An initiative to improve mental health practice in primary care in Caribbean countries.

Objectives: The aim of this initiative was to assess whether a novel training program - Understanding Stigma and Strengthening Cognitive Behavioral Interpersonal Skills - could improve primary health care providers' confidence in the quality of mental health care they provide in the Caribbean setting by using the Plan-Do-Study-Act rapid cycle for learning improvement. Methods: We conducted a prospective observational study of the impact of this training program. The training was refined during three cycles: first, the relevance of the program for practice improvement in the Caribbean was assessed. Second, pilot training of 15 local providers was conducted to adapt the program to the culture and context. Third, the course was launched in fall 2021 with 96 primary care providers. Pre- and post-program outcomes were assessed by surveys, including providers' confidence in the quality of the mental health care they provided, changes in stigma among the providers and their use of and comfort with the tools. This paper describes an evaluation of the results of cycle 3, the official launch. Results: A total of 81 participants completed the program. The program improved primary care providers' confidence in the quality of mental health care that they provided to people with lived experience of mental health disorders, and it reduced providers' stigmatization of people with mental health disorders. Conclusions: The program's quality improvement model achieved its goals in enhancing health care providers' confidence in the quality of the mental health care they provided in the Caribbean context; the program provides effective tools to support the work and it helped to empower and engage clients.

An initiative to improve mental health practice in primary care in Caribbean countries

[ABSTRACT]. Objectives. The aim of this initiative was to assess whether a novel training program – Understanding Stigma and Strengthening Cognitive Behavioral Interpersonal Skills – could improve primary health care providers’ confidence in the quality of mental health care they provide in the Caribbean setting by using the Plan-Do- Study-Act rapid cycle for learning improvement. Methods. We conducted a prospective observational study of the impact of this training program. The training was refined during three cycles: first, the relevance of the program for practice improvement in the Caribbean was assessed. Second, pilot training of 15 local providers was conducted to adapt the program to the culture and context. Third, the course was launched in fall 2021 with 96 primary care providers. Pre- and post-program outcomes were assessed by surveys, including providers’ confidence in the quality of the mental health care they provided, changes in stigma among the providers and their use of and comfort with the tools. This paper describes an evaluation of the results of cycle 3, the official launch. Results. A total of 81 participants completed the program. The program improved primary care providers’ confidence in the quality of mental health care that they provided to people with lived experience of mental health disorders, and it reduced providers’ stigmatization of people with mental health disorders. Conclusions. The program’s quality improvement model achieved its goals in enhancing health care provid- ers’ confidence in the quality of the mental health care they provided in the Caribbean context; the program provides effective tools to support the work and it helped to empower and engage clients.

[RESUMEN]. Objetivos. La finalidad de esta iniciativa fue determinar si un nuevo programa de capacitación, titulado Under- standing Stigma and Strengthening Cognitive Behavioral Interpersonal Skills (Comprender la estigmatización y fortalecer las competencias interpersonales cognitivas y conductuales), podría mejorar la confianza de los prestadores de atención primaria de salud en la calidad de la atención de salud mental que proporcionan en los países del Caribe, mediante el uso del ciclo rápido Planificación-Realización-Estudio-Acción para la mejora del aprendizaje. Métodos. Realizamos un estudio de observación prospectivo sobre el impacto de este programa de capac- itación. La formación se perfeccionó a lo largo de tres ciclos: en primer lugar, se evaluó la pertinencia del programa para la mejora de las prácticas en el Caribe; en segundo lugar, se llevó a cabo una capacitación piloto de 15 prestadores locales para adaptar el programa a la cultura y el contexto; en tercer lugar, en el otoño del 2021 se puso en marcha el curso con 96 prestadores de atención primaria. Los resultados anteri- ores y posteriores al programa se evaluaron mediante encuestas que incluían la confianza de los prestadores en la calidad de la atención de salud mental que proporcionaban, los cambios aparecidos en los prestadores en cuanto a la estigmatización, y su uso y conocimiento de las herramientas. En este artículo se describe una evaluación de los resultados del ciclo 3, correspondiente a la puesta en marcha oficial. Resultados. Un total de 81 participantes completaron el programa. El programa mejoró la confianza de los prestadores de atención primaria en la calidad de la atención de salud mental que proporcionaban a las per- sonas que presentaban trastornos de la salud mental y redujo la estigmatización de las personas con este tipo de trastornos por parte de los prestadores de la atención. Conclusiones. El modelo de mejora de la calidad del programa logró sus objetivos en cuanto a mejorar la confianza de los prestadores de atención de salud en la calidad de la atención de salud mental que propor- cionan en los países del Caribe; el programa aporta herramientas eficaces para sustentar esta tarea y ayudó a empoderar e involucrar a las personas usuarias.

