Search

Abstract Background Several FIDELIS projects (Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB) in Tanzania were conducted by the National Tuberculosis and Leprosy Programme (NTLP) during the years 2004-2008 to strengthen diagnostic and treatment services. These projects collected information on treatment delay and some of it was available for research purposes. With this database our objective was to assess the duration and determinants of treatment delay among new smear positive pulmonary tuberculosis (TB) patients in FIDELIS projects, and to compare delay according to provider visited prior to diagnosis. Methods Treatment delay among new smear positive TB patients was recorded for each patient at treatment initiation and this information was available and fairly complete in 6 out of 57 districts with FIDELIS projects enrolling patients between 2004 and 2007; other districts had discarded their forms at the time of analysis. It was analysed as a cross sectional study. Results We included 1161 cases, 10% of all patients recruited in the FIDELIS projects in Tanzania. Median delay was 12 weeks. The median duration of cough, weight loss and haemoptysis was 12, 8 and 3 weeks, respectively. Compared to Hai district Handeni had patients with longer delays and Mbozi had patients with shorter delays. Urban and rural patients reported similar delays. Patients aged 15-24 years and patients of 65 years or older had longer delays. Patients reporting contact with traditional healers before diagnosis had a median delay of 15 weeks compared to 12 weeks among those who did not. Patients with dyspnoea and with diarrhoea had longer delays. Conclusion In this patient sample in Tanzania half of the new smear positive pulmonary tuberculosis patients had a treatment delay longer than 12 weeks. Delay was similar in men and women and among urban and rural patients, but longer in the young and older age groups. Patients using traditional healers had a 25% longer median delay.

BackgroundThe STREAM trial demonstrated that a 9-11-month "short" regimen had non-inferior efficacy and comparable safety to a 20+ month "long" regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation.MethodsFirstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses.ResultsCure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3-4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide.ConclusionFive alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

ObjectiveTo investigate cost changes for health systems and participants, resulting from switching to short treatment regimens for multidrug-resistant (MDR) tuberculosis.MethodsWe compared the costs to health systems and participants of long (20 to 22 months) and short (9 to 11 months) MDR tuberculosis regimens in Ethiopia and South Africa. Cost data were collected from participants in the STREAM phase-III randomized controlled trial and we estimated health-system costs using bottom-up and top-down approaches. A cost-effectiveness analysis was performed by calculating the incremental cost per unfavourable outcome avoided.FindingsHealth-care costs per participant in South Africa were 8340.7 United States dollars (US$) with the long and US$ 6618.0 with the short regimen; in Ethiopia, they were US$ 6096.6 and US$ 4552.3, respectively. The largest component of the saving was medication costs in South Africa (67%; US$ 1157.0 of total US$ 1722.8) and social support costs in Ethiopia (35%, US$ 545.2 of total US$ 1544.3). In Ethiopia, trial participants on the short regimen reported lower expenditure for supplementary food (mean reduction per participant: US$ 225.5) and increased working hours (i.e. 667 additional hours over 132 weeks). The probability that the short regimen was cost-effective was greater than 95% when the value placed on avoiding an unfavourable outcome was less than US$ 19 000 in Ethiopia and less than US$ 14 500 in South Africa.ConclusionThe short MDR tuberculosis treatment regimen was associated with a substantial reduction in health-system costs and a lower financial burden for participants.

BackgroundIn contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection.Methods/designSTREAM is a multi-centre randomized trial of non-inferiority design comparing a nine-month regimen to the treatment currently recommended by the World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites.DiscussionThe results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM trial together with data from ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB.Trial registrationThis trial was registered with clincaltrials.gov (registration number: ISRCTN78372190) on 14 October 2010.

