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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)., Competing Interests: JE, SB, BF, FG, KH, SH, IL, Fv, HN, HN, MQ, AR, ET, RW, KZ, FC, RH No competing interests declared, PD has received consultancy fees from WHO (TB burden estimation) and participates as chair of SAB for NIHR grant on TBI screening. The author has no other competing interests to declare, GM acts as President of the International Union Against TB & Lung Disease. The author has no other competing interests to declare, IO has received grants from National TB Program Cambodia, WHO and DFAT (Australia) and has received consulting fees from WHO Myanmar Office. The author is on the Board of the Directors, UNION IUATLD and WHO’s Global Task Force on TB Impact Measurement. The author has no other competing interests to declare, NS received a grant from the Bill and Melinda Gates Foundation and owns stock/stock options in Sanofi Aventis Pharma LTD. The author has no other competing interests to declare, (© 2023, Emery et al.)

Traditional understanding of the risk of progression from Mycobacterium tuberculosis ( Mtb ) infection to tuberculosis (TB) overlooks diverse presentations across a spectrum of disease. We developed a deterministic model of Mtb infection and minimal (pathological damage but not infectious), subclinical (infectious but no reported symptoms), and clinical (infectious and symptomatic) TB, informed by a rigorous evaluation of data from a systematic review of TB natural history. Using a Bayesian approach, we calibrated the model to data from historical cohorts that followed tuberculin-negative individuals to tuberculin conversion and TB, as well as data from cohorts that followed progression and regression between disease states, disease state prevalence ratios, disease duration, and mortality. We estimated incidence, pathways, and 10-y outcomes following Mtb infection for a simulated cohort. Then, 92.0% (95% uncertainty interval, UI, 91.4 to 92.5) of individuals self-cleared within 10 y of infection, while 7.9% (95% UI 7.4 to 8.5) progressed to TB. Of those, 68.6% (95% UI 65.4 to 72.0) developed infectious disease, and 33.2% (95% UI 29.9 to 36.4) progressed to clinical disease. While 98% of progression to minimal disease occurred within 2 y of infection, only 71% and 44% of subclinical and clinical disease, respectively, occurred within this period. Multiple progression pathways from infection were necessary to calibrate the model and 49.5% (95% UI 45.6 to 53.7) of those who developed infectious disease undulated between disease states. We identified heterogeneous pathways across disease states after Mtb infection, highlighting the need for clearly defined disease thresholds to inform more effective prevention and treatment efforts to end TB.

