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Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens. La majorite des essais de phase III relatifs a la tuberculose pharmacoreslstante soit n'etaient pas assez puissants pour quantifier les fluctuations au niveau des criteres microbiologiques, soit etaient trop longs, se poursuivant parfois pendant dix ans. Les criteres primaires composites, domines par des differences dans l'interruption du traitement et les changements de schema, pourraient dissimuler d'importantes variations en termes d'echec therapeutique et de rechute. Bien que les nouveaux traitements contre la tuberculose pharmacoresistante semblent tres efficaces, la resistance aux nouveaux medicaments evolue rapidement. Il est donc necessaire d'opter pour des traitements plus courts, plus surs et mieux toleres, y compris ceux actifs contre la tuberculose resistant a la bedaquiline. Delaisser la multitude d'essais opposant un schema de traitement A a un schema de traitement B pour se diriger vers un unique essai plateforme de phase III de grande envergure permettrait d'obtenir plus vite des estimations solides concernant l'innocuite et l'efficacite relative. En outre, adopter des modeles de plateforme modernes et adaptatifs contribuerait a de meilleures performances. Enfin, la collaboration entre investigateurs, representants des communautes concernees, bailleurs de fonds et organismes de reglementation est essentielle a l'elaboration de ce type d'essai plateforme de phase III sur les traitements contre la tuberculose pharmacoresistante. La mayoria de los ensayos en fase III sobre tuberculosis resistente a los farmacos no ha tenido la potencia suficiente para cuantificar diferencias en los criterios de valoracion microbiologicos o ha tardado hasta una decada en completarse. Los criterios de valoracion principales compuestos, dominados por las diferencias en la interrupcion del tratamiento y los cambios de regimen, pueden ocultar diferencias importantes en el fracaso del tratamiento y la recaida. Aunque los nuevos regimenes de tratamiento para la tuberculosis resistente a los farmacos parecen muy eficaces, la resistencia a los nuevos farmacos esta apareciendo rapidamente. Se necesitan regimenes de tratamiento mas cortos, seguros y tolerables, incluidos los activos contra la tuberculosis resistente a la bedaquilina. La transicion de multiples ensayos de regimen A frente a regimen B a un unico gran ensayo de plataforma en fase III aceleraria la obtencion de estimaciones solidas de la eficacia y seguridad relativas. Podrian lograrse mayores eficiencias si se adoptaran disenos de plataforma adaptativos modernos. La colaboracion entre los autores de los ensayos, los representantes de las comunidades afectadas, los financiadores y los reguladores es esencial para desarrollar un ensayo de plataforma en fase III de este tipo para los regimenes de tratamiento de la tuberculosis resistente a los farmacos., Introduction Rifampicin and isoniazid are key drugs in treatment regimens for drug-susceptible tuberculosis. Rifampicin-resistant tuberculosis and multidrug-resistant tuberculosis (tuberculosis which is resistant to both isoniazid and rifampicin) are managed similarly, [...]

BackgroundEarlier detection of chronic obstructive pulmonary disease (COPD) exacerbations may facilitate more rapid treatment with reduced risk of hospitalization. Changes in pulse oximetry may permit early detection of exacerbations. We hypothesized that overnight pulse oximetry would be superior to once-daily monitoring for the early detection of exacerbations. ObjectiveThis study aims to evaluate whether measuring changes in heart rate and oxygen saturation overnight is superior to once-daily monitoring of both parameters and to assess symptom changes in facilitating earlier detection of COPD exacerbations. MethodsA total of 83 patients with COPD were randomized to once-daily or overnight pulse oximetry. Both groups completed the COPD assessment test questionnaire daily. The baseline mean and SD for each pulse oximetry variable were calculated from 14 days of stable monitoring. Changes in exacerbation were expressed as Z scores from this baseline. ResultsThe mean age of the patients was 70.6 (SD 8.1) years, 52% (43/83) were female, and the mean FEV1 was 53.0% (SD 18.5%) predicted. Of the 83 patients, 27 experienced an exacerbation. Symptoms were significantly elevated above baseline from 5 days before to 12 days after treatment initiation. Day-to-day variation in pulse oximetry during the stable state was significantly less in the overnight group than in the once-daily group. There were greater relative changes at exacerbation in heart rate than oxygen saturation. An overnight composite score of change in heart rate and oxygen saturation changed significantly from 7 days before initiation of treatment for exacerbation and had a positive predictive value for exacerbation of 91.2%. However, this was not statistically better than examining changes in symptoms alone. ConclusionsOvernight pulse oximetry permits earlier detection of COPD exacerbations compared with once-daily monitoring. Monitoring physiological variables was not superior to monitoring symptoms, and the latter would be a simpler approach, except where there is a need for objective verification of exacerbations. Trial RegistrationClinicalTrials.gov NCT03003702; https://clinicaltrials.gov/ct2/show/NCT03003702