Tuberculosis was declared a global public health emergency in 1993. In 2003, only 45% of the world's estimated new smear-positive tuberculosis cases were detected-well below the 70% global case detection target set by the World Health Organization.The FIDELIS (Fund for Innovative DOTS Expansion Through Local Initiatives to Stop TB) initiative is a new global disease control initiative that has been developed to rapidly assess and implement innovative approaches to increase tuberculosis case detection. To date, 32 projects have been approved-covering approximately 378 million people in 13 countries-24 (75%) of which are in the world's 6 highest-burden countries. A wide range of target populations and interventions have been incorporated into successful FIDELIS projects. The FIDELIS initiative may serve as a model to discover best practices to address other urgent global public health problems. [ABSTRACT FROM AUTHOR]

Examines the impact of prenatal diagnosis and pregnancy termination on overall infant mortality in Canada. Implications of selective pregnancy termination for reducing infant deaths; Relative risk percentage of pregnancy terminations; Decrease in congenital anomaly related infant mortality.

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.)

Background: Stage 1 of the STREAM trial demonstrated that the 9 month (Short) regimen developed in Bangladesh was non-inferior to the 20 month (Long) 2011 World Health Organization recommended regimen. We assess the association between HIV infection and radiographic manifestations of tuberculosis and factors associated with time to culture conversion in Stage 1 of the STREAM trial., Methods: Reading of chest radiographs was undertaken independently by two clinicians, and films with discordant reading were read by a third reader. Recording of abnormal opacity of the lung parenchyma included location (right upper, right lower, left upper, and left lower) and extent of disease (minimal, moderately-advanced, and far advanced). Time to culture conversion was defined as the number of days from initiation of treatment to the first of two consecutive negative culture results, and compared using the log-rank test, stratified by country. Cox proportional hazards models, stratified by country and adjusted for HIV status, were used to identify factors associated with culture conversion., Results: Of the 364 participants, all but one had an abnormal chest X-ray: 347 (95%) had opacities over upper lung fields, 318 (87%) had opacities over lower lung fields, 124 (34%) had far advanced pulmonary involvement, and 281 (77%) had cavitation. There was no significant association between HIV and locations of lung parenchymal opacities, extent of opacities, the presence of cavitation, and location of cavitation. Participants infected with HIV were significantly less likely to have the highest positivity grade (3+) of sputum culture (p = 0.035) as compared to participants not infected with HIV. Cavitation was significantly associated with high smear positivity grades (p < 0.001) and high culture positivity grades (p = 0.004) among all participants. Co-infection with HIV was associated with a shorter time to culture conversion (hazard ratio 1.59, 95% CI 1.05-2.40)., Conclusions: Radiographic manifestations of tuberculosis among the HIV-infected in the era of anti-retroviral therapy may not differ from that among those who were not infected with HIV. Radiographic manifestations were not consistently associated with time to culture conversion, perhaps indicating that the Short regimen is sufficiently powerful in achieving sputum conversion across the spectrum of radiographic pulmonary involvements., Trial Registration: ISRCTN ISRCTN78372190. Registered 14/10/2010. The date of first registration 10/02/2016., (© 2024. The Author(s).)

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: Design and implementation of multi-country clinical trials for multidrug-resistant tuberculosis (MDR-TB) are complex for several reasons, including trial duration, varying levels of experience and infrastructure across settings, and different regulatory requirements. STREAM was an MDR-TB clinical trial that recruited over 1000 participants. We documented challenges and best practices/lessons learned from the site perspective to improve implementation of future trials., Methods: We conducted a voluntary survey of trial staff at all sites to obtain information on challenges encountered and best practices/lessons learned from implementation of the STREAM trial. Respondents were asked to identify substantive aspects of trial implementation from a list that included: trial administration, laboratory strengthening/infrastructure, pharmacy and supply chain management, community engagement, regulatory and ethics requirements, health economics, and other (respondent designated) about which a practical guide would be useful to improve future trial implementation. For each aspect of trial implementation selected, respondents were asked to report challenges and best practices/lessons learned during STREAM. Lastly, respondents were asked to list up to three things they would do differently when implementing future trials. Summary statistics were generated for quantitative data and thematic analysis was undertaken for qualitative data., Results: Of 67 responses received from 13 of 15 sites, 47 (70%) were included in the analyses, after excluding duplicate or incomplete responses. Approximately half the respondents were investigators or trial coordinators. The top three aspects of trial implementation identified for a best practices/lessons learned practical guide to improve future trial implementation were: trial administration, community engagement, and laboratory strengthening/infrastructure. For both challenges and best practices/lessons learned, three common themes were identified across different aspects of trial implementation. Investment in capacity building and ongoing monitoring; investment in infrastructure and well-designed trial processes; and communication and coordination between staff and meaningful engagement of stakeholders were all thought to be critical to successful trial implementation., Conclusions: Existing practices for clinical trial implementation should be reevaluated. Sponsors should consider the local context and the need to increase upfront investment in the cross-cutting thematic areas identified to improve trial implementation., (© 2023. The Author(s).)

