Addressing the needs of people with extensively drug-resistant TB through pre-approval access to drugs and research.

Multiple therapeutic options exist for people with drug-resistant TB (DR-TB), but there is an urgent need to improve access to novel compounds and regimens for people with difficult to treat forms of TB. In additional to formal research studies and clinical trials, other mechanisms of accessing promising new TB compounds need to be introduced as soon as these drugs have shown efficacy and safety in phase II trials. Pre-approval access programs for newer TB drugs such as bedaquiline, delamanid, and pretomanid all suffered from shortcomings. These can be addressed for the next generation of new TB drugs through a series of concerted actions by stakeholders at multiple levels. In this viewpoint, we advocate for transparent, accessible pre-approval access as a core element of person-centered care for DR-TB.

Il existe de nombreuses options thérapeutiques pour les personnes atteintes de TB résistante aux médicaments (DR-TB), mais il est urgent d'améliorer l'accès aux nouvelles molécules et aux nouveaux schémas thérapeutiques pour les personnes atteintes de formes de TB difficiles à traiter. Outre les études de recherche formelles et les essais cliniques, d'autres mécanismes d'accès aux nouvelles molécules prometteuses contre la TB doivent être mis en place dès que ces médicaments ont démontré leur efficacité et leur innocuité lors des essais de phase II. Les programmes d'accès avant approbation pour les nouveaux médicaments contre la TB tels que la bédaquiline, le delamanid et le pretomanid ont tous souffert de lacunes. Ces problèmes peuvent être résolus pour la prochaine génération de nouveaux médicaments contre la TB grâce à une série d'actions concertées entre les parties prenantes à différents niveaux. Dans cette optique, nous préconisons un accès transparent et accessible avant approbation, en tant qu'élément central des soins centrés sur la personne pour la DR-TB.

Shorter TB treatment regimens should be safer as well.

Most ongoing and planned TB therapeutic trials are focused on shortening the duration of treatment while giving less consideration to other aspects of TB care that are important to people with TB. Here we argue that other variables besides duration of TB treatment should also be considered when developing new TB treatment regimens, including drug toxicity, time spent in monitoring and overall quality of life while on therapy. We examine the specific use of linezolid in treatment-shortening trials for drug-susceptible TB and propose additional endpoints that should be prioritised in TB treatment studies.

La majorité des essais thérapeutiques en cours et prévus sur la TB se concentrent sur la réduction de la durée du traitement tout en accordant moins d'attention à d'autres aspects des soins de la TB qui sont importants pour les personnes atteintes de la TB. Nous soutenons ici que d'autres variables que la durée du traitement de la TB devrait également être prises en compte lors de l'élaboration de nouveaux schémas thérapeutiques, notamment la toxicité des médicaments, le temps passé à la surveillance et la qualité de vie globale pendant le traitement. Nous examinons l'utilisation spécifique du linézolide dans les essais de raccourcissement du traitement de la TB sensible aux médicaments et proposons des critères d'évaluation supplémentaires qui devraient être prioritaires dans les études sur le traitement de la TB.

One size does not fit all: community views on choices for TB treatment and prevention.

Treatment and prevention paradigms in TB have been dominated by a 'one-size-fits-all' approach, in which all persons are given the same treatment regimens. This stands in contrast to other health conditions, where differentiated models of care have been shown to be effective. In this Viewpoint, we make the case for considering multiple factors when deciding which regimens should be offered to people with TB infection and disease. Choice about which regimens to use should be made in conjunction with people who have TB and consider efficacy, safety, duration, pill burden, formulation, drug interactions, time spent in monitoring, drug susceptibility, compatibility with other areas of life, and availability of support services. Ideally, these choices should be considered within an equity framework with the most intensified services being offered to those considered most vulnerable.

Les paradigmes de traitement et de prévention de la TB ont été dominés par une approche « unique ¼, dans laquelle toutes les personnes reçoivent les mêmes schémas thérapeutiques. Cette approche contraste avec d'autres problèmes de santé, pour lesquels des modèles de soins différenciés se sont avérés efficaces. Dans ce point de vue, nous plaidons en faveur de la prise en compte de multiples facteurs au moment de décider des schémas thérapeutiques à proposer aux personnes atteintes de infection tuberculeuse et de TB maladie. Le choix des traitements doit être fait en collaboration avec les personnes atteintes de TB et tenir compte de l'efficacité, de l'innocuité, de la durée, du nombre de comprimés, de la formulation, des interactions médicamenteuses, du temps consacré à la surveillance, de la sensibilité aux médicaments, de la compatibilité avec d'autres domaines de la vie et de la disponibilité des services d'aide. Idéalement, ces choix devraient être envisagés dans un cadre d'équité, les services les plus intensifs étant proposés aux personnes considérées comme les plus vulnérables.

Hear us! Accounts of people treated with injectables for drug-resistant TB.

BACKGROUND: WHO drug-resistant TB (DR-TB) treatment recommendations now emphasize all-oral regimens, recommending against certain injectable agents and deprioritizing others due to inferior safety and efficacy. Despite increasing focus on patient-centered care, we are not aware of systematic attempts to qualitatively document patients' perspectives on injectable agents. This may inform implementation of WHO guidelines, emphasizing the importance of consultation with affected communities. METHODS: Testimonies were provided by TB survivors who experienced hearing loss from treatment with injectable agents. Testimonies were submitted in writing in response to minimal, standardized, open-ended prompts. Participants provided a signed consent form (with options to participate anonymously or as a named co-author), and later gave input into the overall shape and recommendations of the article. RESULTS: Fourteen TB survivors in 12 countries contributed testimonies. The following common themes emerged: lack of access to appropriate testing, information, treatment, or a collaborative treatment environment; the power of supportive care and social environments; stigma and isolation from TB treatment itself and resultant disability; and inaccessibility of cochlear implants. CONCLUSIONS: Survivor testimonies indicate strong preferences for avoidance of injectable agents, supporting rapid implementation of revised WHO guidelines, as well as for quality and supportive care for both TB and disabilities.

