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The growing burden of diabetes worldwide is a threat to tuberculosis (TB) control. Drug-induced liver injury (DILI) due to TB drugs is a significant concern and there is currently limited evidence on the effect of diabetes on TB DILI. This study sought to investigate the effect of diabetes as a risk factor for DILI and to further study any potential co-factors. An unmatched case-control study. Cases were TB patients on 2RHZE/4RH presenting with DILI from 2013-2017 in Porto Alegre, Brazil. Controls were contemporaneous TB patients without DILI being treated in any one of the same five Porto Alegre TB clinics. The exposure variables were diabetes (main exposure variable), age, sex, alcohol misuse, human immunodeficiency virus (HIV), hepatitis C (HCV) and B (HBV) viruses, concomitant hepatotoxic drugs, other liver diseases and TB site. The outcome variable was the occurrence of DILI. Odds of DILI were increased by: older age group 51-60, 61-70 and 71-93 years (adjusted OR 2.39, 95%CI 1.30-4,38; adjusted OR 4.37, 2.28-8,35; adjusted OR 12.91, 5.81-28,66, respectively), HIV positive status (adjusted OR 3.59, 95%CI 2.25-5.73), HCV positive status (adjusted OR 3.49, 95%CI 1.96-6.21) and having concurrent pulmonary and extrapulmonary TB (adjusted OR 3.16, 95%CI 1.93-5.19). Diabetes, gender, and other hepatotoxic drugs were not associated with DILI. This study confirms the association between TB DILI and well-known risk factors but did not demonstrate increased odds of TB DILI in patients with diabetes.

Mobile text messaging and medication monitors (medication monitor boxes) have the potential to improve adherence to tuberculosis (TB) treatment and reduce the need for directly observed treatment (DOT), but to our knowledge they have not been properly evaluated in TB patients. We assessed the effectiveness of text messaging and medication monitors to improve medication adherence in TB patients. In a pragmatic cluster-randomised trial, 36 districts/counties (each with at least 300 active pulmonary TB patients registered in 2009) within the provinces of Heilongjiang, Jiangsu, Hunan, and Chongqing, China, were randomised using stratification and restriction to one of four case-management approaches in which patients received reminders via text messages, a medication monitor, combined, or neither (control). Patients in the intervention arms received reminders to take their drugs and reminders for monthly follow-up visits, and the managing doctor was recommended to switch patients with adherence problems to more intensive management or DOT. In all arms, patients took medications out of a medication monitor box, which recorded when the box was opened, but the box gave reminders only in the medication monitor and combined arms. Patients were followed up for 6 mo. The primary endpoint was the percentage of patient-months on TB treatment where at least 20% of doses were missed as measured by pill count and failure to open the medication monitor box. Secondary endpoints included additional adherence and standard treatment outcome measures. Interventions were not masked to study staff and patients. From 1 June 2011 to 7 March 2012, 4,292 new pulmonary TB patients were enrolled across the 36 clusters. A total of 119 patients (by arm: 33 control, 33 text messaging, 23 medication monitor, 30 combined) withdrew from the study in the first month because they were reassessed as not having TB by their managing doctor (61 patients) or were switched to a different treatment model because of hospitalisation or travel (58 patients), leaving 4,173 TB patients (by arm: 1,104 control, 1,008 text messaging, 997 medication monitor, 1,064 combined). The cluster geometric mean of the percentage of patient-months on TB treatment where at least 20% of doses were missed was 29.9% in the control arm; in comparison, this percentage was 27.3% in the text messaging arm (adjusted mean ratio [aMR] 0.94, 95% CI 0.71, 1.24), 17.0% in the medication monitor arm (aMR 0.58, 95% CI 0.42, 0.79), and 13.9% in the combined arm (aMR 0.49, 95% CI 0.27, 0.88). Patient loss to follow-up was lower in the text messaging arm than the control arm (aMR 0.42, 95% CI 0.18-0.98). Equipment malfunction or operation error was reported in all study arms. Analyses separating patients with and without medication monitor problems did not change the results. Initiation of intensive management was underutilised. This study is the first to our knowledge to utilise a randomised trial design to demonstrate the effectiveness of a medication monitor to improve medication adherence in TB patients. Reminders from medication monitors improved medication adherence in TB patients, but text messaging reminders did not. In a setting such as China where universal use of DOT is not feasible, innovative approaches to support patients in adhering to TB treatment, such as this, are needed. Current Controlled Trials, ISRCTN46846388.