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.)

BACKGROUND: STREAM (Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) Stage 1 was a randomised trial of a Short (9-month) regimen for rifampicin-resistant TB (RR-TB). QT or QTcF prolongation ≥500 ms occurred in 31 (11%) of 282 Short regimen participants. The frequent ECG monitoring employed might be challenging for treatment programmes. This analysis aimed to determine whether those at higher risk of severe QT prolongation could be identified early for more targeted monitoring. METHODS: Data from the first month of treatment were used to investigate whether participants were at risk of developing QT/QTcF ≥500 ms. QTcF increases from baseline at different time points were examined. Absolute QTcF measurements were categorised in 5 ms increments at each time-point. The most discriminating time points and QTcF cut-offs were combined to optimise sensitivity and specificity. RESULTS: Absolute QTcF values were more discriminating than magnitude of increase from baseline. More participants who developed QT/QTcF ≥500 ms had a QTcF of respectively ≥425 ms and ≥430 ms at 4 h and Week 3 ( P < 0.05) than those who did not. By combining QTcF values ≥425 ms at 4 h and ≥430 ms at Week 3, we identified high-risk participants with 97% sensitivity and 99% negative predictive value. CONCLUSION: Reduced ECG monitoring may be possible for many Short regimen participants.

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen. METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event. RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model. CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen.

Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial's design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally.Trial registration: ISRCTN ISRCTN18148631 . Registered 10 February 2016., (© 2022. The Author(s).)

BACKGROUND: STREAM (Standardized Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) Stage 1 demonstrated non-inferior efficacy of a shortened regimen (the Short regimen) for rifampicin-resistant TB (RR-TB) compared to the contemporaneous WHO-recommended regimen. This regimen included moxifloxacin and clofazimine, known to cause QT prolongation, and severe prolongation was more common on the Short regimen. Here we investigate risk factors for QT prolongation with the Short regimen. METHODS: Data from patients prescribed the Short regimen ( n = 282) were analysed to identify risk factors for severe QT prolongation (QT/QTcF ≥500 ms or ≥60 ms increase in QTcF from baseline). RESULTS: Of the 282 patients on the Short regimen, 94 (33.3%) developed severe QT prolongation: 31 QT/QTcF ≥500 ms; 92 experienced ≥60 ms QTcF increase from baseline. The median time to QT/QTcF ≥500 ms was 20 weeks (IQR 8-28), and the time to ≥60 ms increase from baseline was 18 weeks (IQR 8-28). Prolongation ≥500 ms was most frequent in patients from Mongolia (10/22, 45.5%) compared with 3.5-11.9% at other sites, P < 0.001. Higher baseline QTcF increased risk of prolongation to ≥500 ms (QTcF ≥400 ms: OR 5.99, 95% CI 2.04-17.62). CONCLUSION: One third of patients on the Short regimen developed severe QT prolongation. QT/QTcF ≥500 ms was more common in patients from Mongolia and in those with a higher baseline QTcF, which may have implications for implementation of treatment.

