Target regimen profiles for tuberculosis treatment.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.

Des traitements de la tuberculose plus simples, plus courts, plus sûrs et plus efficaces, facilement accessibles à toutes les personnes atteintes de tuberculose, font cruellement défaut. En 2016, l'Organisation mondiale de la santé (OMS) a élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose, afin de sensibiliser les concepteurs de médicaments aux caractéristiques importantes des schémas thérapeutiques et aux besoins des patients et des programmes au niveau national. Compte tenu des avancées récentes dans le traitement de la tuberculose, l'OMS a révisé et mis à jour ces profils de schéma thérapeutique. Nous avons appliqué un processus similaire à celui des profils de 2016, y compris une analyse de base des différentes possibilités thérapeutiques, une enquête initiale auprès des parties prenantes, des études de modélisation estimant l'impact et le rapport coût-efficacité des nouveaux schémas thérapeutiques pour la tuberculose, ainsi qu'une vaste consultation des parties prenantes. Nous avons élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose sensible à la rifampicine ou résistant à la rifampicine, ainsi qu'un schéma multiforme qui conviendrait aux patients atteints de n'importe quel type de tuberculose. Nous décrivons les caractéristiques du profil révisé de schéma thérapeutique cible, avec les objectifs minimaux et optimaux spécifiques à atteindre, le raisonnement et les aspects pertinents pour tous les profils de schéma thérapeutique cible (tests de sensibilité aux médicaments, observance thérapeutique et manque d'observance («forgiveness¼), stratégies de traitement, maladie pulmonaire post-tuberculeuse et considérations de coût et d'accès). Nous discutons des compromis des caractéristiques proposées pour la prise de décisions au niveau du développement ou au niveau opérationnel. Nous espérons qu'à la suite de ces révisions du profil de schéma thérapeutique cible, les concepteurs de traitements antituberculeux produiront des schémas dont la qualité est assurée, qui sont abordables et largement disponibles et qui répondent aux besoins des populations touchées.

Se necesitan con urgencia tratamientos más sencillos, breves, seguros y eficaces contra la tuberculosis que sean fácilmente accesibles para todas las personas con tuberculosis. En 2016, la Organización Mundial de la Salud (OMS) elaboró perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis con el fin de que los fabricantes de medicamentos conocieran tanto las características importantes de estos esquemas como las necesidades programáticas y de los pacientes en cada país. Teniendo en cuenta los recientes avances pioneros en el tratamiento de la tuberculosis, la OMS ha revisado y actualizado estos perfiles de esquemas terapéuticos. Se ha seguido un proceso similar al de los perfiles de 2016, que incluye un análisis de referencia del panorama terapéutico, una encuesta inicial a las partes interesadas, estudios de modelización para estimar el impacto y la rentabilidad de los nuevos esquemas terapéuticos para el tratamiento de la tuberculosis, y una amplia consulta a las partes interesadas. Se desarrollaron perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis sensibles a la rifampicina y resistente a la rifampicina, así como un esquema farmacológico capaz de tratar todas las formas de tuberculosis que sería apropiado para pacientes con cualquier tipo de tuberculosis. Se describieron las características revisadas de los perfiles objetivo de los esquemas terapéuticos, con los objetivos mínimos y óptimos específicos que deben alcanzarse, los fundamentos y la justificación, y los aspectos relevantes para todos los perfiles objetivo de los esquemas terapéuticos (pruebas de sensibilidad a los fármacos, adherencia y olvido, estrategias de tratamiento, enfermedad pulmonar postuberculosa, y consideraciones de coste y acceso). Se discutieron las ventajas y desventajas de las características propuestas para la toma de decisiones a nivel de desarrollo u operativo. Se espera que, tras estas revisiones de los perfiles objetivo de los esquemas terapéuticos, las personas encargadas del desarrollo de tratamientos para la tuberculosis elaboren esquemas terapéuticos de calidad garantizada, asequibles y ampliamente disponibles, y que respondan a las necesidades de las poblaciones afectadas.

Target product profiles: tests for tuberculosis treatment monitoring and optimization.

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.