[RESUMO]. Objetivos. O objetivo da iniciativa foi avaliar se um novo programa de capacitação, Compreensão do estigma e fortalecimento das competências cognitivas e comportamentais interpessoais, seria capaz de aumentar a confiança dos profissionais de atenção primária à saúde na qualidade da atenção à saúde mental que ofere- cem a pacientes no Caribe, utilizando o ciclo rápido Plan-Do-Study-Act (planejar, fazer, avaliar e agir) para melhorar o aprendizado. Métodos. Este foi um estudo observacional prospectivo sobre o impacto desse programa de capacitação. A capacitação foi aperfeiçoada ao longo de três ciclos. Inicialmente, avaliou-se a relevância do programa para o aprimoramento da prática no Caribe. A seguir, foi realizada uma capacitação-piloto de 15 profissionais locais para adaptar o programa à cultura e ao contexto. No terceiro ciclo, realizado no outono de 2021, o curso foi lançado, com a participação de 96 profissionais de atenção primária. Os resultados antes e depois do programa foram avaliados por meio de questionários, que incluíam a confiança dos provedores na qualidade da atenção à saúde mental oferecida, mudanças no estigma entre os profissionais e a utilização das ferramentas e o conforto dos profissionais em usá-las. Este documento apresenta a avaliação dos resul- tados do ciclo 3, o lançamento oficial do curso. Resultados. Oitenta e um participantes completaram o programa. O programa melhorou a confiança dos profissionais de atenção primária na qualidade dos cuidados de saúde mental que ofereciam às pessoas com experiência vivida relacionada a problemas de saúde mental. Além disso, reduziu a estigmatização das pessoas com problemas de saúde mental pelos profissionais de saúde. Conclusão. O modelo de melhoria da qualidade do programa atingiu suas metas de aumentar a confiança dos prestadores de serviços de saúde na qualidade dos serviços de saúde mental que prestavam no Caribe; o programa fornece ferramentas efetivas de apoio ao trabalho e ajudou a empoderar e envolver os clientes.

Using a medication event monitoring system to evaluate self-report and pill count for determining treatment completion with self-administered, once-weekly isoniazid and rifapentine.

BACKGROUND: Treatment completion is essential for the effectiveness of any latent tuberculosis infection (LTBI) regimen. The Tuberculosis Trials Consortium (TBTC) Study 33 (iAdhere) combined self-report and pill counts - standard of care (SOC) with a medication event monitoring system (MEMS) to determine treatment completion for 12-dose once-weekly isoniazid and rifapentine (3HP). Understanding the performance of SOC relative to MEMS can inform providers and suggest when interventions may be applied to optimize LTBI treatment completion. METHOD: iAdhere randomized participants to directly observed therapy (DOT), SAT, or SAT with text reminders in Hong Kong, South Africa, Spain and the United States (U.S.). This post-hoc secondary analysis evaluated treatment completion in both SAT arms, and compared completion based on SOC with MEMS to completion based on SOC only. Treatment completion proportions were compared. Characteristics associated with discordance between SOC and SOC with MEMS were identified. RESULTS: Overall 80.8% of 665 participants completed treatment per SOC, compared to 74.7% per SOC with MEMS, a difference of 6.1% (95%CI: 4.2%, 7.8%). Among U.S. participants only, this difference was 3.3% (95% CI: 1.8%, 4.9%). Differences in completion was 3.1% (95% CI: -1.1%, 7.3%) in Spain, and 36.8% (95% CI: 24.3%, 49.4%) in South Africa. There was no difference in Hong Kong. CONCLUSION: When used for monitoring 3HP, SOC significantly overestimated treatment completion in U.S. and South Africa. However, SOC still provides a reasonable estimate of treatment completion of the 3HP regimen, in U.S., Spain, and Hong Kong.

Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349).

BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts ≥100 cells/µL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/µL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/µL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772.

An initiative to improve mental health practice in primary care in Caribbean countries / Una iniciativa para mejorar la práctica de la salud mental en la atención primaria en los países del Caribe / Uma iniciativa para melhorar a atenção primária em saúde mental nos países caribenhos

ABSTRACT Objectives. The aim of this initiative was to assess whether a novel training program - Understanding Stigma and Strengthening Cognitive Behavioral Interpersonal Skills - could improve primary health care providers' confidence in the quality of mental health care they provide in the Caribbean setting by using the Plan-Do-Study-Act rapid cycle for learning improvement. Methods. We conducted a prospective observational study of the impact of this training program. The training was refined during three cycles: first, the relevance of the program for practice improvement in the Caribbean was assessed. Second, pilot training of 15 local providers was conducted to adapt the program to the culture and context. Third, the course was launched in fall 2021 with 96 primary care providers. Pre- and post-program outcomes were assessed by surveys, including providers' confidence in the quality of the mental health care they provided, changes in stigma among the providers and their use of and comfort with the tools. This paper describes an evaluation of the results of cycle 3, the official launch. Results. A total of 81 participants completed the program. The program improved primary care providers' confidence in the quality of mental health care that they provided to people with lived experience of mental health disorders, and it reduced providers' stigmatization of people with mental health disorders. Conclusions. The program's quality improvement model achieved its goals in enhancing health care providers' confidence in the quality of the mental health care they provided in the Caribbean context; the program provides effective tools to support the work and it helped to empower and engage clients.

RESUMEN Objetivos. La finalidad de esta iniciativa fue determinar si un nuevo programa de capacitación, titulado Understanding Stigma and Strengthening Cognitive Behavioral Interpersonal Skills (Comprender la estigmatización y fortalecer las competencias interpersonales cognitivas y conductuales), podría mejorar la confianza de los prestadores de atención primaria de salud en la calidad de la atención de salud mental que proporcionan en los países del Caribe, mediante el uso del ciclo rápido Planificación-Realización-Estudio-Acción para la mejora del aprendizaje. Métodos. Realizamos un estudio de observación prospectivo sobre el impacto de este programa de capacitación. La formación se perfeccionó a lo largo de tres ciclos: en primer lugar, se evaluó la pertinencia del programa para la mejora de las prácticas en el Caribe; en segundo lugar, se llevó a cabo una capacitación piloto de 15 prestadores locales para adaptar el programa a la cultura y el contexto; en tercer lugar, en el otoño del 2021 se puso en marcha el curso con 96 prestadores de atención primaria. Los resultados anteriores y posteriores al programa se evaluaron mediante encuestas que incluían la confianza de los prestadores en la calidad de la atención de salud mental que proporcionaban, los cambios aparecidos en los prestadores en cuanto a la estigmatización, y su uso y conocimiento de las herramientas. En este artículo se describe una evaluación de los resultados del ciclo 3, correspondiente a la puesta en marcha oficial. Resultados. Un total de 81 participantes completaron el programa. El programa mejoró la confianza de los prestadores de atención primaria en la calidad de la atención de salud mental que proporcionaban a las personas que presentaban trastornos de la salud mental y redujo la estigmatización de las personas con este tipo de trastornos por parte de los prestadores de la atención. Conclusiones. El modelo de mejora de la calidad del programa logró sus objetivos en cuanto a mejorar la confianza de los prestadores de atención de salud en la calidad de la atención de salud mental que proporcionan en los países del Caribe; el programa aporta herramientas eficaces para sustentar esta tarea y ayudó a empoderar e involucrar a las personas usuarias.