Real-time operational research can be defined as research on strategies or interventions to assess if they are feasible, working as planned, scalable and effective. The research involves primary data collection, periodic analysis during the conduct of the study and dissemination of the findings to policy makers for timely action. This paper aims to illustrate the use of real-time operational research and discuss how to make it happen. Four case studies are presented from the field of tuberculosis. These include (i) mis-registration of recurrent tuberculosis in Malawi; (ii) HIV testing and adjunctive cotrimoxazole to reduce mortality in TB patients in Malawi; (iii) screening TB patients for diabetes mellitus in India; and (iv) mitigating the impact of COVID-19 on TB case detection in capital cities in Kenya, Malawi and Zimbabwe. The important ingredients of real-time operational research are sound ethics; relevant research; adherence to international standards of conducting and reporting on research; consideration of comparison groups; timely data collection; dissemination to key stakeholders; capacity building; and funding. Operational research can improve the delivery of established health interventions and ensure the deployment of new interventions as they become available, irrespective of diseases. This is particularly important when public health emergencies, including pandemics, threaten health services.

When COVID-19 was declared a pandemic, there was concern that TB and HIV services in Zimbabwe would be severely affected. We set up real-time monthly surveillance of TB and HIV activities in 10 health facilities in Harare to capture trends in TB case detection, TB treatment outcomes and HIV testing and use these data to facilitate corrective action. Aggregate data were collected monthly during the COVID-19 period (March 2020-February 2021) using EpiCollect5 and compared with monthly data extracted for the pre-COVID-19 period (March 2019-February 2020). Monthly reports were sent to program directors. During the COVID-19 period, there was a decrease in persons with presumptive pulmonary TB (40.6%), in patients registered for TB treatment (33.7%) and in individuals tested for HIV (62.8%). The HIV testing decline improved in the second 6 months of the COVID-19 period. However, TB case finding deteriorated further, associated with expiry of diagnostic reagents. During the COVID-19 period, TB treatment success decreased from 80.9 to 69.3%, and referral of HIV-positive persons to antiretroviral therapy decreased from 95.7 to 91.7%. Declining trends in TB and HIV case detection and TB treatment outcomes were not fully redressed despite real-time monthly surveillance. More support is needed to transform this useful information into action.

When the COVID-19 pandemic was announced in March 2020, there was concern that TB and HIV programme services in Malawi would be severely affected. We set up real-time monthly surveillance of TB and HIV activities in eight health facilities in Lilongwe to see if it was possible to counteract the anticipated negative impact on TB case detection and treatment and HIV testing. Aggregate data were collected monthly during the COVID-19 period (March 2020-February 2021) using an EpiCollect5 application and compared with monthly data collected during the pre-COVID-19 period (March 2019-February 2020); these reports were sent monthly to programme directors. During COVID-19, there was an overall decrease in persons presenting with presumptive pulmonary TB (45.6%), in patients registered for TB treatment (19.1%), and in individuals tested for HIV (39.0%). For presumptive TB, children and females were more affected, but for HIV testing, adults and males were more affected. During COVID-19, the TB treatment success rate (96.1% in pre-COVID-19 and 96.0% during COVID-19 period) and referral of HIV-positive persons to antiretroviral therapy (100% in pre-COVID-19 and 98.6% during COVID-19 period) remained high and largely unchanged. Declining trends in TB and HIV case detection were not redressed despite real-time monthly surveillance.

There was concern that the COVID-19 pandemic would adversely affect TB and HIV programme services in Kenya. We set up real-time monthly surveillance of TB and HIV activities in 18 health facilities in Nairobi so that interventions could be implemented to counteract anticipated declining trends. Aggregate data were collected and reported monthly to programme heads during the COVID-19 period (March 2020-February 2021) using EpiCollect5 and compared with monthly data collected during the pre-COVID period (March 2019-February 2020). During the COVID-19 period, there was an overall decrease in people with presumptive pulmonary TB (31.2%), diagnosed and registered with TB (28.0%) and in those tested for HIV (50.5%). Interventions to improve TB case detection and HIV testing were implemented from August 2020 and were associated with improvements in all parameters during the second six months of the COVID-19 period. During the COVID-19 period, there were small increases in TB treatment success (65.0% to 67.0%) and referral of HIV-positive persons to antiretroviral therapy (91.2% to 92.9%): this was more apparent in the second six months after interventions were implemented. Programmatic interventions were associated with improved case detection and treatment outcomes during the COVID-19 period, suggesting that monthly real-time surveillance is useful during unprecedented events.

Background: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011., Methods: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority., Results: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively., Conclusions: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.)., (Copyright © 2019 Massachusetts Medical Society.)

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

Setting: Three projects of the Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB. Objectives: To assess unfavourable treatment outcomes (UTOs), including failure, died, loss to follow-up (LTFU), transferred out and unknown outcome, and to identify risk factors associated with UTOs. Design: This was a cross-sectional study using routine programme data. Results: Of 30 277 new smear-positive tuberculosis (TB) patients, 4261 (14.1%) had UTOs: 2048 (6.8%) LTFU, 1418 (4.7%) transferred out, 390 (1.3%) died, 340 (1.1%) failed and 65 (0.2%) had an unknown outcome. Risk factors for LTFU (including LTFU, transfer out and unknown outcome) were residing in Anhui, age > 55 years, service delay > 10 days, patient delay < 30 days, directly observed treatment (DOT) provided by a family member or others and unknown DOT provider. The outcome of 'died' was associated with residing in Shaanxi, age > 55 years, male sex, patient delay > 30 days and unknown DOT provider. 'Failed' was associated with having unlimited access to health services, patient delay of >30 days and unknown DOT provider. Conclusion: This study highlights the predominance of lost patients among UTOs. Patients with family members or other non-medical DOT providers or unknown DOT providers had a high risk of a UTO. There is an urgent need to address these service-related factors., Competing Interests: Conflicts of interest: none declared.

Setting: The first phase of the Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB (FIDELIS) projects in China started in 2003. Objective: To determine whether the FIDELIS projects contributed to the increased case detection rate for new smear-positive pulmonary tuberculosis (PTB) in China. Methods: We compared the case notification rates (CNRs) in the intervention year with those of the previous year in the FIDELIS areas, then compared the difference between the CNRs of the intervention year and the previous year in the FIDELIS areas with those in the non-FI-DELIS areas within the province. Results: There was an increase in the CNR in the intervention year compared with the previous year for all the project sites. The differences between the CNR in the intervention year and the previous year ranged from 6.4 to 31.1 per 100 000 population in the FIDELIS areas and from 2.9 to 20.4/100 000 in the non-FIDELIS areas. Differences-in-differences analysis shows that the differences in the CNRs in the FIDELIS areas were not statistically significantly different from those in the non-FIDELIS areas ( P = 0.393). Conclusion: The FIDELIS projects may have contributed to the increase in case detection of new smear-positive PTB in China, but the level of evidence is low.

Objective: 1) To assess patient delay among new smear-positive pulmonary tuberculosis (PTB) patients in accessing health services in seven FIDELIS (Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB) projects from 2003 to 2008 in China; 2) to compare treatment delay by province; and 3) to assess factors associated with delay., Method: Records of new smear-positive PTB patients were reviewed. Data sources were the consultation book, laboratory register, patient record, treatment card and the PWLAHS (people with limited access to health services) evaluation form. Data were collected using a standard questionnaire, cross-checked by staff from the sites and by the International Union Against Tuberculosis and Lung Disease (The Union) and analysed by The Union., Results: Of the 75 401 new smear-positive PTB patients included in the study, 63-89% were PWLAHS. The average gross domestic product of the project sites and at national level were respectively US$557 and US$998. The median patient delay was 93 days (range 68-128). Delays were longer among females, older patients, rural residents and PWLAHS. Delayed access to health services was significantly associated with a greater number of symptoms., Conclusion: Patient delay in accessing health care in China was lengthy; TB care and control needs to be improved.

