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.

Strengthening accountability for tuberculosis policy implementation in South Africa: perspectives from policymakers, civil society, and communities.

Background: Translating health policy into effective implementation is a core priority for responding effectively to the tuberculosis (TB) crisis. The national TB Recovery Plan was developed in response to the negative impact that the COVID-19 pandemic had on TB care in South Africa. We aimed to explore the implementation of the TB Recovery Plan and develop recommendations for strengthening accountability for policy implementation for this and future TB policies. Methods: We interviewed 24 participants working on or impacted by TB policy implementation in South Africa. This included perspectives from national, provincial, and local health department representatives, civil society, and community representatives. In-depth interviews were conducted in English and isiXhosa and we drew on reflexive thematic methods for analysis. Results: Participants felt that there was potential for COVID-19 innovations and urgency to influence TB policy development and implementation, including the use of data dashboards. Implementation of the TB Recovery Plan predominantly used a top-down approach to implementation (cascading from national policy to local implementers) but experienced bottlenecks at provincial level. Recommendations for closing the TB policy-implementation gap included using phased implementation and enhancing provincial-level accountability. Civil society organisations were concerned about the lack of provincial implementation data which impeded advocacy for improved accountability and inadequate resourcing for implementation. Community health workers were viewed as key to implementation but were not engaged in the policy development process and were often not aware of new TB policies. At local level, there were also opportunities to strengthen community engagement in policy implementation including through community-led monitoring. Participants recommended broader multi-stakeholder engagement that includes community and community health worker representatives in the development and implementation phases of new TB policies. Conclusions: Communities affected by TB, with the support of civil society organisations, could play a bigger role in monitoring policy implementation at local level and need to be capacitated to do this. This bottom-up approach could complement existing top-down strategies and contribute to greater accountability for TB policy implementation. Supplementary Information: The online version contains supplementary material available at 10.1186/s44263-024-00077-y.

Bedaquiline: what might the future hold?

Tuberculosis drug development has stagnated for decades, so the recent availability of bedaquiline is welcome. Bedaquiline-containing regimens, now the first-line therapy recommended by WHO, have transformed the treatment of drug-resistant tuberculosis, offering safer and more effective oral treatment options. However, key obstacles need to be overcome to ensure global access and prevent the rapid development of resistance against this promising class of drugs. In this Personal View, building on an international workshop held in 2023, we evaluate the current evidence and suggest possible ways forward, recognising the tension between increasing use and slowing the rise of resistance. We also discuss problems in accessing bedaquiline-containing regimens, the potential widening of their use beyond drug-resistant tuberculosis, and lessons for utilising new drugs as they are developed.

"This is an illness. No one is supposed to be treated badly": community-based stigma assessments in South Africa to inform tuberculosis stigma intervention design.

Background: Though tuberculosis (TB)-related stigma is a recognized barrier to care, interventions are lacking, and gaps remain in understanding the drivers and experiences of TB-related stigma. We undertook community-based mixed methods stigma assessments to inform stigma intervention design. Methods: We adapted the Stop TB Partnership stigma assessment tool and trained three peer research associates (PRAs; two TB survivors, one community health worker) to conduct surveys with people with TB (PWTB, n = 93) and caregivers of children with TB (n = 24) at peri-urban and rural clinic sites in Khayelitsha, Western Cape, and Hammanskraal, Gauteng Province, South Africa. We descriptively analyzed responses for each stigma experience (anticipated, internal, and enacted), calculated stigma scores, and undertook generalized linear regression analysis. We conducted 25 in-depth interviews with PWTB (n = 21) and caregivers of children with TB (n = 4). Using inductive thematic analysis, we performed open coding to identify emergent themes, and selective coding to identify relevant quotes. Themes were organized using the Constraints, Actions, Risks, and Desires (CARD) framework. Results: Surveys revealed almost all PWTB (89/93, 96%) experienced some form of anticipated, internal, and/or enacted stigma, which affected engagement throughout the care cascade. Participants in the rural setting (compared to peri-urban) reported higher anticipated, internal, and enacted stigma (ß-coefficient 0.72, 0.71, 0.74). Interview participants described how stigma experiences, including HIV intersectional stigma, act individually and together as key constraints to impede care, leading to decisions not to disclose a TB diagnosis, isolation, and exclusion. Stigma resilience arose through the understanding that TB can affect anyone and should not diminish self-worth. Risks of stigma, driven by fears related to disease severity and infectiousness, led to care disengagement and impaired psychological well-being. Participants desired counselling, identifying a specific role for TB survivors as peer counselors, and community education. Conclusions: Stigma is highly prevalent and negatively impacts TB care and the well-being of PWTB, warranting its assessment as a primary outcome rather than an intermediary contributor to poor outcomes. Multi-component, multi-level stigma interventions are needed, including counseling for PWTB and education for health workers and communities. Such interventions must incorporate contextual differences based on gender or setting, and use survivor-guided messaging to foster stigma resilience. Supplementary Information: The online version contains supplementary material available at 10.1186/s44263-024-00070-5.

Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise.

The current active-latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.

"As a patient I do not belong to the clinic, I belong to the community." Co-developing a multi-level, person-centred tuberculosis stigma intervention in Cape Town, South Africa.

Background: Anticipated, internal, and enacted stigma are major barriers to TB care engagement, and directly impact patient well-being. Unfortunately, targeted stigma interventions are lacking. We aimed to co-develop a person-centred stigma intervention with TB-affected community members and health workers in South Africa. Methods: Using a community-based participatory research approach, we conducted ten group discussions with people diagnosed with TB (past or present), caregivers, and health workers (total n=87) in Khayelitsha, Cape Town. Group discussions were facilitated by TB survivors. Discussion guides explored experiences and drivers of stigma and used human-centred design principles to co-develop solutions. Recordings were transcribed, coded, thematically analysed and then further interpreted using the socio-ecological model. Results: Intervention components across socio-ecological levels shared common behaviour change strategies, namely education, empowerment, engagement, and innovation. At the individual level, participants recommended counselling to improve TB knowledge and provide ongoing support. TB survivors can guide messaging to nurture stigma resilience by highlighting that TB can affect anyone and is curable, and provide lived experiences of TB to decrease internal stigma. At the interpersonal level, support clubs and family-centred counselling were suggested to dispel TB-related myths and foster support. At the institutional level, health worker stigma reduction training informed by TB survivor perspectives was recommended. Consideration of how integration of TB/HIV care services may exacerbate TB/HIV intersectional stigma and ideas for restructured service delivery models were suggested to decrease anticipated and enacted stigma. At the community level, participants recommended awareness-raising events led by TB survivors, including TB information in school curricula. At the policy level, solutions focused on reducing the visibility generated by a TB diagnosis and resultant stigma in health facilities and shifting tasks to community health workers. Conclusions: Decreasing TB stigma requires a multi-level approach. Co-developing a person-centred intervention with affected communities is feasible and generates stigma intervention components that are directed and implementable. Such community-informed intervention components should be prioritised by TB programs, including integrated TB/HIV care services.

"This is an illness. No one is supposed to be treated badly": Community-based stigma assessments in South Africa to inform TB stigma intervention design.

Background: Though TB-related stigma is a recognized barrier to care, interventions are lacking and gaps remain in understanding the drivers and experiences of TB-related stigma. We undertook community-based mixed methods stigma assessments to inform stigma intervention design. Methods: We adapted the Stop TB Partnership stigma assessment tool, and trained three peer research associates (PRAs; two TB survivors, one community health worker) to conduct surveys with people with TB (PWTB, n=93) and caregivers of children with TB (n=24) at peri-urban and rural clinic sites in Khayelitsha, Western Cape, and Hammanskraal, Gauteng Province, South Africa. We descriptively analyzed responses for each stigma experience (anticipated, internal, and enacted), calculated stigma scores, and undertook generalized linear regression analysis. We further conducted 25 in-depth interviews with PWTB (n=22) and caregivers TB (n=3). Using inductive thematic analysis, we performed open coding to identify emergent themes, and selective coding to identify relevant quotes. Themes were organised using the CARD (Constraints, Actions, Risks and Desires) framework. Results: Surveys revealed at least one-third of PWTB and one-quarter of caregivers report experiences of anticipated, internal, and/or enacted stigma, which affected engagement throughout the care cascade. Participants in rural locations (compared to peri-urban) reported higher anticipated, internal, and enacted stigma (ß-coefficient 0.72, 0.71, and 0.74). Interview participants described how stigma experiences, including HIV intersectional stigma, act individually and in concert as key constraints to impede care, and underpins failure to disclose a TB diagnosis, isolation, and exclusion. Stigma resilience arose through understanding that TB can affect anyone and should not diminish self-worth. Risks of stigma, driven by fears related to disease severity and infectiousness, led to care disengagement and impaired psychological wellbeing. Participants desired counselling, identifying a specific role for TB survivors as peer counsellors, and community education. Conclusions: Stigma is highly prevalent and negatively impacts TB care and the well-being of PWTB, warranting its assessment as a primary outcome indicator rather than intermediary contributor to poor cascade outcomes. Multicomponent stigma interventions are needed, including counselling for PWTB and education for health workers and communities. Such interventions must incorporate contextual differences based on gender or setting, and use survivor-guided messaging to foster stigma resilience.