RESUMO Objetivos. O objetivo da iniciativa foi avaliar se um novo programa de capacitação, Compreensão do estigma e fortalecimento das competências cognitivas e comportamentais interpessoais, seria capaz de aumentar a confiança dos profissionais de atenção primária à saúde na qualidade da atenção à saúde mental que oferecem a pacientes no Caribe, utilizando o ciclo rápido Plan-Do-Study-Act (planejar, fazer, avaliar e agir) para melhorar o aprendizado. Métodos. Este foi um estudo observacional prospectivo sobre o impacto desse programa de capacitação. A capacitação foi aperfeiçoada ao longo de três ciclos. Inicialmente, avaliou-se a relevância do programa para o aprimoramento da prática no Caribe. A seguir, foi realizada uma capacitação-piloto de 15 profissionais locais para adaptar o programa à cultura e ao contexto. No terceiro ciclo, realizado no outono de 2021, o curso foi lançado, com a participação de 96 profissionais de atenção primária. Os resultados antes e depois do programa foram avaliados por meio de questionários, que incluíam a confiança dos provedores na qualidade da atenção à saúde mental oferecida, mudanças no estigma entre os profissionais e a utilização das ferramentas e o conforto dos profissionais em usá-las. Este documento apresenta a avaliação dos resultados do ciclo 3, o lançamento oficial do curso. Resultados. Oitenta e um participantes completaram o programa. O programa melhorou a confiança dos profissionais de atenção primária na qualidade dos cuidados de saúde mental que ofereciam às pessoas com experiência vivida relacionada a problemas de saúde mental. Além disso, reduziu a estigmatização das pessoas com problemas de saúde mental pelos profissionais de saúde. Conclusão. O modelo de melhoria da qualidade do programa atingiu suas metas de aumentar a confiança dos prestadores de serviços de saúde na qualidade dos serviços de saúde mental que prestavam no Caribe; o programa fornece ferramentas efetivas de apoio ao trabalho e ajudou a empoderar e envolver os clientes.

Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models.

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

In-Person vs Electronic Directly Observed Therapy for Tuberculosis Treatment Adherence: A Randomized Noninferiority Trial.

Importance: Electronic directly observed therapy (DOT) is used increasingly as an alternative to in-person DOT for monitoring tuberculosis treatment. Evidence supporting its efficacy is limited. Objective: To determine whether electronic DOT can attain a level of treatment observation as favorable as in-person DOT. Design, Setting, and Participants: This was a 2-period crossover, noninferiority trial with initial randomization to electronic or in-person DOT at the time outpatient tuberculosis treatment began. The trial enrolled 216 participants with physician-suspected or bacteriologically confirmed tuberculosis from July 2017 to October 2019 in 4 clinics operated by the New York City Health Department. Data analysis was conducted between March 2020 and April 2021. Interventions: Participants were asked to complete 20 medication doses using 1 DOT method, then switched methods for another 20 doses. With in-person therapy, participants chose clinic or community-based DOT; with electronic DOT, participants chose live video-conferencing or recorded videos. Main Outcomes and Measures: Difference between the percentage of medication doses participants were observed to completely ingest with in-person DOT and with electronic DOT. Noninferiority was demonstrated if the upper 95% confidence limit of the difference was 10% or less. We estimated the percentage of completed doses using a logistic mixed effects model, run in 4 modes: modified intention-to-treat, per-protocol, per-protocol with 85% or more of doses conforming to the randomization assignment, and empirical. Confidence intervals were estimated by bootstrapping (with 1000 replicates). Results: There were 173 participants in each crossover period (median age, 40 years [range, 16-86 years]; 140 [66%] men; 80 [37%] Asian and Pacific Islander, 43 [20%] Black, and 71 [33%] Hispanic individuals) evaluated with the model in the modified intention-to-treat analytic mode. The percentage of completed doses with in-person DOT was 87.2% (95% CI, 84.6%-89.9%) vs 89.8% (95% CI, 87.5%-92.1%) with electronic DOT. The percentage difference was -2.6% (95% CI, -4.8% to -0.3%), consistent with a conclusion of noninferiority. The 3 other analytic modes yielded equivalent conclusions, with percentage differences ranging from -4.9% to -1.9%. Conclusions and Relevance: In this trial, the percentage of completed doses under electronic DOT was noninferior to that under in-person DOT. This trial provides evidence supporting the efficacy of this digital adherence technology, and for the inclusion of electronic DOT in the standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03266003.

Efavirenz Pharmacokinetics and Human Immunodeficiency Virus Type 1 (HIV-1) Viral Suppression Among Patients Receiving Tuberculosis Treatment Containing Daily High-Dose Rifapentine.

BACKGROUND: A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB). METHODS: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target. RESULTS: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%. CONCLUSIONS: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment. CLINICAL TRIALS REGISTRATION: NCT02410772.

