The plasma kynurenine-to-tryptophan ratio as a biomarker of tuberculosis disease in people living with HIV on antiretroviral therapy: an exploratory nested case-control study.

BACKGROUND: Non-sputum-based tests are needed to predict or diagnose tuberculosis (TB) disease in people living with HIV (PWH). The enzyme indoleamine 2, 3-dioxygenase-1 (IDO1) is expressed in tuberculoid granuloma and catabolizes tryptophan (Trp) to kynurenine (Kyn). IDO1 activity compromises innate and adaptive immune responses, promoting mycobacterial survival. The plasma Kyn-to-Trp (K/T) ratio is a potential TB diagnostic and/or predictive biomarker in PWH on long-term antiretroviral therapy (ART). METHODS: We compared plasma K/T ratios in samples from PWH, who were followed up prospectively and developed TB disease after ART initiation. Controls were matched for age and duration of ART. Kyn and Trp were measured at 3 timepoints; at TB diagnosis, 6 months before TB diagnosis and 6 months after TB diagnosis, using ultra performance liquid chromatography combined with mass spectrometry. RESULTS: The K/T ratios were higher for patients with TB disease at time of diagnosis (median, 0.086; IQR, 0.069-0.123) compared to controls (0.055; IQR 0.045-0.064; p = 0.006), but not before or after TB diagnosis. K/T ratios significantly declined after successful TB treatment, but increased upon treatment failure. The K/T ratios showed a parabolic correlation with CD4 cell counts in participants with TB (p = 0.005), but there was no correlation in controls. CONCLUSIONS: The plasma K/T ratio helped identify TB disease and may serve as an adjunctive biomarker for for monitoring TB treatment in PWH. Validation studies to ascertain these findings and evaluate the optimum cut-off for diagnosis of TB disease in PWH should be undertaken in well-designed prospective cohorts. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00411983.

Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status.

Potential Mycobacterium tuberculosis (Mtb) transmission during different pulmonary tuberculosis (TB) disease states is poorly understood. We quantified viable aerosolized Mtb from TB clinic attendees following diagnosis and through six months' follow-up thereafter. Presumptive TB patients (n=102) were classified by laboratory, radiological, and clinical features into Group A: Sputum-Xpert Ultra-positive TB (n=52), Group B: Sputum-Xpert Ultra-negative TB (n=20), or Group C: TB undiagnosed (n=30). All groups were assessed for Mtb bioaerosol release at baseline, and subsequently at 2 wk, 2 mo, and 6 mo. Groups A and B were notified to the national TB program and received standard anti-TB chemotherapy; Mtb was isolated from 92% and 90% at presentation, 87% and 74% at 2 wk, 54% and 44% at 2 mo and 32% and 20% at 6 mo, respectively. Surprisingly, similar numbers were detected in Group C not initiating TB treatment: 93%, 70%, 48% and 22% at the same timepoints. A temporal association was observed between Mtb bioaerosol release and TB symptoms in all three groups. Persistence of Mtb bioaerosol positivity was observed in ~30% of participants irrespective of TB chemotherapy. Captured Mtb bacilli were predominantly acid-fast stain-negative and poorly culturable; however, three bioaerosol samples yielded sufficient biomass following culture for whole-genome sequencing, revealing two different Mtb lineages. Detection of viable aerosolized Mtb in clinic attendees, independent of TB diagnosis, suggests that unidentified Mtb transmitters might contribute a significant attributable proportion of community exposure. Additional longitudinal studies with sputum culture-positive and -negative control participants are required to investigate this possibility.

Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data meta-analysis.

