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Objective: To understand reasons for suboptimal and delayed uptake of antiretroviral therapy (ART) by describing the patterns of HIV testing and counselling (HTC) and outcomes of ART eligibility assessments in primary clinic attendees.Methods: All clinic attendances and episodes of HTC were recorded at two clinics in Blantyre. A cohort of newly diagnosed HIV-positive adults (>15 years) was recruited and exit interviews undertaken. Logistic regression models were constructed to investigate factors associated with referral to start ART. Qualitative interviews were conducted with providers and patients.Results: There were 2398 episodes of HTC during 18,021 clinic attendances (13.3%) between January and April 2011. The proportion of clinic attendees undergoing HTC was lowest in non-pregnant women (6.3%) and men (8.5%), compared with pregnant women (47.2%). Men had more advanced HIV infection than women (79.7% WHO stage 3 or 4 vs. 56.4%). Problems with WHO staging and access to CD4 counts affected ART eligibility assessments; only 48% completed ART eligibility assessment, and 54% of those reporting WHO stage 3/4 illnesses were not referred to start ART promptly. On multivariate analysis, HIV-positive pregnant women were significantly less likely to be referred directly for ART initiation (adjusted OR: 0.29, 95% CI: 0.13-0.63).Conclusions: These data show that provider-initiated testing and counselling (PITC) has not yet been fully implemented at primary care clinics. Suboptimal ART eligibility assessments and referral (reflecting the difficulties of WHO staging in primary care) mean that simplified eligibility assessment tools are required to reduce unnecessary delay and attrition in the pre-ART period. Simplified initiation criteria for pregnant women, as being introduced in Malawi, should improve linkage to ART. [ABSTRACT FROM AUTHOR]

Up to 14% of Malawian adults die during the intensive phase of tuberculosis treatment. In a prospective cohort of 199 Malawian adults with microbiologically confirmed pulmonary tuberculosis, clinical and laboratory parameters were compared between those who died or deteriorated with those who had an uneventful recovery. Baseline tumor necrosis factor alpha responses to stimulation with heat-killed Mycobacterium tuberculosis and lipopolysaccharide were reduced among the 22 patients with poor outcome (P = .017). Low body mass index (P = .002) and elevated respiratory rate (P = .01) at tuberculosis diagnosis independently predicted poor outcome. Validation of a clinical score identifying high-risk individuals is warranted, together with further investigation of immunological derangements. [ABSTRACT FROM AUTHOR]

Background: China is facing a significant tuberculosis epidemic among rural-to-urban migrants, which poses a threat to TB control. This study aimed to understand the health seeking behaviour of and health systems responses to migrants and permanent urban residents suffering from chronic cough, in order to identify the factors influencing delays for both groups in receiving a TB diagnosis in urban China. Methods: Combining a prospective cohort study of adult suspect TB patients and a qualitative study, the Piot model was used to analyze the health seeking behaviour of TB suspects among migrants and permanent urban residents, the factors influencing their decision and the responses by general health providers. Methods included a patient survey, focus group discussions with migrants in the general population, qualitative interviews with migrant and permanent resident TB suspects and TB patients as well as key stakeholders related to TB control and the management of migrants. Results: Sixty eight percent of migrants delayed for more than two weeks before seeking care for symptoms suggestive of TB, compared to 54% of residents (p < 0.01). When they first decided to seek professional care, migrants were 1.5 times more likely than residents to use less expensive, community-level health services. Only 5% were ultimately referred to a TB dispensary. Major reasons for both patient and provider delay included lack of knowledge and mistrust of the TB control programme, lack of knowledge about TB (patients), and profit-seeking behaviour (providers). In the follow up survey, 61% of the migrants and 41% of the residents who still had symptoms gave up continuing to seek professional care, with a statistically significant difference between the two groups (p < 0.05). Conclusion: Rural-to-urban migrants are more likely than permanent residents to delay in seeking care for symptoms suggestive of TB in urban Chongqing. 'Patient-' and 'provider-' related factors interact to pose barriers to TB diagnosis for migrants, including: low awareness, and poor knowledge among both the general public and TB suspects about TB as a disease and about the TB control programme; low financial capacity to pay for care and diagnostic tests; and inadequate use of diagnostic tests and referral to TB dispensaries by general health providers. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the relative costs of accessing a TB diagnosis for the poor and for women in urban Lilongwe, Malawi, a setting where public health services are accessible within 6 kilometers and provided free of charge. METHODS: Patient and household direct and opportunity costs were assessed from a survey of 179 TB patients, systematically sampled from all public and mission health facilities in Lilongwe. Poverty status was determined from the 1998 Malawi Integrated Household Survey (MIHS). FINDINGS: On average, patients spent US$ 13 (MK 996 or 18 days' income) and lost 22 days from work while accessing a TB diagnosis. For non-poor patients, the total costs amounted to 129% of total monthly income, or 184% after food expenditures. For the poor, this cost rose to 248% of monthly income or 574% after food. When a woman or when the poor are sick, the opportunity costs faced by their households are greater. CONCLUSION: Patient and household costs of TB diagnosis are prohibitively high even where services are provided free of charge. In scaling up TB services to reach the Millennium Development Goals, there is an urgent need to identify strategies for diagnosing TB that are cost-effective for the poor and their households. Copyright © 2007 World Health Organization [ABSTRACT FROM AUTHOR]

Private--public mix (PPM) DOTS is widely advocated as a DOTS adaptation for promoting progress towards the international tuberculosis (TB) control targets of detecting 70% of TB cases and successfully treating 85% of these. Private health care plays a central role in health-care provision in many developing countries that have a high burden of TB. It is therefore encouraging that PPM projects are being set up in various countries around the world to explore possible interaction between the national TB programmes and other partners in the fight against TB. The objective of this review was to use the published literature to assess the range of providers included in PPMs for their ability to provide case-detection services for the vulnerable. From a case-detection perspective, we identify the essential elements of a pro-poor PPM model, namely, cost-effectiveness from a patient perspective, accessibility, acceptability and quality. The review revealed that a very large part of the total spectrum of potential PPM-participating partners has not yet been explored; current models focus on private-for-profit health-care providers and nongovernmental organizations. We conclude that it is important to think critically about the type of private providers who are best suited to meeting the needs of the poor, and that more should be done to document the socioeconomic status of patients accessing services through PPM pilots. Copyright © 2006 World Health Organization [ABSTRACT FROM AUTHOR]

