Insights into tuberculosis burden in Karachi, Pakistan: A concurrent adult tuberculosis prevalence and child Mycobacterium tuberculosis infection survey.

Pakistan is one of the five highest tuberculosis burden countries globally. We estimated prevalence of adult bacteriologically confirmed pulmonary tuberculosis and annual risk of Mycobacterium tuberculosis (M. tuberculosis) infection in children aged 2-4 years in Karachi, Pakistan. The survey design enabled exploration of tuberculosis burden by whether the population had previously been exposed to widespread tuberculosis active case-finding (ACF) activities or not. We conducted a concurrent adult pulmonary tuberculosis prevalence survey and a child M. tuberculosis infection survey using interferon gamma release assays in four districts (Korangi, South, West and Central). A cluster-based unequal probability random sampling method was employed with the a priori plan to oversample Korangi district which had been the focus of tuberculosis ACF activities since 2011. We defined Korangi district as the 'prior ACF' zone and remaining districts as the 'no prior ACF' zone. Between March 2018 and May 2019, 34,962 adults (78·5% of those eligible) and 1,505 children (59·9%) participated. Overall estimated prevalence of bacteriologically confirmed pulmonary tuberculosis was 387 cases per 100,000 population (95% CI 276-498) with a prevalence of 421 cases [95% CI 276-567] per 100,000 in the 'no prior ACF' and 279 cases [95% CI 155-403] per 100,000 in the 'prior ACF' zone. We estimated the annual risk of M. tuberculosis infection in children to be 1·1% (95% CI 0·7-1·5) in the 'no prior ACF' zone and 0·6% (95% CI 0·3-1·1) in the 'prior ACF' zone. We observed consistent differences in the population distribution of tuberculosis between the 'prior ACF' and 'no prior' ACF zones with a trend towards lower estimates of burden and M. tuberculosis transmission in the 'prior ACF' zone. A plausible explanation is that intensive ACF activities that have been ongoing in Korangi district for the preceding years have noticeably reduced the burden of tuberculosis and transmission.

Scale-Up of Rifapentine and Isoniazid for Tuberculosis Prevention Among Household Contacts in 2 Urban Centers: An Effectiveness Assessment.

BACKGROUND: Scaling up a shorter preventive regimen such as weekly isoniazid and rifapentine (3HP) for 3 months is a priority for tuberculosis (TB) preventive treatment (TPT). However, there are limited data on 3HP acceptability and completion from high-burden-TB countries. METHODS: We scaled up 3HP from 2018 to 2021 in 2 cities in Pakistan. Eligible participants were household contacts of persons diagnosed with TB disease. Participants were prescribed 3HP after ruling out TB disease. Treatment was self-administered. We analyzed the proportion who completed 3HP. RESULTS: In Karachi, we verbally screened 22 054 household contacts of all ages. Of these, 83% were clinically evaluated and 3% were diagnosed with TB. Of household contacts without TB disease, 59% initiated the 3HP regimen, of which 69% completed treatment. In Peshawar, we verbally screened 6389 household contacts of all ages. We evaluated 95% of household contacts, of whom 2% were diagnosed with TB disease. Among those without TB disease, 65% initiated 3HP, of which 93% completed. Factors associated with higher 3HP completion included residence in Peshawar (risk ratio [RR], 1.35 [95% confidence interval {CI}: 1.32-1.37]), index patient being a male (RR, 1.03 [95% CI: 1.01-1.05]), and index patient with extrapulmonary TB compared to bacteriologically positive pulmonary TB (RR, 1.10 [95% CI: 1.06-1.14]). The age of the index patient was inversely associated with completion. CONCLUSIONS: We observed a high level of acceptance and completion of 3HP in programs implemented in 2 cities in Pakistan, with differences observed across the cities. These findings suggest that 3HP can be effectively scaled up in urban settings to improve the reach and impact of TPT.

Artificial intelligence-reported chest X-ray findings of culture-confirmed pulmonary tuberculosis in people with and without diabetes.

Objectives: We applied computer-aided detection (CAD) software for chest X-ray (CXR) analysis to determine if diabetes affects the radiographic presentation of tuberculosis. Methods: From March 2017-July 2018, we consecutively enrolled adults being evaluated for pulmonary tuberculosis in Karachi, Pakistan. Participants had same-day CXR, two sputum mycobacterial cultures, and random blood glucose measurement. We identified diabetes through self-report or glucose >11.1mMol/L. We included participants with culture-confirmed tuberculosis for this analysis. We used linear regression to estimate associations between CAD-reported tuberculosis abnormality score (range 0.00 to 1.00) and diabetes, adjusting for age, body mass index, sputum smear-status, and prior tuberculosis. We also compared radiographic abnormalities between participants with and without diabetes. Results: 63/272 (23%) of included participants had diabetes. After adjustment, diabetes was associated with higher CAD tuberculosis abnormality scores (p < 0.001). Diabetes was not associated with frequency of CAD-reported radiographic abnormalities apart from cavitary disease; participants with diabetes were more likely to have cavitary disease (74.6% vs 61.2% p = 0.07), particularly non-upper zone cavitary disease (17% vs 7.8%, p = 0.09). Conclusions: CAD analysis of CXR suggests diabetes is associated with more extensive radiographic abnormalities and with greater likelihood of cavities outside upper lung zones.

Drug-Resistant Tuberculosis Treatment Outcomes among Children and Adolescents in Karachi, Pakistan.

BACKGROUND: Significant data gaps exist for children and adolescents with drug-resistant (DR) TB, particularly from high TB incidence settings. This report provides a descriptive analysis of programmatic outcomes among children and adolescents treated for DR-TB in Pakistan. METHODS: We extracted programmatic data from January 2014 to December 2019 from a tertiary care hospital with specialised child and adolescent DR-TB services. A physician assessed all children and adolescents (0-19 years) with presumptive DR-TB, including details of exposure to DR-TB, medical history, radiology, and laboratory results. All patients received treatment as per national DR-TB management guidelines based on WHO recommendations. RESULTS: There were 262 treatment episodes for 247 patients enrolled during the study period. The median age of the cohort was 16 years (IQR: 13-18 years) with 16 (6.1%) children being under 5 years; 237 (90.5%) patients had pulmonary TB. The majority of the patients (194 or 74.1%) experienced a favourable treatment outcome and 26 (9.9%) died while on treatment. Female patients (78.5%) were more likely to experience favourable outcomes compared to males (64.7%; chi-sqr p-value = 0.02). CONCLUSIONS: We found high rates of favourable outcomes in children and adolescents treated for DR-TB. However, there were few young children in our cohort and there was a considerable gender gap that enhanced efforts to diagnose DR-TB in young children and to elucidate and mitigate the reasons for poor outcomes amongst males.

Diagnostic accuracy of a commercially available, deep learning-based chest X-ray interpretation software for detecting culture-confirmed pulmonary tuberculosis.

BACKGROUND: Few evaluations of computer-aided detection (CAD) software for analyzing chest radiographs for tuberculosis have used mycobacterial culture as the reference standard. METHODS: Using data from a prospective study of symptomatic adults and household contacts of persons with tuberculosis who were seeking care in Karachi, we evaluated the accuracy of LUNIT INSIGHT version 3.1.0.0 (LUNIT, South Korea) for detecting pulmonary tuberculosis in the triage use case. The reference standard was liquid culture. We estimated the diagnostic accuracy using three developer-recommended threshold scores for tuberculosis: 15, 30, and 45. RESULTS: A total 269 of 2190 (12%) participants had culture-confirmed pulmonary tuberculosis. LUNIT-reported abnormalities of nodule, consolidation, fibrosis, and pleural effusion were more common with culture-confirmed tuberculosis. At the tuberculosis threshold score of 30, sensitivity and specificity were, respectively, 87.7% [95% CI: 83.2-91.4%] and 64.3% [62.1-66.4%]. Sensitivity was similar at scores of 15, 88.1% [95% CI: 83.6-91.7%] and 45, 86.6% [82.0 - 90.5%]; and specificity was 57.9% [55.7-60.2%] and 69.9% [67.8-71.9%], respectively. Sensitivity was lower for smear-negative disease, and specificity was lower with increasing age, previous tuberculosis, and decreasing body mass index. Diabetes and tobacco smoking did not modify accuracy. CONCLUSION: In a population where most tuberculosis was smear-positive, LUNIT-reported radiographic abnormalities were associated with culture-confirmed disease. Manufacturer-recommended threshold scores had limited sensitivity.

Re-evaluating the merits of decentralization as a core strategy for effective delivery of drug-resistant tuberculosis care in Pakistan.

Decentralized, person-centred models of care delivery for drug-resistant tuberculosis (DR-TB) continue to be under-resourced in high-burden TB countries. The implementation of such models-made increasingly urgent by the COVID-19 pandemic-are key to addressing gaps in DR-TB care. We abstracted data of rifampicin-resistant (RR)/multidrug-resistant tuberculosis (MDR-TB) patients initiated on treatment at 11 facilities between 2010 and 2017 in Sindh and Balochistan provinces of Pakistan. We analysed trends in treatment outcomes relating to programme expansion to peri-urban and rural areas and estimated driving distance from patient residence to treatment facility. Among the 5586 RR/MDR-TB patients in the analysis, overall treatment success decreased from 82% to 66% between 2010 and 2017, as the programme expanded. The adjusted risk ratio for unfavourable outcomes was 1.013 (95% confidence interval 1.005-1.021) for every 20 km of driving distance. Our analysis suggests that expanding DR-TB care to centralized hubs added to increased unfavourable outcomes for people accessing care in peri-urban and rural districts. We propose that as enrolments increase, expanding DR-TB services close to or within affected communities is essential.

Chest X-ray Analysis With Deep Learning-Based Software as a Triage Test for Pulmonary Tuberculosis: An Individual Patient Data Meta-Analysis of Diagnostic Accuracy.

BACKGROUND: Automated radiologic analysis using computer-aided detection software (CAD) could facilitate chest X-ray (CXR) use in tuberculosis diagnosis. There is little to no evidence on the accuracy of commercially available deep learning-based CAD in different populations, including patients with smear-negative tuberculosis and people living with human immunodeficiency virus (HIV, PLWH). METHODS: We collected CXRs and individual patient data (IPD) from studies evaluating CAD in patients self-referring for tuberculosis symptoms with culture or nucleic acid amplification testing as the reference. We reanalyzed CXRs with three CAD programs (CAD4TB version (v) 6, Lunit v3.1.0.0, and qXR v2). We estimated sensitivity and specificity within each study and pooled using IPD meta-analysis. We used multivariable meta-regression to identify characteristics modifying accuracy. RESULTS: We included CXRs and IPD of 3727/3967 participants from 4/7 eligible studies. 17% (621/3727) were PLWH. 17% (645/3727) had microbiologically confirmed tuberculosis. Despite using the same threshold score for classifying CXR in every study, sensitivity and specificity varied from study to study. The software had similar unadjusted accuracy (at 90% pooled sensitivity, pooled specificities were: CAD4TBv6, 56.9% [95% confidence interval {CI}: 51.7-61.9]; Lunit, 54.1% [95% CI: 44.6-63.3]; qXRv2, 60.5% [95% CI: 51.7-68.6]). Adjusted absolute differences in pooled sensitivity between PLWH and HIV-uninfected participants were: CAD4TBv6, -13.4% [-21.1, -6.9]; Lunit, +2.2% [-3.6, +6.3]; qXRv2: -13.4% [-21.5, -6.6]; between smear-negative and smear-positive tuberculosis was: were CAD4TBv6, -12.3% [-19.5, -6.1]; Lunit, -17.2% [-24.6, -10.5]; qXRv2, -16.6% [-24.4, -9.9]. Accuracy was similar to human readers. CONCLUSIONS: For CAD CXR analysis to be implemented as a high-sensitivity tuberculosis rule-out test, users will need threshold scores identified from their own patient populations and stratified by HIV and smear status.

Triage of Persons With Tuberculosis Symptoms Using Artificial Intelligence-Based Chest Radiograph Interpretation: A Cost-Effectiveness Analysis.

BACKGROUND: In settings without access to rapid expert radiographic interpretation, artificial intelligence (AI)-based chest radiograph (CXR) analysis can triage persons presenting with possible tuberculosis (TB) symptoms, to identify those who require additional microbiological testing. However, there is limited evidence of the cost-effectiveness of this technology as a triage tool. METHODS: A decision analysis model was developed to evaluate the cost-effectiveness of triage strategies with AI-based CXR analysis for patients presenting with symptoms suggestive of pulmonary TB in Karachi, Pakistan. These strategies were compared to the current standard of care using microbiological testing with smear microscopy or GeneXpert, without prior triage. Positive triage CXRs were considered to improve referral success for microbiologic testing, from 91% to 100% for eligible persons. Software diagnostic accuracy was based on a prospective field study in Karachi. Other inputs were obtained from the Pakistan TB Program. The analysis was conducted from the healthcare provider perspective, and costs were expressed in 2020 US dollars. RESULTS: Compared to upfront smear microscopy for all persons with presumptive TB, triage strategies with AI-based CXR analysis were projected to lower costs by 19%, from $23233 per 1000 persons, and avert 3%-4% disability-adjusted life-years (DALYs), from 372 DALYs. Compared to upfront GeneXpert, AI-based triage strategies lowered projected costs by 37%, from $34346 and averted 4% additional DALYs, from 369 DALYs. Reinforced follow-up for persons with positive triage CXRs but negative microbiologic tests was particularly cost-effective. CONCLUSIONS: In lower-resource settings, the addition of AI-based CXR triage before microbiologic testing for persons with possible TB symptoms can reduce costs, avert additional DALYs, and improve TB detection.

Safety and feasibility of 1 month of daily rifapentine plus isoniazid to prevent tuberculosis in children and adolescents: a prospective cohort study.

BACKGROUND: Shorter regimens for tuberculosis prevention can improve completion rates and protection against developing active tuberculosis disease after tuberculosis exposure. We aimed to assess the safety and feasibility of 1 month of daily isoniazid and rifapentine (1HP) in children and adolescents in a low-resource setting in south Asia with low prevalence of HIV. METHODS: This prospective cohort study was done in eight tuberculosis facilities in Karachi, Pakistan. Eligible participants were aged 2-19 years and were household contacts of patients with drug-susceptible tuberculosis infection. After clinical, radiological, and laboratory evaluation to rule out tuberculosis disease, participants were prescribed 1HP as a preventive regimen. Isoniazid was administered as 100 mg or 300 mg oral tablets and rifapentine was administered as 150 mg oral tablets. Dosing was according to participant bodyweight. The primary endpoints were the cumulative probability of a household contact completing all stages of the preventive care cascade, assessed in all eligible participants, and the proportion of household contacts completing 1HP, assessed among all those who initiated the regimen. Safety was assessed in all household contacts who initiated the 1HP regimen. FINDINGS: Between Dec 21, 2019, and March 20, 2020, 1395 household contacts of 253 patients with tuberculosis were identified, including 678 household contacts who were eligible to participate. 628 (93%) completed evaluation, of whom ten (2%) had active tuberculosis disease. Of the 618 individuals eligible for tuberculosis prevention, 408 (66%) initiated 1HP, 385 (94%) of whom completed the regimen. The median duration of 1HP was 31 days (IQR 30-32) in those who completed the regimen. The cumulative probability of completing all steps of the tuberculosis prevention cascade was 58%. A girl aged 11 years developed tuberculosis disease within 6 months of completing 1HP. A boy aged 14 years developed a burning sensation during 1HP therapy and discontinued the regimen. No other adverse events were observed. INTERPRETATION: 1HP can be safely and feasibly implemented as tuberculosis prevention in children and adolescents in programmatic settings. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria.

Impact of integrating mental health services within existing tuberculosis treatment facilities.

Introduction: Depression and anxiety among tuberculosis (TB) patients can adversely affect TB treatment adherence and completion. Aim: We studied whether integrating mental health services into existing TB treatment programs would reduce symptoms of depression and anxiety and improve treatment completion among patients with drug-susceptible TB. Methods: Integrated practice units (IPUs) for TB and mental health were established within six existing TB treatment facilities in Karachi, Pakistan. Patients were screened for depression and anxiety and, if symptomatic, offered a mental health intervention consisting of at least four counseling sessions. We measured changes in reported levels of depression and anxiety symptoms from baseline following completion of counseling sessions, and rates of TB treatment completion. Results: Between February 2017 and June 2018, 3500 TB patients were screened for depression and anxiety. 1057 (30.2%) symptomatic patients received a baseline adherence session. 1012 enrolled for a mental health intervention received at least 1 counseling session. 522 (51.5%) reported no symptoms after four to six sessions. Symptomatic patients who completed at least four counseling sessions had higher rates of TB treatment completion than those who did not (92.9% vs 75.1%; p < 0.0001). Conclusion: Mental health interventions integrated within TB programs can help reduce symptoms of depression and anxiety and improve TB treatment completion.

Cost of Delivering 12-Dose Isoniazid and Rifapentine Versus 6 Months of Isoniazid for Tuberculosis Infection in a High-Burden Setting.

