An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study.

BACKGROUND: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. METHODS: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. RESULTS: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. CONCLUSION: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. TRIAL REGISTRATION: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

Informing the public health response to COVID-19: a systematic review of risk factors for disease, severity, and mortality.

BACKGROUND: Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) has challenged public health agencies globally. In order to effectively target government responses, it is critical to identify the individuals most at risk of coronavirus disease-19 (COVID-19), developing severe clinical signs, and mortality. We undertook a systematic review of the literature to present the current status of scientific knowledge in these areas and describe the need for unified global approaches, moving forwards, as well as lessons learnt for future pandemics. METHODS: Medline, Embase and Global Health were searched to the end of April 2020, as well as the Web of Science. Search terms were specific to the SARS-CoV-2 virus and COVID-19. Comparative studies of risk factors from any setting, population group and in any language were included. Titles, abstracts and full texts were screened by two reviewers and extracted in duplicate into a standardised form. Data were extracted on risk factors for COVID-19 disease, severe disease, or death and were narratively and descriptively synthesised. RESULTS: One thousand two hundred and thirty-eight papers were identified post-deduplication. Thirty-three met our inclusion criteria, of which 26 were from China. Six assessed the risk of contracting the disease, 20 the risk of having severe disease and ten the risk of dying. Age, gender and co-morbidities were commonly assessed as risk factors. The weight of evidence showed increasing age to be associated with severe disease and mortality, and general comorbidities with mortality. Only seven studies presented multivariable analyses and power was generally limited. A wide range of definitions were used for disease severity. CONCLUSIONS: The volume of literature generated in the short time since the appearance of SARS-CoV-2 has been considerable. Many studies have sought to document the risk factors for COVID-19 disease, disease severity and mortality; age was the only risk factor based on robust studies and with a consistent body of evidence. Mechanistic studies are required to understand why age is such an important risk factor. At the start of pandemics, large, standardised, studies that use multivariable analyses are urgently needed so that the populations most at risk can be rapidly protected. REGISTRATION: This review was registered on PROSPERO as CRD42020177714 .

What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis.

INTRODUCTION: Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy. METHODS: Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained. RESULTS: 12 604 records were retrieved and 118 remained postextraction, representing 59 studies-27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12-0.81)). In a random-effects model all estimates crossed the null. CONCLUSIONS: Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014015025.

Determinants of non-adherence to anti-TB treatment in high income, low TB incidence settings: a scoping review.

BACKGROUND: Improving adherence to anti-TB treatment is a public health priority in high-income, low incidence (HILI) regions. We conducted a scoping review to identify reported determinants of non-adherence in HILI settings.METHODS: Key terms related to TB, treatment and adherence were used to search MEDLINE, EMBASE, Web of Science, PsycINFO and CINAHL in June 2019. Quantitative studies examining determinants (demographic, clinical, health systems or psychosocial) of non-adherence to anti-TB treatment in HILI settings were included.RESULTS: From 10,801 results, we identified 24 relevant studies from 10 countries. Definitions and methods of assessing adherence were highly variable, as were documented levels of non-adherence (0.9-89%). Demographic factors were assessed in all studies and clinical factors were frequently assessed (23/24). Determinants commonly associated with non-adherence were homelessness, incarceration, and alcohol or drug misuse. Health system (8/24) and psychosocial factors (6/24) were less commonly evaluated.CONCLUSION: Our review identified some key factors associated with non-adherence to anti-TB treatment in HILI settings. Modifiable determinants such as psychosocial factors are under-evidenced and should be further explored, as these may be better targeted by adherence support. There is an urgent need to standardise definitions and measurement of adherence to more accurately identify the strongest determinants.

First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.

Reports of ChAdOx1 vaccine-associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0-27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41-13.83), with an estimated incidence of 1.13 (0.62-1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29-3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12-1.34) 0-27 d after vaccination, with an SCCS RR of 0.97 (0.93-1.02). For hemorrhagic events 0-27 d after vaccination, the aRR was 1.48 (1.12-1.96), with an SCCS RR of 0.95 (0.82-1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.

Tuberculosis infection and disease in people living with HIV in countries with low tuberculosis incidence.

In countries with low tuberculosis (TB) incidence, TB is concentrated in vulnerable populations, including people living with the human immunodeficiency virus (PLHIV), who have a substantially greater risk of TB than people without HIV. We searched PubMed, EMBASE and Web of Science for studies evaluating the risk factors for latent tuberculous infection (LTBI) or active TB in PLHIV in countries with TB incidence 10 per 100 000 population. Due to the number of risk factors evaluated and heterogeneity in study designs, we present summary data and a narrative synthesis. We included 45 studies: 17 reported data on the risk factors for LTBI and 32 on active TB. Black, Asian or Hispanic ethnicity, birth or long-term residence in a country with high TB incidence, and HIV acquisition via injecting drug use (IDU) or heterosexual sex were strong predictors of both LTBI and active TB. History of contact, a greater degree of immunosuppression at diagnosis or higher viral load increased the TB risk. Early HIV diagnosis to allow timely initiation of antiretroviral therapy is essential for the prevention of TB in PLHIV. Screening and treating PLHIV for LTBI to reduce the risk of progression to active TB disease should also be considered to further reduce the burden of active TB in low TB incidence settings. Research to support the expansion of TB and HIV prevention and treatment globally is essential to eliminate TB in low-incidence settings.