Background: Delusional infestation (DI) is a well-recognized delusional disorder presenting as the persisting belief of being infested. Combined clinics have been run by dermatology and psychiatry in a small number of centres. In this article we focus on our Liverpool University Hospitals NHS Foundation Trust clinic hosted at the Liverpool School of Tropical Medicine, UK, where we run a specialist clinic for DI., Methods: We describe the specific set-up and approach of our clinic as a guide for clinicians working in specialties likely to see patients with DI (including tropical medicine, infectious diseases and dermatology) who may either want to set up similar clinics or be better equipped to manage DI patients promptly within existing practice., Results: We describe the details of the clinic's approach. Between 2018 and 2023, the service saw 208 patients, of which 82.7% could be assessed and 55.7% had DI. The female:male ratio was 2:1., Conclusion: Interdisciplinary combined clinics with medical and psychiatry consultants working together offer an approach to managing this rare, challenging and high-consequence condition., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks., Methods: We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda). Participants were randomly assigned 1:2:2:2 (via permuted blocks and stratified by site and HIV status plus CD4 cell count) to the 2011 WHO long regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of an injectable antituberculous drug. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome, reported previously, was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable) at week 76. Here we report efficacy outcomes at week 132, analysed in the modified intention-to-treat (mITT) population. Safety assessments continued to 132 weeks and were in all participants who received at least one dose of the study regimen. All comparisons used concurrently randomised participants. This trial is registered on ISRCTN (ISRCTN18148631) and is now completed., Findings: Between March 28, 2016, and Jan 28, 2020, 588 participants were randomly assigned to the long (n=32), control (n=202), oral (n=211), or 6-month (n=143) treatment regimens; 352 (60%) were male and 236 (40%) were female. Of the 556 participants on the three shorter regimens, 517 were included in the mITT population (187 in control group, 196 in oral group, and 134 in 6-month group) and 465 in the per-protocol analyses. Six additional participants had an unfavourable outcome that occurred between week 76 and the end of efficacy follow-up (one in control group, four in oral group, one in 6-month group). In the mITT population, the proportion of patients with an unfavourable outcome at the end of follow-up was 19·6% (95% CI 14·3 to 24·9) in the oral group and 29·3% (23·3 to 36·5) in the control group (-9·7 percentage points difference [95% CI -18·7 to -1·8]; p superiority =0·024). An estimated 9·8% (95% CI 4·6 to 14·9) of participants on the 6-month regimen had an unfavourable outcome, which was significantly lower than for those concurrently on the control regimen (32·5% [23·7 to 40·2]; p superiority <0·0001) or the oral regimen (23·8% [16·9 to 31·1]; p superiority =0·013). Few serious or severe adverse events were reported after week 76, with no indication of a difference between the regimens. At week 132, treatment-emergent hearing loss was recorded in significantly fewer participants on the oral regimen (7/205; 3%) than the control regimen (16/198; 8%; p=0.041); there was no significant difference in severe hearing loss between the oral regimen (6/139; 4%) and the 6-month regimen (5/143; 4%; p=0·72). Death rates were low: 1·01 (95% CI 0·48 to 2·12) per 100 person-years in participants allocated to bedaquiline (ie, oral and 6-month regimen, n=287) compared with 1·52 (0·63 to 3·66) in participants on the control regimen (n=140; p=0·49)., Interpretation: Both of the bedaquiline-containing regimens maintained superiority to the control regimen, without evidence of increased mortality, providing two additional evidence-based treatment options for patients; previous mortality concerns for bedaquiline were not substantiated., Funding: US Agency for International Development and Janssen Research & Development., Competing Interests: Declaration of interests MR sat on the South African Bedaquiline, Pretomanid and Linezolid Clinical Access Program data monitoring committee and the BEAT Tuberculosis Trial data monitoring committee. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., ((c) 2024 The authors; licensee World Health Organization.)

Current strategies to promptly, effectively, and equitably screen people with tuberculosis (TB) and link them to diagnosis and care are insufficient; new approaches are required to find the millions of people around the world with TB who are missed each year. Interventions also need to be designed considering how people interact with health care facilities and where appropriate should be suitable for use in the community. Here, the historical, new, and reemerging technologies that are being utilised for TB diagnosis globally are discussed, whilst highlighting that how we use and evaluate tests is just as important as the tests themselves., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: E. R. A. is the Chief Impact Officer for Global Access Diagnostics, Bedford England. The remaining authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Data remain scarce for the first-line antipsychotic choice in treating delusional infestation (DI)., Objectives: We evaluated the treatment responses associated with different antipsychotics in DI patients., Methods: We undertook a multicentre, retrospective observational study using anonymised electronic patient records from two hospitals in the United Kingdom from 1 January 2011 to 1 January 2023. Eligible participants were adults (≥18 years) diagnosed with DI treated with an antipsychotic, and had both an assigned baseline and follow-up Clinical Global Impression Scale (CGI-S) score. The CGI-S is a validated psychiatric research tool. Participants were excluded if they had known limited or non-adherence to an antipsychotic, or if no CGI-S scores were present at follow-up. First clinic visits before the initiation of an antipsychotic were assigned as the baseline CGI-S score. The last available CGI-S score before the patient either changed antipsychotic or left the clinic for any reason was used to assign follow-up CGI-S scores. The primary outcome was the response to each individual antipsychotic treatment, measured by the difference in the baseline and last available follow-up CGI-S scores. Differences in CGI-S changes between antipsychotic episodes were tested by analysis of variance (ANOVA)., Results: In total, 414 patient records were analysed, and data were extracted. The mean age was 61.8 years (SD 14.1). One hundred seventy (41%) of 414 patients were men and 244 (59%) were women. In total, 156 (38%) of 414 patients were eligible, yielding a total of 315 antipsychotic prescribing episodes. The ANOVA, ranking in order of treatment response, showed that the highest mean score (expressing highest treatment response) was observed in amisulpride (31 [67%] of 46) and risperidone (95 [57%] of 167), followed by some distance by quetiapine (9 [36%] of 25), aripiprazole (13 [28%] of 46) and olanzapine (7 [25%] of 28)., Conclusions: Amisulpride and risperidone were associated with a higher treatment response than quetiapine, aripiprazole and olanzapine. Amisulpride and risperidone should therefore be considered the first-line treatment options in DI patients., (© 2024 European Academy of Dermatology and Venereology.)