The role of counselling in tuberculosis diagnostic evaluation and contact tracing: scoping review and stakeholder consultation of knowledge and research gaps.

BACKGROUND: Tuberculosis (TB) care cascade analyses show large gaps at early stages, including care-seeking and diagnostic evaluation, where promising interventions to decrease attrition are urgently needed. Person-centered care is prioritized in the World Health Organization's End TB strategy; yet little is known about how it is delivered and can be optimized. Recommendations for counselling, a core component of person-centered care, are largely limited to its role in improving TB treatment adherence. The role of counselling to close key diagnostic gaps in the care cascade is poorly understood. METHODS: We conducted a scoping review to identify evidence on the use of counselling at TB diagnosis, for both people with presumptive TB and index patients to promote patient retention and contact tracing. Using search terms for TB, diagnosis and counselling, we systematically searched PubMed, EMBASE and Web of Science. Two independent reviewers screened all abstracts, full-texts, extracted data and conducted a quality assessment. We used thematic analysis to identify key themes. RESULTS: After screening 1785 articles, we extracted data from 15 studies and determined that the major themes best corresponded to the following gaps in the TB care cascade: care-seeking, pre-diagnosis, and pre-treatment. Studies were conducted across varied settings including pharmacies, primary health centres, and clinics, primarily in high TB incidence countries. No study directly evaluated the impact of counselling on outcomes such as treatment initiation or retention in care. Included studies suggested counselling may play an important role in improving the uptake of diagnostic testing and contact tracing. Barriers to counselling included time and personnel requirements. Stakeholder consultation emphasized the importance of high-quality counselling as a core tenet of TB care. CONCLUSION: Data on the impact of counselling to improve TB case detection are absent from the literature. The shift towards person-centred care for TB presents an opportunity to incorporate counselling during earlier stages of the TB care cascade; however, evidence-based approaches are needed. Implementation research is needed to operationalize and evaluate counselling to strengthen high-quality TB care delivery.

Analysing interventions designed to reduce tuberculosis-related stigma: A scoping review.

Stigma is a critical barrier for TB care delivery; yet data on stigma reduction interventions is limited. This review maps the available literature on TB stigma reduction interventions, using the Health Stigma and Discrimination framework and an implementation analysis to identify research gaps and inform intervention design. Using search terms for TB and stigma, we systematically searched PubMed, EMBASE and Web of Science. Two independent reviewers screened all abstracts, full-texts, extracted data, conducted a quality assessment, and assessed implementation. Results were categorized by socio-ecological level, then sub-categorized by the stigma driver or manifestation targeted. After screening 1865 articles, we extracted data from nine. Three studies were implemented at the individual and interpersonal level using a combination of TB clubs and interpersonal support to target internal and anticipated stigma among persons with TB. Two studies were implemented at the interpersonal level using counselling or a video based informational tool delivered to households to reduce stigma drivers and manifestations. Three studies were implemented at the organizational level, targeting drivers of stigma among healthcare workers (HW) and enacted stigma among HWs. One study was implemented at the community level using an educational campaign for community members. Stakeholder consultation emphasized the importance of policy level interventions and education on the universality of risk to destigmatize TB. Review findings suggest that internal and anticipated TB stigma may be addressed effectively with interventions targeted towards individuals using counselling or support groups. In contrast, enacted TB stigma may be better addressed with information-based interventions implemented at the organizational or community level. Policy level interventions were absent but identified as critical by stakeholders. Implementation barriers included the lack of high-quality training and integration with mental health services. Three key gaps must be addressed in future research: consistent stigma definitions, standardized stigma measurement, and measurement of implementation outcomes.

Access to new medications for the treatment of drug-resistant tuberculosis: patient, provider and community perspectives.

Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions.