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      Antiretroviral Treatment Scale-Up and Tuberculosis Mortality in High TB/HIV Burden Countries: An Econometric Analysis

      1 , 2 , 3 , 4 , 5 , *

      PLoS ONE

      Public Library of Science

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          Abstract

          Introduction

          Antiretroviral therapy (ART) reduces mortality in patients with active tuberculosis (TB), but the population-level relationship between ART coverage and TB mortality is untested. We estimated the reduction in population-level TB mortality that can be attributed to increasing ART coverage across 41 high HIV-TB burden countries.

          Methods

          We compiled TB mortality trends between 1996 and 2011 from two sources: (1) national program-reported TB death notifications, adjusted for annual TB case detection rates, and (2) WHO TB mortality estimates. National coverage with ART, as proportion of HIV-infected people in need, was obtained from UNAIDS. We applied panel linear regressions controlling for HIV prevalence (5-year lagged), coverage of TB interventions (estimated by WHO and UNAIDS), gross domestic product per capita, health spending from domestic sources, urbanization, and country fixed effects.

          Results

          Models suggest that that increasing ART coverage was followed by reduced TB mortality, across multiple specifications. For death notifications at 2 to 5 years following a given ART scale-up, a 1% increase in ART coverage predicted 0.95% faster mortality rate decline (p = 0.002); resulting in 27% fewer TB deaths in 2011 alone than would have occurred without ART. Based on WHO death estimates, a 1% increase in ART predicted a 1.0% reduced TB death rate (p<0.001), and 31% fewer deaths in 2011. TB mortality was higher at higher HIV prevalence (p<0.001), but not related to coverage of isoniazid preventive therapy, cotrimoxazole preventive therapy, or other covariates.

          Conclusion

          This econometric analysis supports a substantial impact of ART on population-level TB mortality realized already within the first decade of ART scale-up, that is apparent despite variable-quality mortality data.

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          Most cited references 37

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          Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.

          Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. Bill & Melinda Gates Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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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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              Increases in adult life expectancy in rural South Africa: valuing the scale-up of HIV treatment.

              The scale-up of antiretroviral therapy (ART) is expected to raise adult life expectancy in populations with high HIV prevalence. Using data from a population cohort of over 101,000 individuals in rural KwaZulu-Natal, South Africa, we measured changes in adult life expectancy for 2000-2011. In 2003, the year before ART became available in the public-sector health system, adult life expectancy was 49.2 years; by 2011, adult life expectancy had increased to 60.5 years--an 11.3-year gain. Based on standard monetary valuation of life, the survival benefits of ART far outweigh the costs of providing treatment in this community. These gains in adult life expectancy signify the social value of ART and have implications for the investment decisions of individuals, governments, and donors.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 August 2016
                2016
                : 11
                : 8
                Affiliations
                [1 ]Department of Economics and Finance, City University of Hong Kong, Kowloon, Hong Kong
                [2 ]Division of General Medical Disciplines, Stanford University, Stanford, California, United States of America
                [3 ]Center for Health Policy and the Center for Primary Care and Outcomes Research, Stanford University, Stanford, California, United States of America
                [4 ]Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
                [5 ]Avenir Health, Geneva, Switzerland
                Fundacao Oswaldo Cruz, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: EK, EB, IY.

                • Performed the experiments: IY.

                • Analyzed the data: EK, IY, EB.

                • Contributed reagents/materials/analysis tools: EK, IY, EB.

                • Wrote the paper: EK, IY, EB.

                Article
                PONE-D-16-03800
                10.1371/journal.pone.0160481
                4990253
                27536864
                © 2016 Yan 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.

                Page count
                Figures: 3, Tables: 2, Pages: 16
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000862, Doris Duke Charitable Foundation;
                Award Recipient :
                Funded by: Dr. George Rosenkranz Prize for Health Care Research in Developing Countries
                Award Recipient :
                EB was supported by the National Institute for Drug Abuse (DA015612) and by the Doris Duke Charitable Foundation. IY acknowledges support by the National Natural Science Foundation (project no. 71403061) and by the Global Research Unit (GRU) at the City University of Hong Kong. The funders of the study had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.
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                All data are available from within the paper, S1 Table, and their quoted public sources, notably including: WHO Stop TB country databases: http://www.who.int/tb/country/data/download/en/, AIDS Info Online, UNAIDS: http://www.aidsinfoonline.org/devinfo/libraries/aspx/Home.aspx, World Health Organization. 2011. Indicator and Measurement Registry version 1.7.0. Geneva. http://apps.who.int/gho/indicatorregistry/App_Main/view_indicator.aspx?iid=3430 and World Bank. World Development Indicators database. http://siteresources.worldbank.org/DATASTATISTICS/Resources/GNI.pdf.

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