Enhanced tuberculosis diagnosis with computer-aided chest X-ray and urine LAM in adults with HIV admitted to hospital (CASTLE study): A cluster randomised trial.

BACKGROUND: People with HIV (PHIV) admitted to hospital have high mortality, with tuberculosis (TB) being the major cause of death. Systematic use of new TB diagnostics could improve TB diagnosis and might improve outcomes. METHODS: We conducted a cluster randomised trial among adult PHIV admitted to Zomba Central Hospital, Malawi. Admission-days were randomly assigned to: enhanced TB diagnostics using urine lipoarabinomannan (LAM) antigen tests (SILVAMP-LAM, Fujifilm, Japan and Determine-LAM, Alere/Abbot, USA), digital chest X-ray with computer aided diagnosis (dCXR-CAD, CAD4TBv6, Delft, Netherlands), plus usual care ("enhanced TB diagnostics"); or usual care alone ("usual care"). The primary outcome was TB treatment initiation during admission. Secondary outcomes were 56-day mortality, TB diagnosis within 24-hours, and undiagnosed TB at discharge, ascertained by culture of one admission sputum sample. FINDINGS: Between 2 September 2020 and 15 February 2022, we recruited 419 people. Four people were excluded post-recruitment, leaving 415 adults recruited during 207 randomly assigned admission-days in modified intention-to-treat analysis. At admission, 90.8% (377/415) were taking antiretroviral therapy (ART) with median (IQR) CD4 cell count 240 cells/mm3. In the enhanced diagnostic arm, median CAD4TBv6 score was 60 (IQR: 51-71), 4.4% (9/207) had SILVAMP-LAM-positive and 14.4% (29/201) had Determine-LAM positive urine with three samples positive by both urine tests. TB treatment was initiated in 46/208 (22%) in enhanced TB diagnostics arm and 24/207 (12%) in usual care arm (risk ratio [RR] 1.92, 95% CI 1.20-3.08). There was no difference in mortality by 56 days (enhanced TB diagnosis: 54/208, 26%; usual care: 52/207, 25%; hazard ratio 1.05, 95% CI 0.72-1.53); TB treatment initiation within 24 hours (enhanced TB diagnosis: 8/207, 3.9%; usual care: 5/208, 2.4%; RR 1.61, 95% CI 0.53-4.71); or undiagnosed microbiological-confirmed TB at discharge (enhanced TB diagnosis, 0/207 (0.0%), usual care arm 2/208 (1.0%) (p = 0.50). INTERPRETATION: Urine SILVAMP-LAM/Determine-LAM plus dCXR-CAD diagnostics identified more hospitalised PHIV with TB than usual care. The increase in TB treatment appeared mainly due to greater use of Determine-LAM, rather than SILVAMP-LAM or dCXR-CAD. Poor concordance between Determine-LAM and SILVAMP-LAM urine tests requires further investigation. Inpatient mortality for adults with HIV remains unacceptability high.

Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis.

Background: Globally, over one-third of pulmonary tuberculosis (TB) disease diagnoses are made based on clinical criteria after a negative diagnostic test result. Understanding factors associated with clinicians' decisions to initiate treatment for individuals with negative test results is critical for predicting the potential impact of new diagnostics. Methods: We performed a systematic review and individual patient data meta-analysis using studies conducted between January/2010 and December/2022 (PROSPERO: CRD42022287613). We included trials or cohort studies that enrolled individuals evaluated for TB in routine settings. In these studies participants were evaluated based on clinical examination and routinely-used diagnostics, and were followed for ≥1 week after the initial test result. We used hierarchical Bayesian logistic regression to identify factors associated with treatment initiation following a negative result on an initial bacteriological test (e.g., sputum smear microscopy, Xpert MTB/RIF). Findings: Multiple factors were positively associated with treatment initiation: male sex [adjusted Odds Ratio (aOR) 1.61 (1.31-1.95)], history of prior TB [aOR 1.36 (1.06-1.73)], reported cough [aOR 4.62 (3.42-6.27)], reported night sweats [aOR 1.50 (1.21-1.90)], and having HIV infection but not on ART [aOR 1.68 (1.23-2.32)]. Treatment initiation was substantially less likely for individuals testing negative with Xpert [aOR 0.77 (0.62-0.96)] compared to smear microscopy and declined in more recent years. Interpretation: Multiple factors influenced decisions to initiate TB treatment despite negative test results. Clinicians were substantially less likely to treat in the absence of a positive test result when using more sensitive, PCR-based diagnostics.

Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

BACKGROUND: Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence. METHODS: The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator. RESULTS: When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power. CONCLUSIONS: When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

Experience of social harms among female sex workers following HIV self-test distribution in Malawi: results of a cohort study.

BACKGROUND: In Malawi, female sex workers (FSW) have high HIV incidence and regular testing is suggested. HIV self-testing (HIVST) is a safe and acceptable alternative to standard testing services. This study assessed; whether social harms were more likely to be reported after HIVST distribution to FSW by peer distributors than after facility-based HIV testing and whether FSW regretted HIVST use or experienced associated relationship problems. METHODS: Peer HIVST distributors, who were FSW, were recruited in Blantyre district, Malawi between February and July 2017. Among HIVST recipients a prospective cohort was recruited. Interviews were conducted at baseline and at end-line, 3 months later. Participants completed daily sexual activity diaries. End-line data were analysed using logistic regression to assess whether regret or relationship problems were associated with HIVST use. Sexual activity data were analysed using Generalised Estimating Equations to assess whether HIVST use was temporally associated with an increase in social harms. RESULTS: Of 265 FSW recruited and offered HIVST, 131 completed both interviews. Of these, 31/131(23.7%) reported initial regret after HIVST use, this reduced to 23/131(17.6%) at the 3-month follow-up. Relationship problems were reported by 12/131(9.2%). Regret about HIVST use was less commonly reported in those aged 26-35 years compared to those aged 16-25 years (OR immediate regret-0.40 95% CI 0.16-1.01) (OR current regret-0.22 95% CI 0.07 - 0.71) and was not associated with the HIVST result. There was limited evidence that reports of verbal abuse perpetrated by clients in the week following HIVST use were greater than when there was no testing in the preceding week. There was no evidence for increases in any other social harms. There was some evidence of coercion to test, most commonly initiated by the peer distributor. CONCLUSIONS: Little evidence was found that the peer distribution model was associated with increased levels of social harms, however programmes aimed at reaching FSW need to carefully consider possible unintended consequences of their service delivery approaches, including the potential for peer distributors to coerce individuals to test or disclose their test results and alternative distribution models may need to be considered.

Haemoglobin thresholds to define anaemia from age 6 months to 65 years: estimates from international data sources.

BACKGROUND: Detection of anaemia is crucial for clinical medicine and public health. Current WHO anaemia definitions are based on statistical thresholds (fifth centiles) set more than 50 years ago. We sought to establish evidence for the statistical haemoglobin thresholds for anaemia that can be applied globally and inform WHO and clinical guidelines. METHODS: In this analysis we identified international data sources from populations in the USA, England, Australia, China, the Netherlands, Canada, Ecuador, and Bangladesh with sufficient clinical and laboratory information collected between 1998 and 2020 to obtain a healthy reference sample. Individuals with clinical or biochemical evidence of a condition that could reduce haemoglobin concentrations were excluded. We estimated haemoglobin thresholds (ie, 5th centiles) for children aged 6-23 months, 24-59 months, 5-11 years, and 12-17 years, and adults aged 18-65 years (including during pregnancy) for individual datasets and pooled across data sources. We also collated findings from three large-scale genetic studies to summarise genetic variants affecting haemoglobin concentrations in different ancestral populations. FINDINGS: We identified eight data sources comprising 18 individual datasets that were eligible for inclusion in the analysis. In pooled analyses, the haemoglobin fifth centile was 104·4 g/L (90% CI 103·5-105·3) in 924 children aged 6-23 months, 110·2 g/L (109·5-110·9) in 1874 children aged 24-59 months, and 114·4 g/L (113·6-115·2) in 1839 children aged 5-11 years. Values diverged by sex in adolescents and adults. In pooled analyses, the fifth centile was 122·2 g/L (90% CI 121·3-123·1) in 1741 female adolescents aged 12-17 years and 128·2 g/L (126·4-130·0) in 1103 male adolescents aged 12-17 years. In pooled analyses of adults aged 18-65 years, the fifth centile was 119·7 g/L (90% CI 119·1-120·3) in 3640 non-pregnant females and 134·9 g/L (134·2-135·6) in 2377 males. Fifth centiles in pregnancy were 110·3 g/L (90% CI 109·5-111·0) in the first trimester (n=772) and 105·9 g/L (104·0-107·7) in the second trimester (n=111), with insufficient data for analysis in the third trimester. There were insufficient data for adults older than 65 years. We did not identify ancestry-specific high prevalence of non-clinically relevant genetic variants that influence haemoglobin concentrations. INTERPRETATION: Our results enable global harmonisation of clinical and public health haemoglobin thresholds for diagnosis of anaemia. Haemoglobin thresholds are similar between sexes until adolescence, after which males have higher thresholds than females. We did not find any evidence that thresholds should differ between people of differering ancestries. FUNDING: World Health Organization and the Bill & Melinda Gates Foundation.