L'Organisation mondiale de la santé a élaboré des profils de produits cibles contenant des cibles minimales et optimales pour les caractéristiques principales des essais destinés au suivi et à l'optimisation du traitement de la tuberculose. L'optimisation du traitement de la tuberculose fait référence à l'instauration d'un régime de traitement efficace de la tuberculose ou à l'adoption d'un tel régime, avec une probabilité élevée d'obtenir de bons résultats thérapeutiques. Les profils de produits cibles couvrent également les essais de guérison effectués à l'issue du traitement. Les profils de produits cibles ont été élaborés sur la base d'un sondage auprès des parties prenantes, d'une analyse coût-efficacité et d'une analyse du parcours de soins du patient. Des retours supplémentaires des parties prenantes ont été obtenus au moyen d'un processus créé selon la méthode Delphi, d'une consultation technique et d'un appel à commentaires publics sur un projet de document. Un groupe d'élaboration scientifique s'est mis d'accord sur les objectifs finaux lors d'une réunion de concertation. En ce qui concerne les caractéristiques jugées les plus importantes, le document énumère ce qui suit: (i) une grande précision diagnostique (sensibilité et spécificité); (ii) un délai idéal d'obtention des résultats ≤ 2 heures et au maximum de 1 jour; (iii) le type d'échantillon requis doit être peu invasif et facile à obtenir, comme l'urine, l'haleine ou le sang capillaire, ou bien un échantillon respiratoire au-delà des expectorations; (iv) idéalement, l'essai pourrait avoir lieu dans un établissement de santé périphérique sans laboratoire ; et (v) l'essai devrait être abordable pour les pays à revenu faible et intermédiaire et permettre un accès large et équitable ainsi qu'une mise à l'échelle. L'utilisation de ces profils de produits cibles devrait faciliter la mise au point de nouveaux essais de surveillance et d'optimisation du traitement de la tuberculose qui soient précis et accessibles à toutes les personnes suivant un traitement pour la tuberculose.

La Organización Mundial de la Salud ha elaborado perfiles de productos objetivo que contienen objetivos mínimos y óptimos para las características principales de las pruebas de seguimiento y optimización del tratamiento de la tuberculosis. La optimización del tratamiento de la tuberculosis consiste en iniciar o cambiar a un régimen eficaz de tratamiento de la tuberculosis que ofrezca una alta probabilidad de un buen resultado terapéutico. Los perfiles de productos objetivo también abarcan las pruebas de curación realizadas al final del tratamiento. La elaboración de los perfiles de los productos objetivo se basó en una encuesta a las partes interesadas, un análisis de rentabilidad y un análisis de la vía de atención al paciente. Se obtuvo información adicional de las partes interesadas mediante un proceso tipo Delphi, una consulta técnica y una convocatoria de comentarios públicos sobre un borrador del documento. Un grupo de desarrollo científico acordó los objetivos finales en una reunión de consenso. Para las características clasificadas de mayor importancia, el documento enumera: (i) alta precisión diagnóstica (sensibilidad y especificidad); (ii) tiempo hasta el resultado de óptimamente ≤ 2 horas y no más de 1 día; (iii) el tipo de muestra requerida debe ser mínimamente invasiva, fácil de obtener, como orina, aliento o sangre capilar, o una muestra respiratoria que vaya más allá del esputo; (iv) idealmente la prueba podría realizarse en un centro sanitario periférico sin laboratorio; y (v) la prueba debe ser asequible para los países de ingresos bajos y medios y permitir un acceso amplio y equitativo y su expansión. El uso de estos perfiles de producto objetivo debería facilitar el desarrollo de pruebas nuevas de seguimiento y optimización del tratamiento de la tuberculosis que sean precisas y accesibles para todas las personas que reciben tratamiento antituberculoso.

Unfavourable treatment outcomes in tuberculosis patients with different vitamin D status and blood glucose levels in a programme setting in China.