BACKGROUND: Subclinical pulmonary tuberculosis, which presents without recognisable symptoms, is frequently detected in community screening. However, the disease category is poorly clinically defined. We explored the prevalence of subclinical pulmonary tuberculosis according to different case definitions. METHODS: We did a one-stage individual participant data meta-analysis of nationally representative surveys that were conducted in countries with high incidence of tuberculosis between 2007 and 2020, that reported the prevalence of pulmonary tuberculosis based on chest x-ray and symptom screening in participants aged 15 years and older. Screening and diagnostic criteria were standardised across the surveys, and tuberculosis was defined by positive Mycobacterium tuberculosis sputum culture. We estimated proportions of subclinical tuberculosis for three case definitions: no persistent cough (ie, duration ≥2 weeks), no cough at all, and no symptoms (ie, absence of cough, fever, chest pain, night sweats, and weight loss), both unadjusted and adjusted for false-negative chest x-rays and uninterpretable culture results. FINDINGS: We identified 34 surveys, of which 31 were eligible. Individual participant data were obtained and included for 12 surveys (620 682 participants) across eight countries in Africa and four in Asia. Data on 602 863 participants were analysed, of whom 1944 had tuberculosis. The unadjusted proportion of subclinical tuberculosis was 59·1% (n=1149/1944; 95% CI 55·8-62·3) for no persistent cough and 39·8% (773/1944; 36·6-43·0) for no cough of any duration. The adjusted proportions were 82·8% (95% CI 78·6-86·6) for no persistent cough and 62·5% (56·6-68·7) for no cough at all. In a subset of four surveys, the proportion of participants with tuberculosis but without any symptoms was 20·3% (n=111/547; 95% CI 15·5-25·1) before adjustment and 27·7% (95% CI 21·0-36·4) after adjustment. Tuberculosis without cough, irrespective of its duration, was more frequent among women (no persistent cough: adjusted odds ratio 0·79, 95% CI 0·63-0·97; no cough: adjusted odds ratio 0·76, 95% CI 0·62-0·93). Among participants with tuberculosis, 29·1% (95% CI 25·2-33·3) of those without persistent cough and 23·1% (18·8-27·4) of those without any cough had positive smear examinations. INTERPRETATION: The majority of people in the community who have pulmonary tuberculosis do not report cough, a quarter report no tuberculosis-suggestive symptoms at all, and a quarter of those not reporting any cough have positive sputum smears, suggesting infectiousness. In high-incidence settings, subclinical tuberculosis could contribute considerably to the tuberculosis burden and to Mycobacterium tuberculosis transmission. FUNDING: Mr Willem Bakhuys Roozeboom Foundation.

Tuberculosis treatment monitoring tests during routine practice: study design guidance.

SCOPE: The current tools for tuberculosis (TB) treatment monitoring, smear microscopy and culture, cannot accurately predict poor treatment outcomes. Research into new TB treatment monitoring tools (TMTs) is growing, but data are unreliable. In this article, we aim to provide guidance for studies investigating and evaluating TB TMT for use during routine clinical care. Here, a TB TMT would guide treatment during the course of therapy, rather than testing for a cure at the regimen's end. This article does not cover the use of TB TMTs as surrogate endpoints in the clinical trial context. METHODS: Guidelines were initially informed by experiences during a systematic review of TB TMTs. Subsequently, a small content expert group was consulted for feedback on initial recommendations. After revision, feedback from substantive experts across sectors was sought. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: The proposed considerations and recommendations for studies evaluating TB TMTs for use during the treatment in routine clinical care fall into eight domains. We provide specific recommendations regarding study design and recruitment, outcome definitions, reference standards, participant follow-up, clinical setting, study population, treatment regimen reporting, and index tests and data presentation. Overall, TB TMTs should be evaluated in a manner similar to diagnostic tests, but TB TMT accuracy must be assessed at multiple timepoints throughout the treatment course, and TB TMTs should be evaluated in study populations who have already received a diagnosis of TB. Study design and outcome definitions must be aligned with the developmental phase of the TB TMT under evaluation. There is no reference standard for TB treatment response, so different reference standards and comparator tests have been proposed, the selection of which will vary depending on the developmental phase of the TMT under assessment. The use of comparator tests can assist in generating evidence. Clarity is required when reporting of timepoints, TMT read-outs, and analysis results. Implementing these recommendations will lead to higher quality TB TMT studies that will allow data to be meaningfully compared, thereby facilitating the development of novel tools to guide individual TB therapy and improve treatment outcomes.

Monocyte to lymphocyte ratio and hemoglobin level to predict tuberculosis after antiretroviral therapy initiation.

OBJECTIVE: To determine the performance of the baseline monocyte to lymphocyte ratio (MLR), baseline anemia severity and combination of these biomarkers, to predict tuberculosis (TB) incidence in people with HIV (PWH) after antiretroviral therapy (ART) initiation. DESIGN: Multicenter, retrospective cohort study. METHODS: We utilized the data from study A5175 (Prospective Evaluation of Antiretroviral Therapy in Resource-limited Settings: PEARLS). We assessed the utility of MLR, anemia severity and in combination, for predicting TB in the first year after ART. Cox regression was used to assess associations of MLR and anemia with incident TB. Harrell's C index was used to describe single model discrimination. RESULTS: A total of 1455 participants with a median age of 34 [interquartile range (IQR) 29, 41] were included. Fifty-four participants were diagnosed with TB. The hazard ratio (HR) for incident TB was 1.77 [95% confidence interval (CI) 1.01-3.07]; P  = 0.04 for those with MLR ≥0.23. The HR for mild/mod anemia was 3.35 (95% CI 1.78-6.29; P  < 0.001) and 18.16 (95% CI 5.17-63.77; P  < 0.001) for severe anemia. After combining parameters, there were increases in adjusted HR (aHR) for MLR ≥0.23 to 1.83 (95% CI 1.05-3.18), and degrees of anemia to 3.38 (95% CI 1.80-6.35) for mild/mod anemia and 19.09 (95% CI 5.43-67.12) for severe anemia. CONCLUSIONS: MLR and hemoglobin levels which are available in routine HIV care can be used at ART initiation for identifying patients at high risk of developing TB disease to guide diagnostic and management decisions.