Feasibility and acceptability of the smart pillbox and medication label with differentiated care to support person-centered tuberculosis care among ASCENT trial participants - A multicountry study.

Introduction: Digital adherence technologies (DATs) can offer alternative approaches to support tuberculosis treatment medication adherence. Evidence on their feasibility and acceptability in high TB burden settings is limited. We conducted a cross-sectional survey among adults with drug-sensitive tuberculosis (DS-TB), participating in pragmatic cluster-randomized trials for the Adherence Support Coalition to End TB project in Ethiopia (PACTR202008776694999), the Philippines, South Africa and Tanzania (ISRCTN 17706019). Methods: From each country we selected 10 health facilities implementing the DAT intervention (smart pillbox or medication labels, with differentiated care support), ensuring inclusion of urban/rural and public/private facilities. Adults on DS-TB regimen using a DAT were randomly selected from each facility. Feasibility of the DATs was assessed using a standardized tool. Acceptability was measured using a 5-point Likert-scale, using the Capability, Opportunity, Motivation, Behavior (COM-B) model. Mean scores of Likert-scale responses within each COM-B category were estimated, adjusted for facility-level clustering. Data were summarized by country and DAT type. Results: Participants using either the pillbox (n = 210) or labels (n = 169) were surveyed. Among pillbox users, phone ownership (79%), use of pillbox reminders (87%) and taking treatment without the pillbox (22%) varied by country. Among label users, phone ownership (81%), paying extra to use the labels (8%) and taking treatment without using labels (41%) varied by country. Poor network, problems with phone charging and access, not having the pillbox and forgetting to send text were reasons for not using DATs. Overall, people with TB had a favorable impression of both DATs, with mean composite scores between 4·21 to 4·42 across COM-B categories. Some disclosure concerns were reported. Conclusion: From client-perspective, pillboxes and medication labels with differentiated care support were feasible to implement and acceptable in variety of settings. However, implementation challenges related to network, phone access, stigma, additional costs to people with TB to use DATs need to be addressed.

Quantifying non-adherence to anti-tuberculosis treatment due to early discontinuation: a systematic literature review of timings to loss to follow-up.

BACKGROUND: The burden of non-adherence to anti-tuberculosis (TB) treatment is poorly understood. One type is early discontinuation, that is, stopping treatment early. Given the implications of early discontinuation for treatment outcomes, we undertook a systematic review to estimate its burden, using the timing of loss to follow-up (LFU) as a proxy measure. METHODS: Web of Science, Embase and Medline were searched up to 14 January 2021 using terms covering LFU, TB and treatment. Studies of adults (≥ 18 years) on the standard regimen for drug-sensitive TB reporting the timing of LFU (WHO definition) were included. A narrative synthesis was conducted and quality assessment undertaken using an adapted version of Downs and Black. Papers were grouped by the percentage of those who were ultimately LFU who were LFU by 2 months. Three groups were created: <28.3% LFU by 2 months, ≥28.3-<38.3%, ≥38.3%). The percentage of dose-months missed due to early discontinuation among (1) those LFU, and (2) all patients was calculated. RESULTS: We found 40 relevant studies from 21 countries. The timing of LFU was variable within and between countries. 36/40 papers (90.0%) reported the percentage of patients LFU by the end of 2 months. 31/36 studies (86.1%) reported a higher than or as expected percentage of patients becoming LFU by 2 months. The percentage of dose-months missed by patients who became LFU ranged between 37% and 77% (equivalent to 2.2-4.6 months). Among all patients, the percentage of dose-months missed ranged between 1% and 22% (equivalent to 0.1-1.3 months). CONCLUSIONS: A larger than expected percentage of patients became LFU within the first 2 months of treatment. These patients missed high percentages of dose months of treatment due to early discontinuation. Interventions to promote adherence and retain patients in care must not neglect the early months of treatment. PROSPERO REGISTRATION NUMBER: CRD42021218636.

Beyond tuberculosis: a person-centred and rights-based approach to screening for household contacts.

Households affected by tuberculosis have syndemic vulnerability, reflecting a concentration of and interactions between multiple biomedical, psychosocial, and structural determinants of health. Traditional approaches to tuberculosis screening do not address pre-existing risks, such as undernutrition and other chronic conditions, or the indirect effects of tuberculosis, such as loss of livelihood. These pre-existing risks and consequences not only perpetuate the global tuberculosis epidemic but, for those affected, lead to poor health and deepen poverty. We propose reimagining tuberculosis screening as an opportunity to deliver a contextually relevant package of services that address the needs of households affected by tuberculosis. This approach puts people and their rights at the centre of efforts to end tuberculosis, and has equity at the core. This approach could support progress towards universal health coverage, benefiting communities and health systems. Leadership, flexibility in funding allocation, and innovative care models will be required to realise this approach at scale.

Prevalence of chronic conditions and multimorbidity among healthcare workers in Zimbabwe: Results from a screening intervention.

The burden of non-communicable diseases (NCDs) in southern Africa is expanding and is superimposed on high HIV prevalence. Healthcare workers are a scarce resource; yet are vital to health systems. There are very limited studies on the burden of chronic conditions among healthcare workers in Africa, and none exploring multimorbidity (≥2 chronic conditions). We describe the epidemiology of infectious (HIV) and non-communicable chronic conditions, and multimorbidity, among Zimbabwean healthcare workers. Healthcare workers (≥18 years) in eight Zimbabwean provinces were invited to a voluntary, cross-sectional health-check, including HIV, diabetes, hypertension and mental health screening. Statistical analyses described the prevalence and risk factors for multimorbidity (two or more of HIV, diabetes, hypertension or common mental disorder) and each condition. Missing data were handled using multiple imputation. Among 6598 healthcare workers (July 2020-July 2022) participating in the health-check, median age was 37 years (interquartile range 29-44), 79% were women and 10% knew they were living with HIV. Half had at least one chronic condition: 11% were living with HIV, 36% had elevated blood pressure, 12% had elevated HbA1c and 11% had symptoms of common mental disorder. The overall prevalence of multimorbidity was 15% (95% CI: 13-17%); 39% (95% CI: 36-43%) among people aged 50 and older. Whilst most HIV was diagnosed and treated, other chronic conditions were usually undiagnosed or uncontrolled. Limiting our definition of multimorbidity to two or more screened conditions sought to reduce bias due to access to diagnosis, however, may have led to a lower reported prevalence than that found using a wider definition. Half of healthcare workers screened were living with a chronic condition; one in seven had multimorbidity. Other than HIV, most conditions were undiagnosed or untreated. Multisectoral action to implement contextually relevant, chronic disease services in Africa is urgently needed. Specific attention on health workers is required to protect and retain this critical workforce.

Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial.

BACKGROUND: Around 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis. METHODS: This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete. FINDINGS: Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related. INTERPRETATION: The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis. FUNDING: Médecins Sans Frontières.

Effectiveness of a community-based approach for the investigation and management of children with household tuberculosis contact in Cameroon and Uganda: a cluster-randomised trial.

BACKGROUND: Globally, the uptake of tuberculosis-preventive treatment (TPT) among children with household tuberculosis contact remains low, partly due to the necessity of bringing children to health facilities for investigations. This study aimed to evaluate the effect on TPT initiation and completion of community-based approaches to tuberculosis contact investigations in Cameroon and Uganda. METHODS: We did a parallel, cluster-randomised, controlled trial across 20 clusters (consisting of 25 district hospitals and primary health centres) in Cameroon and Uganda, which were randomised (1:1) to receive a community-based approach (intervention group) or standard-of-care facility-based approach to contact screening and management (control group). The community-based approach consisted of symptom-based tuberculosis screening of all household contacts by community health workers at the household, with referral of symptomatic contacts to local facilities for investigations. Initiation of TPT (3-month course of rifampicin-isoniazid) was done by a nurse in the household, and home visits for TPT follow-up were done by community health workers. Index patients were people aged 15 years or older with bacteriologically confirmed, drug-susceptible, pulmonary tuberculosis diagnosed less than 1 month before inclusion and who declared at least one child or young adolescent (aged 0-14 years) household contact. The primary endpoint was the proportion of declared child contacts in the TPT target group (those aged <5 years irrespective of HIV status, and children aged 5-14 years living with HIV) who commenced and completed TPT, assessed in the modified intention-to-treat population (excluding enrolled index patients and their contacts who did not fit the eligibility criteria). Descriptive cascade of care assessment and generalised linear mixed modelling were used for comparison. This study is registered with ClinicalTrials.gov (NCT03832023). FINDINGS: The study included nine clusters in the intervention group (after excluding one cluster that did not enrol any index patients for >2 months) and ten in the control group. Between Oct 14, 2019 and Jan 13, 2022, 2894 child contacts were declared by 899 index patients with bacteriologically confirmed tuberculosis. Among all child contacts declared, 1548 (81·9%) of 1889 in the intervention group and 475 (47·3%) of 1005 in the control group were screened for tuberculosis. 1400 (48·4%) child contacts were considered to be in the TPT target group: 941 (49·8%) of 1889 in the intervention group and 459 (45·7%) of 1005 in the control group. In the TPT target group, TPT was commenced and completed in 752 (79·9%) of 941 child contacts in the intervention group and 283 (61·7%) of 459 in the control group (odds ratio 3·06 [95% CI 1·24-7·53]). INTERPRETATION: A community-based approach using community health workers can significantly increase contact investigation coverage and TPT completion among eligible child contacts in a tuberculosis-endemic setting. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Risk factors for poor engagement with a smart pillbox adherence intervention among persons on tuberculosis treatment in Ethiopia.

BACKGROUND: Non-adherence to tuberculosis treatment increases the risk of poor treatment outcomes. Digital adherence technologies (DATs), including the smart pillbox (EvriMED), aim to improve treatment adherence and are being widely evaluated. As part of the Adherence Support Coalition to End TB (ASCENT) project we analysed data from a cluster-randomised trial of DATs and differentiated care in Ethiopia to examine individual-factors for poor engagement with the smart pillbox. METHODS: Data were obtained from a cohort of trial participants with drug-sensitive tuberculosis (DS-TB) whose treatment started between 1 December 2020 and 1 May 2022, and who were using the smart pillbox. Poor engagement with the pillbox was defined as (i) > 20% days with no digital confirmation and (ii) the count of days with no digital confirmation, and calculated over a two evaluation periods (56-days and 168-days). Logistic random effects regression was used to model > 20% days with no digital confirmation and negative binomial random effects regression to model counts of days with no digital confirmation, both accounting for clustering of individuals at the facility-level. RESULTS: Among 1262 participants, 10.8% (133/1262) over 56-days and 15.8% (200/1262) over 168-days had > 20% days with no digital confirmation. The odds of poor engagement was less among participants in the higher stratum of socio-economic position (SEP) over 56-days. Overall, 4,689/67,315 expected doses over 56-days and 18,042/199,133 expected doses over 168-days were not digitally confirmed. Compared to participants in the poorest SEP stratum, participants in the wealthiest stratum had lower rates of days not digitally confirmed over 168-days (adjusted rate ratio [RRa]:0.79; 95% confidence interval [CI]: 0.65, 0.96). In both evaluation periods (56-days and 168-days), HIV-positive status (RRa:1.29; 95%CI: 1.02, 1.63 and RRa:1.28; 95%CI: 1.07, 1.53), single/living independent (RRa:1.31; 95%CI: 1.03, 1.67 and RRa:1.38; 95%CI: 1.16, 1.64) and separated/widowed (RRa:1.40; 95%CI: 1.04, 1.90 and RRa:1.26; 95%CI: 1.00, 1.58) had higher rates of counts of days with no digital confirmation. CONCLUSION: Poorest SEP stratum, HIV-positive status, single/living independent and separated/ widowed were associated with poor engagement with smart pillbox among people with DS-TB in Ethiopia. Differentiated care for these sub-groups may reduce risk of non-adherence to TB treatment.

Acceptability of using the medication monitor and experience of a differentiated care approach for TB treatment adherence among people living with TB in South Africa.

BACKGROUND: The introduction of digital adherence technologies (DATs) such as medication monitors in tuberculosis (TB) programmes supports treatment adherence among people with tuberculosis (PWTB). We evaluated the acceptability of using medication monitors (Wisepill evriMED) prompting a stepwise differentiated care approach (DCA), involving short message service (SMS), phone calls, home visits and motivational counselling, among PWTB in South Africa. METHODS: We conducted 62 in-depth interviews with participants in local languages across three provinces (January-October 2020), purposively selected by treatment month, adherence history and gender. Interviews were audio recorded, transcribed verbatim and translated. Using a deductive approach and the Theoretical Framework for Acceptability (TFA), we explored acceptability across the sample attributes. RESULTS: PWTB across adherence histories showed a positive attitude to using the evriMED device and receiving the DCA support. PWTB described the SMS reminders and phone calls as effective reminders, though home visits were less acceptable, due to perceived stigma. Despite willingness to participate in the intervention, the large size of the monitor and sound of the alarm drew attention, potentially causing embarrassment and stigma. Due to perceived stigma, some PWTB adapted the intervention by leaving the monitor at home after removing the pills to ensure that someone else tracked usage, while the PWTB used alternative reminders such as cell phones to take their medication. CONCLUSION: Although PWTB showed a positive attitude towards the intervention, perceived stigma contributed to participants adapting their lifestyle to meet treatment adherence requirements without using the monitor. However, the medication monitor was a tool that seemed to prompt this personal change in behaviour. Achieving people-centered TB care, including the introduction of DATs, will require that TB programmes incorporate PWTB insights to maximize their use and effectiveness.

Iron deficiency, pregnancy, and neonatal development.

Anemia affects 36% of pregnant women worldwide. Of those affected, around 40% is due to iron deficiency (ID). Iron is an essential micronutrient involved in vital processes such as erythropoiesis, immune responses, and importantly-during pregnancy-placental and fetal development. Although menstrual bleeding can impact the incidence of ID even before the onset of pregnancy, this narrative review is pregnancy focused and will explore the impact of ID on placental development and iron uptake, fetal development and immunity, and maternal and infant susceptibility to infection. Although there have been advances in this area of research, much is needed to understand the regulation of iron and the effects of ID during pregnancy. Notably, more human studies are essential to generate the best evidence to advance strategies to reduce the incidence of ID during pregnancy to improve maternal, neonatal, and infant health.

Statistical haemoglobin thresholds to define anaemia across the lifecycle.

Detection of anaemia is critical for clinical medicine and public health. Current WHO values that define anaemia are statistical thresholds (5 th centile) set over 50 years ago, and are presently <110g/L in children 6-59 months, <115g/L in children 5-11 years, <110g/L in pregnant women, <120g/L in children 12-14 years of age, <120g/L in non-pregnant women, and <130g/L in men. Haemoglobin is sensitive to iron and other nutrient deficiencies, medical illness and inflammation, and is impacted by genetic conditions; thus, careful exclusion of these conditions is crucial to obtain a healthy reference population. We identified data sources from which sufficient clinical and laboratory information was available to determine an apparently healthy reference sample. Individuals were excluded if they had any clinical or biochemical evidence of a condition that may diminish haemoglobin concentration. Discrete 5 th centiles were estimated along with two-sided 90% confidence intervals and estimates combined using a fixed-effect approach. Estimates for the 5 th centile of the healthy reference population in children were similar between sexes. Thresholds in children 6-23 months were 104.4g/L [90% CI 103.5, 105.3]; in children 24-59 months were 110.2g/L [109.5, 110.9]; and in children 5-11 years were 114.1g/L [113.2, 115.0]. Thresholds diverged by sex in adolescents and adults. In females and males 12-17 years, thresholds were 122.2g/L [121.3, 123.1] and 128.2 [126.4, 130.0], respectively. In adults 18-65 years, thresholds were 119.7g/L [119.1, 120.3] in non-pregnant females and 134.9g/L [134.2, 135.6] in males. Limited analyses indicated 5 th centiles in first-trimester pregnancy of 110.3g/L [109.5, 111.0] and 105.9g/L [104.0, 107.7] in the second trimester. All thresholds were robust to variations in definitions and analysis models. Using multiple datasets comprising Asian, African, and European ancestries, we did not identify novel high prevalence genetic variants that influence haemoglobin concentration, other than variants in genes known to cause important clinical disease, suggesting non-clinical genetic factors do not influence the 5 th centile between ancestries. Our results directly inform WHO guideline development and provide a platform for global harmonisation of laboratory, clinical and public health haemoglobin thresholds.

Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study.

INTRODUCTION: The ICH E9 addendum outlining the estimand framework for clinical trials was published in 2019 but provides limited guidance around how to handle intercurrent events for non-inferiority studies. Once an estimand is defined, it is also unclear how to deal with missing values using principled analyses for non-inferiority studies. METHODS: Using a tuberculosis clinical trial as a case study, we propose a primary estimand, and an additional estimand suitable for non-inferiority studies. For estimation, multiple imputation methods that align with the estimands for both primary and sensitivity analysis are proposed. We demonstrate estimation methods using the twofold fully conditional specification multiple imputation algorithm and then extend and use reference-based multiple imputation for a binary outcome to target the relevant estimands, proposing sensitivity analyses under each. We compare the results from using these multiple imputation methods with those from the original study. RESULTS: Consistent with the ICH E9 addendum, estimands can be constructed for a non-inferiority trial which improves on the per-protocol/intention-to-treat-type analysis population previously advocated, involving respectively a hypothetical or treatment policy strategy to handle relevant intercurrent events. Results from using the 'twofold' multiple imputation approach to estimate the primary hypothetical estimand, and using reference-based methods for an additional treatment policy estimand, including sensitivity analyses to handle the missing data, were consistent with the original study's reported per-protocol and intention-to-treat analysis in failing to demonstrate non-inferiority. CONCLUSIONS: Using carefully constructed estimands and appropriate primary and sensitivity estimators, using all the information available, results in a more principled and statistically rigorous approach to analysis. Doing so provides an accurate interpretation of the estimand.

IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners.