OBJECTIVE: Tuberculosis (TB) treatment success rates are high in China, but there are still a considerable number of cases who have unfavourable treatment outcomes (UTO). We aimed to determine the proportion of TB patients with UTO and to assess whether baseline characteristics that included glycaemic status [normal fasting blood glucose (FBG), transient hyperglycaemia and diabetes mellitus (DM)] and vitamin D status were associated with UTO. METHOD: Prospective cohort study conducted between November 2015 and July 2016 at six clinics within routine TB services in Jilin province, where persons with TB were consecutively recruited. Data analysis was performed using the chi-squared test and multivariate logistic regression. RESULTS: Of the 306 recruited TB patients, 96 (31.4%) had smear-positive pulmonary TB, 187 (61.1%) had smear-negative pulmonary TB and 23 (7.5%) had extrapulmonary TB (EPTB). Of these, 95 (31.1%) had normal blood glucose, 83 (27.1%) had transient hyperglycaemia and 128 (41.8%) had DM. 227 (74.2%) patients had vitamin D deficiency/severe deficiency. There were 125 (40.8%) patients with UTO of whom the majority were lost to follow-up (57.6%) or not evaluated (28.8%). UTO was significantly associated with smear-negative pulmonary TB (P = 0.009), EPTB (P < 0.001) and DM (P = 0.007). CONCLUSION: The proportion of TB patients with UTO increased with smear-negative pulmonary TB, EPTB and DM. TB programmes need to pay more attention to these issues and ensure intensive patient support to those at risk and early detection of DM.

OBJECTIF: Les taux de succès du traitement de la tuberculose (TB) sont élevés en Chine, mais il existe encore un nombre considérable de cas avec des résultats de traitement défavorables (RTD). Nous avons cherché à déterminer la proportion de patients TB avec un RTD et d'évaluer si les caractéristiques de base comprenant le statut glycémique [glycémie normale à jeun (GJ), hyperglycémie transitoire et diabète sucré (DS)] et le statut en vitamine D étaient associés à un RTD. MÉTHODE: Etude de cohorte prospective réalisée entre novembre 2015 et juillet 2016 dans six cliniques des services anti-TB de routine de la province de Jilin, où des personnes atteintes de TB ont été recrutées consécutivement. L'analyse des données a été réalisée à l'aide du test du chi carré et de la régression logistique multivariée. RÉSULTATS: Sur 306 patients TB recrutés, 96 (31.4%) avaient une TB pulmonaire à frottis positif, 187 (61.1%) avaient une TB pulmonaire à frottis négatif et 23 (7.5%) avaient une TB extra pulmonaire (TBEP). Parmi ceux-ci, 95 (31.1%) avaient une glycémie normale, 83 (27.1%) avaient une hyperglycémie transitoire et 128 (41.8%) avaient un DS. 227 (74.2%) patients avaient une déficience/déficience sévère en vitamine D. Il y avait 125 (40.8%) patients avec un RTD dont la majorité (57.6%) ont été perdus de vue ou ont été non évalués (28.8%). Le RTD était significativement associé à la TB pulmonaire à frottis négatif (p = 0.009), la TBEP (P < 0.001) et le DS (P = 0.007). CONCLUSION: La proportion de patients TB avec un RTD augmentait avec la TB pulmonaire à frottis négatif, la TBEP et le DS. Les programmes anti-TB devraient accorder plus d'attention à ces problèmes et assurer un soutien intensif au patient pour les personnes à risque et une détection précoce du DS.

Global Progress and Challenges in Implementing New Medications for Treating Multidrug-Resistant Tuberculosis.

Two new drugs-bedaquiline and delamanid-have recently been approved by stringent regulatory authorities to treat multidrug-resistant tuberculosis (TB) and recommended by the World Health Organization for use under defined programmatic conditions. Introducing the medications in TB programs worldwide has not kept pace with the need for these drugs. In response, the DR-TB STAT (Drug-Resistant TB Scale-up Treatment Action Team) task force was formed in April 2015 to monitor progress and help overcome challenges. Information was collected from multiple sources and assessed monthly. Some progress has been made in introducing bedaquiline: as of October 2015, a total of 1,258 persons were on the medication under programmatic conditions. For delamanid, >100 patients, but few under programmatic conditions, have received the medication. Coordinated global action might help assist making these medications accessible for persons who need them most.

Principles for designing future regimens for multidrug-resistant tuberculosis.

Fewer than 20% of patients with multidrug-resistant (MDR) tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.

Moins de 20% des patients atteints de tuberculose multirésistante (MDR) reçoivent actuellement un traitement et il est urgent de renforcer les programmes de traitement. Un des plus grands obstacles à ce renforcement est le schéma thérapeutique qui est long, complexe, inefficace, mal toléré et coûteux. Pour la première fois en plus de 50 ans, de nouveaux médicaments ont été développés spécifiquement pour traiter la tuberculose, dont la bedaquiline et potentiellement la delamanid qui devraient être bientôt disponibles pour traiter les cas de MDR. Cependant, si les nouveaux médicaments sont juste ajoutés au schéma thérapeutique actuel, le nouveau schéma thérapeutique sera au moins aussi long, lourd et toxique que celui qui existe déjà. Il est urgent d'élaborer une stratégie et d'obtenir des preuves concernant la façon de maximiser le potentiel des nouveaux médicaments pour améliorer les résultats et raccourcir la durée du traitement. Nous avons mis au point huit principes clés pour la conception des futurs schémas thérapeutiques afin de s'assurer que, une fois qu'ils aient été éprouvés comme sûrs dans des essais cliniques, ils soient cliniquement efficaces et utilisables dans le cadre d'un programme. Les schémas thérapeutiques doivent comprendre au moins une nouvelle classe de médicament; être généralement applicables pour une utilisation contre les MDR et plus largement contre les souches complexes de Mycobacterium tuberculosis multirésistantes; comprendre trois des cinq médicaments efficaces, chacun provenant d'une classe de médicament différent; être administré par voie orale; avoir un schéma posologique simple; avoir un bon profil d'effets secondaires permettant un suivi limité; durer au moins 6 mois et avoir le moins d'interaction possible avec les antirétroviraux. Suivre ces principes maximisera le potentiel des nouveaux composés et permettra de surmonter les inconvénients cliniques et programmatiques, ainsi que les contraintes qui plombent le schéma thérapeutique actuel.

Menos del 20 % de los pacientes con tuberculosis multirresistente (MDR) recibe tratamiento, al tiempo que existe una necesidad apremiante de ampliar los programas de tratamiento. Uno de los mayores obstáculos para la ampliación es el propio programa de tratamiento, el cual resulta largo, complejo, ineficaz, caro y no se tolera bien. Por primera vez en más de 50 años se han desarrollado fármacos nuevos específicos para tratar la tuberculosis y se espera que la bedaquilina y, potencialmente, la delamanida estén disponibles pronto para tratar los casos de tuberculosis multirresistente. Sin embargo, si se limitan a introducir los fármacos nuevos al programa de tratamiento actual, el programa nuevo será, como mínimo, tan largo, complicado y tóxico como el presente. Es, por tanto, muy urgente diseñar una estrategia y reunir pruebas sobre cómo maximizar el potencial de los fármacos nuevos para mejorar los resultados y acortar el tratamiento. Hemos establecido ocho principios esenciales para el diseño de los programas de tratamiento futuros a fin de garantizar que, una vez que se hayan probado en ensayos clínicos, sean eficaces desde el punto de vista clínico y viables mediante programación. Los programas deben contener, al menos, un tipo nuevo de fármaco, poder aplicarse de forma amplia para su uso contra la tuberculosis multirresistente y las cepas complejas de Mycobacterium tuberculosis ultrarresistentes, contener de tres a cinco medicamentos eficaces, cada uno de una clase de fármaco diferente; suministrarse por vía oral, tener un horario de dosificación simple y un perfil adecuado de efectos secundarios que permita una supervisión restringida, durar un máximo de 6 meses y tener una interacción mínima con antirretrovirales. Si se siguen estos principios, se maximizará el potencial de los compuestos nuevos y será más fácil superar los inconvenientes clínicos y programáticos, así como las barreras a la ampliación que abundan en el programa actual.

Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Current anti-tuberculosis therapeutics are not sufficiently effective against drug-resistant tuberculosis (DR-TB), and there is a need for new drugs and therapeutic approaches. It has been proposed that repurposing clofazimine for DR-TB treatment might be one way to increase therapeutic options. METHODS: We conducted a systematic review of studies reporting on the efficacy and safety of clofazimine as part of combination therapy for DR-TB. Six databases and six conference abstract sites were searched from inception until April 2012. All studies involving the use of clofazimine in the treatment of DR-TB were included. RESULTS: Twelve studies, comprising 3489 patients across 10 countries, were included in this review. Treatment success ranged from 16.5% (95% CI 2.7%-38.7%) to 87.8% (95% CI 76.8%-95.6%), with an overall pooled proportion of 61.96% achieving treatment success (95% CI 52.79%-71.12%) (τ(2) 0.07). Mortality, treatment interruptions, defaulting and adverse events were all in line with DR-TB treatment outcomes overall. The most commonly reported adverse events were gastrointestinal disturbances and skin pigmentation. CONCLUSIONS: The available evidence to date suggests that clofazimine could be considered as an additional therapeutic option in the treatment of DR-TB. The optimal dose of clofazimine and duration of use require further investigation.

