Estimating the prevalence of latent tuberculosis in a low-incidence setting: Australia.

Migration is a key driver of tuberculosis (TB) in many low-incidence settings, with the majority of TB cases attributed to reactivation of latent TB (LTBI) acquired overseas. A greater understanding of LTBI risk in heterogeneous migrant populations would aid health planning. We aimed to estimate the LTBI prevalence and distribution among locally born and overseas-born Australians.Annual risks of TB infection estimates were applied to population cohorts (by country of birth, year of arrival and age) in Australian census data in 2006, 2011 and 2016.Both the absolute number and proportion of Australian residents with LTBI increased from 4.6% (interquartile range (IQR) 4.2-5.2%) in 2006 to 5.1% (IQR 4.7-5.5%) in 2016, due to the increasing proportion of the population born overseas (23.8% in 2006 to 28.3% in 2016). Of all residents estimated to have LTBI in 2016; 93.2% were overseas born, 21.6% were aged <35 years and 34.4% had migrated to Australia since 2007.The overall prevalence of LTBI in Australia is low. Some residents, particularly migrants from high-incidence settings, may have considerably higher risk of LTBI, and these findings allow for tailored public health interventions to reduce the risk and impact of future TB disease

Modeling of Novel Diagnostic Strategies for Active Tuberculosis – A Systematic Review: Current Practices and Recommendations

Introduction: The field of diagnostics for active tuberculosis (TB) is rapidly developing. TB diagnostic modeling can help to inform policy makers and support complicated decisions on diagnostic strategy, with important budgetary implications. Demand for TB diagnostic modeling is likely to increase, and an evaluation of current practice is important. We aimed to systematically review all studies employing mathematical modeling to evaluate cost-effectiveness or epidemiological impact of novel diagnostic strategies for active TB. Methods: Pubmed, personal libraries and reference lists were searched to identify eligible papers. We extracted data on a wide variety of model structure, parameter choices, sensitivity analyses and study conclusions, which were discussed during a meeting of content experts. Results & Discussion From 5619 records a total of 36 papers were included in the analysis. Sixteen papers included population impact/transmission modeling, 5 were health systems models, and 24 included estimates of cost-effectiveness. Transmission and health systems models included specific structure to explore the importance of the diagnostic pathway (n = 4), key determinants of diagnostic delay (n = 5), operational context (n = 5), and the pre-diagnostic infectious period (n = 1). The majority of models implemented sensitivity analysis, although only 18 studies described multi-way sensitivity analysis of more than 2 parameters simultaneously. Among the models used to make cost-effectiveness estimates, most frequent diagnostic assays studied included Xpert MTB/RIF (n = 7), and alternative nucleic acid amplification tests (NAATs) (n = 4). Most (n = 16) of the cost-effectiveness models compared new assays to an existing baseline and generated an incremental cost-effectiveness ratio (ICER). Conclusion: Although models have addressed a small number of important issues, many decisions regarding implementation of TB diagnostics are being made without the full benefits of insight from mathematical models. Further models are needed that address a wider array of diagnostic and epidemiological settings, that explore the inherent uncertainty of models and that include additional epidemiological data on transmission implications of false-negative diagnosis and the pre-diagnostic period

The Impact of Antiretroviral Therapy on Mortality in HIV Positive People during Tuberculosis Treatment: A Systematic Review and Meta-Analysis

Objective: To quantify the impact of antiretroviral therapy (ART) on mortality in HIV-positive people during tuberculosis (TB) treatment. Design: We conducted a systematic literature review and meta-analysis. Studies published from 1996 through February 15, 2013, were identified by searching electronic resources (Pubmed and Embase) and conference books, manual searches of references, and expert consultation. Pooled estimates for the outcome of interest were acquired using random effects meta-analysis. Subjects The study population included individuals receiving ART before or during TB treatment. Main Outcome Measures: Main outcome measures were: (i) TB-case fatality ratio (CFR), defined as the proportion of individuals dying during TB treatment and, if mortality in HIV-positive people not on ART was also reported, (ii) the relative risk of death during TB treatment by ART status. Results: Twenty-one studies were included in the systematic review. Random effects pooled meta-analysis estimated the CFR between 8% and 14% (pooled estimate 11%). Among HIV-positive TB cases, those receiving ART had a reduction in mortality during TB treatment of between 44% and 71% (RR = 0.42, 95%CI: 0.29–0.56). Conclusion: Starting ART before or during TB therapy reduces the risk of death during TB treatment by around three-fifths in clinical settings. National programmes should continue to expand coverage of ART for HIV positive in order to control the dual epidemic

Sex Differences in Tuberculosis Burden and Notifications in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis

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

Migration and tuberculosis transmission in a middle-income country: a cross-sectional study in a central area of São Paulo, Brazil.