Estimating the contribution of subclinical tuberculosis disease to transmission: An individual patient data analysis from prevalence surveys.

Background: Individuals with bacteriologically confirmed pulmonary tuberculosis (TB) disease who do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at the time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. Methods: We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual-level data on representative populations for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high-burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission. Results: We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, the Philippines, and Viet Nam) and one case-finding trial in Viet Nam. The odds ratio for infection in a household with a clinical versus subclinical index case (irrespective of sputum smear status) was 1.2 (0.6-2.3, 95% confidence interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% prediction interval [PrI]). Fourteen countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB. Conclusions: Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination. Funding: JCE, KCH, ASR, NS, and RH have received funding from the European Research Council (ERC) under the Horizon 2020 research and innovation programme (ERC Starting Grant No. 757699) KCH is also supported by UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to KCH); however, the views expressed do not necessarily reflect the UK government's official policies. PJD was supported by a fellowship from the UK Medical Research Council (MR/P022081/1); this UK-funded award is part of the EDCTP2 programme supported by the European Union. RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 and INV-001754), and the WHO (2020/985800-0).

Target product profiles: tests for tuberculosis treatment monitoring and optimization.

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.

L'Organisation mondiale de la santé a élaboré des profils de produits cibles contenant des cibles minimales et optimales pour les caractéristiques principales des essais destinés au suivi et à l'optimisation du traitement de la tuberculose. L'optimisation du traitement de la tuberculose fait référence à l'instauration d'un régime de traitement efficace de la tuberculose ou à l'adoption d'un tel régime, avec une probabilité élevée d'obtenir de bons résultats thérapeutiques. Les profils de produits cibles couvrent également les essais de guérison effectués à l'issue du traitement. Les profils de produits cibles ont été élaborés sur la base d'un sondage auprès des parties prenantes, d'une analyse coût-efficacité et d'une analyse du parcours de soins du patient. Des retours supplémentaires des parties prenantes ont été obtenus au moyen d'un processus créé selon la méthode Delphi, d'une consultation technique et d'un appel à commentaires publics sur un projet de document. Un groupe d'élaboration scientifique s'est mis d'accord sur les objectifs finaux lors d'une réunion de concertation. En ce qui concerne les caractéristiques jugées les plus importantes, le document énumère ce qui suit: (i) une grande précision diagnostique (sensibilité et spécificité); (ii) un délai idéal d'obtention des résultats ≤ 2 heures et au maximum de 1 jour; (iii) le type d'échantillon requis doit être peu invasif et facile à obtenir, comme l'urine, l'haleine ou le sang capillaire, ou bien un échantillon respiratoire au-delà des expectorations; (iv) idéalement, l'essai pourrait avoir lieu dans un établissement de santé périphérique sans laboratoire ; et (v) l'essai devrait être abordable pour les pays à revenu faible et intermédiaire et permettre un accès large et équitable ainsi qu'une mise à l'échelle. L'utilisation de ces profils de produits cibles devrait faciliter la mise au point de nouveaux essais de surveillance et d'optimisation du traitement de la tuberculose qui soient précis et accessibles à toutes les personnes suivant un traitement pour la tuberculose.

La Organización Mundial de la Salud ha elaborado perfiles de productos objetivo que contienen objetivos mínimos y óptimos para las características principales de las pruebas de seguimiento y optimización del tratamiento de la tuberculosis. La optimización del tratamiento de la tuberculosis consiste en iniciar o cambiar a un régimen eficaz de tratamiento de la tuberculosis que ofrezca una alta probabilidad de un buen resultado terapéutico. Los perfiles de productos objetivo también abarcan las pruebas de curación realizadas al final del tratamiento. La elaboración de los perfiles de los productos objetivo se basó en una encuesta a las partes interesadas, un análisis de rentabilidad y un análisis de la vía de atención al paciente. Se obtuvo información adicional de las partes interesadas mediante un proceso tipo Delphi, una consulta técnica y una convocatoria de comentarios públicos sobre un borrador del documento. Un grupo de desarrollo científico acordó los objetivos finales en una reunión de consenso. Para las características clasificadas de mayor importancia, el documento enumera: (i) alta precisión diagnóstica (sensibilidad y especificidad); (ii) tiempo hasta el resultado de óptimamente ≤ 2 horas y no más de 1 día; (iii) el tipo de muestra requerida debe ser mínimamente invasiva, fácil de obtener, como orina, aliento o sangre capilar, o una muestra respiratoria que vaya más allá del esputo; (iv) idealmente la prueba podría realizarse en un centro sanitario periférico sin laboratorio; y (v) la prueba debe ser asequible para los países de ingresos bajos y medios y permitir un acceso amplio y equitativo y su expansión. El uso de estos perfiles de producto objetivo debería facilitar el desarrollo de pruebas nuevas de seguimiento y optimización del tratamiento de la tuberculosis que sean precisas y accesibles para todas las personas que reciben tratamiento antituberculoso.