Isoniazid-resistant tuberculosis: a cause for concern?

The drug isoniazid (INH) is a key component of global tuberculosis (TB) control programmes. It is estimated, however, that 16.1% of TB disease cases in the former Soviet Union countries and 7.5% of cases outside of these settings have non-multidrug-resistant (MDR) INH resistance. Resistance has been linked to poorer treatment outcomes, post-treatment relapse and death, at least for specific sites of disease. Multiple genetic loci are associated with phenotypic resistance; however, the relationship between genotype and phenotype is complex, and restricts the use of rapid sequencing techniques as part of the diagnostic process to determine the most appropriate treatment regimens for patients. The burden of resistance also influences the usefulness of INH preventive therapy. Despite seven decades of INH use, our knowledge in key areas such as the epidemiology of resistant strains, their clinical consequences, whether tailored treatment regimens are required and the role of INH resistance in fuelling the MDR-TB epidemic is limited. The importance of non-MDR INH resistance needs to be re-evaluated both globally and by national TB control programmes.

Tuberculosis treatment outcomes among disadvantaged patients in India.

Setting: Urban slums and poor rural areas in India, 2012-2014. Objective: To describe the characteristics of tuberculosis (TB) patients enrolled in treatment through Operation ASHA, a non-governmental organisation serving disadvantaged populations in India, and to identify risk factors for unfavourable treatment outcomes. Design: This was a retrospective cohort study. Patient characteristics were assessed for their relationship with treatment outcomes using mixed effects logistic regression, adjusting for clustering by treatment centre and Indian state. Outcomes were considered favourable (cured/treatment completed) or unfavourable (treatment failure, loss to follow-up, death, switch to multidrug-resistant TB treatment, transfer out). Results: Of 8415 patients, 7148 (84.9%) had a favourable outcome. On multivariable analysis, unfavourable outcomes were more common among men (OR 1.31, 95%CI 1.15-1.51), older patients (OR 1.12, 95%CI 1.04-1.21) and previously treated patients (OR 2.05, 95%CI 1.79-2.36). Compared to pulmonary smear-negative patients, those with extra-pulmonary disease were less likely to have unfavourable outcomes (OR 0.72, 95%CI 0.60-0.87), while smear-positive pulmonary patients were more likely to have unfavourable outcomes (OR 1.38, 95%CI 1.15-1.66 for low [scanty/1+] and OR 1.71, 95%CI 1.44-2.04 for high [2+/3+] positive smears). Conclusion: The treatment success rate within Operation ASHA is comparable to that reported nationally for India. Men, older patients, retreatment cases and smear-positive pulmonary TB patients may need additional interventions to ensure a favourable outcome.

Contexte: Bidonvilles urbains et zones rurales pauvres, Inde, 2012­2014.Objectif: Décrire les caractéristiques des patients atteints de tuberculose (TB) enrôlés dans un traitement à travers l'Opération ASHA, une organisation non-gouvernementale au service des populations désavantagées en Inde, et identifier les facteurs de risque de résultat défavorable du traitement.Schéma: Etude rétrospective de cohorte. Les caractéristiques des patients ont été évaluées en fonction de leur relation avec les résultats du traitement grâce à une régression logistique à effets mixtes ajustée sur le regroupement par centre de traitement et par l'état d'Inde. Le résultat a été considéré comme favorable (guéri/traitement achevé) ou défavorable (échec du traitement, perte de vue, décès, évolution vers un traitement de TB multirésistante, transfert).Résultats: De 8415 patients, 7148 (84,9%) ont eu un résultat favorable. En analyse multi-variable, les résultats défavorables ont été plus fréquents parmi les hommes (OR 1,31 ; IC 95% 1,15­1,51), les patients plus âgés (OR 1,12 ; IC95% 1,04­1,21) et les patients déjà traités (OR 2,05 ; IC95% 1,79­2,36). Comparés aux patients atteints de TB pulmonaire à frottis négatif, les patients atteints de TB extra-pulmonaire ont été moins susceptibles d'avoir un résultat défavorable (OR 0,72 ; IC95% 0,60­0,87), tandis que les patients atteints de TB pulmonaire à frottis positif ont été plus susceptibles d'avoir un résultat défavorable (OR 1,38 ; IC95% 1,15­1,66 pour les frottis positifs faibles [rares/1+] et OR 1,71 ; IC95% 1,44­2,04 pour les frottis élevés [2+/3+]).Conclusion: Le taux de succès du traitement dans le cadre de l'Opération ASHA est comparable à celui rapporté au niveau national en Inde. Les hommes, les patients plus âgés, les cas en retraitement et les patients atteints de TB pulmonaire à frottis positif pourraient avoir besoin d'interventions supplémentaires afin d'assurer un résultat favorable.