BACKGROUND: Successful delivery and completion of tuberculosis preventive treatment are necessary for tuberculosis elimination. Shorter preventive treatment regimens currently have higher medication costs, but patients spend less time in care and are more likely to complete treatment. It is unknown how economic costs of successful delivery differ between longer and shorter regimens in high-tuberculosis-burden settings. METHODS: We developed survey instruments to collect costs from program and patient sources, considering costs incurred from when household contacts first entered the health system. We compared the cost per completed course of preventive treatment with either 6 months of daily isoniazid (6H) or 3 months of weekly isoniazid and rifapentine (3HP), delivered by the Indus Health Network tuberculosis program in Karachi, Pakistan, between October 2016 and February 2018. RESULTS: During this period, 459 individuals initiated 6H and 643 initiated 3HP; 39% and 61% completed treatment, respectively. Considering costs to both the program and care recipients, the cost per completed course was 394 US dollars (USD) for 6H and 333 USD for 3HP. Using a new 2020 price for rifapentine reduced the cost per completed course of 3HP to 290 USD. Under varying assumptions about drug prices and costs incurred by care recipients, the cost per completed course was lower for 3HP in all scenarios, and the largest cost drivers were the salaries of clinical staff. CONCLUSIONS: In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion.

Concurrent adult pulmonary tuberculosis prevalence survey using digital radiography and Xpert MTB/RIF Ultra and child interferon-gamma release assay Mycobacterium tuberculosis infection survey in Karachi, Pakistan: a study protocol.

Background: Assessment of the effectiveness of tuberculosis control strategies requires the periodic measurement of M. tuberculosis transmission in populations, which is notoriously difficult. One well-established method is to measure the prevalence of infectious pulmonary tuberculosis in the population which is then repeated at a second time point after a period of 'intervention', such as scale up of the Search-Treat-Prevent strategy of the Zero TB Cities initiative, allowing for a 'before and after' comparison.  Protocol: The concurrent adult pulmonary tuberculosis prevalence survey (using digital radiography and Xpert MTB/RIF Ultra) and child M. tuberculosis infection survey (using QuantiFERON-TB® Gold Plus) will primarily provide a baseline measure of the burden of adult infectious tuberculosis in Karachi and assess whether a large-scale interferon gamma release assay survey in children aged 2 to 4 years is feasible. The target population for the prevalence survey is comprised of a stratified random sample of all adults aged 15 years and above and all children aged 2 to 4 years resident in four districts in Karachi. The survey procedures and analyses to estimate pulmonary tuberculosis prevalence are based on the World Health Organization methodology for tuberculosis prevalence surveys. Ethics and dissemination: The study protocol has been approved by the Interactive Research Development / The Indus Hospital Research Centre Research Ethics Committee in Karachi, Pakistan and the London School of Hygiene & Tropical Medicine Research Ethics Committee. Due to non-representative sampling in this setting, where a large proportion of the population are illiterate and are reluctant to provide fingerprints due to concerns about personal security, verbal informed consent will be obtained from each eligible participant or guardian. Results will be submitted to international peer-reviewed journals, presented at international conferences and shared with participating communities and with the Provincial and National TB programme.

Tuberculosis Preventive Therapy for Individuals Exposed to Drug-resistant Tuberculosis: Feasibility and Safety of a Community-based Delivery of Fluoroquinolone-containing Preventive Regimen.

BACKGROUND: Observational studies have demonstrated the effectiveness of a fluoroquinolone-based regimen to treat individuals presumed to be infected with drug-resistant tuberculosis (DR-TB). We sought to assess the feasibility of this approach in an urban setting in South Asia. METHODS: From February 2016 until March 2017, all household contacts of DR-TB patients enrolled at the Indus Hospital were screened for TB symptoms at home. Children aged 0-17 years, symptomatic adults, and those with an immunocompromising condition (human immunodeficiency virus, diabetes, or malnutrition) were evaluated for TB disease. Contacts diagnosed with TB disease were started on treatment. Contacts without TB disease aged <5 years, contacts aged between 5 and 17 years with either a positive tuberculin skin test or an immunocompromising condition, or contacts aged ≥18 years with an immunocompromising condition were offered 6 months of treatment with a fluoroquinolone. RESULTS: One hundred households with 800 contacts were enrolled: 353 (44.1%) individuals aged ≤17 years with a median age of 19 years (interquartile range, 10-32); 423 (52.9%) were males. In total, 737 (92.1%) individuals were screened, of which 8 were already on treatment for TB (1.1%); another 3 (0.4%) contacts were diagnosed with TB disease and started on treatment. Of 215 eligible for infection treatment, 172 (80.0%) contacts initiated and 121 (70.3%) completed treatment. No TB disease or significant adverse events were observed during 12 months of follow-up. CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB infection is feasible and well tolerated in a high TB burden setting.

