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      The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling

      1 , 2 , * , , 3

      PLoS Medicine

      Public Library of Science

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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

          In this mathematical modelling study, Rein Houben and colleagues provide updated estimates of latent tuberculosis infection worldwide and its implications of this reservoir with respect to goals for eliminating tuberculosis.

          Author Summary

          Why Was This Study Done?
          • Addressing the latent TB infection reservoir is critical to achieving TB elimination.

          • The current estimate that “one-third” of the global population is infected with tuberculosis is widely cited but has not been formally estimated for nearly 20 y.

          • Changes in demography, the size and distribution of TB burden, as well as new scientific insights and the availability of new data mean a re-estimation is needed.

          What Did the Researchers Do and Find?
          • We generated an annual risk of infection between 1934 and 2014 and applied this to a country-level demographic model, quantifying uncertainty wherever possible.

          • We estimated that approximately 1.7 billion individuals were infected with LTBI in 2014; just under a quarter of the global population.

          • If left unaddressed, the current LTBI burden alone will likely prevent achieving the global TB targets for TB elimination.

          What Do These Findings Mean?
          • For long-term TB control to be successful, an aggressive approach to LTBI is needed.

          • Research and development should focus on developing better tools to identify individuals who will benefit from LTBI treatment.

          • Estimates would be strengthened by additional empirical data from new population-based studies of LTBI prevalence.

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          Most cited references 25

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          The growing burden of tuberculosis: global trends and interactions with the HIV epidemic.

          The increasing global burden of tuberculosis (TB) is linked to human immunodeficiency virus (HIV) infection. We reviewed data from notifications of TB cases, cohort treatment outcomes, surveys of Mycobacterium tuberculosis infection, and HIV prevalence in patients with TB and other subgroups. Information was collated from published literature and databases held by the World Health Organization (WHO), the Joint United Nations Programme on HIV/Acquired Immunodeficiency Syndrome (UNAIDS), the US Census Bureau, and the US Centers for Disease Control and Prevention. There were an estimated 8.3 million (5th-95th centiles, 7.3-9.2 million) new TB cases in 2000 (137/100,000 population; range, 121/100,000-151/100,000). Tuberculosis incidence rates were highest in the WHO African Region (290/100,000 per year; range, 265/100,000-331/100,000), as was the annual rate of increase in the number of cases (6%). Nine percent (7%-12%) of all new TB cases in adults (aged 15-49 years) were attributable to HIV infection, but the proportion was much greater in the WHO African Region (31%) and some industrialized countries, notably the United States (26%). There were an estimated 1.8 million (5th-95th centiles, 1.6-2.2 million) deaths from TB, of which 12% (226 000) were attributable to HIV. Tuberculosis was the cause of 11% of all adult AIDS deaths. The prevalence of M tuberculosis-HIV coinfection in adults was 0.36% (11 million people). Coinfection prevalence rates equaled or exceeded 5% in 8 African countries. In South Africa alone there were 2 million coinfected adults. The HIV pandemic presents a massive challenge to global TB control. The prevention of HIV and TB, the extension of WHO DOTS programs, and a focused effort to control HIV-related TB in areas of high HIV prevalence are matters of great urgency.
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            • Article: not found

            Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project.

            To estimate the risk and prevalence of Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) incidence, prevalence, and mortality, including disease attributable to human immunodeficiency virus (HIV), for 212 countries in 1997. A panel of 86 TB experts and epidemiologists from more than 40 countries was chosen by the World Health Organization (WHO), with final agreement being reached between country experts and WHO staff. Incidence of TB and mortality in each country was determined by (1) case notification to the WHO, (2) annual risk of infection data from tuberculin surveys, and (3) data on prevalence of smear-positive pulmonary disease from prevalence surveys. Estimates derived from relatively poor data were strongly influenced by panel member opinion. Objective estimates were derived from high-quality data collected recently by approved procedures. Agreement was reached by (1) participants reviewing methods and data and making provisional estimates in closed workshops held at WHO's 6 regional offices, (2) principal authors refining estimates using standard methods and all available data, and (3) country experts reviewing and adjusting these estimates and reaching final agreement with WHO staff. In 1997, new cases of TB totaled an estimated 7.96 million (range, 6.3 million-11.1 million), including 3.52 million (2.8 million-4.9 million) cases (44%) of infectious pulmonary disease (smear-positive), and there were 16.2 million (12.1 million-22.5 million) existing cases of disease. An estimated 1.87 million (1.4 million-2.8 million) people died of TB and the global case fatality rate was 23% but exceeded 50% in some African countries with high HIV rates. Global prevalence of MTB infection was 32% (1.86 billion people). Eighty percent of all incident TB cases were found in 22 countries, with more than half the cases occurring in 5 Southeast Asian countries. Nine of 10 countries with the highest incidence rates per capita were in Africa. Prevalence of MTB/HIV coinfection worldwide was 0.18% and 640000 incident TB cases (8%) had HIV infection. The global burden of tuberculosis remains enormous, mainly because of poor control in Southeast Asia, sub-Saharan Africa, and eastern Europe, and because of high rates of M tuberculosis and HIV coinfection in some African countries.
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              Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness.

               B. Trunz,  P E Fine,  C. Dye (2006)
              BCG vaccine has shown consistently high efficacy against childhood tuberculous meningitis and miliary tuberculosis, but variable efficacy against adult pulmonary tuberculosis and other mycobacterial diseases. We assess and compare the costs and effects of BCG as an intervention against severe childhood tuberculosis in different regions of the world. We calculated the number of tuberculous meningitis and miliary tuberculosis cases that have been and will be prevented in all children born in 2002, by combining estimates of the annual risk of tuberculosis infection, the proportion of infections that lead to either of these diseases in unvaccinated children, the number of children vaccinated, and BCG efficacy. We estimated that the 100.5 million BCG vaccinations given to infants in 2002 will have prevented 29,729 cases of tuberculous meningitis (5th-95th centiles, 24,063-36,192) in children during their first 5 years of life, or one case for every 3435 vaccinations (2771-4177), and 11,486 cases of miliary tuberculosis (7304-16,280), or one case for every 9314 vaccinations (6172-13,729). The numbers of cases prevented would be highest in South East Asia (46%), sub-Saharan Africa (27%), the western Pacific region (15%), and where the risk of tuberculosis infection and vaccine coverage are also highest. At US2-3 dollars per dose, BCG vaccination costs US206 dollars (150-272) per year of healthy life gained. BCG vaccination is a highly cost-effective intervention against severe childhood tuberculosis; it should be retained in high-incidence countries as a strategy to supplement the chemotherapy of active tuberculosis.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                25 October 2016
                October 2016
                : 13
                : 10
                Affiliations
                [1 ]TB Modelling Group, TB Centre, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [2 ]Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [3 ]School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom
                University of California San Francisco, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: RMGJH PJD.

                • Investigation: RMGJH PJD.

                • Methodology: RMGJH PJD.

                • Writing – original draft: RMGJH PJD.

                • Writing – review & editing: RMGJH PJD.

                Article
                PMEDICINE-D-16-01092
                10.1371/journal.pmed.1002152
                5079585
                27780211
                © 2016 Houben, Dodd

                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.

                Page count
                Figures: 3, Tables: 2, Pages: 13
                Product
                Funding
                Funded by: Bill and Melinda Gates Foundation (US)
                Award ID: OPP1084276
                Award Recipient :
                RMGJH was partly funded by the Bill and Melinda Gates Foundation (TB Modelling and Analysis Consortium: OPP1084276). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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