Towards comprehensive clinical trials for new tuberculosis drug regimens: policy recommendations from a stakeholder analysis.

BACKGROUND: Research and development (R&D) of new drugs and regimens against tuberculosis (TB) is evolving to meet new challenges and face limited investments in the sector. To effectively improve and fill existing gaps, researchers and trialists should engage a broad spectrum of stakeholders. With this study, we aim to map the interests in TB R&D raised by the main stakeholders in the TB field. METHODS: We conducted semistructured, short interviews to gather insight and viewpoints on innovation on TB drugs and regimens R&D of policy-makers, national TB programme officers, donors, funders, non-governmental organisations and research institutions.A composite measure of the relevance of topics that emerged was computed by implementing different models considering the importance for researchers and the urgency to implement those changes during the trial, the number of citations each topic received, and the maximum value of the influence of stakeholders who had raised the topic. RESULTS: 50 stakeholders, out of 56 identified, were interviewed and almost half were policy-makers and governmental institutions. Several stakeholders highlighted the importance of disseminating information about clinical trials' methodology and emerging preliminary results, followed by the need to pursue early discussion around access and pricing of safe and effective TB innovations, although different categories of stakeholders prioritised different topics. Using different methods for ranking topics, the results remained almost unchanged. Notably, post-trial operational research ranked higher in models with higher weight for the parameter considering the number of citations. CONCLUSION: Researchers and research consortia embarking on phase 2 and 3 clinical trials should consider a broad set of elements when planning and designing trials' protocols, all aiming at lowering the price and improving access to emerging TB innovations, besides meeting regulatory criteria. This can only be achieved by consulting and engaging relevant stakeholders in the discussion.

Factors Associated with Unfavorable Treatment Outcomes in New and Previously Treated TB Patients in Uzbekistan: A Five Year Countrywide Study.

BACKGROUND: TB is one of the main health priorities in Uzbekistan and relatively high rates of unfavorable treatment outcomes have recently been reported. This requires closer analysis to explain the reasons and recommend interventions to improve the situation. Thus, by using countrywide data this study sought to determine trends in unfavorable outcomes (lost-to-follow-ups, deaths and treatment failures) and describe their associations with socio-demographic and clinical factors. METHOD: A countrywide retrospective cohort study of all new and previously treated TB patients registered in the National Tuberculosis programme between January 2006 and December 2010. RESULTS: Among 107,380 registered patients, 67% were adults, with smaller proportions of children (10%), adolescents (4%) and elderly patients (19%). Sixty per cent were male, 66% lived in rural areas, 1% were HIV-infected and 1% had a history of imprisonment. Pulmonary TB (PTB) was present in 77%, of which 43% were smear-positive and 53% were smear-negative. Overall, 83% of patients were successfully treated, 6% died, 6% were lost-to-follow-up, 3% failed treatment and 2% transferred out. Factors associated with death included being above 55 years of age, HIV-positive, sputum smear positive, previously treated, jobless and living in certain provinces. Factors associated with lost-to-follow-up were being male, previously treated, jobless, living in an urban area, and living in certain provinces. Having smear-positive PTB, being an adolescent, being urban population, being HIV-negative, previously treated, jobless and residing in particular provinces were associated with treatment failure. CONCLUSION: Overall, 83% treatment success rate was achieved. However, our study findings highlight the need to improve TB services for certain vulnerable groups and in specific areas of the country. They also emphasize the need to develop unified monitoring and evaluation tools for drug-susceptible and drug-resistant TB, and call for better TB surveillance and coordination between provinces and neighbouring countries.

Framework for Selecting Best Practices in Public Health: A Systematic Literature Review.

Evidence-based public health has commonly relied on findings from empirical studies, or research-based evidence. However, this paper advocates that practice-based evidence derived from programmes implemented in real-life settings is likely to be a more suitable source of evidence for inspiring and guiding public health programmes. Selection of best practices from the array of implemented programmes is one way of generating such practice-based evidence. Yet the lack of consensus on the definition and criteria for practice-based evidence and best practices has limited their application in public health so far. To address the gap in literature on practice-based evidence, this paper hence proposes measures of success for public health interventions by developing an evaluation framework for selection of best practices. The proposed framework was synthesised from a systematic literature review of peer-reviewed and grey literature on existing evaluation frameworks for public health programmes as well as processes employed by health-related organisations when selecting best practices. A best practice is firstly defined as an intervention that has shown evidence of effectiveness in a particular setting and is likely to be replicable to other situations. Regardless of the area of public health, interventions should be evaluated by their context, process and outcomes. A best practice should hence meet most, if not all, of eight identified evaluation criteria: relevance, community participation, stakeholder collaboration, ethical soundness, replicability, effectiveness, efficiency and sustainability. Ultimately, a standardised framework for selection of best practices will improve the usefulness and credibility of practice-based evidence in informing evidence-based public health interventions. Significance for public healthBest practices are a valuable source of practice-based evidence on effective public health interventions implemented in real-life settings. Yet, despite the frequent branding of interventions as best practices or good practices, there is no consensus on the definition and desirable characteristics of such best practices. Hence, this is likely to be the first systematic review on the topic of best practices in public health. Having a single widely accepted framework for selecting best practices will ensure that the selection processes by different agencies are fair and comparable, as well as enable public health workers to better appreciate and adopt best practices in different settings. Ultimately, standardisation will improve the credibility and usefulness of practice-based evidence to that of research-based evidence.