Background Socially complex groups, including people experiencing homelessness, prisoners and drug users, have very high levels of tuberculosis, often complicated by late diagnosis and difficulty in adhering to treatment. Objective To assess a series of interventions to improve tuberculosis control in socially complex groups. Design A series of observational surveys, evaluations and trials of interventions. Setting The pan-London Find&Treat service, which supports tuberculosis screening and case management in socially complex groups across London. Participants Socially complex groups with tuberculosis or at risk of tuberculosis, including people experiencing homelessness, prisoners, drug users and those at high risk of poor adherence to tuberculosis treatment. Interventions and main outcome measures We screened 491 people in homeless hostels and 511 people in prison for latent tuberculosis infection, human immunodeficiency virus, hepatitis B and hepatitis C. We evaluated an NHS-led prison radiographic screening programme. We conducted a cluster randomised controlled trial (2348 eligible people experiencing homelessness in 46 hostels) of the effectiveness of peer educators (22 hostels) compared with NHS staff (24 hostels) at encouraging the uptake of mobile radiographic screening. We initiated a trial of the use of point-of-care polymerase chain reaction diagnostics to rapidly confirm tuberculosis alongside mobile radiographic screening. We undertook a randomised controlled trial to improve treatment adherence, comparing face-to-face, directly observed treatment with video-observed treatment using a smartphone application. The primary outcome was completion of ≥ 80% of scheduled treatment observations over the first 2 months following enrolment. We assessed the cost-effectiveness of latent tuberculosis screening alongside radiographic screening of people experiencing homelessness. The costs of video-observed treatment and directly observed treatment were compared. Results In the homeless hostels, 16.5% of people experiencing homelessness had latent tuberculosis infection, 1.4% had current hepatitis B infection, 10.4% had hepatitis C infection and 1.0% had human immunodeficiency virus infection. When a quality-adjusted life-year is valued at £30,000, the latent tuberculosis screening of people experiencing homelessness was cost-effective provided treatment uptake was ≥ 25% (for a £20,000 quality-adjusted life-year threshold, treatment uptake would need to be > 50%). In prison, 12.6% of prisoners had latent tuberculosis infection, 1.9% had current hepatitis B infection, 4.2% had hepatitis C infection and 0.0% had human immunodeficiency virus infection. In both settings, levels of latent tuberculosis infection and blood-borne viruses were higher among injecting drug users. A total of 1484 prisoners were screened using chest radiography over a total of 112 screening days (new prisoner screening coverage was 43%). Twenty-nine radiographs were reported as potentially indicating tuberculosis. One prisoner began, and completed, antituberculosis treatment in prison. In the cluster randomised controlled trial of peer educators to increase screening uptake, the median uptake was 45% in the control arm and 40% in the intervention arm (adjusted risk ratio 0.98, 95% confidence interval 0.80 to 1.20). A rapid diagnostic service was established on the mobile radiographic unit but the trial of rapid diagnostics was abandoned because of recruitment and follow-up difficulties. We randomly assigned 112 patients to video-observed treatment and 114 patients to directly observed treatment. Fifty-eight per cent of those recruited had a history of homelessness, addiction, imprisonment or severe mental health problems. Seventy-eight (70%) of 112 patients on video-observed treatment achieved the primary outcome, compared with 35 (31%) of 114 patients on directly observed treatment (adjusted odds ratio 5.48, 95% confidence interval 3.10 to 9.68; p