Setting: Programme-based operational research is instrumental for the enhancement of tuberculosis (TB) control. In 2012, the Ethiopian Federal Ministry of Health launched an initiative for capacity building in operational research (OR)., Objective: To develop sustainable capacity for OR in Ethiopia in a multiyear initiative., Design: The initiative was developed in collaboration with regional, national and international experts. Teams representing regions in Ethiopia conducted OR addressing national and regional priorities. To make use of local expertise and increase sustainability, a domestic mentor training programme was included. Existing capacity was enhanced through a competitive grant scheme providing TB researchers with financial and technical support. The Ethiopian Tuberculosis Research Advisory Committee was also supported in its functions. Regional ethics review bodies were strengthened or established where they did not exist., Results: Fifty-two people were trained and conducted 13 OR projects, of which six have been published to date. In addition, eight protocols were supported through grants. Ethics review bodies were strengthened in all regions., Conclusion: The initiative trained participants from all regions and succeeded in the completion of all stages of the OR process. The success of the programme can be attributed to the team approach, 'learning while doing', integrated mentorship programme and strong national ownership.

Setting: Fourteen primary health care facilities in Cape Town, South Africa., Objective: To determine the proportion and characteristics of infectious adult tuberculosis (TB) cases that identify children aged <5 years who qualify for isoniazid preventive therapy (IPT), and to determine the proportion of children who initiate and complete IPT., Design: A retrospective clinical record review conducted as a stratified cluster survey., Results: Of 1179 records of infectious adult cases, 33.3% had no documentation of contacts. Of the remaining 786 records, 525 contacts aged <5 years were identified, representing 0.7 child contacts per infectious adult case. Older age, male, human immunodeficiency virus (HIV) positive, smear-negative and retreatment TB cases were all associated with no documentation of contacts. Of the 525 child contacts identified, less than half were screened for TB, 141 initiated IPT and 19 completed it., Conclusion: Less than 67% of infectious TB case records had documentation of contacts. Younger, female, HIV-negative and new smear-positive TB cases were more likely to have had contacts identified. Less than 14% of children already initiated on IPT completed 6 months of treatment.

Xpert ® MTB/RIF offers new and important possibilities for the diagnosis of sputum smear-negative tuberculosis (TB) and/or rifampicin (RMP) resistance, and many are encouraging rapid and widespread implementation. This simple test can be implemented almost everywhere, and it provides results within a few hours. In low-income countries (LICs), however, its cost, environmental limitations (stable and regular electricity, adequate room temperature) and difficulties involved in supply and maintenance are major obstacles. While it may be suitable for major reference hospitals, operational research is needed to evaluate the test and its additional yield above high-quality smear microscopy and clinical algorithms before its use at the peripheral level. In the meantime, direct microscopy should remain the initial diagnostic test for TB suspects. In most LICs, the prevalence of RMP resistance among new TB patients is very low; an Xpert MTB/RIF result indicating RMP resistance will thus always need confirmation by another test. In a population at high risk of RMP resistance (> 15%), however, the positive predictive value for RMP resistance by Xpert MTB/RIF is high, and identification of RMP resistance is an excellent proxy for multidrug-resistant TB (MDR-TB). The assay should be widely used for this purpose if, and only if, excellent MDR-TB management is available, both for ethical reasons and to reduce the risk of extensively drug-resistant TB.

Setting: Five districts and four cities of Bangladesh., Objective: To study the role of informal health practitioners in delays in initiating tuberculosis (TB) treatment in new smear-positive TB patients., Design: A cross-sectional study of all patients registered within specific projects in Bangladesh using routine records from projects. Definitions were as follows: 1) total delay: duration from onset of symptoms to initiation of treatment; 2) patient delay: onset of symptoms to first visit to any practitioner; and 3) health system delay: first visit to practitioner to treatment initiation., Results: A total of 7280 cases were enrolled. Prolonged delay was calculated as ≥ 5 weeks for patient delay, ≥ 10 weeks for health system delay and ≥ 13 weeks for total delay. Prolonged patient delay was less frequent when patients first consulted informal as compared to qualified health practitioners (30% vs. 68%). Similar figures for prolonged health system delay were respectively 52% and 16%, while those for total delay were 47% and 27%. The differences were statistically significant (P < 0.05)., Conclusion: Patients seeking care from informal practitioners access care more promptly, but have prolonged delays in initiating treatment. Further investigation on how to involve these practitioners in the programme should be evaluated.