Review of the national tuberculosis programme in Romania

Romania has the highest incidence of TB in the European Union (EU)/European Economic Area (EEA),representing one quarter of the EU/EEA TB burden. A review of the national TB programme in Romaniawas jointly organized by the WHO Regional Office for Europe and the European Centre for DiseasePrevention and Control, with WHO leading all operations, from 10 to 21 March 2014. The reviewacknowledged the high rates of detection and treatment success achieved among patients with drugsusceptibleforms of TB; it also pointed to the large proportion of patients with multidrug-resistant TB whoare not detected or are poorly treated. The review identified major challenges to be addressed atprogramme level as well as at health system level and gave the Ministry of Health and the national TBprogramme 14 main recommendations for improvement.

Multidrug-resistant tuberculosis in Belarus: the size of the problem and associated risk factors.

OBJECTIVE: To assess the problem of multidrug-resistant tuberculosis (MDR-TB) throughout Belarus and investigate the associated risk factors. METHODS: In a nationwide survey in 2010-2011, 1420 tuberculosis (TB) patients were screened and 934 new and 410 previously treated cases of TB were found to meet the inclusion criteria. Isolates of Mycobacterium tuberculosis from each eligible patient were tested for susceptibility to anti-TB drugs. Sociobehavioural information was gathered in interviews based on a structured questionnaire. FINDINGS: MDR-TB was found in 32.3% and 75.6% of the new and previously treated patients, respectively, and, 11.9% of the 612 patients found to have MDR-TB had extensively drug-resistant TB (XDR-TB). A history of previous treatment for TB was the strongest independent risk factor for MDR-TB (odds ratio, OR: 6.1; 95% confidence interval, CI: 4.8-7.7). The other independent risk factors were human immunodeficiency virus (HIV) infection (OR: 2.2; 95% CI: 1.4-3.5), age < 35 years (OR: 1.4; 95% CI: 1.0-1.8), history of imprisonment (OR: 1.5; 95% CI: 1.1-2.0), disability sufficient to prevent work (OR: 1.9; 95% CI: 1.2-3.0), alcohol abuse (OR: 1.3; 95% CI: 1.0-1.8) and smoking (OR: 1.5; 95% CI: 1.1-2.0). CONCLUSION: MDR-TB is very common among TB patients throughout Belarus. The numerous risk factors identified for MDR-TB and the convergence of the epidemics of MDR-TB and HIV infection call not only for stronger collaboration between TB and HIV control programmes, but also for the implementation of innovative measures to accelerate the detection of TB resistance and improve treatment adherence.

Résumé OBJECTIF: Évaluer le problème de la tuberculose multirésistante (TB-MR) sur le territoire biélorusse et explorer les facteurs de risque associés. MÉTHODES: Au cours d'une enquête nationale menée en 2010-2011, 1420 cas de tuberculose (TB) ont été dépistés et 934 cas nouveaux ainsi que 410 cas précédemment traités ont été jugés conformes aux critères d'inclusion. Des isolats de Mycobacterium tuberculosis provenant de chaque patient admissible ont été testés pour leur sensibilité envers les médicaments antituberculeux. Des informations sociocomportementales ont été recueillies lors d'entretiens basés sur un questionnaire structuré. RÉSULTATS: La TB-MR a été détectée dans respectivement 32,3% et 75,6% des cas nouveaux et des cas traités antérieurement, et 11,9% des 612 patients porteurs de la TB-MR présentaient une forme de tuberculose ultrarésistante (TB-UR). Un historique de traitement antérieur pour la TB représentait le principal facteur de risque indépendant pour la TB-MR (rapport des cotes, RC: 6,1; intervalle de confiance à 95%, IC: 4,8 à 7,7). Les autres facteurs de risque indépendants comprenaient l'infection par le virus d'immunodéficience humaine (VIH) (RC: 2,2; IC à 95%: 1,4 à 3,5), l'âge <35 ans (RC: 1,4 ; IC à 95%: 1,0 à 1,8), un historique d'emprisonnement (RC: 1,5; IC à 95%: 1,1 à 2,0), une invalidité suffisante pour empêcher le travail (RC: 1,9 ; IC à 95%: 1,2 à 3,0), l'alcoolisme (RC: 1,3; IC à 95%: 1,0 à 1,8) et le tabagisme (RC: 1,5; IC à 95%: 1,1 à 2,0). CONCLUSION: La TB-MR est très fréquente chez les patients atteints de tuberculose en Bélarus. Les nombreux facteurs de risque identifiés pour la TB-MR et la convergence entre l'épidémie de TB-MR et l'infection par le VIH exigent non seulement de renforcer la collaboration entre les programmes antituberculeux et de lutte contre le VIH, mais aussi la mise en œuvre de mesures innovantes pour accélérer la détection de la résistance à la tuberculose et améliorer l'observance du traitement.