2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

BackgroundDirectly observed treatment (DOT) has been the standard of care for tuberculosis since the early 1990s, but it is inconvenient for patients and service providers. Video-observed therapy (VOT) has been conditionally recommended by WHO as an alternative to DOT. We tested whether levels of treatment observation were improved with VOT.MethodsWe did a multicentre, analyst-blinded, randomised controlled superiority trial in 22 clinics in England (UK). Eligible participants were patients aged at least 16 years with active pulmonary or non-pulmonary tuberculosis who were eligible for DOT according to local guidance. Exclusion criteria included patients who did not have access to charging a smartphone. We randomly assigned participants to either VOT (daily remote observation using a smartphone app) or DOT (observations done three to five times per week in the home, community, or clinic settings). Randomisation was done by the SealedEnvelope service using minimisation. DOT involved treatment observation by a health-care or lay worker, with any remaining daily doses self-administered. VOT was provided by a centralised service in London. Patients were trained to record and send videos of every dose ingested 7 days per week using a smartphone app. Trained treatment observers viewed these videos through a password-protected website. Patients were also encouraged to report adverse drug events on the videos. Smartphones and data plans were provided free of charge by study investigators. DOT or VOT observation records were completed by observers until treatment or study end. The primary outcome was completion of 80% or more scheduled treatment observations over the first 2 months following enrolment. Intention-to-treat (ITT) and restricted (including only patients completing at least 1 week of observation on allocated arm) analyses were done. Superiority was determined by a 15% difference in the proportion of patients with the primary outcome (60% vs 75%). This trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN26184967.FindingsBetween Sept 1, 2014, and Oct 1, 2016, we randomly assigned 226 patients; 112 to VOT and 114 to DOT. Overall, 131 (58%) patients had a history of homelessness, imprisonment, drug use, alcohol problems or mental health problems. In the ITT analysis, 78 (70%) of 112 patients on VOT achieved ≥80% scheduled observations successfully completed during the first 2 months compared with 35 (31%) of 114 on DOT (adjusted odds ratio [OR] 5·48, 95% CI 3·10-9·68; p

Introduction: Ethnicity can influence susceptibility to SARS-CoV-2 infection, hospitalisation and death. Its association with ongoing symptomatic COVID-19 is unclear. We assessed if, among a population followed up after discharge from hospital with COVID-19, adults from Asian, black, mixed and other backgrounds are at increased risk of physical and mental health symptoms. Methods: Adults discharged after hospitalisation with COVID-19 between 03/03/2020 and 27/11/2021 were routinely offered follow-up six to 12 weeks post-discharge and reviewed for ongoing symptomatic COVID-19, as defined by persisting physical symptoms (respiratory symptoms, fatigue, impaired sleep and number of other symptoms), mental health symptoms and inability to return to work if employed. Descriptive statistics and multiple regression analyses were used to compare differences in characteristics, follow-up outcomes and blood tests between ethnic groups. To account for possible selection bias, analyses were adjusted for propensity scores. Results: 986 adults completed follow-up: 202 (20.5%) Asian, 105 (10.6%) black, 18 (1.8%) mixed, 468 (47.5%) white and 111 (11.3%) from other backgrounds. Differences between groups included white adults being older than those from Asian/'other' backgrounds and black adults being more likely from deprived areas than those from Asian/white/'other' backgrounds. After adjusting for these differences, at follow-up, black adults had fewer respiratory (adjusted odds ratio 0.49 (0.25–0.96)) and other symptoms (adjusted count ratio 0.68 (0.34–0.99)) compared to white adults. There were otherwise no significant differences between ethnic groups in terms of physical health, mental health or ability to return to work if employed. These findings were not altered after adjustment for propensity scores. Conclusions: In our population, despite having more co-morbidities associated with worse outcomes, adults from Asian, black, mixed and other ethnic backgrounds are not more likely to develop ongoing symptomatic COVID-19. However, it is important that healthcare services remain vigilant in ensuring the provision of timely patient-centred care. [ABSTRACT FROM AUTHOR]