Background Cluster randomised trials (CRTs) are often designed with a small number of clusters, but it is not clear which analysis methods are optimal when the outcome is binary. This simulation study aimed to determine (i) whether cluster-level analysis (CL), generalised linear mixed models (GLMM), and generalised estimating equations with sandwich variance (GEE) approaches maintain acceptable type-one error including the impact of non-normality of cluster effects and low prevalence, and if so (ii) which methods have the greatest power. We simulated CRTs with 8–30 clusters, altering the cluster-size, outcome prevalence, intracluster correlation coefficient, and cluster effect distribution. We analysed each dataset with weighted and unweighted CL; GLMM with adaptive quadrature and restricted pseudolikelihood; GEE with Kauermann-and-Carroll and Fay-and-Graubard sandwich variance using independent and exchangeable working correlation matrices. P-values were from a t-distribution with degrees of freedom (DoF) as clusters minus cluster-level parameters; GLMM pseudolikelihood also used Satterthwaite and Kenward-Roger DoF. Results Unweighted CL, GLMM pseudolikelihood, and Fay-and-Graubard GEE with independent or exchangeable working correlation matrix controlled type-one error in > 97% scenarios with clusters minus parameters DoF. Cluster-effect distribution and prevalence of outcome did not usually affect analysis method performance. GEE had the least power. With 20–30 clusters, GLMM had greater power than CL with varying cluster-size but similar power otherwise; with fewer clusters, GLMM had lower power with common cluster-size, similar power with medium variation, and greater power with large variation in cluster-size. Conclusion We recommend that CRTs with ≤ 30 clusters and a binary outcome use an unweighted CL or restricted pseudolikelihood GLMM both with DoF clusters minus cluster-level parameters.

Universal test and treat (UTT) is a population-based strategy that aims to ensure widespread HIV testing and rapid antiretroviral therapy (ART) for all who have tested positive regardless of CD4 count to decrease HIV incidence and improve health outcomes. Little is known about the specific resources required to implement UTT in correctional facilities for incarcerated people. The primary aim of this study was to describe the resources used to implement UTT and to provide detailed costing to inform UTT scale-up in similar settings. The costing study was a cross-sectional descriptive study conducted in three correctional complexes, Johannesburg Correctional Facility in Johannesburg (>4000 inmates) South Africa, and Brandvlei (~3000 inmates), South Africa and Lusaka Central (~1400 inmates), Zambia. Costing was determined through a survey conducted between September and December 2017 that identified materials and labour used for three separate components of UTT: HIV testing services (HTS), ART initiation, and ART maintenance. Our study participants were staff working in the correctional facilities involved in any activity related to UTT implementation. Unit costs were reported as cost per client served while total costs were reported for all clients seen over a 12-month period. The cost of HIV testing services (HTS) per client was $ 92.12 at Brandvlei, $ 73.82 at Johannesburg, and $ 65.15 at Lusaka. The largest cost driver for HIV testing at Brandvlei were staff costs at 55.6% of the total cost, while at Johannesburg (56.5%) and Lusaka (86.6%) supplies were the largest contributor. The cost per client initiated on ART was $917 for Brandvlei, $421.8 for Johannesburg, and $252.1 for Lusaka. The activity cost drivers were adherence counselling at Brandvlei (59%), and at Johannesburg and Lusaka it was the actual ART initiation at 75.6% and 75.8%, respectively. The annual unit cost for ART maintenance was $2,640.6 for Brandvlei, $710 for Johannesburg, and $385.5 for Lusaka. The activity cost drivers for all three facilities were side effect monitoring, and initiation of isoniazid preventive treatment (IPT), cotrimoxazole, and fluconazole, with this comprising 44.7% of the total cost at Brandvlei, 88.9% at Johannesburg, and 50.5% at Lusaka. Given the needs of this population, the opportunity to reach inmates at high risk for HIV, and overall national and global 95-95-95 goals, the UTT policies for incarcerated individuals are of vital importance. Our findings provide comparator costing data and highlight key drivers of UTT cost by facility.

Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment. For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation. This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment. Systematic review registration: PROSPERO 85226.