Resumen OBJETIVO: Evaluar el problema de la tuberculosis multirresistente (TB-MR) en Bielorrusia e investigar los factores de riesgo asociados. MÉTODOS: En una encuesta a nivel nacional llevada a cabo entre 2010 y 2011, se evaluó a 1420 pacientes con tuberculosis (TB) y se consideró que 934 nuevos casos de TB y 410 casos de TB previamente tratados reunían los criterios de inclusión. Se analizaron cepas de Mycobacterium tuberculosis de cada paciente elegible con el fin de determinar la susceptibilidad a los fármacos antituberculosos. Se recopiló información socioconductual mediante entrevistas basadas en un cuestionario estructurado. RESULTADOS: Se detectó TB-MR en el 32,3% y el 75,6% de los pacientes de nuevo diagnóstico y tratados previamente, respectivamente, y se observó que el 11,9% de los 612 pacientes con TB-MR presentaba tuberculosis ultrarresistente (TB-XR). Los antecedentes de tratamiento previo de la TB resultaron ser el factor de riesgo independiente que más predispone a sufrir TB-MR (razón de posibilidades, OR: 6,1; intervalo de confianza del 95%, IC: 4,8­7,7). Los demás factores de riesgo independientes fueron el virus de la inmunodeficiencia humana (VIH) (OR: 2,2; IC del 95%: 1,4­3,5), edad < 35 años (OR: 1,4; IC del 95%: 1,0­1,8), antecedentes de encarcelamiento (OR: 1,5; IC del 95%: 1,1­2,0), incapacidad suficiente para impedir el trabajo (OR: 1,9; IC del 95%: 1,2­3,0), alcoholismo (OR: 1,3; IC del 95%: 1,0­1,8) y tabaquismo (OR: 1,5; IC del 95%: 1,1­2,0). CONCLUSIÓN: La TB.MR es muy frecuente entre los pacientes con tuberculosis en Bielorrusia. Los numerosos factores de riesgo identificados para la TB-MR, unidos a la convergencia de las epidemias de TB-MR y la infección por el VIH, exigen no solo una mayor colaboración entre los programas de control de la TB y del VIH, sino también la aplicación de medidas innovadoras destinadas a acelerar la detección de la resistencia a la TB y mejorar el cumplimiento terapéutico.

Обзорная оценка Национальной программы по туберкулезу в Республике Молдова: 4–15 февраля 2013 года

Республика Молдова входит в число 18 приоритетных стран для борьбы с туберкулезом (ТБ) в Европейском регионе ВОЗ и 27 стран мира с высоким бременем ТБ с множественной лекарственной устойчивостью (МЛУ-ТБ). Согласно классификации Глобального фонда для борьбы со СПИДом, туберкулезом и малярией, Республика Молдова занимает второе место среди 110 стран по уровню средств, выделяемых на душу населения. Вторая фаза реализации консолидированного гранта в рамках раундов 8 и 9 была одобрена в декабре 2012 года с условием представления на следующем этапе обзорной оценки Национальной программы по туберкулезу и стратегического плана (на основе этой обзорной оценки) по усилению приверженности лечению и снижению числа пациентов, результаты лечения которых неизвестны. Серьезную озабоченность вызывал тот факт, что, как показала оценка, осуществление мер вмешательства и поддержка оказали лишь ограниченное воздействие на улучшение результатов лечения. В октябре 2012 года Министерство здравоохранения обратилось в Европейское региональное бюро ВОЗ с просьбой обеспечить координацию обзорной оценки Национальной программы по туберкулезу.