A key metric in tuberculosis epidemiology is the annual risk of infection (ARI), which is usually derived from tuberculin skin test (TST) and interferon-γ release assay (IGRA) prevalence surveys carried out in children. Derivation of the ARI assumes that immunoreactivity is persistent over time; however, reversion of immunoreactivity has long been documented. We used a deterministic, compartmental model of Mycobacterium tuberculosis (Mtb) infection to explore the impact of reversion on ARI estimation using age-specific reversion probabilities for the TST and IGRA. Using empirical data on TST reversion (22.2%/year for persons aged ≤19 years), the true ARI was 2-5 times higher than that estimated from immunoreactivity studies in children aged 8-12 years. Applying empirical reversion probabilities for the IGRA (9.9%/year for youths aged 12-18 years) showed a 1.5- to 2-fold underestimation. ARIs are increasingly underestimated in older populations, due to the cumulative impact of reversion on population reactivity over time. Declines in annual risk did not largely affect the results. Ignoring reversion leads to a stark underestimation of the true ARI in populations and our interpretation of Mtb transmission intensity. In future surveys, researchers should adjust for the reversion probability and its cumulative effect with increasing age to obtain a more accurate reflection of the burden and dynamics of Mtb infection., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Mathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis disease. Recent research provides evidence that self-clearance of Mtb infection may be common, which may affect the potential impact of new vaccines that only take in infected or uninfected individuals. We explored how the inclusion of self-clearance in models of tuberculosis affects the estimates of vaccine impact in China and India., Methods: For both countries, we calibrated a tuberculosis model to a scenario without self-clearance and to various scenarios with self-clearance. To account for the current uncertainty in self-clearance properties, we varied the rate of self-clearance, and the level of protection against reinfection in self-cleared individuals. We introduced potential new vaccines in 2025, exploring vaccines that work in uninfected or infected individuals only, or that are effective regardless of infection status, and modelling scenarios with different levels of vaccine efficacy in self-cleared individuals. We then estimated the relative disease incidence reduction in 2050 for each vaccine compared with the no vaccination scenario., Findings: The inclusion of self-clearance increased the estimated relative reductions in incidence in 2050 for vaccines effective only in uninfected individuals, by a maximum of 12% in China and 8% in India. The inclusion of self-clearance increased the estimated impact of vaccines only effective in infected individuals in some scenarios and decreased it in others, by a maximum of 14% in China and 15% in India. As would be expected, the inclusion of self-clearance had minimal impact on estimated reductions in incidence for vaccines that work regardless of infection status., Interpretations: Our work suggests that the neglect of self-clearance in mathematical models of tuberculosis vaccines does not result in substantially biased estimates of tuberculosis vaccine impact. It may, however, mean that we are slightly underestimating the relative advantages of vaccines that work in uninfected individuals only compared with those that work in infected individuals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.tuberculosis infection status at baseline in Karonga District, Northern Malawi., Materials and Methods: Population-based surveys of tuberculin skin testing (TST) from the 1980s were linked with follow-up and TB surveillance in Karonga district. We compared rates of microbiologically-confirmed TB by baseline TST induration <5mm (no evidence of M.tuberculosis infection) and those with baseline TST >17mm (evidence of M.tuberculosis infection), using hazard ratios by time since baseline and attributable risk percent. The attributable risk percent was calculated to estimate the proportion of TB in those infected that can be attributed to that prior infection. We analysed whole genome sequences of M.tuberculosis strains to identify recent transmission., Results: Over 412,959 person-years, 208 incident TB episodes were recorded. Compared to the small induration group, rates of TB were much higher in the first two years in the large induration group, and remained higher to 20 years: age, sex and area-adjusted hazard ratios (HR) 2-9 years post-TST 4.27 (95%CI 2.56-7.11); 10-19 years after TST 2.15 (1.10-4.21); ≥20 years post-TST 1.88 (0.76-4.65). The attributable risk percent of remote infection was 76.6% (60.9-85.9) 2-9 years post-TST, and 53.5% (9.1-76.2) 10-19 years post-TST. Individuals with large TST indurations had higher rates of unique-strain TB (HR adjusted for age, sex and area = HR 6.56 (95% CI 1.96-22.99)), suggesting disease following remote infection, but not of linked-strain TB (recent transmission)., Conclusions: M.tuberculosis infection can increase the risk of TB far beyond 10 years, accounting for a substantial proportion of TB occurring among those remotely infected., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Glynn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Elevated rates of tuberculosis in healthcare workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb ) transmission in health facilities in high-burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of conventional and novel IPC measures on Mtb transmission to patients and other clinic attendees., Methods: An individual-based model of patient movements through clinics, ventilation in waiting areas, and Mtb transmission was developed, and parameterised using empirical data from eight clinics in two provinces in South Africa. Seven interventions-codeveloped with health professionals and policy-makers-were simulated: (1) queue management systems with outdoor waiting areas, (2) ultraviolet germicidal irradiation (UVGI) systems, (3) appointment systems, (4) opening windows and doors, (5) surgical mask wearing by clinic attendees, (6) simple clinic retrofits and (7) increased coverage of long antiretroviral therapy prescriptions and community medicine collection points through the Central Chronic Medicine Dispensing and Distribution (CCMDD) service., Results: In the model, (1) outdoor waiting areas reduced the transmission to clinic attendees by 83% (IQR 76%-88%), (2) UVGI by 77% (IQR 64%-85%), (3) appointment systems by 62% (IQR 45%-75%), (4) opening windows and doors by 55% (IQR 25%-72%), (5) masks by 47% (IQR 42%-50%), (6) clinic retrofits by 45% (IQR 16%-64%) and (7) increasing the coverage of CCMDD by 22% (IQR 12%-32%)., Conclusions: The majority of the interventions achieved median reductions in the rate of transmission to clinic attendees of at least 45%, meaning that a range of highly effective intervention options are available, that can be tailored to the local context. Measures that are not traditionally considered to be IPC interventions, such as appointment systems, may be as effective as more traditional IPC measures, such as mask wearing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Previous analyses suggest that children with tuberculosis (TB) are no more or no less likely to have multidrug (MDR)- or rifampicin-resistant (RR)-TB than adults. However, the availability of new data, particularly for high MDR/RR-TB burden countries, suggest updates of country-specific estimates are warranted.We used data from population-representative surveys and surveillance collected between 2000 and 2018 to compare the odds ratio of MDR/RR-TB among children (aged <15 years) with TB, compared to the odds of MDR/RR-TB among adults (aged ≥15 years) with TB.In most settings (45 out of 55 countries), and globally as a whole, there is no evidence that age is associated with odds of MDR/RR-TB. However, in some settings, such as former Soviet Union countries in general, and Georgia, Kazakhstan, Lithuania, Tajikistan and Uzbekistan in particular, as well as Peru, MDR/RR-TB is positively associated with age ≥15 years. Meanwhile, in Western Europe in general, and the United Kingdom, Poland, Finland and Luxembourg in particular, MDR/RR-TB is positively associated with age <15 years. 16 countries had sufficient data to compare over time between 2000-2011 and 2012-2018, with evidence for decreases in the odds ratio in children compared to adults in Germany, Kazakhstan and the United States of America.Our results support findings that in most settings a child with TB is as likely as an adult with TB to have MDR/RR-TB. However, setting-specific heterogeneity requires further investigation. Furthermore, the odds ratio for MDR/RR-TB in children compared to adults is generally either stable or decreasing. There are important gaps in detection, recording and reporting of drug resistance among paediatric TB cases, limiting our understanding of transmission risks and measures needed to combat the global TB epidemic., Competing Interests: Conflict of interest: C.F. McQuaid has nothing to disclose. Conflict of interest: T. Cohen has nothing to disclose. Conflict of interest: A.S. Dean has nothing to disclose. Conflict of interest: R.M.G.J. Houben has nothing to disclose. Conflict of interest: G.M. Knight has nothing to disclose. Conflict of interest: M. Zignol has nothing to disclose. Conflict of interest: R.G. White has nothing to disclose., (Copyright ©ERS 2021.)

Background : it is widely assumed that individuals with Mycobacterium tuberculosis ( Mtb ) infection remain at lifelong risk of tuberculosis (TB) disease. However, there is substantial evidence that self-clearance of Mtb infection can occur. We infer a curve of self-clearance by time since infection and explore its implications for TB epidemiology. Methods and findings : data for self-clearance were inferred using post-mortem and tuberculin-skin-test reversion studies. A cohort model allowing for self-clearance was fitted in a Bayesian framework before estimating the lifetime risk of TB disease and the population infected with Mtb in India, China and Japan in 2019. We estimated that 24.4% (17.8-32.6%, 95% uncertainty interval (UI)) of individuals self-clear within 10 years of infection, and 73.1% (64.6-81.7%) over a lifetime. The lifetime risk of TB disease was 17.0% (10.9-22.5%), compared to 12.6% (10.1-15.0%) assuming lifelong infection. The population at risk of TB disease in India, China and Japan was 35-80% (95% UI) smaller in the self-clearance scenario. Conclusions : the population with a viable Mtb infection may be markedly smaller than generally assumed, with such individuals at greater risk of TB disease. The ability to identify these individuals could dramatically improve the targeting of preventive programmes and inform TB vaccine development, bringing TB elimination within reach of feasibility.

Background: Mixed, polyclonal Mycobacterium tuberculosis infection occurs in natural populations. Developing an effective method for detecting such cases is important in measuring the success of treatment and reconstruction of transmission between patients. Using whole genome sequence (WGS) data, we assess two methods for detecting mixed infection: (i) a combination of the number of heterozygous sites and the proportion of heterozygous sites to total SNPs, and (ii) Bayesian model-based clustering of allele frequencies from sequencing reads at heterozygous sites., Results: In silico and in vitro artificially mixed and known pure M. tuberculosis samples were analysed to determine the specificity and sensitivity of each method. We found that both approaches were effective in distinguishing between pure strains and mixed infection where there was relatively high (> 10%) proportion of a minor strain in the mixture. A large dataset of clinical isolates (n = 1963) from the Karonga Prevention Study in Northern Malawi was tested to examine correlations with patient characteristics and outcomes with mixed infection. The frequency of mixed infection in the population was found to be around 10%, with an association with year of diagnosis, but no association with age, sex, HIV status or previous tuberculosis., Conclusions: Mixed Mycobacterium tuberculosis infection was identified in silico using whole genome sequence data. The methods presented here can be applied to population-wide analyses of tuberculosis to estimate the frequency of mixed infection, and to identify individual cases of mixed infections. These cases are important when considering the evolution and transmission of the disease, and in patient treatment.