Background: Despite widespread use of combination antiretroviral therapy, people with HIV (PWH) continue to have an increased risk of admission to and mortality in the intensive care unit (ICU). Mortality risk after hospital discharge is not well described. Using retrospective data on adult PWH (≥18 years) admitted to ICU from 2000-2019 in an HIV-referral centre, we describe trends in 1-year mortality after ICU admission. Methods: One-year mortality was calculated from index ICU admission to date of death; with follow-up right-censored at day 365 for people remaining alive at 1 year, or day 7 after ICU discharge if lost-to-follow-up after hospital discharge. Cox regression was used to describe the association with calendar year before and after adjustment for patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation II [APACHE II] score, CD4+ T-cell count, and recent HIV diagnosis) at ICU admission. Analyses were additionally restricted to those discharged alive from ICU using a left-truncated design, with further adjustment for respiratory failure at ICU admission in these analyses. Results: Two hundred and twenty-one PWH were admitted to ICU (72% male, median [interquartile range] age 45 [38–53] years) of whom 108 died within 1-year (cumulative 1-year survival: 50%). Overall, the hazard of 1-year mortality was decreased by 10% per year (crude hazard ratio (HR): 0.90 (95% confidence interval: 0.87-0.93)); the association was reduced to 7% per year (adjusted HR: 0.93 (0.89-0.98)) after adjustment. Conclusions were similar among the subset of 136 patients discharged alive (unadjusted: 0.91 (0.84-0.98); adjusted 0.92 (0.84, 1.02)). Conclusions: Between 2000 and 2019, 1-year mortality after ICU admission declined at this ICU. Our findings highlight the need for multi-centre studies and the importance of continued engagement in care after hospital discharge among PWH. [ABSTRACT FROM AUTHOR]

BackgroundThe use of early morning sputum samples (EMS) to diagnose tuberculosis (TB) can result in treatment delay given the need for the patient to return to the clinic with the EMS, increasing the chance of patients being lost during their diagnostic workup. However, there is little evidence to support the superiority of EMS over spot sputum samples. In this new analysis of the REMoxTB study, we compare the diagnostic accuracy of EMS with spot samples for identifying Mycobacterium tuberculosis pre- and post-treatment.MethodsPatients who were smear positive at screening were enrolled into the study. Paired sputum samples (one EMS and one spot) were collected at each trial visit pre- and post-treatment. Microscopy and culture on solid LJ and liquid MGIT media were performed on all samples; those missing corresponding paired results were excluded from the analyses.ResultsData from 1115 pre- and 2995 post-treatment paired samples from 1931 patients enrolled in the REMoxTB study were analysed. Patients were recruited from South Africa (47%), East Africa (21%), India (20%), Asia (11%), and North America (1%); 70% were male, median age 31 years (IQR 24-41), 139 (7%) co-infected with HIV with a median CD4 cell count of 399 cells/μL (IQR 318-535). Pre-treatment spot samples had a higher yield of positive Ziehl-Neelsen smears (98% vs. 97%, P = 0.02) and LJ cultures (87% vs. 82%, P = 0.006) than EMS, but there was no difference for positivity by MGIT (93% vs. 95%, P = 0.18). Contaminated and false-positive MGIT were found more often with EMS rather than spot samples. Surprisingly, pre-treatment EMS had a higher smear grading and shorter time-to-positivity, by 1 day, than spot samples in MGIT culture (4.5 vs. 5.5 days, P

In this interview, we talk to leading tuberculosis (TB) experts from University College London and the London School of Hygiene and Tropical Medicine about the current challenges in TB research. The video of this interview is available here: https://www.youtube.com/watch?v=75Die7MQBec&feature=youtu.be . The video can also be downloaded via Additional file 1.

INTRODUCTION: The number of cases of drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has risen rapidly in recent years. This has led to the resurgence in repurposing existing drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), for anti-TB treatment. SOURCES OF DATA: Evidence from novel drug screening in vitro, in vivo, pharmacokinetic/pharmacodynamics analyses and clinical trials has been used for the preparation of this systematic review of the potential of NSAIDs for use as an adjunct in new TB chemotherapies. AREAS OF AGREEMENT: Certain NSAIDs have demonstrated inhibitory properties towards actively replicating, dormant and drug-resistant clinical isolates of M. tuberculosis cells. AREAS OF CONTROVERSY: NSAIDs are a diverse class of drugs, which have reported off-target activities, and their endogenous antimicrobial mechanism(s) of action is still unclear. GROWING POINTS: It is essential that clinical trials of NSAIDs continue, in order to assess their suitability for addition to the current TB treatment regimen. Repurposing molecules such as NSAIDs is a vital, low-risk strategy to combat the trend of rapidly increasing antibiotic resistance.