Pediatric Tuberculosis Research and Development: Progress, Priorities and Funding Opportunities.

In this article, we highlight technological pediatric TB research advances across the TB care cascade; discuss recently completed or ongoing work in adults and corresponding significant research gaps for children; and offer recommendations and opportunities to increase investments and accelerate pediatric TB R&D.

Tuberculosis recurrence over a 7-year follow-up period in successfully treated patients in a routine program setting in China: a prospective longitudinal study.

OBJECTIVES: To determine tuberculosis (TB) recurrence in previously successfully treated patients in a routine program setting and baseline characteristics associated with TB recurrence. METHODS: A prospective longitudinal study in Jiangxi Province, China. Patients, ≥14 years old, were consecutively registered and were followed up for seven years to assess TB recurrence against a patients' individual baseline data that had been entered into a database at TB registration. RESULTS: There were 800 TB patients registered at baseline, and 634 (79.2%) of them completed anti-TB treatments. Fifty-nine (9.3%) died, and 21 (3.3%) were lost to follow-up over the follow-up period. There were 96 patients with recurrent episodes (total incidence 15.2% or annual incidence 2,200/100,000). Of the recurrent cases, 53 (55.2%) happened within 2-year after completion of anti-TB treatments. After controlling confounding factors, the risk of TB recurrence was significantly higher in the age range 34-73 years (P<0.01) and current smokers (P<0.01). CONCLUSIONS: Overall recurrence rate among previously treated TB patients was much higher than the initial incidence in the same population (61-98/100,000) and settings with similar TB incidence. TB programs should consider closer monitoring of these patients for early detection of recurrence. Particular attention should be given to those between 34-73 years and those who use tobacco products.

Why tobacco control should be a priority agenda item of Joint External Monitoring Missions for TB control?

INTRODUCTION: Tobacco smoking is a significant risk factor for developing tuberculosis (TB), contributing to diagnostic delays, poor treatment outcomes and an increased risk of death and relapse. The World Health Organization (WHO) has reported that TB rates could decline by as much as 20% if smoking were eliminated. Tobacco smoking was a risk factor in at least 860,000 TB cases in 2018, and has been documented as one of the leading contributors to TB in India, Indonesia, Myanmar, Nepal and Philippines. METHODS: Joint External Monitoring Missions (JEMM) are arranged by WHO to review the progress, challenges and plans for national TB control programs and provide guidance for improvement of policies, planning and implementation. During May and June 2021, JEMM reports from five South-East Asian countries that had a JEMM in 2019 and early 2020 were reviewed. Reports reviewed from India, Indonesia, Myanmar, Nepal and the Philippines. Any mention of the association of TB and smoking, TB and tobacco use, impact of tobacco use/smoking on TB outcomes, current practices and challenges of TB and tobacco in the TB control program and proposed actions were documented. RESULTS: Of the five country JEMM, Myanmar's did not recognise the impact of smoking tobacco on TB at all, and only one of the five countries, India, identified a very limited number of current TB-Tobacco practises including that a collaborative framework for TB/tobacco was in place. Nepal's 2019 JEMM acknowledged that there was no smoking cessation within the TB Control program and health providers were not aware about the brief advice and smoking cessation program. The Philippines and Myanmar reported neither current practices nor challenges in implementing tobacco intervention in TB control programs. CONCLUSION: Given the importance of tobacco smoking as a key risk factor for TB, assessing its burden on the national TB epidemic should be included as one of the key indicators in the JEMM framework. Key interventions include brief cessation support through regular TB services and the use of Nicotine Replacement Therapy (NRT) and other medications as part of a comprehensive package of care for people with TB to improve the quality of the services they receive. Multisectoral efforts to stop smoking also contribute the non-communicable disease agenda as well as protecting against poor outcomes for COVID-19. The support of TB programs to integrate tobacco control is critical and will contribute to national TB control program targets that support WHO's End TB Strategy.

The time to act is now: pseudo-systematic review.