Background: The proportion of tuberculosis attributable to transmission from close contacts is not well known. Comparison of the genome of strains from index patients and prior contacts allows transmission to be confirmed or excluded., Methods: In Karonga District, Malawi, all tuberculosis patients are asked about prior contact with others with tuberculosis. All available strains from culture-positive patients were sequenced. Up to 10 single nucleotide polymorphisms between index patients and their prior contacts were allowed for confirmation, and ≥ 100 for exclusion. The population attributable fraction was estimated from the proportion of confirmed transmissions and the proportion of patients with contacts., Results: From 1997-2010 there were 1907 new culture-confirmed tuberculosis patients, of whom 32% reported at least one family contact and an additional 11% had at least one other contact; 60% of contacts had smear-positive disease. Among case-contact pairs with sequences available, transmission was confirmed from 38% (62/163) smear-positive prior contacts and 0/17 smear-negative prior contacts. Confirmed transmission was more common in those related to the prior contact (42.4%, 56/132) than in non-relatives (19.4%, 6/31, p = 0.02), and in those with more intense contact, to younger index cases, and in more recent years. The proportion of tuberculosis attributable to known contacts was estimated to be 9.4% overall., Conclusions: In this population known contacts only explained a small proportion of tuberculosis cases. Even those with a prior family contact with smear positive tuberculosis were more likely to have acquired their infection elsewhere.

Background: Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain., Methods: In a population-based study in northern Malawi, patients with tuberculosis diagnosed from 1996 to 2010 were actively followed after the end of treatment. Whole-genome sequencing with approximately 100-fold coverage was performed on all available cultures. Results of IS6110 restriction fragment-length polymorphism analyses were available for cultures performed up to 2008., Results: Based on our data, a difference of ≤10 single-nucleotide polymorphisms (SNPs) was used to define relapse, and a difference of >100 SNPs was used to define reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 had relapse, and 20 had reinfection; for 64 type of recurrence was unclassified. Almost all relapses occurred in the first 2 years. Human immunodeficiency virus infection was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was overrepresented and lineage-1 underrepresented among the reinfecting strains (P = .004)., Conclusions: While some of the factors determining recurrence depend on the patient and their treatment, differences in the Mycobacterium tuberculosis genome appear to have a role in both relapse and reinfection., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Tuberculosis (TB) patients with strains common to other recent cases ('clustering') suggest recent transmission. HIV status and age may affect proportions clustered. We investigated TB clustering by HIV and age in a population-based study in Malawi. Among 746 patients, HIV infection increased the proportion clustered. Sex-period-adjusted odds ratios for the association of HIV and clustering were 1.26 (95% CI 0.4-4.1) for ages 15-25 years, 1.40 (0.9-2.3) for 25-50 years and 10.44 (2.3-47.9) for >50 years and remained stable over two periods examined. These results suggest that HIV increases the proportion of TB due to recent transmission in the elderly.

Objectives: The proportion of tuberculosis cases in a population that are clustered (i.e. share identical strains of Mycobacterium tuberculosis) reflects ongoing M. tuberculosis transmission. It varies markedly, but it is unclear how much of this variation reflects measurable differences in study design, setting and the patient population. We aimed to assess the relative impact of these factors and develop a tool to improve interpretation of the proportion clustered from an individual study., Methods: We systematically reviewed all population-based TB clustering studies that used IS6110 RFLP as their main DNA fingerprinting technique. Meta-regression was used to see how much of the variation in the proportion clustered between studies could be explained by variables describing study design, setting and population. We compared expected clustering, based on study design and setting, with that observed., Results: Forty-six studies were included. Just four factors related to study design and setting-study duration, sampling fraction, handling of low band strains and tuberculosis incidence-explained 28% of the variation in the proportion clustered. Additionally including average patient age and proportion foreign born explained 60% of the variation in clustering for industrialized countries. Comparison of expected and observed proportions showed that for some studies the expected proportion clustered differed strongly from that observed., Conclusions: We were able to account for much of the variation in the proportion clustered. The comparison of expected and observed clustering allows for a more valid comparison of studies and provides a tool for identifying outliers that warrant further investigation.