Background: The psychosocial consequences of tuberculosis (TB) are key barriers to ending TB globally. We evaluated and compared stigma, depression, and quality of life (QoL) among people with TB diagnosed through active (ACF) and passive (PCF) case-finding in Nepal., Methods: We prospectively recruited adults with TB diagnosed through ACF and PCF in four districts of Nepal between August 2018 and April 2019. Participants were interviewed at 8-12 weeks (baseline) and 22-26 weeks (follow-up) following treatment initiation. TB stigma was measured using an adapted Van Rie Stigma Scale (0 = no stigma to 30 = highest stigma). Depression was measured using a locally-validated Patient Health Questionnaire (PHQ-9). Mild and major depression were indicated by  PHQ-9 scores 5-9 and ≥ 10, respectively. QoL was measured using the EuroQoL 5-Dimension 5-level (EQ-5D-5L) from 0 to 1 (optimal QoL); and self-rated health from 0 to 100 (optimal self-rated health)., Results: We recruited 221 participants (111 ACF; 110 PCF) with a mean age of 48 years (standard deviation [SD] =  ± 16), of whom 147/221 (67%) were men. The mean TB stigma score was 12 (SD = 7.3) at baseline and 12 (SD = 6.7) at follow-up. The most commonly perceived elements of TB stigma at baseline were that people with TB experienced guilt (110/221, 50%) and feared disclosure outside their household (114/221, 52%). Self-rated health and EQ-5D-5L scores increased from baseline to follow-up (69.3 to 80.3, p < 0.001; 0.92 to 0.9, p = 0.009). Nearly one-third of participants (68/221, 31%) had mild or major depression at baseline. The proportion of participants with major depression decreased from baseline to follow-up (11.5% vs. 5%, p = 0.012). There was a moderate, significant positive correlation between depression and stigma scores (r = 0.41, p < 0.001). There were no differences found in TB stigma, self-rated health, QoL, or prevalence of mild/major depression between ACF and PCF participants., Conclusions: We found a substantial, persistent, and clustered psychosocial impact among adults with TB diagnosed through both ACF and PCF strategies in Nepal. These findings suggest an urgent need to develop effective, evidence-based psychosocial support interventions with the potential to be integrated with existing ACF strategies and routine TB service activities., Competing Interests: Declarations. Ethics approval and consent to participate: The study conformed to the principles outlined in the Declaration of Helsinki. The study received ethical approval from the University of Liverpool, UK (approval number 2436) and Nepal Health Research Council (approval number 320/2018). Participants were provided with a leaflet that detailed the objective, duration, risks and benefits of participating in the study [99]. Written informed consent was obtained from all the participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Pulmonary TB survivors face a high burden of post-TB lung disease (PTLD) after TB treatment completion. In this secondary data analysis we investigate the performance of parameters measured at TB treatment completion in predicting morbidity over the subsequent year, to inform programmatic approaches to PTLD screening in low-resource settings. Cohort data from urban Blantyre, Malawi were used to construct regression models for five morbidity outcomes (chronic respiratory symptoms or functional limitation, ongoing health seeking, spirometry decline, self-reported financial impact of TB disease, and death) in the year after PTB treatment, using three modelling approaches: logistic regression; penalised regression with pre-selected predictors; elastic net penalised regression using the full parent dataset. Predictors included demographic, clinical, symptom, spirometry and chest x-ray variables. The predictive performance of models were examined using the area under the receiver-operator curve (ROC AUC) values. Key predictors were identified, and their positive and negative predictive values (NPV) determined. The presence of respiratory symptoms at TB treatment completion was the strongest predictor of morbidity outcomes. TB survivors reporting breathlessness had higher odds of spirometry decline (aOR 20.5, 95%CI:3-199.1), health seeking (aOR 10.2, 2.4-50), and symptoms or functional limitation at 1-year (aOR 16.7, 3.3-133.4). Those reporting activity limitation were more likely to report symptoms or functional limitation at 1-year (aOR 4.2, 1.8-10.3), or severe financial impact of TB disease (aOR2.3, 1.0-5.0). Models were not significantly improved by including spirometry or imaging parameters. ROC AUCs were between 0.65-0.77 for the morbidity outcomes. Activity limitation at treatment completion had a NPV value of 78-98% for adverse outcomes. Our data suggest that whilst challenging to predict the development of post-TB morbidity, the use of symptom screening tools at TB treatment completion to prioritise post-TB care should be explored. We identified little benefit from the additional use of spirometry or CXR imaging., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Meghji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study compares the yield and additionality of community-based active tuberculosis (TB) active case-finding strategies using either smear microscopy or GeneXpert as the TB diagnostic test. Active case-finding strategies screened social contacts of index cases and high-risk groups in four districts of Nepal in July 2017-2019. Two districts (Chitwan and Dhanusha) applied GeneXpert testing and two districts (Makwanpur and Mahotarri) used smear microscopy. Two control districts implemented standard national TB program activities. Districts implementing GeneXpert testing screened 23,657 people for TB, tested 17,114 and diagnosed 764 TB cases, producing a yield of 4.5%. Districts implementing smear microscopy screened 19,961 people for TB, tested 13,285 and diagnosed 437 cases, producing a yield of 3.3%. The screening numbers required were 31 for GeneXpert and 45.7 for smear districts. The test numbers required were 22.4 and 30.4 for GeneXpert and smear. Using the TB REACH additionality method, social contact tracing for TB through GeneXpert testing contributed to a 20% (3958/3322) increase in district-level TB notifications, smear microscopy 12.4% (3146/2798), and -0.5% (2553/2566) for control districts. Therefore, social contact tracing of TB index cases using GeneXpert testing should be implemented throughout Nepal within the TB FREE initiative to close the notification gap and accelerate progress toward END TB strategy targets.

Background: The use of molecular amplification as-says for TB diagnosis is limited by their costs and cartridge stocks. Pooling multiple samples to test them together is reported to have similar accuracy to individual testing and to save costs., Methods: Two surveys of individuals with presumptive TB were conducted to assess the performance of pooled testing using Xpert® MTB/RIF (MTB/RIF) and Xpert® Ultra (Ultra)., Results: A total of 500 individuals were tested using MTB/RIF, with 72 (14.4%) being MTB-positive. The samples were tested in 125 pools, with 50 pools having ⩾1 MTB-positive and 75 only MTB-negative samples: 46/50 (92%, 95% CI 80.8-97.8) MTB-positive pools tested MTB-positive and 71/75 (94.7%, 95% CI 86.9-98.5) MTB-negative pools tested MTB-negative in the pooled test (agreement: 93.6%, κ = 0.867). Five hundred additional samples were tested using Ultra, with 60 (12%) being MTB-positive. Samples were tested in 125 pools, with 42 having ⩾1 MTB-positive and 83 only MTB-negative samples: 35/42 (83.6%, 95% CI 68.6-93.0) MTB-positive pools tested MTB-positive and 82/83 (98.8%, 95% CI 93.5-100.0) MTB-negative pools tested MTB-negative in the pooled test (agreement: 93.6%, κ = 0.851; P > 0.1 between individual and pooled testing). Pooled testing saved 35% (MTB/RIF) and 46% (Ultra) of cartridges., Conclusions: Pooled and individual testing has a high level of agreement and improves testing efficiency., Competing Interests: Conflicts of interest: none declared., (© 2023 The Union.)

