city led to a success rate for "source" patients of 88.7% in 2004 (new pulmonary TB cases, smear positive). The late discovery of some cases and failure of re-treatments explain mainly the fact that, between 2002 and 2004, in Bucharest were registered about 200 TB deaths every year. Tuberculosis continues to be one of the main public health problems in Bucharest.

[International standards for tuberculosis management]. / Standarde internationale pentru ingrijirea tuberculozei.

International Standards for TB Care describe the international accepted levels of care for TB patients and suspects. The basic principles are the same worldwide: early correct diagnosis, standardized treatment insuring support and supervision, monitoring of the treatment results and highlighting all the public health responsibilities. The Standards provide the possibility to adhere to policies and practices necessary for an efficient control of the disease by all factors involved, including private or other areas. The Standards do not intend to replace local guidelines, but are focused on the relationship between individual care and the control based on community intervention. The article presents briefly the standards for diagnosis and treatment and the responsibilities of public health domain.