Marco de referencia: Barriadas urbanas y zonas rurales pobres en la India del 2012 al 2014.Objetivo: Describir las características de los pacientes con tuberculosis (TB) inscritos en tratamiento en el marco de la Operación ASHA, que es una organización no gubernamental que atiende a las poblaciones desfavorecidas en la India, y determinar los factores de riesgo de obtener desenlaces terapéuticos desfavorables.Método: Un estudio retrospectivo de cohortes. Las características de los pacientes se evaluaron con respecto a los desenlaces terapéuticos, mediante un análisis de regresión logística de efectos mixtos y ajuste con relación a los conglomerados, según el centro de tratamiento y el estado de la India. Los desenlaces se consideraron favorables (curación o tratamiento completo) o desfavorables (fracaso terapéutico, pérdida durante el seguimiento, muerte, cambio de tratamiento por TB multirresistente o transferencia a otro centro).Resultados: De los 8415 pacientes, en 7148 el desenlace fue favorable (84,9%). El análisis multivariante reveló que los desenlaces desfavorables eran más frecuentes en los hombres (OR 1,31; IC95% 1,15­1,51), los ancianos (OR 1,12; IC95% 1,04­1,21) y en los pacientes con antecedente de tratamiento antituberculoso (OR 2,05; IC95% 1,79­2,36). Tomando como referencia a los pacientes con baciloscopia negativa, los desenlaces desfavorables fueron menos probables en los pacientes con TB extrapulmonar (OR 0,72; IC95% 0,60­0,87) y más probables en los pacientes con TB pulmonar y baciloscopia positiva (OR 1,38; IC95% 1,15­1,66 para las baciloscopias bajas, de escasos bacilos a 1+ y OR 1,71; IC95% 1,44­2,04 para las baciloscopia altas, de 2+ o 3+).Conclusión: La tasa de éxito del tratamiento antituberculoso en el marco de la Operación ASHA es equivalente a la notificada a escala nacional en la India. Los pacientes de sexo masculino, los ancianos, los casos en retratamiento y los que presentan una TB pulmonar con baciloscopia positiva pueden necesitar intervenciones complementarias a fin de fomentar los desenlaces favorables.

Treatment regimens for rifampicin-resistant tuberculosis: highlighting a research gap.

Treatment guidance for non-multidrug-resistant (MDR) rifampicin-resistant (RMP-R) tuberculosis (TB) is variable. We aimed to undertake a systematic review and meta-analysis of the randomised controlled trial (RCT) data behind such guidelines to identify the most efficacious treatment regimens. Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Despite 12 604 records being retrieved, only three studies reported treatment outcomes by regimen for patients with non-MDR RMP-R disease, preventing meta-analysis. Our systematic review highlights a substantial gap in the literature regarding evidence-based treatment regimens for RMP-R TB.

Active case finding for tuberculosis among high-risk groups in low-incidence countries.

In low-incidence countries, tuberculosis (TB) is now largely concentrated in high-risk groups such as migrants, homeless people, illicit drug users, alcoholics and prisoners. This has led to increased efforts to implement targeted active case finding for TB among specific populations. This review examines the evidence supporting active case finding in migrants and social risk groups, as well as the cost-effectiveness of interventions. While data from observational studies support active case finding in defined high-risk groups, further research to determine the effectiveness of specific tools and the cost-effectiveness of screening strategies is needed to inform evidence-based control methods in low-incidence countries. Inevitably, addressing TB in low-incidence countries will depend on effective disease control in high-burden countries.

Active case finding for pulmonary tuberculosis using mobile digital chest radiography: an observational study.

BACKGROUND: Mobile digital chest radiography (CXR) is used routinely to screen for pulmonary tuberculosis (PTB) in London among homeless populations, persons accessing drug treatment services and prisoners. OBJECTIVE: 1) To establish the sensitivity and specificity of mobile digital CXR, and 2) to test the hypothesis that actively identified cases have reduced odds of sputum smear positivity vs. those presenting passively to health care services from the same populations. METHODS: Sensitivity and specificity were calculated using a gold standard comparator of culture-confirmed cases of PTB reported to the national surveillance system within 90 days of screening. Logistic regression was used to determine whether actively detected cases had reduced odds of smear positivity compared to passively detected cases after adjustment for confounding. RESULTS: The intervention had a sensitivity of 81.8% (95%CI 64.5-93.0) and a specificity of 99.2% (95%CI 99.1-99.3). After adjusting for confounding, there was evidence that cases identified through screening were less likely to be smear-positive than passively identified cases (OR 0.34, 95%CI 0.14-0.85; likelihood ratio test P = 0.022). CONCLUSION: Digital CXR achieves a high level of sensitivity and specificity in an operational setting; targeted mobile radiographic screening can reduce the risk of onward transmission by identifying cases before they become infectious.