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.

BACKGROUND: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. METHODS: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. RESULTS: Among 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. CONCLUSIONS: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Advances in clinical trial design: Weaving tomorrow's TB treatments.

Christian Lienhardt and co-authors discuss the conclusions of the PLOS Medicine Collection on advances in clinical trial design for development of new tuberculosis treatments.

High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial.

INTRODUCTION: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. METHODS/DESIGN: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. DISCUSSION: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels. TRIAL REGISTRATION: NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1.

The importance of adherence in tuberculosis treatment clinical trials and its relevance in explanatory and pragmatic trials.

Andrew Vernon and co-authors discuss adherence to therapy and its measurement in tuberculosis treatment trials.

Development of new TB regimens: Harmonizing trial design, product registration requirements, and public health guidance.

Christian Lienhardt and colleagues discuss the importance of communication and coordination between regulators, researchers, and policy makers to ensure tuberculosis trials provide high-quality evidence for policy decisions.

Isoniazid-Rifapentine for Latent Tuberculosis Infection: A Systematic Review and Meta-analysis.

CONTEXT: Latent tuberculosis infection diagnosis and treatment is a strategic priority for eliminating tuberculosis in the U.S. The Centers for Disease Control and Prevention has recommended the short-course regimen of 3-month isoniazid-rifapentine administered by directly observed therapy. However, longer-duration regimens remain the most widely prescribed latent tuberculosis infection treatments. Limitation on adoption of 3-month isoniazid-rifapentine in the U.S. might be because of patients' preference for self-administered therapy, providers' lack of familiarity with 3-month isoniazid-rifapentine, or lack of resources to support directly observed therapy. This review examines the most recent evidence regarding 3-month isoniazid-rifapentine's effectiveness, safety, and treatment completion when directly compared with other latent tuberculosis infection regimens primarily comprising 9-month isoniazid treatment. EVIDENCE ACQUISITION: Using Community Guide methodology, reviewers identified, evaluated, and summarized available evidence published during January 2006-June 2017. Analysis of the data was completed in 2017. EVIDENCE SYNTHESIS: The analysis included 15 unique studies. Three-month isoniazid-rifapentine was determined to be equal to other latent tuberculosis infection regimens in effectiveness (OR=0.89, 95% CI=0.46, 1.70), and has higher treatment completion (87.5%, 95% CI=83.2%, 91.3%) compared with other latent tuberculosis infection regimens (65.9%, 95% CI=53.5%, 77.3%). Three-month isoniazid-rifapentine was associated with similar risk to other latent tuberculosis infection regimens for adverse events (relative risk=0.59, 95% CI=0.23, 1.52); discontinuing treatment because of adverse events (relative risk=0.48, 95% CI=0.17, 1.34); and death (relative risk=0.79, 95% CI=0.56, 1.11). CONCLUSIONS: The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates.

Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection.

Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of LTBI, with limitations for use in children aged <12 years and persons with human immunodeficiency virus (HIV) infection (1). CDC identified the use of 3HP in those populations, as well as self-administration of the 3HP regimen, as areas to address in updated recommendations. In 2017, a CDC Work Group conducted a systematic review and meta-analyses of the 3HP regimen using methods adapted from the Guide to Community Preventive Services. In total, 19 articles representing 15 unique studies were included in the meta-analysis, which determined that 3HP is as safe and effective as other recommended LTBI regimens and achieves substantially higher treatment completion rates. In July 2017, the Work Group presented the meta-analysis findings to a group of TB experts, and in December 2017, CDC solicited input from the Advisory Council for the Elimination of Tuberculosis (ACET) and members of the public for incorporation into the final recommendations. CDC continues to recommend 3HP for treatment of LTBI in adults and now recommends use of 3HP 1) in persons with LTBI aged 2-17 years; 2) in persons with LTBI who have HIV infection, including acquired immunodeficiency syndrome (AIDS), and are taking antiretroviral medications with acceptable drug-drug interactions with rifapentine; and 3) by DOT or self-administered therapy (SAT) in persons aged ≥2 years.

Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials.

RATIONALE: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy. OBJECTIVES: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H). METHODS: Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. RESULTS: Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. CONCLUSIONS: Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.