Background: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens., Methods: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631., Findings: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia, $1900 in India, $3950 in Moldova, and $7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia, $3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from $1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India., Interpretation: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable., Funding: USAID and Janssen Research & Development., Competing Interests: Declaration of interests LR reports consulting fees from GSK (paid to institution) and support for attending trial-related meetings from Janssen Research & Development and the US Agency for International Development (USAID; paid to institution). JJM reports support for attending meetings or travel from the Liverpool School of Tropical Medicine. EMT reports consulting fees from GSK (paid to institution) and support for attending meetings from USAID (paid to institution). MM, PB, RD, GN, AKBh, BK, SKM, AJN, GB, IDR, and EW report support for attending trial-related meetings from Janssen Research & Development and USAID (paid to institution). ET reports support for attending meetings from USAID (paid to institution). SBS reports a research grant on tuberculosis research (paid to institution) from the UK Foreign & Commonwealth Development Office, support for attending trial-related meetings from Janssen Research & Development and USAID (paid to institution), and is co-chair of the Scientific Working Group on Implementation Research for the Tropical Disease Research Foundation (unpaid). All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

BACKGROUND:  The World Health Organization's End TB (tuberculosis) Strategy advocates social and economic support for TB-affected households but evidence from low-income settings is scarce. We will evaluate the feasibility and acceptability of a locally-appropriate socioeconomic support intervention for TB-affected households in Nepal. METHODS:  We will conduct a pilot randomised-controlled trial with mixed-methods process evaluation in four TB-endemic, impoverished districts of Nepal: Pyuthan, Chitwan, Mahottari, and Morang. We will recruit 128 people with TB notified to the Nepal National TB Program (NTP) and 40 multisectoral stakeholders including NTP staff, civil-society members, policy-makers, and ASCOT (Addressing the Social Determinants and Consequences of Tuberculosis) team members. People with TB will be randomised 1:1:1:1 to four study arms (n=32 each): control; social support; economic support; and combined social and economic (socioeconomic) support. Social support will be TB education and peer-led mutual-support TB Clubs providing TB education and stigma-reduction counselling. Economic support will be monthly unconditional cash transfers during TB treatment with expectations (not conditions) of meeting NTP goals. At 0, 2, and 6 months following TB treatment initiation, participants will be asked to complete a survey detailing the social determinants and consequences of TB and their feedback on ASCOT. Complementary process evaluation will use focus group discussions (FGD), key informant interviews (KII), and a workshop with multi-sectoral stakeholders to consider the challenges to ASCOT's implementation and scale-up. A sample of ~100 people with TB is recommended to estimate TB-related costs. Information power is estimated to be reached with approximately 25 FGD and 15 KII participants. CONCLUSIONS:  The ASCOT pilot trial will both generate robust evidence on a locally-appropriate, socioeconomic support intervention for TB-affected households in Nepal and inform a large-scale future ASCOT trial, which will evaluate the intervention's impact on catastrophic costs mitigation and TB outcomes. The trial is registered with the ISRCTN ( ISRCTN17025974)., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Rai B et al.)

Background: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen., Methods: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631., Findings: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss., Interpretation: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss., Funding: USAID and Janssen Research & Development., Competing Interests: Declaration of interests SBS received a grant from the UK Foreign & Commonwealth Development Office for tuberculosis research through his institution. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Community-based screening for tuberculosis (TB) could improve detection but is resource intensive. We set out to evaluate the accuracy of computer-aided TB screening using digital chest X-ray (CXR) to determine if this approach met target product profiles (TPP) for community-based screening. CXR images from participants in the 2016 Kenya National TB Prevalence Survey were evaluated using CAD4TBv6 (Delft Imaging), giving a probabilistic score for pulmonary TB ranging from 0 (low probability) to 99 (high probability). We constructed a Bayesian latent class model to estimate the accuracy of CAD4TBv6 screening compared to bacteriologically-confirmed TB across CAD4TBv6 threshold cut-offs, incorporating data on Clinical Officer CXR interpretation, participant demographics (age, sex, TB symptoms, previous TB history), and sputum results. We compared model-estimated sensitivity and specificity of CAD4TBv6 to optimum and minimum TPPs. Of 63,050 prevalence survey participants, 61,848 (98%) had analysable CXR images, and 8,966 (14.5%) underwent sputum bacteriological testing; 298 had bacteriologically-confirmed pulmonary TB. Median CAD4TBv6 scores for participants with bacteriologically-confirmed TB were significantly higher (72, IQR: 58-82.75) compared to participants with bacteriologically-negative sputum results (49, IQR: 44-57, p<0.0001). CAD4TBv6 met the optimum TPP; with the threshold set to achieve a mean sensitivity of 95% (optimum TPP), specificity was 83.3%, (95% credible interval [CrI]: 83.0%-83.7%, CAD4TBv6 threshold: 55). There was considerable variation in accuracy by participant characteristics, with older individuals and those with previous TB having lowest specificity. CAD4TBv6 met the optimal TPP for TB community screening. To optimise screening accuracy and efficiency of confirmatory sputum testing, we recommend that an adaptive approach to threshold setting is adopted based on participant characteristics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Mungai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rationale: Pulmonary tuberculosis (PTB) can cause post-TB lung disease (PTLD) associated with respiratory symptoms, spirometric and radiological abnormalities. Understanding of the predictors and natural history of PTLD is limited., Objectives: To describe the symptoms and lung function of Malawian adults up to 3 years following PTB-treatment completion, and to determine the evolution of PTLD over this period., Methods: Adults successfully completing PTB treatment in Blantyre, Malawi were followed up for 3 years and assessed using questionnaires, post-bronchodilator spirometry, 6 min walk tests, chest X-ray and high-resolution CT. Predictors of lung function at 3 years were identified by mixed effects regression modelling., Measurement and Main Results: We recruited 405 participants of whom 301 completed 3 years follow-up (mean (SD) age 35 years (10.2); 66.6% males; 60.4% HIV-positive). At 3 years, 59/301 (19.6%) reported respiratory symptoms and 76/272 (27.9%) had abnormal spirometry. The proportions with low FVC fell from 57/285 (20.0%) at TB treatment completion to 33/272 (12.1%), while obstruction increased from and 41/285 (14.4%) to 43/272 (15.8%) at 3 years. Absolute FEV 1 and FVC increased by mean 0.03 L and 0.1 L over this period, but FEV 1 decline of more than 0.1 L was seen in 73/246 (29.7%). Higher spirometry values at 3 years were associated with higher body mass index and HIV coinfection at TB-treatment completion., Conclusion: Spirometric measures improved over the 3 years following treatment, mostly in the first year. However, a third of PTB survivors experienced ongoing respiratory symptoms and abnormal spirometry (with accelerated FEV 1 decline). Effective interventions are needed to improve the care of this group of patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: There is growing awareness of the burden of post-TB morbidity, and its impact on the lives and livelihoods of TB affected households. However little work has been done to determine how post-TB care might be delivered in a feasible and sustainable way, within existing National TB Programmes (NTPs) and health systems, in low-resource, high TB-burden settings. In this programme of stakeholder engagement around post-TB care, we identified actors with influence and interest in TB care in Kenya and Malawi, including TB-survivors, healthcare providers, policy-makers, researchers and funders, and explored their perspectives on post-TB morbidity and care., Methods: Stakeholder mapping was completed to identify actors with interest and influence in TB care services in each country, informed by the study team's local, regional and international networks. Key international TB organisations were included to provide a global perspective. In person or online one-to-one interviews were completed with purposively selected stakeholders. Snowballing was used to expand the network. Data were recorded, transcribed and translated, and a coding frame was derived. Data were coded using NVivo 12 software and were analysed using thematic content analysis. Online workshops were held with stakeholders from Kenya and Malawi to explore areas of uncertainty and validate findings., Results: The importance of holistic care for TB patients, which addresses both TB comorbidities and sequelae, was widely recognised by stakeholders. Key challenges to implementation include uncertainty around the burden of post-TB morbidity, leadership of post-TB services, funding constraints, staff and equipment limitations, and the need for improved integration between national TB and non-communicable disease (NCD) programmes for care provision and oversight. There is a need for local data on the burden and distribution of morbidity, evidence-informed clinical guidelines, and pilot data on models of care. Opportunities to learn from existing HIV-NCD services were emphasised., Discussion: This work addresses important questions about the practical implementation of post-TB services in two African countries, exploring if, how, where, and for whom these services should be provided, according to a broad range of stakeholders. We have identified strong interest in the provision of holistic care for TB patients in Kenya and Malawi, and key evidence gaps which must be addressed to inform decision making by policy makers, TB programmes, and funders around investment in post-TB services. There is a need for pilot studies of models of integrated TB care, and for cross-learning between countries and from HIV-NCD services., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Karanja et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Despite growing evidence of the long-term impact of tuberculosis (TB) on quality of life, Global Burden of Disease (GBD) estimates of TB-related disability-adjusted life years (DALYs) do not include post-TB morbidity, and evaluations of TB interventions typically assume treated patients return to pre-TB health. Using primary data, we estimate years of life lost due to disability (YLDs), years of life lost due to premature mortality (YLL) and DALYs associated with post-TB cardiorespiratory morbidity in a low-income country., Methods: Adults aged ≥15 years who had successfully completed treatment for drug-sensitive pulmonary TB in Blantyre, Malawi (February 2016-April 2017) were followed-up for 3 years with 6-monthly and 12-monthly study visits. In this secondary analysis, St George's Respiratory Questionnaire data were used to match patients to GBD cardiorespiratory health states and corresponding disability weights (DWs) at each visit. YLDs were calculated for the study period and estimated for remaining lifespan using Malawian life table life expectancies. YLL were estimated using study mortality data and aspirational life expectancies, and post-TB DALYs derived. Data were disaggregated by HIV status and gender., Results: At treatment completion, 222/403 (55.1%) participants met criteria for a cardiorespiratory DW, decreasing to 15.6% after 3 years, at which point two-thirds of the disability burden was experienced by women. Over 90% of projected lifetime-YLD were concentrated within the most severely affected 20% of survivors. Mean DWs in the 3 years post-treatment were 0.041 (HIV-) and 0.025 (HIV+), and beyond 3 years estimated as 0.025 (HIV-) and 0.010 (HIV+), compared with GBD DWs of 0.408 (HIV+) and 0.333 (HIV-) during active disease. Our results imply that the majority of TB-related morbidity occurs post-treatment ., Conclusion: TB-related DALYs are greatly underestimated by overlooking post-TB disability. The total disability burden of TB is likely undervalued by both GBD estimates and economic evaluations of interventions, particularly those aimed at early diagnosis and prevention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Rapid molecular methods such as the line probe assay (LPA) and Xpert® MTB/RIF assay (Xpert) have been recommended by the World Health Organization for drug-resistant tuberculosis (DR-TB) diagnosis. We conducted an interventional trial in DR-TB reference centers in Brazil to evaluate the impact of the use of LPA and Xpert., Methods: Patients with DR-TB were eligible if their drug susceptibility testing results were available to the treating physician at the time of consultation. The standard reference MGITTM 960 was compared with Xpert (arm 1) and LPA (arm 2). Effectiveness was considered as the start of the appropriate TB regimen that matched drug susceptibility testing (DST) and the proportions of culture conversion and favorable treatment outcomes after 6 months., Results: A higher rate of empirical treatment was observed with MGIT alone than with the Xpert assay (97.0% vs. 45.0%) and LPA (98.2% vs. 67.5%). Patients started appropriate TB treatment more quickly than those in the MGIT group (median 15.0 vs. 40.5 days; p<0.01) in arm 1. Compared to the MGIT group, culture conversion after 6 months was higher for Xpert in arm 1 (90.9% vs. 79.3%, p=0.39) and LPA in arm 2 (80.0% vs. 83.0%, p=0.81)., Conclusions: In the Xpert arm, there was a significant reduction in days to the start of appropriate anti-TB treatment and a trend towards greater culture conversion in the sixth month.