BACKGROUND: Little is known about the impact of growing migration on the pattern of tuberculosis (TB) transmission in middle-income countries. We estimated TB recent transmission and its associated factors and investigated the presence of cross-transmission between South American migrants and Brazilians. METHODS: We studied a convenient sample of cases of people with pulmonary TB in a central area of São Paulo, Brazil, diagnosed between 2013 and 2014. Cases with similar restriction fragment length polymorphism (IS6110-RFLP) patterns of their Mycobacterium tuberculosis complex isolates were grouped in clusters (recent transmission). Clusters with both Brazilian and South American migrants were considered mixed (cross-transmission). Risk factors for recent transmission were studied using logistic regression. RESULTS: Isolates from 347 cases were included, 76.7% from Brazilians and 23.3% from South American migrants. Fifty clusters were identified, which included 43% South American migrants and 60.2% Brazilians (odds ratio = 0.50, 95% confidence interval = 0.30-0.83). Twelve cross-transmission clusters were identified, involving 24.6% of all clustered cases and 13.8% of all genotyped cases, with migrants accounting for either an equal part or fewer cases in 11/12 mixed clusters. CONCLUSIONS: Our results suggest that TB disease following recent transmission is more common among Brazilians, especially among those belonging to high-risk groups, such as drug users. Cross-transmission between migrants and Brazilians was present, but we found limited contributions from migrants to Brazilians in central areas of São Paulo and vice versa

The impact of social protection and poverty elimination on global tuberculosis incidence: a statistical modelling analysis of Sustainable Development Goal 1.

BACKGROUND: The End TB Strategy and the Sustainable Development Goals (SDGs) are intimately linked by their common targets and approaches. SDG 1 aims to end extreme poverty and expand social protection coverage by 2030. Achievement of SDG 1 is likely to affect the tuberculosis epidemic through a range of pathways. We estimate the reduction in global tuberculosis incidence that could be obtained by reaching SDG 1. METHODS: We developed a conceptual framework linking key indicators of SDG 1 progress to tuberculosis incidence via well described risk factor pathways and populated it with data from the SDG data repository and the WHO tuberculosis database for 192 countries. Correlations and mediation analyses informed the strength of the association between the SDG 1 subtargets and tuberculosis incidence, resulting in a simplified framework for modelling. The simplified framework linked key indicators for SDG 1 directly to tuberculosis incidence. We applied an exponential decay model based on linear associations between SDG 1 indicators and tuberculosis incidence to estimate tuberculosis incidence in 2035. FINDINGS: Ending extreme poverty resulted in a reduction in global incidence of tuberculosis of 33·4% (95% credible interval 15·5-44·5) by 2035 and expanding social protection coverage resulted in a reduction in incidence of 76·1% (45·2-89·9) by 2035; both pathways together resulted in a reduction in incidence of 84·3% (54·7-94·9). INTERPRETATION: Full achievement of SDG 1 could have a substantial effect on the global burden of tuberculosis. Cross-sectoral approaches that promote poverty reduction and social protection expansion will be crucial complements to health interventions, accelerating progress towards the End TB targets. FUNDING: World Health Organization

Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.

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

Subclinical Tuberculosis Disease-A Review and Analysis of Prevalence Surveys to Inform Definitions, Burden, Associations, and Screening Methodology.

While it is known that a substantial proportion of individuals with tuberculosis disease (TB) present subclinically, usually defined as bacteriologically-confirmed but negative on symptom screening, considerable knowledge gaps remain. Our aim was to review data from TB prevalence population surveys and generate a consistent definition and framework for subclinical TB, enabling us to estimate the proportion of TB that is subclinical, explore associations with overall burden and program indicators, and evaluate the performance of screening strategies. We extracted data from all publicly available prevalence surveys conducted since 1990. Between 36.1% and 79.7% (median, 50.4%) of prevalent bacteriologically confirmed TB was subclinical. No association was found between prevalence of subclinical and all bacteriologically confirmed TB, patient diagnostic rate, or country-level HIV prevalence (P values, .32, .4, and .34, respectively). Chest Xray detected 89% (range, 73%-98%) of bacteriologically confirmed TB, highlighting the potential of optimizing current TB case-finding policies