The Impact of Funding on Childhood TB Case Detection in Pakistan.

This study is a review of routine programmatically collected data to describe the 5-year trend in childhood case notification in Jamshoro district, Pakistan from January 2013 to June 2018 and review of financial data for the two active case finding projects implemented during this period. The average case notification in the district was 86 per quarter before the start of active case finding project in October 2014. The average case notification rose to 322 per quarter during the implementation period (October 2014 to March 2016) and plateaued at 245 per quarter during the post-implementation period (April 2016 to June 2018). In a specialized chest center located in the district, where active case finding was re-introduced during the post implementation period (October 2016), the average case notification was 218 per quarter in the implementation period and 172 per quarter in the post implementation period. In the rest of the district, the average case notification was 160 per quarter in the implementation period and 78 during the post implementation period. The cost per additional child with TB found ranged from USD 28 to USD 42 during the interventions. A continuous stream of resources is necessary to sustain high notifications of childhood TB.

Correction to: The cost-effectiveness of incentive-based active case finding for tuberculosis (TB) control in the private sector Karachi, Pakistan.

In the original publication of this article [1], an author's name needs to be revised from Jacob Creswel to Jacob Creswell.

The cost-effectiveness of incentive-based active case finding for tuberculosis (TB) control in the private sector Karachi, Pakistan.

BACKGROUND: In Asia, over 50% of patients with symptoms of tuberculosis (TB) access health care from private providers. These patients are usually not notified to the National TB Control Programs, which contributes to low notification rates in many countries. METHODS: From January 1, 2011 to December 31, 2012, Karachi's Indus Hospital - a private sector partner to the National TB Programme - engaged 80 private family clinics in its catchment area in active case finding using health worker incentives to increase notification of TB disease. The costs incurred were estimated from the perspective of patients, health facility and the program providing TB services. A Markov decision tree model was developed to calculate the cost-effectiveness of the active case finding as compared to case detection through the routine passive TB centers. Pakistan has a large private health sector, which can be mobilized for TB screening using an incentivized active case finding strategy. Currently, TB screening is largely performed in specialist public TB centers through passive case finding. Active and passive case finding strategies are assumed to operate independently from each other. RESULTS: The incentive-based active case finding program costed USD 223 per patient treated. In contrast, the center based non-incentive arm was 23.4% cheaper, costing USD 171 per patient treated. Cost-effectiveness analysis showed that the incentive-based active case finding program was more effective and less expensive per DALY averted when compared to the baseline passive case finding as it averts an additional 0.01966 DALYs and saved 15.74 US$ per patient treated. CONCLUSION: Both screening strategies appear to be cost-effective in an urban Pakistan context. Incentive driven active case findings of TB in the private sector costs less and averts more DALYs per health seeker than passive case finding, when both alternatives are compared to a common baseline situation of no screening.

The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens.

BACKGROUND: At a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development of acquired resistance. As part of the endTB Project, we aimed to address these barriers by generating evidence on safety and efficacy of bedaquiline or delamanid based MDR-TB regimens. METHODS: This is a protocol for a multi-center prospective cohort study to enroll 2600 patients from April 2015 through September 2018 in 17 countries. The protocol describes inclusion of patients started on treatment with bedaquiline- or delamanid- containing regimens under routine care, who consented to participate in the endTB observational study. Patient follow-up was according to routine monitoring schedules recommended for patients receiving bedaquiline or delamanid as implemented at each endTB site. Therefore, no additional tests were performed as a part of the study. Data were to be collected in a customized, open-source electronic medical record (EMR) system developed as a part of the endTB Project across all 17 countries. DISCUSSION: The endTB observational study will generate evidence on safety and efficacy of bedaquiline- and delamanid-containing regimens in a large, extremely heterogeneous group of MDR-TB patients, from 17 epidemiologically diverse countries. The systematic, prospective data collection of repeated effectiveness and safety measures, and analyses performed on these data, will improve the quality of evidence available to inform MDR-TB treatment and policy decisions. Further, the resources available to countries through implementation of the endTB project will have permitted countries to: gain experience with the use of these drugs in MDR-TB regimens, improve local capacity to record and report adverse events (pharmacovigilance), and enhance significantly the body of data available for safety evaluation of these drugs and other novel treatments. TRIAL REGISTRATION: This study was registered on 24 August 2017 at clincaltrials.gov (Registration number: NCT03259269).