Background: Inclusive universal health coverage requires access to quality health care without financial barriers. Receipt of palliative care after advanced cancer diagnosis might reduce household poverty, but evidence from low-income and middle-income settings is sparse., Methods: In this prospective study, the primary objective was to investigate total household costs of cancer-related health care after a diagnosis of advanced cancer, with and without the receipt of palliative care. Households comprising patients and their unpaid family caregiver were recruited into a cohort study at Queen Elizabeth Central Hospital in Malawi, between Jan 16 and July 31, 2019. Costs of cancer-related health-care use (including palliative care) and health-related quality-of-life were recorded over 6 months. Regression analysis explored associations between receipt of palliative care and total household costs on health care as a proportion of household income. Catastrophic costs, defined as 20% or more of total household income, sale of assets and loans taken out (dissaving), and their association with palliative care were computed., Findings: We recruited 150 households. At 6 months, data from 89 (59%) of 150 households were available, comprising 89 patients (median age 50 years, 79% female) and 64 caregivers (median age 40 years, 73% female). Patients in 55 (37%) of the 150 households died and six (4%) were lost to follow-up. 19 (21%) of 89 households received palliative care. Catastrophic costs were experienced by nine (47%) of 19 households who received palliative care versus 48 (69%) of 70 households who did not (relative risk 0·69, 95% CI 0·42 to 1·14, p=0·109). Palliative care was associated with substantially reduced dissaving (median US$11, IQR 0 to 30 vs $34, 14 to 75; p=0·005). The mean difference in total household costs on cancer-related health care with receipt of palliative care was -36% (95% CI -94 to 594; p=0·707)., Interpretation: Vulnerable households in low-income countries are subject to catastrophic health-related costs following a diagnosis of advanced cancer. Palliative care might result in reduced dissaving in these households. Further consideration of the economic benefits of palliative care is justified., Funding: Wellcome Trust; National Institute for Health Research; and EMMS International., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Many tuberculosis (TB) patients incur catastrophic costs. Active case finding (ACF) may have socio-protective properties that could contribute to the WHO End TB Strategy target of zero TB-affected families suffering catastrophic costs, but available evidence remains limited. This study measured catastrophic cost incurrence and socioeconomic impact of an episode of TB and compared those socioeconomic burdens in patients detected by ACF versus passive case finding (PCF)., Methods: This cross-sectional study fielded a longitudinal adaptation of the WHO TB patient cost survey alongside an ACF intervention from March 2018 to March 2019. The study was conducted in six intervention (ACF) districts and six comparison (PCF) districts of Ho Chi Minh City, Viet Nam. Fifty-two TB patients detected through ACF and 46 TB patients in the PCF cohort were surveyed within two weeks of treatment initiation, at the end of the intensive phase of treatment, and after treatment concluded. The survey measured income, direct and indirect costs, and socioeconomic impact based on which we calculated catastrophic cost as the primary outcome. Local currency was converted into US$ using the average exchange rates reported by OANDA for the study period (VNĐ1 = US$0.0000436, 2018-2019). We fitted logistic regressions for comparisons between the ACF and PCF cohorts as the primary exposures and used generalized estimating equations to adjust for autocorrelation., Results: ACF patients were poorer than PCF patients (multidimensional poverty ratio: 16 % vs. 7 %; p = 0.033), but incurred lower median pre-treatment costs (US$18 vs. US$80; p < 0.001) and lower median total costs (US$279 vs. US$894; p < 0.001). Fewer ACF patients incurred catastrophic costs (15 % vs. 30 %) and had lower odds of catastrophic cost (aOR = 0.17; 95 % CI: [0.05, 0.67]; p = 0.011), especially during the intensive phase (OR = 0.32; 95 % CI: [0.12, 0.90]; p = 0.030). ACF patient experienced less social exclusion (OR = 0.41; 95 % CI: [0.18, 0.91]; p = 0.030), but more often resorted to financial coping mechanisms (OR = 5.12; 95 % CI: [1.73, 15.14]; p = 0.003)., Conclusions: ACF can be effective in reaching vulnerable populations and mitigating the socioeconomic burden of TB, and can contribute to achieving the WHO End TB Strategy goals. Nevertheless, as TB remains a catastrophic life event, social protection efforts must extend beyond ACF., (© 2021. The Author(s).)

Objective: Psychosocial and economic (socioeconomic) barriers, including poverty, stigma and catastrophic costs, impede access to tuberculosis (TB) services in low-income countries. We aimed to characterise the socioeconomic barriers and facilitators of accessing TB services in Nepal to inform the design of a locally appropriate socioeconomic support intervention for TB-affected households., Design: From August 2018 to July 2019, we conducted an exploratory qualitative study consisting of semistructured focus group discussions (FGDs) with purposively selected multisectoral stakeholders. The data were managed in NVivo V.12, coded by consensus and analysed thematically., Setting: The study was conducted in four districts, Makwanpur, Chitwan, Dhanusha and Mahottari, which have a high prevalence of poverty and TB., Participants: Seven FGDs were conducted with 54 in-country stakeholders, grouped by stakeholders, including people with TB (n=21), community stakeholders (n=13) and multidisciplinary TB healthcare professionals (n=20) from the National TB Programme., Results: The perceived socioeconomic barriers to accessing TB services were: inadequate TB knowledge and advocacy; high food and transportation costs; income loss and stigma. The perceived facilitators to accessing TB care and services were: enhanced championing and awareness-raising about TB and TB services; social protection including health insurance; cash, vouchers and/or nutritional allowance to cover food and travel costs; and psychosocial support and counselling integrated with existing adherence counselling from the National TB Programme., Conclusion: These results suggest that support interventions that integrate TB education, psychosocial counselling and expand on existing cash transfer schemes would be locally appropriate and could address the socioeconomic barriers to accessing and engaging with TB services faced by TB-affected households in Nepal. The findings have been used to inform the design of a socioeconomic support intervention for TB-affected households. The acceptability, feasibility and impact of this intervention on TB-related costs, stigma and TB treatment outcomes, is now being evaluated in a pilot implementation study in Nepal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD)., Methods and Findings: In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon., Conclusions: DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment., Trial Registration: clinicaltrials.gov NCT03519425., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MP is a member of the Editorial Board of PLOS Medicine.