The current active–latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies. [ABSTRACT FROM AUTHOR]

Background: it is widely assumed that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis (TB) disease. However, there is substantial evidence that self-clearance of Mtb infection can occur. We infer a curve of self-clearance by time since infection and explore its implications for TB epidemiology. Methods and findings: data for self-clearance were inferred using post-mortem and tuberculin-skin-test reversion studies. A cohort model allowing for self-clearance was fitted in a Bayesian framework before estimating the lifetime risk of TB disease and the population infected with Mtb in India, China and Japan in 2019. We estimated that 24.4% (17.8–32.6%, 95% uncertainty interval (UI)) of individuals self-clear within 10 years of infection, and 73.1% (64.6–81.7%) over a lifetime. The lifetime risk of TB disease was 17.0% (10.9–22.5%), compared to 12.6% (10.1–15.0%) assuming lifelong infection. The population at risk of TB disease in India, China and Japan was 35–80% (95% UI) smaller in the self-clearance scenario. Conclusions: the population with a viable Mtb infection may be markedly smaller than generally assumed, with such individuals at greater risk of TB disease. The ability to identify these individuals could dramatically improve the targeting of preventive programmes and inform TB vaccine development, bringing TB elimination within reach of feasibility. [ABSTRACT FROM AUTHOR]

The authors responds to a commentary on their article about identifying the annual rate of tuberculosis infection, particularly on where the true annual risk of infection (ARI) of Mycobacterium tuberculosis lies. Cited are their consideration of the reversion of the observed process of waning immunoreactivity, rather than an underlying mechanism such as self-cure, and their agreement on the need for better and well-characterized data on the rate of reversion to feed into their model.

Background: it is widely assumed that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis (TB) disease. However, there is substantial evidence that self-clearance of Mtb infection can occur. We infer a curve of self-clearance by time since infection and explore its implications for TB epidemiology. Methods and findings: data for self-clearance were inferred using post-mortem and tuberculin-skin-test reversion studies. A cohort model allowing for self-clearance was fitted in a Bayesian framework before estimating the lifetime risk of TB disease and the population infected with Mtb in India, China and Japan in 2019. We estimated that 24.4% (17.8–32.6%, 95% uncertainty interval (UI)) of individuals self-clear within 10 years of infection, and 73.1% (64.6–81.7%) over a lifetime. The lifetime risk of TB disease was 17.0% (10.9–22.5%), compared to 12.6% (10.1–15.0%) assuming lifelong infection. The population at risk of TB disease in India, China and Japan was 35–80% (95% UI) smaller in the self-clearance scenario. Conclusions: the population with a viable Mtb infection may be markedly smaller than generally assumed, with such individuals at greater risk of TB disease. The ability to identify these individuals could dramatically improve the targeting of preventive programmes and inform TB vaccine development, bringing TB elimination within reach of feasibility. [ABSTRACT FROM AUTHOR]

Background: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI.Methods and Findings: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI.Conclusions: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) case notification rates are usually higher in men than in women, but notification data are insufficient to measure sex differences in disease burden. This review set out to systematically investigate whether sex ratios in case notifications reflect differences in disease prevalence and to identify gaps in access to and/or utilisation of diagnostic services.Methods and Findings: In accordance with the published protocol (CRD42015022163), TB prevalence surveys in nationally representative and sub-national adult populations (age ≥ 15 y) in low- and middle-income countries published between 1 January 1993 and 15 March 2016 were identified through searches of PubMed, Embase, Global Health, and the Cochrane Database of Systematic Reviews; review of abstracts; and correspondence with the World Health Organization. Random-effects meta-analyses examined male-to-female (M:F) ratios in TB prevalence and prevalence-to-notification (P:N) ratios for smear-positive TB. Meta-regression was done to identify factors associated with higher M:F ratios in prevalence and higher P:N ratios. Eighty-three publications describing 88 surveys with over 3.1 million participants in 28 countries were identified (36 surveys in Africa, three in the Americas, four in the Eastern Mediterranean, 28 in South-East Asia and 17 in the Western Pacific). Fifty-six surveys reported in 53 publications were included in quantitative analyses. Overall random-effects weighted M:F prevalence ratios were 2.21 (95% CI 1.92-2.54; 56 surveys) for bacteriologically positive TB and 2.51 (95% CI 2.07-3.04; 40 surveys) for smear-positive TB. M:F prevalence ratios were highest in South-East Asia and in surveys that did not require self-report of signs/symptoms in initial screening procedures. The summary random-effects weighted M:F ratio for P:N ratios was 1.55 (95% CI 1.25-1.91; 34 surveys). We intended to stratify the analyses by age, HIV status, and rural or urban setting; however, few studies reported such data.Conclusions: TB prevalence is significantly higher among men than women in low- and middle-income countries, with strong evidence that men are disadvantaged in seeking and/or accessing TB care in many settings. Global strategies and national TB programmes should recognise men as an underserved high-risk group and improve men's access to diagnostic and screening services to reduce the overall burden of TB more effectively and ensure gender equity in TB care. [ABSTRACT FROM AUTHOR]