Review of the National Tuberculosis Programme in the Republic of Moldova: 4–15 February 2013

The Republic of Moldova is among the WHO European Region’s 18 high-priority countries for tuberculosis (TB) control and among the world’s 27 high multidrug-resistant TB (MDR-TB) burden countries. The Global Fund to Fight AIDS, Tuberculosis and Malaria ranks the Republic of Moldova second among 110 countries by level of funds provided per capita. The second phase of implementation of its consolidated Round 8 and 9 TB grant was approved in December 2012 with a request to submit, at a later stage, a review of the National TB Programme and a strategic plan (based on the review) to improve treatment compliance and reduce loss to treatment follow up. A major concern highlighted was that supported interventions have shown only a limited impact in improving treatment success. In October 2012 the Ministry of Health asked the WHO Regional Office for Europe to coordinate the review of the National TB Programme.The review took place from 4 to 15 February 2013. Twelve international and seven national experts participated, visiting 18 districts and three municipalities, the autonomous region of Gagauzia and the Transnistria region. The review team developed a strategic plan to improve treatment compliance and reduce loss to treatment follow up immediately after the review; this appears as part of the roadmap attached to this report (Annex 1). The team members conveyed their key findings and recommendations at the end of the mission to the Minister of Health.

Minimum package for cross-border TB control and care in the WHO European region: a Wolfheze consensus statement.

The World Health Organization (WHO) European region estimates that more than 400,000 tuberculosis (TB) cases occur in Europe, a large proportion of them among migrants. A coordinated public health mechanism to guarantee TB prevention, diagnosis, treatment and care across borders is not in place. A consensus paper describing the minimum package of cross-border TB control and care was prepared by a task force following a literature review, and with input from the national TB control programme managers of the WHO European region and the Wolfheze 2011 conference. A literature review focused on the subject of TB in migrants was carried out, selecting documents published during the 11-yr period 2001-2011. Several issues were identified in cross-border TB control and care, varying from the limited access to early TB diagnosis, to the lack of continuity of care and information during migration, and the availability of, and access to, health services in the new country. The recommended minimum package addresses the current shortcomings and intends to improve the situation by covering several areas: political commitment (including the implementation of a legal framework for TB cross-border collaboration), financial mechanisms and adequate health service delivery (prevention, infection control, contact management, diagnosis and treatment, and psychosocial support).

Exploring TB-Related Knowledge, Attitude, Behaviour, and Practice among Migrant Workers in Tajikistan.

A knowledge, attitude, behaviour, and practice survey was conducted among labour migrants in Tajikistan to elucidate key factors influencing access to tuberculosis diagnosis and care both in their labour destination country and at home. 509 labour migrants were interviewed in Khaton and Rasht Valley regions in Tajikistan using a standardised questionnaire. In addition, in-depth interviews were conducted among ten tuberculosis patients who had recently worked abroad. The study showed that migrants have increased vulnerability to tuberculosis due to the working and living conditions in the destination country and that access to health services is limited due to their legal status or the high cost of health services abroad. The average knowledge of migrants regarding tuberculosis is low and misconceptions are frequent. In Tajikistan, although tuberculosis drugs are usually provided free of charge, tuberculosis diagnosis and ancillary treatment are charged, thus creating a significant financial burden for patients and their families. Improving the access of labour migrants to affordable early diagnosis and treatment in both host countries and Tajikistan is a priority.

Review of the National Tuberculosis Programme in Ukraine: 10–22 October 2010

Ukraine has the second-highest burden of tuberculosis (TB) in the WHO European Region. In February 2010, the Minister of Health asked WHO to review the National Tuberculosis Programme and make recommendations that could be used to help develop the Programme plan for 2012–2016. On 10–22 October, 13 international and 23 national experts reviewed documents, visited institutions and interviewed people in eight oblasts and Kyiv. The reviewers found a range of problems, from inconsistent implementation of the Stop TB Strategy between and within oblasts to TB services designed for health providers, not patients. Non-supportive legislation and an outdated health system, based on hospital care and with inflexible financing, limit current efforts to improve services. Action is urgently needed to stop the increase in multidrug- and extensively drug-resistant TB (MDR-TB/XDR-TB) cases, the acceleration of HIV co-infection and high nosocomial TB transmission. The report of the review includes 14 recommendations made to the Government, the Ministry of Health and its partners.

European framework to decrease the burden of TB/HIV

Tuberculosis in Europe is declining in countries in western and central Europe, but the burden is still high and increasing in eastern Europe. HIV/AIDS is increasing dramatically in eastern Europe. HIV-related tuberculosis (TB/HIV) morbidity and mortality are expected to accelerate significantly in the future. This framework aims to guide European countries in developing their national plan for reducing TB/HIV morbidity and mortality. It results from an extensive consultation process undertaken by the WHO Regional Office for Europe and by those responsible for HIV/AIDS and tuberculosis programmes and their partners. It builds on strategies developed globally and in Europe for tuberculosis control and for HIV/AIDS prevention and care. This framework sets out the rationale for effective collaboration between HIV/AIDS and tuberculosis national programmes. It identifies five strategic components (political commitment, collaborative prevention, intensified case-finding, coordinated treatment and strengthened surveillance) and eight key operations (central coordination, policy development, surveillance, training, supply management, service delivery, health promotion and research).