Operational research (OR) has become a hot topic at national meetings, international conferences and donor fora. The International Union Against Tuberculosis and Lung Disease (The Union) and Médecins Sans Frontières (MSF) Operational Centre Brussels strongly promote and implement OR with colleagues in low- and middle-income countries. Here we describe how the two organisations define OR, and explain the guiding principles and methodology that underpin the strategy for developing and expanding OR in those countries. We articulate The Union's and MSF's approach to supporting OR, highlighting the main synergies and differences. Then, using the Malawi National Tuberculosis Control Programme as an example, we show how OR can be embedded within tuberculosis control activities, leading to changes in policy and practice at the national level. We discuss the difficult, yet vitally important, issue of capacity building, and share our vision of a new paradigm of product-related training and performance-based OR fellowships as two ways of developing the necessary skills at country level to ensure research is actually performed. Finally, we highlight the need to consider and incorporate into practice the ethical components of OR. This is a key moment to be involved in OR. We are confident that in partnership with interested stakeholders, including the World Health Organization, we can stimulate the implementation of quality, relevant OR as an integral part of health service delivery that in turn will lead to better health for people, particularly for those living in the poorer parts of the world.

Setting: Low-income, high tuberculosis (TB) burden countries., Objective: To compare case finding of new smear-positive pulmonary TB patients in projects funded to apply innovative approaches., Design: Prospective application of innovative approaches to case finding within routine services to determine the numbers of additional cases detected and the cost per additional case detected, according to the type of approach applied., Results: Between 2003 and 2007, 51 FIDELIS projects were implemented in 18 countries; 273,239 cases were reported, of which 85,267 were additional to the number reported in the previous year. The median cost per additional case was US$103. The interventions employed were: 1) social mobilisation and information, education and communication; 2) engagement of the private sector; 3) innovative approaches for microscopy services; 4) enhanced or semi-active case finding; 5) health systems strengthening; and 6) use of incentives. None of these was significantly more likely to detect additional cases or to have a lower cost per additional case than any of the others., Conclusion: While there was a substantial increase in cases detected, at a moderate cost per additional case, we were unable to show that any single intervention had an advantage over the others.

Setting: One peri-urban and four rural districts in Uganda., Objectives: To determine the level of and factors associated with human immunodeficiency virus (HIV) testing among tuberculosis (TB) patients., Design: A cross-sectional study was conducted in five selected districts from August to November 2007. Patients aged > or = 18 years returning for TB treatment refills at facilities offering TB and HIV services were included. Patients were excluded if they were very sick or unable to speak English or any of the local study languages. The outcome was self-reported HIV testing after TB diagnosis, validated using clinic registers., Results: Of 261 patients analysed, 169 (65%) had been tested for HIV following TB diagnosis. In a multivariate analysis, age >45 years (OR 0.27, 95%CI 0.08-0.87), not receiving information about the TB-HIV association (OR 0.35, 95%CI 0.15-0.77), not being offered HIV testing by health provider (OR 0.02, 95%CI 0.006-0.042), dissatisfaction with privacy (OR 2.49, 95%CI 1.11-5.55) and spending 30-60 min at the clinic (OR 4.48, 95%CI 1.66-12.10) significantly influenced level of HIV testing., Conclusion: The level of HIV testing among TB patients was suboptimal, as per policy all patients should be tested. The Uganda Ministry of Health should continue to scale-up HIV testing and other collaborative TB-HIV services at health facilities.