Competing Interests: TW is supported by grants from the Wellcome Trust (209075/Z/17/Z and Joint Global Health Trials, MR/V004832/1), the Medical Research Council (MRC), Department for International Development, the Academy of Medical Sciences, and the Swedish Health Research Council. LEC is supported by grants from the European and Developing Countries Clinical Trial Partnership (EDCTP, DRIA2014-309), the MRC, the TB REACH Initiative of the Stop TB Partnership (STBP/TBREACH//GSA/W5-07), the Wellcome Trust (contract pending), and the Health Protection Research Unit for Emerging and Zoonotic Infections. PM is funded by the Wellcome Trust (206575/Z/17/Z). KAM works on projects funded with UK aid from the UK Government. SBS is supported by the National Institute for Health Research Global Health Research Unit on Lung Health and TB in Africa at the Liverpool School of Tropical Medicine (16/136/35) and the Foreign, Commonwealth and Development Office Research Programme Consortium Leaving no-one behind, transforming gendered pathways to health for TB (LIGHT PO8614). All authors declare no competing interests.

Background: The prevalence of diseases other than TB detected during chest X-ray (CXR) screening is unknown in sub-Saharan Africa. This represents a missed opportunity for identification and treatment of potentially significant disease. Our aim was to describe and quantify non-TB abnormalities identified by TB-focused CXR screening during the 2016 Kenya National TB Prevalence Survey., Methods: We reviewed a random sample of 1140 adult (≥15 years) CXRs classified as 'abnormal, suggestive of TB' or 'abnormal other' during field interpretation from the TB prevalence survey. Each image was read (blinded to field classification and study radiologist read) by two expert radiologists, with images classified into one of four major anatomical categories and primary radiological findings. A third reader resolved discrepancies. Prevalence and 95% CIs of abnormalities diagnosis were estimated., Findings: Cardiomegaly was the most common non-TB abnormality at 259 out of 1123 (23.1%, 95% CI 20.6% to 25.6%), while cardiomegaly with features of cardiac failure occurred in 17 out of 1123 (1.5%, 95% CI 0.9% to 2.4%). We also identified chronic pulmonary pathology including suspected COPD in 3.2% (95% CI 2.3% to 4.4%) and non-specific patterns in 4.6% (95% CI 3.5% to 6.0%). Prevalence of active-TB and severe post-TB lung changes was 3.6% (95% CI 2.6% to 4.8%) and 1.4% (95% CI 0.8% to 2.3%), respectively., Interpretation: Based on radiological findings, we identified a wide variety of non-TB abnormalities during population-based TB screening. TB prevalence surveys and active case finding activities using mass CXR offer an opportunity to integrate disease screening efforts., Funding: National Institute for Health Research (IMPALA-grant reference 16/136/35)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Mitigating the socioeconomic impact of tuberculosis (TB) is key to the WHO End TB Strategy. However, little known about socioeconomic well-being beyond TB-treatment completion. In this mixed-methods study, we describe socioeconomic outcomes after TB-disease in urban Blantyre, Malawi, and explore pathways and barriers to financial recovery., Methods: Adults ≥15 years successfully completing treatment for a first episode of pulmonary TB under the National TB Control Programme were prospectively followed up for 12 months. Socioeconomic, income, occupation, health seeking and cost data were collected. Determinants and impacts of ongoing financial hardship were explored through illness narrative interviews with purposively selected participants., Results: 405 participants were recruited from February 2016 to April 2017. Median age was 35 years (IQR: 28-41), 67.9% (275/405) were male, and 60.6% (244/405) were HIV-positive. Employment and incomes were lowest at TB-treatment completion, with limited recovery in the following year: fewer people were in paid work (63.0% (232/368) vs 72.4% (293/405), p=0.006), median incomes were lower (US$44.13 (IQR: US$0-US$106.15) vs US$72.20 (IQR: US$26.71-US$173.29), p<0.001), and more patients were living in poverty (earning

GeneXpert-based testing with Xpert MTB/RIF or Ultra assays is essential for tuberculosis diagnosis. However, testing may be affected by cartridge and staff shortages. More efficient testing strategies could help, especially during the coronavirus disease pandemic. We searched the literature to systematically review whether GeneXpert-based testing of pooled sputum samples achieves sensitivity and specificity similar to testing individual samples; this method could potentially save time and preserve the limited supply of cartridges. From 6 publications, we found 2-sample pools using Xpert MTB/RIF had 87.5% and 96.0% sensitivity (average sensitivity 94%; 95% CI 89.0%-98.0%) (2 studies). Four-sample pools averaged 91% sensitivity with Xpert MTB/RIF (2 studies) and 98% with Ultra (2 studies); combining >4 samples resulted in lower sensitivity. Two studies reported that pooling achieved 99%-100% specificity and 27%-31% in cartridge savings. Our results show that pooling may improve efficiency of GeneXpert-based testing.

Background: Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities, but implementation is challenging. We investigated completion of recommended TB screening steps in Blantyre, Malawi., Methods: A prospective cohort recruited adult outpatients attending Bangwe primary clinic. Entry interviews were linked to exit interviews. The proportion of participants progressing through each step of the diagnostic pathway were estimated. Factors associated with request for sputum were investigated using multivariable logistic regression., Results: Of 5442 clinic attendances 2397 (44%) had exit interviews. In clinically indicated participants (n = 445) 256 (57.5%) were asked about cough, 36 (8.1%) were asked for sputum, 21 (4.7%) gave sputum and 1 (0.2%) received same-day results. Significant associations with request for sputum were: any TB symptom (aOR:3.20, 95%CI:2.02-5.06), increasing age (aOR:1.02, 95%CI:1.01-1.04 per year) and for HIV-negative participants only, a history of previous TB (aOR:3.37, 95%CI:1.45-7.81). Numbers requiring sputum tests (26/day) outnumbered diagnostic capacity (8-12/day)., Conclusions: Patients were lost at every stage of the TB care cascade, with same day sputum submission following all steps of the diagnosis cascade achieved in only 4.7% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput screening interventions, such as digital CXR, that can achieve same-day TB diagnosis are urgently needed to meet WHO End TB goals.