BACKGROUND: The prevalence of tuberculosis among men who work in the gold mines of South Africa is among the highest in the world, but a fraction of miners demonstrate consistently negative results upon tuberculin skin test (TST) and IFN-γ release assay (IGRA). We hypothesized that these "resisters" (RSTRs) may display unconventional immune signatures of exposure to M. tuberculosis (M.tb). METHODS: In a cohort of RSTRs and matched controls with latent TB infection (LTBI), we profiled the functional breadth of M.tb antigen-specific T cell and antibody responses using multi-parameter flow cytometry and systems serology, respectively. FINDINGS: RSTRs and LTBI controls both exhibited IFN-γ independent T-cell and IgG antibody responses to M.tb-specific antigens ESAT-6 and CFP-10. Antigen-specific antibody Fc galactosylation and sialylation were higher among RSTRs. In a combined T-cell and antibody analysis, M.tb lysate-stimulated TNF secretion by T cells correlated positively with levels of purified protein derivative-specific IgG. A multivariate model of the combined data was able to differentiate RSTR and LTBI subjects. INTERPRETATION: IFN-γ independent immune signatures of exposure to M.tb, which are not detected by approved clinical diagnostics, are readily detectable in an occupational cohort uniquely characterized by intense and long-term infection pressure. Further, TNF may mediate a coordinated response between M.tb-specific T-cells and B-cells. FUNDING: This work was supported by the US National Institutes of Health (R01-AI124348 to Boom, Stein, and Hawn; R01-AI125189 and R01-AI146072 to Seshadri; and 75N93019C00071 to Fortune, Alter, Seshadri, and Boom), the Doris Duke Charitable Foundation (Davies), the Bill & Melinda Gates Foundation (OPP1151836 and OPP1109001 to Hawn; and OPP1151840 to Alter), Mass Life Science Foundation (Fortune), and Good Ventures Fund (Fortune).

Does diabetes mellitus comorbidity increase the risk of drug-induced liver injury during tuberculosis treatment?

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Digital adherence technologies to improve tuberculosis treatment outcomes in China: a cluster-randomised superiority trial.

BACKGROUND: Drug-sensitive tuberculosis treatment requires 6 months of therapy, so adherence problems are common. Digital adherence technologies might improve tuberculosis treatment outcomes. We aimed to evaluate the effect of a daily reminder medication monitor, monthly review of adherence data by the health-care provider, and differentiated care for patients with adherence issues, on tuberculosis treatment adherence and outcomes. METHODS: We did a cluster-randomised superiority trial across four prefectures in China. 24 counties or districts (clusters) were randomly assigned (1:1) to intervention or control groups. We enrolled patients aged 18 years or older with GeneXpert-positive, rifampicin-sensitive pulmonary tuberculosis, who were receiving daily fixed-dose combination treatment. Patients in the intervention group received a medication monitor for daily drug-dosing reminders, monthly review of adherence data by health-care provider, and management of poor adherence; and patients in the control group received routine care (silent-mode monitor-measured adherence). Only the independent endpoints review committee who assessed endpoint data for some participants were masked to study group assignment. Patients were followed up (with sputum solid culture) at 12 and 18 months. The primary outcome was a composite of death, loss to follow-up, treatment failure, switch to multidrug-resistant tuberculosis treatment, or tuberculosis recurrence by 18 months from treatment start, analysed in the intention-to-treat population. Analysis accounted for study design with multiple imputation for the primary outcome. This trial is now complete and is registered with ISRCTN, 35812455. FINDINGS: Between Jan 26, 2017, and April 3, 2019, 15 257 patients were assessed for eligibility and 3074 were enrolled, 2686 (87%) of whom were included in the intention-to-treat population. 1909 (71%) of 2686 patients were male, 777 (29%) were female, and the median age was 44 years (IQR 29-58). By 18 months from treatment start, using multiple imputation for missing outcomes, 239 (16% [geometric mean of cluster-level proportion]) of 1388 patients in the control group and 224 (16%) of 1298 in the intervention group had a primary composite outcome event (289 [62%] of 463 events were loss to follow-up during treatment and 42 [9%] were tuberculosis recurrence). The intervention had no effect on risk of the primary composite outcome (adjusted risk ratio 1·01, 95% CI 0·73-1·40). INTERPRETATION: Our digital medication monitor intervention had no effect on unfavourable outcomes, which included loss to follow-up during treatment, tuberculosis recurrence, death, and treatment failure. There was a failure to change patient management following identification of treatment non-adherence at monthly reviews. A better understanding of adherence patterns and how they relate to poor outcomes, coupled with a more timely review of adherence data and improved implementation of differentiated care, may be required. FUNDING: Bill & Melinda Gates Foundation.