The World Health Organization (WHO) aims to reduce tuberculosis (TB) deaths by 95% by 2035; tracking progress requires accurate measurement of TB mortality. International Classification of Diseases (ICD) codes do not differentiate between HIV-associated TB and HIV more generally. Verbal autopsy (VA) is used to estimate cause of death (CoD) patterns but has mostly been validated against a suboptimal gold standard for HIV and TB. This study, conducted among HIV-positive adults, aimed to estimate the accuracy of VA in ascertaining TB and HIV CoD when compared to a reference standard derived from a variety of clinical sources including, in some, minimally-invasive autopsy (MIA). Decedents were enrolled into a trial of empirical TB treatment or a cohort exploring diagnostic algorithms for TB in South Africa. The WHO 2012 instrument was used; VA CoD were assigned using physician-certified VA (PCVA), InterVA-4, and SmartVA-Analyze. Reference CoD were assigned using MIA, research, and health facility data, as available. 259 VAs were completed: 147 (57%) decedents were female; median age was 39 (interquartile range [IQR] 33-47) years and CD4 count 51 (IQR 22-102) cells/μL. Compared to reference CoD that included MIA (n = 34), VA underestimated mortality due to HIV/AIDS (94% reference, 74% PCVA, 47% InterVA-4, and 41% SmartVA-Analyze; chance-corrected concordance [CCC] 0.71, 0.42, and 0.31, respectively) and HIV-associated TB (41% reference, 32% PCVA; CCC 0.23). For individual decedents, all VA methods agreed poorly with reference CoD that did not include MIA (n = 259; overall CCC 0.14, 0.06, and 0.15 for PCVA, InterVA-4, and SmartVA-Analyze); agreement was better at population level (cause-specific mortality fraction accuracy 0.78, 0.61, and 0.57, for the three methods, respectively). Current VA methods underestimate mortality due to HIV-associated TB. ICD and VA methods need modifications that allow for more specific evaluation of HIV-related deaths and direct estimation of mortality due to HIV-associated TB.

Tuberculosis is a major health concern in prisons, particularly where HIV prevalence is high. Our objective was to determine the undiagnosed pulmonary tuberculosis (\"undiagnosed tuberculosis\") prevalence in a representative sample of prisoners in a South African prison. In addition we investigated risk factors for undiagnosed tuberculosis, to explore if screening strategies could be targeted to high risk groups, and, the performance of screening tools for tuberculosis. In this cross-sectional survey, male prisoners were screened for tuberculosis using symptoms, chest radiograph (CXR) and two spot sputum specimens for microscopy and culture. Anonymised HIV antibody testing was performed on urine specimens. The sensitivity, specificity and predictive values of symptoms and investigations were calculated, using Mycobacterium tuberculosis isolated on sputum culture as the gold standard. From September 2009 to October 2010, 1046 male prisoners were offered enrolment to the study. A total of 981 (93.8%) consented (median age was 32 years; interquartile range [IQR] 27-37 years) and were screened for tuberculosis. Among 968 not taking tuberculosis treatment and with sputum culture results, 34 (3.5%; 95% confidence interval [CI] 2.4-4.9%) were culture positive for Mycobacterium tuberculosis. HIV prevalence was 25.3% (242/957; 95% CI 22.6-28.2%). Positive HIV status (adjusted odds ratio [aOR] 2.0; 95% CI 1.0-4.2) and being an ex-smoker (aOR 2.6; 95% CI 1.2-5.9) were independently associated with undiagnosed tuberculosis. Compared to the gold standard of positive sputum culture, cough of any duration had a sensitivity of 35.3% and specificity of 79.6%. CXR was the most sensitive single screening modality (sensitivity 70.6%, specificity 92.2%). Adding CXR to cough of any duration gave a tool with sensitivity of 79.4% and specificity of 73.8%. Undiagnosed tuberculosis and HIV prevalence was high in this prison, justifying routine screening for tuberculosis at entry into the prison, and intensified case finding among existing prisoners.

Background Digital adherence technologies (DATs) are recommended to support patient-centred, differentiated care to improve tuberculosis (TB) treatment outcomes, but evidence that such technologies improve adherence is limited. We aim to implement and evaluate the effectiveness of smart pillboxes and medication labels linked to an adherence data platform, to create a differentiated care response to patient adherence and improve TB care among adult pulmonary TB participants. Our study is part of the Adherence Support Coalition to End TB (ASCENT) project in Ethiopia. Methods/Design We will conduct a pragmatic three-arm cluster-randomised trial with 78 health facilities in two regions in Ethiopia. Facilities are randomised (1:1:1) to either of the two intervention arms or standard of care. Adults aged ≥ 18 years with drug-sensitive (DS) pulmonary TB are enrolled over 12 months and followed-up for 12 months after treatment initiation. Participants in facilities randomised to either of the two intervention arms are offered a DAT linked to the web-based ASCENT adherence platform for daily adherence monitoring and differentiated response to patient adherence for those who have missed doses. Participants at standard of care facilities receive routine care. For those that had bacteriologically confirmed TB at treatment initiation and can produce sputum without induction, sputum culture will be performed approximately 6 months after the end of treatment to measure disease recurrence. The primary endpoint is a composite unfavourable outcome measured over 12 months from TB treatment initiation defined as either poor end of treatment outcome (lost to follow-up, death, or treatment failure) or treatment recurrence measured 6 months after the scheduled end of treatment. This study will also evaluate the effectiveness, feasibility, and cost-effectiveness of DAT systems for DS-TB patients. Discussion This trial will evaluate the impact and contextual factors of medication label and smart pillbox with a differentiated response to patient care, among adult pulmonary DS-TB participants in Ethiopia. If successful, this evaluation will generate valuable evidence via a shared evaluation framework for optimal use and scale-up. Trial registration : Pan African Clinical Trials Registry PACTR202008776694999, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241 , registered on August 11, 2020.