CONTEXTE: Les recommandations de l'OMS pour le traitement de la TB pharmacorésistante (DR-TB) mettent désormais l'accent sur les schémas thérapeutiques entièrement par voie orale, préconisant de ne pas utiliser certains agents injectables et de ne plus donner la priorité à d'autres en raison d'une innocuité et d'une efficacité inférieures. Malgré l'attention accrue portée aux soins centrés sur le patient, nous ne connaissons aucune étude systématique ayant cherché à documenter de manière qualitative le point de vue des patients sur les agents injectables. Ce travail pourrait guider la mise en place des directives de l'OMS, en mettant l'accent sur l'importance de consulter les communautés concernées. MÉTHODES: Des personnes ayant survécu à une TB et ayant connu une perte d'audition due à un traitement par agents injectables ont apporté leurs témoignages. Les témoignages ont été soumis par écrit en réponse à des questions courtes, ouvertes et standardisées. Les participants ont signé un formulaire de consentement (avec possibilité de participer de manière anonyme ou en tant que coauteur nommé) et ont ensuite contribué au format général et aux recommandations de l'article. RÉSULTATS: Quatorze personnes ayant survécu à une TB provenant de 12 pays ont apporté leur témoignage. Les thématiques suivantes ont été fréquemment mentionnées : manque d'accès aux tests, informations et traitements appropriés ou à un environnement thérapeutique collaboratif ; importance des soins de soutien et de l'environnement social ; stigmatisation et isolement dus au traitement antituberculeux et handicaps qui en résultent ; et inaccessibilité aux implants cochléaires. CONCLUSIONS: Le témoignage des personnes ayant survécu à une TB indique qu'elles préfèrent nettement éviter les agents injectables, allant ainsi dans le sens d'une mise en place rapide des directives révisées de l'OMS, et qu'elles préfèrent des soins de qualité et de soutien pour la TB mais aussi pour les handicaps qui en résultent.

Upholding ethical values and human rights at the frontier of TB research.

Until recently, human rights have played a minor role in the fight against tuberculosis (TB), even less so in TB research. This is changing, however. The WHO's End TB Strategy and Ethics Guidance stress respect for human rights and ethical principles in every area of TB care, including research. The desired reductions in TB incidence and mortality are impossible without new tools and strategies to fight the disease. Yet, little suggests that the current state of TB research-including funding levels, evidence being produced, and community involvement-will alleviate concerns related to the availability, accessibility, and acceptability of TB diagnostics, drugs, and prevention in the near future. In this article, we consider these ethics concerns in relation to the right to enjoy the benefits of scientific progress and the right to health. We also reflect on community involvement in research and offer recommendations in the spirit of the rights to health and science, such as involving affected communities in all aspects of research planning, execution, and dissemination. Finally, we argue that states have a responsibility under international law for the continued realization of the right to health. This realization rests, in part, on the realization of the right to science.

Health care gaps in the global burden of drug-resistant tuberculosis.

The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.

The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?

For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

Petrolatum versus Resurfix ointment in the treatment of pressure ulcers.

This study compares the therapeutic effects of a new topically applied, nonprescription medication that has been introduced for re-epithelialization of ulcers and erosions of the skin, with petrolatum in treating pressure ulcers of shallow depth (Stage I and Stage II). A 6-week, randomized, double-blind study was performed on 19 patients with Stage I or Stage II pressure ulcers. The patients received either the new nonprescription medication or petrolatum, which served as a control. After the course of the study, the study ointment effected resolution in a majority of pressure ulcers (9 out of 10), while only one out of three ulcers treated with petrolatum resolved in the same time period. These preliminary results show that the study ointment is a safe and effective treatment for Stage I and II pressure ulcers.

Subcellular fractionation of epiphyseal cartilage: isolation of matrix vesicles and profiles of enzymes, phospholipids, calcium and phosphate.

Epiphyseal cartilage was fractionated into subcellular components by nonenzymatic methods, and analyzed for activity of marker enzymes, for phospholipids, and for calcium and inorganic phosphate. Alkaline phosphatase, a marker enzyme for matrix vesicles and plasma membranes, was concentrated in the 100 000 X g (microsomal) pellet and, upon subsequent fractionation, in the low-density fractions from the sucrose gradient. Mitochondrial and endoplasmic reticular enzymes were localized primarily in the 20 000 X g pellet, lysosomal enzymes predominantly in the supernate from the microsomal pellet. Two phospholipids characteristic of matrix vesicles, sphingomyelin and phosphatidylserine, were enriched in the low-density sucrose fractions; however, unlike matrix vesicles, there was no depletion in phosphatidylcholine or increase in lysophospolipids. Ca and inorganic P were concentrated in the higher-density fractions, the amounts in the lower-density fractions being somewhat lower than those seen in matrix vesicles. The alkaline phosphatase-rich, low-density fractions were thus not identical to matrix vesicles isolated by collagenase digestion, but rather appear to be composed primarily of plasma membranes. Enzyme profiles indicate they were relatively free of mitochondrial, endoplasmic reticular and lysosomal contaminants. the data further indicate that significant modification of the phospholipid, electrolyte, and possibly enzyme content of chondrocyte plasma membranes, must occur during blebbing and matrix vesicle formation.