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Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide.sup.1. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission.sup.1,2. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis. The delivery route and dose of the BCG vaccine profoundly alters the protective outcome after Mycobacterium tuberculosis challenge in non-human primates., Author(s): Patricia A. Darrah [sup.1] , Joseph J. Zeppa [sup.2] , Pauline Maiello [sup.2] , Joshua A. Hackney [sup.1] , Marc H. Wadsworth II [sup.3] [sup.4] [sup.5] , Travis K. [...]

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 potentia 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. Keywords: TB; HIV care continuum; differentiated care; public health; co-infection; treatment, 1 INTRODUCTION Tuberculosis (TB) is a leading cause of mortality among people living with HIV (PLHIV). This population contributes substantially to the global TB burden, with a higher risk of [...]

Objective To analyse the epidemiological trends of tuberculosis in the Siberian and Far Eastern federal districts, the areas with the highest disease burden in the Russian Federation. Methods We applied principal coordinate analysis to study a total of 68 relevant variables on tuberculosis epidemiology, prevention and control. Data on these variables were collected over 2003-2016 in all 21 regions of the Siberian federal district and Far Eastern federal district (total population: 25.5 million) through the federal and departmental reporting system. We identified the regions with a favourable or unfavourable tuberculosis epidemiological profile and ranked them as low or high priority for specific interventions. Findings The median number of tuberculosis notifications in the regions was 123.3 per 100 000 population (range: 54.5-265.7) in 2003, decreasing to 82.3 per 100 000 (range: 52.9-178.3) in 2016. We found large variations in the tuberculosis epidemiological profile across different regions. The principal coordinate analysis revealed that three aggregated indicators accounted for 55% of the variation. The first coordinate corresponded to tuberculosis prevalence and case notifications in the regions; the second to the severity of the disease among patients; and the third to the percentage of multidrug-resistant tuberculosis among tuberculosis patients. The regions where intervention was most urgently needed were Chukotka Autonomous Okrug, Jewish Autonomous Oblast and Tyva Republic. Conclusion The variability in tuberculosis epidemiology across regions was likely due to differences in the quality of antituberculosis services. Precision in defining necessary interventions, as determined through the principal coordinate analysis approach, can guide focused tuberculosis control efforts. Objectif Analyser les tendances epidemiologiques de la tuberculose dans le district federal siberien et le district federal extreme-oriental, qui presentent la charge de morbidite la plus elevee au sein de la Federation de Russie. Methodes Nous avons applique une analyse en coordonnees principales pour etudier un total de 68 variables pertinentes sur l'epidemiologie, la prevention et le controle de la tuberculose. Des donnees sur ces variables ont ete collectees entre 2003 et 2016 dans les 21 regions du district federal siberien et du district federal extreme-oriental (population totale: 25,5 millions) a l'aide du systeme de notification federal et ministeriel. Nous avons determine les regions presentant un profil epidemiologique de la tuberculose favorable ou defavorable, puis nous les avons assimilees a un degre de priorite faible ou eleve concernant des interventions specifiques. Resultats Le nombre median de notifications de cas de tuberculose dans les regions considerees s'elevait a 123,3 pour 100 000 habitants (etendue: 54,5-265,7) en 2003, puis diminuait pour atteindre 82,3 pour 100 000 habitants (etendue: 52,9-178,3) en 2016. Nous avons constate d'importantes variations du profil epidemiologique de la tuberculose entre les differentes regions. L'analyse en coordonnees principales a revele que trois indicateurs agreges contribuaient pour 55% aux variations. La premiere coordonnee correspondait a la prevalence et aux notifications de cas de tuberculose dans les regions considerees; la deuxieme correspondait a la gravite de la maladie chez les patients atteints; et la troisieme correspondait au pourcentage de tuberculose multiresistante chez les patients atteints. Les regions ou les interventions etaient les plus urgentes etaient le district autonome de Tchoukotka, l'oblast autonome juif et la Republique de Touva. Conclusion La variability de l'epidemiologie de la tuberculose entre les regions etait probablement due a des differences dans la qualite des services antituberculeux. Il peut etre utile de definir precisement les interventions necessaires, comme determine a l'aide de la methode d'analyse en coordonnees principales, pour orienter les efforts de lutte contre la tuberculose. Objetivo Analizar las tendencias epidemiologicas de la tuberculosis en los distritos federales de Siberia y Extremo Oriente, las zonas con mayor carga de morbilidad de la Federacion de Rusia. Metodos Se aplico el analisis de coordenadas principales para estudiar un total de 68 variables relevantes en epidemiologia, prevencion y control de la tuberculosis. Los datos sobre estas variables se recopilaron entre 2003 y 2016 en las 21 regiones del distrito federal de Siberia y del distrito federal del Extremo Oriente (poblacion total: 25,5 millones) a traves del sistema de presentacion de informes federal y departamental. Se identificaron las regiones con un perfil epidemiologico favorable o desfavorable de la tuberculosis y se clasificaron como de baja o alta prioridad para intervenciones especificas. Resultados El numero promedio de notificaciones de tuberculosis en las regiones fue de 123,3 por cada 100 000 habitantes (rango: 54,5265,7) en 2003, disminuyendo a 82,3 por cada 100 000 habitantes (rango: 52,9-178,3) en 2016. Se encontraron notables variaciones en el perfil epidemiologico de la tuberculosis entre las diferentes regiones. El analisis de las coordenadas principales revelo que tres indicadores agregados representaban el 55 % de la variacion. La primera coordenada correspondia a la prevalencia de la tuberculosis y las notificaciones de casos en las regiones; la segunda a la gravedad de la enfermedad entre los pacientes; y la tercera al porcentaje de tuberculosis multirresistente entre los pacientes con tuberculosis. Las regiones en las que la intervencion era mas urgente eran el Distrito Autonomo de Chukotka, la Provincia Autonoma Hebrea y la Republica de Tyva. Conclusion La variabilidad en la epidemiologia de la tuberculosis entre regiones se debio probablemente a las diferencias den la calidad de los servicios de tratamiento antituberculoso. La precision en la definicion de las intervenciones necesarias, determinada a traves del enfoque de analisis de coordenadas principales, puede guiar los esfuerzos focalizados de control de la tuberculosis., Introduction During the 1990s the tuberculosis epidemic in the Russian Federation worsened due to an economic recession in the country at that time. National tuberculosis case notifications reached a peak [...]