Background: In order to end tuberculosis (TB), it is necessary to expand coverage of TB care services, including systematic screening initiatives. However, more evidence is needed for groups among whom systematic screening is only conditionally recommended by the World Health Organization. This study evaluated concurrent screening in multiple target groups using community health workers (CHW)., Methods: In our two-year intervention study lasting from October 2017 to September 2019, CHWs in six districts of Ho Chi Minh City, Viet Nam verbally screened three urban priority groups: (1) household TB contacts; (2) close TB contacts; and (3) residents of urban priority areas without clear documented exposure to TB including hotspots, boarding homes and urban slums. Eligible persons were referred for further screening with chest radiography and follow-on testing with the Xpert MTB/RIF assay. Symptomatic individuals with normal or without radiography results were tested on smear microscopy. We described the TB care cascade and characteristics for each priority group, and calculated yield and number needed to screen. Subsequently, we fitted a mixed-effect logistic regression to identify the association of these target groups and secondary patient covariates with TB treatment initiation., Results: We verbally screened 321 020 people including 24 232 household contacts, 3182 social and close contacts and 293 606 residents of urban priority areas. This resulted in 1138 persons treated for TB, of whom 85 were household contacts, 39 were close contacts and 1014 belonged to urban priority area residents. The yield of active TB in these groups was 351, 1226 and 345 per 100 000, respectively, corresponding to numbers needed to screen of 285, 82 and 290. The fitted model showed that close contacts [adjusted odds ratio (aOR) = 2.07; 95% CI: 1.38-3.11; P < 0.001] and urban priority area residents (aOR = 2.18; 95% CI: 1.69-2.79; P < 0.001) had a greater risk of active TB than household contacts., Conclusions: The study detected a large number of unreached persons with TB, but most of them were not among persons in contact with an index patient. Therefore, while programs should continue to optimize screening in contacts, to close the detection gap in high TB burden settings such as Viet Nam, coverage must be expanded to persons without documented exposure such as residents in hotspots, boarding homes and urban slums.

Introduction: Patients with tuberculosis (TB) symptoms have high prevalence of HIV, and should be prioritised for HIV testing., Methods: In a prospective cohort study in Bangwe primary care clinic, Blantyre, Malawi, all adults (18 years or older) presenting with an acute illness were screened for TB symptoms (cough, fever, night sweats, weight loss). Demographic characteristics were linked to exit interview by fingerprint bioidentification. Multivariable logistic regression models were constructed to estimate the proportion completing same-visit HIV testing, comparing between those with and without TB symptoms., Results: There were 5427 adult attendees between 21/5/2018 and 6/9/2018. Exit interviews were performed for 2402 (44%). 276 patients were excluded from the analysis, being already on antiretroviral therapy (ART). Presentation with any TB symptom was common for men (54.6%) and women (57.4%). Overall 27.6% (585/ 2121) attenders reported being offered testing and 21.5% (455/2121) completed provider-initiated HIV testing and counselling (PITC) and received results. The proportions offered testing were similar among participants with and without TB symptoms (any TB symptom: 29.0% vs. 25.7%). This was consistent for each individual symptom; cough, weight loss, fever and night sweats. Multivariable regression models indicated men, younger adults and participants who had previously tested were more likely to complete PITC than women, older adults and those who had never previously tested., Conclusions: Same-visit completion of HIV testing was suboptimal, especially among groups known to have high prevalence of undiagnosed HIV. As countries approach universal coverage of ART, identifying and prioritising currently underserved groups for HIV testing will be essential., Competing Interests: The authors have declared that no competing interests exist.

Background: Implementation of an effective Tuberculosis Routine Surveillance System in low-income countries like Tanzania is problematic, despite being an essential tool for the detection and effective monitoring of drug resistant tuberculosis. Long delays in specimen transportation from the facilities to reference laboratory and results dissemination back to the health facilities, result in poor patient management, particularly where multidrug-resistant tuberculosis disease is present., Methods: Following a detailed qualitative study, a pilot intervention of a revised Tuberculosis Routine Surveillance System was implemented in Mwanza region, Tanzania. This included the use of rapid molecular methods for the detection of both tuberculosis and drug resistance using Xpert MTB/RIF in some Mwanza sites, the use of Xpert MTB/RIF and Line Probe Assay at the Central Tuberculosis Reference Laboratory, a revised communication strategy and interventions to address the issue of poor form completion. A before and after comparison of the intervention on the number of drug resistant tuberculosis cases identified and the time taken for results feedback to the requesting site was reported., Results: The revised system for previously treated cases tested at the Central Reference Laboratory was able to obtain the following findings; the number of cases tested increased from 75 in 2016 to 185 in 2017. The times for specimen transportation from health facilities to the reference laboratory were reduced by 22% (from 9 to 7 days). The median time for the district to receive results was reduced by 36% (from 11 to 7 days). Overall the number of drug resistant tuberculosis cases starting treatment increased by 67% (from 12 to 20)., Conclusion: Detection of drug resistance could significantly be enhanced, and delays reduced by introduction of new technologies and improved routine surveillance system, including better communication using mobile applications such as 'WhatsApp' and close follow-ups. A larger scale study is now merited to ascertain if these benefits are robust across different contexts.

Background:  WHO's 2015 End TB Strategy advocates social and economic (socioeconomic) support for TB-affected households to improve TB control. However, evidence concerning socioeconomic support for TB-affected households remains limited, especially in low-income countries. Protocol:  This mixed-methods study in Nepal will: evaluate the socioeconomic impact of accessing TB diagnosis and care (Project 1); and create a shortlist of feasible, locally-appropriate interventions to mitigate this impact (Project 2). The study will be conducted in the Chitwan, Mahottari, Makawanpur, and Dhanusha districts of Nepal, which have frequent TB and poverty. The study population will include: approximately 200 people with TB (Cases) starting TB treatment with Nepal's National TB Program and 100 randomly-selected people without TB (Controls) in the same sites (Project 1); and approximately 40 key in-country stakeholders from Nepal including people with TB, community leaders, and TB healthcare professionals (Project 2). During Project 1, visits will be made to people with TB's households during months 3 and 6 of TB treatment, and a single visit made to Control households. During visits, participants will be asked about: TB-related costs (if receiving treatment), food insecurity, stigma; TB-related knowledge; household poverty level; social capital; and quality of life. During Project 2, stakeholders will be invited to participate in: a survey and focus group discussion (FGD) to characterise socioeconomic impact, barriers and facilitators to accessing and engaging with TB care in Nepal; and a one-day workshop to review FGD findings and suggest interventions to mitigate the barriers identified. Ethics and dissemination:  The study has received ethical approval. Results will be disseminated through scientific meetings, open access publications, and a national workshop in Nepal.  Conclusions:  This research will strengthen understanding of the socioeconomic impact of TB in Nepal and generate a shortlist of feasible and locally-appropriate socioeconomic interventions for TB-affected households for trial evaluation., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Dixit K et al.)

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI., Methods: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022., Findings: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84)., Interpretation: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients., Funding: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)