OBJECTIVE: To identify any medical or public health rationale for claims that the time to act is now. DESIGN: Pseudo-systematic review. DATA SOURCES: PubMed. STUDY SELECTION: Studies that included the claim "time is now" in the title, with or without exclamation marks. No language or date restriction was applied. RESULTS: 512 articles were included for review. No relationship was identified between time to act and disease burden, severity, or specialty. Claims that the time to act was Christmas were almost entirely without basis. A clustering of claims that it is time to act in the first quarter of the year suggested a possible association with New Year's resolutions. CONCLUSIONS: Now is as good a time as any.

New opportunities in tuberculosis prevention: implications for people living with HIV.

INTRODUCTION: Tuberculosis (TB) is a leading cause of mortality among people living with HIV (PLHIV). An invigorated global END TB Strategy seeks to increase efforts in scaling up TB preventive therapy (TPT) as a central intervention for HIV programmes in an effort to contribute to a 90% reduction in TB incidence and 95% reduction in mortality by 2035. TPT in PLHIV should be part of a comprehensive approach to reduce TB transmission, illness and death that also includes TB active case-finding and prompt, effective and timely initiation of anti-TB therapy among PLHIV. However, the use and implementation of preventive strategies has remained deplorably inadequate and today TB prevention among PLHIV has become an urgent priority globally. DISCUSSION: We present a summary of the current and novel TPT regimens, including current evidence of use with antiretroviral regimens (ART). We review challenges and opportunities to scale-up TB prevention within HIV programmes, including the use of differentiated care approaches and demand creation for effective TB/HIV services delivery. TB preventive vaccines and diagnostics, including optimal algorithms, while important topics, are outside of the focus of this commentary. CONCLUSIONS: A number of new tools and strategies to make TPT a standard of care in HIV programmes have become available. The new TPT regimens are safe and effective and can be used with current ART, with attention being paid to potential drug-drug interactions between rifamycins and some classes of antiretrovirals. More research and development is needed to optimize TPT for small children, pregnant women and drug-resistant TB (DR-TB). Effective programmatic scale-up can be supported through context-adapted demand creation strategies and the inclusion of TPT in client-centred services, such as differentiated service delivery (DSD) models. Robust collaboration between the HIV and TB programmes represents a unique opportunity to ensure that TB, a preventable and curable condition, is no longer the number one cause of death in PLHIV.

Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda.

INTRODUCTION: There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey. METHODS: Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings. RESULTS: Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR-TB patients were also top priorities in their respective categories. Results were internally consistent and robust. DISCUSSION: Priorities retained from the 2008 research agenda include shorter MDR-TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data. CONCLUSION: There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.

New developments in the treatment of drug-resistant tuberculosis: clinical utility of bedaquiline and delamanid.

The current treatment for drug-resistant tuberculosis (TB) is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant TB (MDR-TB). Bedaquiline, a diarylquinoline, and delamanid, a nitromidoxazole, have received conditional stringent regulatory approval and have World Health Organization interim policy guidance for their use. As countries improve and scale up their diagnostic services, increasing number of patients with MDR-TB and extensively drug-resistant TB are identified. These two new drugs offer a real opportunity to improve the outcomes of these patients. This article reviews the evidence for these two new drugs and discusses the clinical questions raised as they are used outside clinical trial settings. It also reviews the importance of the accompanying drugs used with these new drugs. It is important that barriers hindering the use of these two new drugs are addressed and that the existing clinical experience in using these drugs is shared, such that their routine-use programmatic conditions is scaled up, ensuring maximum benefit for patients and countries battling the MDR-TB crisis.

Getting it right for children: improving tuberculosis treatment access and new treatment options.

Children were often the forgotten victims of the global tuberculosis (TB) epidemic, neglected by traditional TB services as well as maternal and child health initiatives. Luckily this is changing with a greater focus on children and the issues regarding their optimal management. A common misconception is that children with TB are always difficult to diagnose and treat. New diagnostic tools are urgently needed, but most children with TB in high-burden settings can be diagnosed with available approaches and treatment outcomes are generally excellent. Increased TB awareness, appropriate training of health care workers and inclusion in integrated management of childhood illness strategies will improve the access and quality of care that children receive. This review highlights what needs to be done to ensure that no child unnecessarily dies from TB and provides a brief overview of new advances in the field.