Background Scaling up shorter regimens for tuberculosis (TB) prevention such as once weekly isoniazid-rifapentine (3HP) taken for 3 months is a key priority for achieving targets set forth in the World Health Organization's (WHO) END TB Strategy. However, there are few data on 3HP patient acceptance and completion in the context of routine HIV care in sub-Saharan Africa. Methods and findings The 3HP Options Trial is a pragmatic, parallel type 3 effectiveness-implementation randomized trial comparing 3 optimized strategies for delivering 3HP-facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between DOT and SAT using a shared decision-making aid-to people receiving care at a large urban HIV clinic in Kampala, Uganda. Participants and healthcare providers were not blinded to arm assignment due to the nature of the 3HP delivery strategies. We conducted an interim analysis of participants who were enrolled and exited the 3HP treatment period between July 13, 2020 and April 30, 2021. The primary outcome, which was aggregated across trial arms for this interim analysis, was the proportion who accepted and completed 3HP ([greater than or equal to]11 of 12 doses within 16 weeks of randomization). We used Bayesian inference analysis to estimate the posterior probability that this proportion would exceed 80% under at least 1 of the 3HP delivery strategies, a coprimary hypothesis of the trial. Through April 2021, 684 participants have been enrolled, and 479 (70%) have exited the treatment period. Of these 479 participants, 309 (65%) were women, mean age was 41.9 years (standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART) was 7.8 years (SD: 4.3). In total, 445 of them (92.9%, 95% confidence interval (CI): [90.2 to 94.9]) accepted and completed 3HP treatment. There were no differences in treatment acceptance and completion by sex, age, or time on ART. Treatment was discontinued due to a documented adverse event (AE) in 8 (1.7%) patients. The probability that treatment acceptance and completion exceeds 80% under at least 1 of the three 3HP delivery strategies was greater than 99%. The main limitations are that the trial was conducted at a single site, and the interim analysis focused on aggregate outcome data to maintain blinding of investigators to arm-specific outcomes. Conclusions 3HP was widely accepted by people living with HIV (PLHIV) in Uganda, and very high levels of treatment completion were achieved in a programmatic setting. These findings show that 3HP can enable effective scale-up of tuberculosis preventive therapy (TPT) in high-burden countries, particularly when delivery strategies are tailored to target known barriers to treatment completion. Trial registration ClinicalTrials.gov NCT03934931., Author(s): Fred C. Semitala 1,2,3, Jillian L. Kadota 4, Allan Musinguzi 2, Juliet Nabunje 2, Fred Welishe 2, Anne Nakitende 2, Lydia Akello 2, Opira Bishop 2, Devika Patel 5, [...]

The World Health Organization End TB Strategy aims to end the global tuberculosis (TB) epidemic by 2035 (1). The US Preventive Service Task Force (2) and Centers for Disease Control [...]

Few diseases have impacted human history as much as tuberculosis (TB). Mycobacterium tuberculosis (MTB) has caused disease in humans for more than 4000 years [1]. Since its scientific discovery in [...]

: Introduction: In 2017, the Aurum Institute, with support from Unitaid, launched an initiative to expand short‐course therapy for the prevention of tuberculosis (TB) in 12 high‐burden countries. This study aimed to investigate the importance of “catalytic” effects beyond the original project timeframe when estimating cost‐effectiveness of such large investments. Methods: We estimated the cost‐effectiveness of the IMPAACT4TB (I4TB) initiative from a health system perspective, using a 10‐year time horizon. We first conservatively estimated costs using a “top‐down” approach considering only the direct health benefits of providing TB preventive therapy to people initiating antiretroviral therapy (ART) through I4TB activities. We then re‐estimated the incremental cost‐effectiveness of I4TB incorporating the costs and health benefits of potential catalytic effects beyond the program itself. Results: We estimated that TB preventive therapy through the I4TB initiative alone would prevent 14 201 cases of active TB and 1562 TB deaths over 10 years with an up‐front investment of $52.5 million; the estimated incremental cost‐effectiveness was $1580 per disability‐adjusted life year (DALY) averted. If this initiative could achieve its desired catalytic effects, an additional 375 648 cases and 41 321 deaths could be averted, at an incremental cost of $546 million and cost‐effectiveness of $713 per DALY averted. Conclusions: Our findings provide donors with reasonable evidence of value for money to support investment in short‐course TB preventive therapy for people initiating ART in high‐burden settings. Our study also illustrates the importance of considering long‐term secondary (“catalytic”) effects when evaluating the cost‐effectiveness of large‐scale initiatives designed to change a global policy landscape., INTRODUCTION Since 1993, the World Health Organization (WHO) has recommended preventive therapy for tuberculosis (TB) for people living with HIV (PLHIV) in whom active TB has been excluded (without testing [...]