An Aspiration to Radically Shorten Phase 3 Tuberculosis Vaccine Trials.

A new tuberculosis vaccine is a high priority. However, the classical development pathway is a major deterrent. Most tuberculosis cases arise within 2 years after Mycobacterium tuberculosis exposure, suggesting a 3-year trial period should be possible if sample size is large to maximize the number of early exposures. Increased sample size could be facilitated by working alongside optimized routine services for case ascertainment, with strategies for enhanced case detection and safety monitoring. Shortening enrolment could be achieved by simplifying screening criteria and procedures and strengthening site capacity. Together, these measures could enable radically shortened phase 3 tuberculosis vaccine trials.

Funding and financial sustainability of pharmacovigilance: suggested models for funding pharmacovigilance in resource-limited African countries.

Background: An important factor hindering the growth of pharmacovigilance (PV) in resource-limited settings is the lack of adequate funds to establish a functional National Pharmacovigilance System. Consequently, the crucial function of monitoring and ensuring the availability of safe medicines in these settings cannot be guaranteed considering the peculiarities of diseases and medicines used. Objectives: The objective of this paper is to provide an overview as to the availability of potential sources of funds, which could be explored to ensure Medicine Safety and to proffer a potential framework likely to ensure sustainable funding of PV in Africa. Methods/processes: The process of developing this framework entailed a review of PV financing in some developed economies, a landscape study of funding of PV in some African countries, an in-depth understanding of the PV system and the organisational structure and nexus between the regulatory agencies and National Pharmacovigilance Centre. Critical points for consideration included the sources of funds, revenue pool, the disbursement of funds, budgeting and expenditure profile and the legal framework. Consultative meetings, webinars and interviews with experts were carried out. Results: The findings showed that most of the PV systems were mainly integrated into the regulatory agencies regarding operational and fiscal governance with few facilities being independent of the regulatory agencies. The main source of funding was from the government with significant donor funding which is ad hoc and non-sustainable. Several potential sources were identified but yet to be exploited. There were no legal provisions for PV financing. A framework likely to ensure sustainable PV financing is suggested to capture all available sources of funding, mine the potential sources providing a sizeable pool of revenue to address its activities and enabling legal framework which will engender autonomy. Furthermore, it will address the nexus between the regulatory agencies and the PV outfits, thus enabling appropriate share of resources and blockage of diversions. Conclusion: In all, addressing the various elements identified in this study and providing the legal provisions which guarantees some degree of autonomy will provide a sustainable mechanism for PV funding in the resource-limited setting of Africa.

Funding models for pharmacovigilance in resource-limited African countries An important factor hindering the growth of pharmacovigilance (PV) in resource-limited settings following their entry into the WHO Programme of International Drug Monitoring is the lack of adequate funds to establish a functional National Pharmacovigilance System. This article provides an overview of various potential sources of funds in these settings and how they can be harnessed to fund PV. We undertook a review of PV financing in developed settings and carried out a landscape study of funding of PV in some African countries, as well as having an in-depth understanding of the PV system and the organisational structure. The nexus between the regulatory agencies and National Pharmacovigilance Centre was noted. We took into account the sources of funds, revenue pool, the disbursement of funds, budgeting and expenditure profile and the legal framework for the different African countries. We also identified the prevalent and potential sources of funds for PV. Consultative meetings, webinars and interviews with experts in PV were carried out as well. We discovered that most of the PV facilities were mainly integrated into the regulatory agencies regarding operational and fiscal governance with few facilities being independent of the regulatory agencies. The main source of funding was from the government with significant donor funding which is ad hoc and non-sustainable. Several potential sources were identified but yet to be exploited. There were no legal provisions for PV financing. We have now proposed funding models that may lead to increased revenue for PV in these countries as well as suggesting that a legal framework be provided to guarantee sustainability and address the nexus between the regulatory agencies and the PV outfits to ensure an appropriate share of resources and blocking diversions.