Trials of isoniazid preventive therapy (IPT) for people living with HIV in southern Africa have shown high rates of tuberculosis disease immediately after cessation of therapy. This could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. Using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-tuberculosis-burden settings. We identified randomized controlled trials that compared IPT to placebo or alternative regimen in HIV-positive, tuberculin skin test positive individuals. A mathematical model describing tuberculosis transmission in a closed cohort of HIV-positive, M. tuberculosis infected, antiretro-viral therapy naive individuals following completion of preventive therapy (or placebo) was fitted to post-therapy tuberculosis rates to estimate the annual risk of M. tuberculosis reinfection and the proportion of individuals whose latent infection was cured after therapy. Three trials met our inclusion criteria. Estimated annual risks of reinfection ranged between 3.7 and 4.9%. Our results suggest 6 mo of isoniazid cured in a small proportion [estimated proportion cured = 0% (interquartile range 0-30.9%)]. The proportion cured for 3-mo regimens containing rifampicin or rifapentine was 19-100%. IPT alone does not cure existing infections in the majority of HIV-infected individuals. In high-incidence settings, continuous IPT should be integrated with HIV care. Where the risk of reinfection is lower, preventive therapy with more curative drugs should be preferred for HIV-positive individuals to achieve durable patient benefit. [ABSTRACT FROM AUTHOR]

Background: To end the global tuberculosis epidemic, latent tuberculosis infection needs to be addressed. All standard treatments for latent tuberculosis contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is resistant. We aimed to estimate the global burden of multidrug-resistant latent tuberculosis infection to inform tuberculosis elimination policy.Methods: By fitting a flexible statistical model to tuberculosis drug resistance surveillance and survey data collated by WHO, we estimated national trends in the proportion of new tuberculosis cases that were caused by MDR strains. We used these data as a proxy for the proportion of new infections caused by MDR M tuberculosis and multiplied trends in annual risk of infection from previous estimates of the burden of latent tuberculosis to generate trends in the annual risk of infection with MDR M tuberculosis. These estimates were used in a cohort model to estimate changes in the global and national prevalence of latent infection with MDR M tuberculosis. We also estimated recent infection levels (ie, in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis in 2035 and 2050.Findings: 19·1 million (95% uncertainty interval [UI] 16·4 million-21·7 million) people were latently infected with MDR tuberculosis in 2014-a global prevalence of 0·3% (95% UI 0·2-0·3). MDR strains accounted for 1·2% (95% UI 1·0-1·4) of the total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6-3·1) of the burden among children younger than 15 years (risk ratio for those younger than 15 years vs those aged 15 years or older 2·65 [95% UI 2·11-3·25]). Recent latent infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million-2·3 million) people globally were at high risk of active MDR tuberculosis in 2015.Interpretation: We estimate that three in every 1000 people globally carry latent MDR tuberculosis infection, and prevalence is around ten times higher among those younger than 15 years. If current trends continue, the proportion of latent tuberculosis caused by MDR strains will increase, which will pose serious challenges for management of latent tuberculosis-a cornerstone of tuberculosis elimination strategies.Funding: UK Medical Research Council, Bill & Melinda Gates Foundation, and European Research Council. [ABSTRACT FROM AUTHOR]