Early mortality among HIV-positive adults starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis (TB) the leading cause of death. However, current methods to estimate TB-related deaths are inadequate and most autopsy studies do not adequately represent those attending primary health clinics (PHCs). This study aimed to determine the autopsy prevalence of TB and other infections in adults enrolled at South African PHCs in the context of a pragmatic trial of empiric TB treatment (\"TB Fast Track\"). Adults with CD4 ≤150 cells/μL, not on ART or TB treatment, were enrolled to TB Fast Track and followed up for at least six months. Minimally invasive autopsy (MIA) was conducted as soon as possible after death. Lungs, liver, and spleen were biopsied; blood, CSF, and urine aspirated; and bronchoalveolar lavage fluid obtained. Samples underwent mycobacterial, bacterial, and fungal culture; molecular testing (including Xpert® MTB/RIF); and histological examination. 34 MIAs were conducted: 18 (53%) decedents were female; median age was 39 (interquartile range 33-44) years; 25 (74%) deaths occurred in hospitals; median time from death to MIA was five (IQR 3-6) days. 16/34 (47%) had evidence of TB (14/16 [88%] with extrapulmonary disease; 6/16 [38%] not started on treatment antemortem); 23 (68%) had clinically important bacterial infections; four (12%) cryptococcal disease; three (9%) non-tuberculous mycobacterial disease; and two (6%) Pneumocystis pneumonia. Twenty decedents (59%) had evidence of two or more concurrent infections; 9/16 (56%) individuals with TB had evidence of bacterial disease and two (13%) cryptococcal disease. TB, followed by bacterial infections, were the leading findings at autopsy among adults with advanced HIV enrolled from primary care clinics. To reduce mortality, strategies are needed to identify and direct those at highest risk into a structured pathway that includes expedited investigation and/or treatment of TB and other infections.

IntroductionGlobally, tuberculosis (TB) remains one of the leading infectious causes of death, with 1.3 million deaths. Digital adherence technologies (DATs) have the potential to provide person-centred care and improve outcomes. Using the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) framework, we conducted a scoping review of DAT implementations for TB treatment.MethodsWe searched seven databases for papers published between January 2000 and April 2023, using keywords for ‘tuberculosis’ and ‘digital adherence technology’. Articles meeting prespecified inclusion criteria and containing data on RE-AIM domains were included. We defined ‘reach’ as comprising cellphone ownership and engagement by people with TB (PWTB) with DATs, ‘adoption’ as engagement by healthcare providers with DAT programmes, ‘implementation’ as the fidelity of the DAT programme implemented and ‘maintenance’ as longer-term uptake of DATs.ResultsOf 10 313 records, 102 contributed to the synthesis. DATs included short message service (SMS), phone, 99DOTS, video-supported therapy (VST) and pillboxes. For ‘reach’, across various settings, cellphone access varied from 50%–100% and 2%–31% of PWTB was excluded from accessing DATs due to technology challenges. 36%–100% of PWTB agreed to use a DAT. The weighted mean of DAT engagement over dose-days was 81% for SMS, 85% for phone, 61% for 99DOTS, 87% for pillbox and 82% for VST. Concerning ‘implementation’, the fidelity of DAT implementations was affected by technological issues such as cellphone coverage, DAT malfunction and provider-facing issues, including failure to initiate intensified patient management following low DAT engagement. Findings related to RE-AIM dimensions of ‘adoption’ and ‘maintenance’ were limited.ConclusionOur findings suggest that the ‘reach’ of DATs may be limited by a cascade of barriers, including limitations in cellphone accessibility and suboptimal sustained DAT engagement by PWTB. Video and pillbox DATs have higher levels of engagement. Implementation challenges included technological and provider-facing issues. Improving implementation outcomes may be important for TB DATs to achieve a broader public health impact.PROSPERO registration numberCRD42022326968