Digital health for all: How digital health could reduce inequality and increase universal health coverage.

Digital transformation in health care has a lot of opportunities to improve access and quality of care. However, in reality not all individuals and communities are benefiting equally from these innovations. People in vulnerable conditions, already in need of more care and support, are often not participating in digital health programs. Fortunately, numerous initiatives worldwide are committed to make digital health accessible to all citizens, stimulating the long-cherished global pursuit of universal health coverage. Unfortunately initiatives are not always familiar with each other and miss connection to jointly make a significant positive impact. To reach universal health coverage via digital health it is necessary to facilitate mutual knowledge exchange, both globally and locally, to link initiatives and apply academic knowledge into practice. This will support policymakers, health care providers and other stakeholders to ensure that digital innovations can increase access to care for everyone, leading towards Digital health for all.

Measuring indirect transmission-reducing effects in tuberculosis vaccine efficacy trials: why and how?

Tuberculosis is the leading bacterial cause of death globally. In 2021, 10·6 million people developed symptomatic tuberculosis and 1·6 million died. Seven promising vaccine candidates that aim to prevent tuberculosis disease in adolescents and adults are currently in late-stage clinical trials. Conventional phase 3 trials provide information on the direct protection conferred against infection or disease in vaccinated individuals, but they tell us little about possible indirect (ie, transmission-reducing) effects that afford protection to unvaccinated individuals. As a result, proposed phase 3 trial designs will not provide key information about the overall effect of introducing a vaccine programme. Information on the potential for indirect effects can be crucial for policy makers deciding whether and how to introduce tuberculosis vaccines into immunisation programmes. We describe the rationale for measuring indirect effects, in addition to direct effects, of tuberculosis vaccine candidates in pivotal trials and lay out several options for incorporating their measurement into phase 3 trial designs.

Drivers determining tuberculosis disease screening yield in four European screening programmes: a comparative analysis.

BACKGROUND: The World Health Organization End TB Strategy emphasises screening for early diagnosis of tuberculosis (TB) in high-risk groups, including migrants. We analysed key drivers of TB yield differences in four large migrant TB screening programmes to inform TB control planning and feasibility of a European approach. METHODS: We pooled individual TB screening episode data from Italy, the Netherlands, Sweden and the UK, and analysed predictors and interactions for TB case yield using multivariable logistic regression models. RESULTS: Between 2005 and 2018 in 2 302 260 screening episodes among 2 107 016 migrants to four countries, the programmes identified 1658 TB cases (yield 72.0 (95% CI 68.6-75.6) per 100 000). In logistic regression analysis, we found associations between TB screening yield and age (≥55 years: OR 2.91 (95% CI 2.24-3.78)), being an asylum seeker (OR 3.19 (95% CI 1.03-9.83)) or on a settlement visa (OR 1.78 (95% CI 1.57-2.01)), close TB contact (OR 12.25 (95% CI 11.73-12.79)) and higher TB incidence in the country of origin. We demonstrated interactions between migrant typology and age, as well as country of origin. For asylum seekers, the elevated TB risk remained similar above country of origin incidence thresholds of 100 per 100 000. CONCLUSIONS: Key determinants of TB yield included close contact, increasing age, incidence in country of origin and specific migrant groups, including asylum seekers and refugees. For most migrants such as UK students and workers, TB yield significantly increased with levels of incidence in the country of origin. The high, country of origin-independent TB risk in asylum seekers above a 100 per 100 000 threshold could reflect higher transmission and re-activation risk of migration routes, with implications for selecting populations for TB screening.

Influence of Sex and Sex-Based Disparities on Prevalent Tuberculosis, Vietnam, 2017-2018.

To assess sex disparities in tuberculosis in Vietnam, we conducted a nested, case-control study based on a 2017 tuberculosis prevalence survey. We defined the case group as all survey participants with laboratory-confirmed tuberculosis and the control group as a randomly selected group of participants with no tuberculosis. We used structural equation modeling to describe pathways from sex to tuberculosis according to an a priori conceptual framework. Our analysis included 1,319 participants, of whom 250 were case-patients. We found that sex was directly associated with tuberculosis prevalence (adjusted odds ratio for men compared with women 3.0 [95% CI 1.7-5.0]) and indirectly associated through other domains. The strong sex difference in tuberculosis prevalence is explained by a complex interplay of factors relating to behavioral and environmental risks, access to healthcare, and clinical manifestations. However, after controlling for all those factors, a direct sex effect remains that might be caused by biological factors.