Sequential adaptive strategies for sampling rare clustered populations.

A new class of sampling strategies is proposed that can be applied to population-based surveys targeting a rare trait that is unevenly spread over an area of interest. Our proposal is characterised by the ability to tailor the data collection to specific features and challenges of the survey at hand. It is based on integrating an adaptive component into a sequential selection, which aims both to intensify the detection of positive cases, upon exploiting the spatial clustering, and to provide a flexible framework to manage logistics and budget constraints. A class of estimators is also proposed to account for the selection bias, that are proved unbiased for the population mean (prevalence) as well as consistent and asymptotically Normal distributed. Unbiased variance estimation is also provided. A ready-to-implement weighting system is developed for estimation purposes. Two special strategies included in the proposed class are presented, that are based on the Poisson sampling and proved more efficient. The selection of primary sampling units is also illustrated for tuberculosis prevalence surveys, which are recommended in many countries and supported by the World Health Organisation as an emblematic example of the need for an improved sampling design. Simulation results are given in the tuberculosis application to illustrate the strengths and weaknesses of the proposed sequential adaptive sampling strategies with respect to traditional cross-sectional non-informative sampling as currently suggested by World Health Organisation guidelines.

Prevalence of bacteriologically confirmed pulmonary tuberculosis in South Africa, 2017-19: a multistage, cluster-based, cross-sectional survey.

BACKGROUND: Tuberculosis remains an important clinical and public health issue in South Africa, which has one of the highest tuberculosis burdens in the world. We aimed to estimate the burden of bacteriologically confirmed pulmonary tuberculosis among people aged 15 years or older in South Africa. METHODS: This multistage, cluster-based, cross-sectional survey included eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people; selected by probability proportional-to-population size sampling). Participants completed face-to-face symptom questionnaires (for cough, weight loss, fever, and night sweats) and manually read digital chest X-ray screening. Screening was recorded as positive if participants had at least one symptom or an abnormal chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples from participants who were screen-positive were tested by the Xpert MTB/RIF Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture (second sample), with optional HIV testing. Participants with a positive Mycobacterium tuberculosis complex culture were considered positive for bacteriologically confirmed pulmonary tuberculosis; when culture was not positive, participants with a positive Xpert MTB/RIF Ultra result with an abnormal chest X-ray suggestive of active tuberculosis and without current or previous tuberculosis were considered positive for bacteriologically confirmed pulmonary tuberculosis. FINDINGS: Between Aug 15, 2017, and July 28, 2019, 68 771 people were enumerated from 110 clusters, with 53 250 eligible to participate in the survey, of whom 35 191 (66·1%) participated. 9066 (25·8%) of 35 191 participants were screen-positive and 234 (0·7%) were identified as having bacteriologically confirmed pulmonary tuberculosis. Overall, the estimated prevalence of bacteriologically confirmed pulmonary tuberculosis was 852 cases (95% CI 679-1026) per 100 000 population; the prevalence was highest in people aged 35-44 years (1107 cases [95% CI 703-1511] per 100 000 population) and those aged 65 years or older (1104 cases [680-1528] per 100 000 population). The estimated prevalence was approximately 1·6 times higher in men than in women (1094 cases [95% CI 835-1352] per 100 000 population vs 675 cases [494-855] per 100 000 population). 135 (57·7%) of 234 participants with tuberculosis screened positive by chest X-ray only, 16 (6·8%) by symptoms only, and 82 (35·9%) by both. 55 (28·8%) of 191 participants with tuberculosis with known HIV status were HIV-positive. INTERPRETATION: Pulmonary tuberculosis prevalence in this survey was high, especially in men. Despite the ongoing burden of HIV, many participants with tuberculosis in this survey did not have HIV. As more than half of the participants with tuberculosis had an abnormal chest X-ray without symptoms, prioritising chest X-ray screening could substantially increase case finding. FUNDING: Global Fund, Bill & Melinda Gates Foundation, USAID.

Addressing the Data Gaps on Child and Adolescent Tuberculosis.

The burden of tuberculosis (TB) among children and young adolescents (<15 years old) is estimated at 1.1 million; however, only 400,000 are treated for TB, indicating a large gap between the number who are cared for and the number estimated to have TB. Accurate data on the burden of pediatric TB is essential to guide action. Despite several improvements in estimating the burden of pediatric TB in the last decade, as well as enhanced data collection efforts, several data gaps remain, both at the global level, but also at the national level where surveillance systems and collaborative research are critical. In this article, we describe recent advances in data collection and burden estimates for TB among children and adolescents, and the remaining gaps. While data collection continues to improve, burden estimates must evolve in parallel, both in terms of their frequency and the methods used. Currently, at the global level, there is a focus on age-disaggregation of TB notifications, the collection of data on TB-HIV, multi-drug resistant (MDR)-TB and treatment outcomes, as well as estimates of the disease burden. Additional data from national surveillance systems or research projects on TB meningitis, as well as other forms of extra-pulmonary TB, would be useful. We must capitalize on the current momentum in child and adolescent TB to close the remaining data gaps for these age groups to better understand the epidemic and further reduce morbidity and mortality due to TB.

Methods for estimating tuberculosis incidence and mortality by age and sex.

AIMS: To develop methods to disaggregate World Health Orgagnization estimates of tuberculosis (TB) incidence and mortality for each country by sex and age. METHODS: For countries where incidence estimates derived from a factor adjustment of notifications and case detection ratio over 0.85, or with <1000 reported TB cases, we disaggregated incidence proportional to notifications. For each other country, a prior was constructed using a hierarchical model of age-stratified prevalence survey data, meta-analysis of sex ratios, and mathematical modelling for children under 15 years. Samples from this prior were used to disaggregate incidence and accepted if incidence exceeded notifications in each age/sex category. Results were inspected and, if implausible, incidence was disaggregated proportional to notifications. Mortality was disaggregated proportional to patterns in vital registration (VR) data in countries with VR data. Where VR data were lacking, a case-fatality ratio (CFR) approach was applied to estimated incidence, with separate CFRs by HIV/ART status, child/adult age groups, and anti-TB treatment status. Uncertainty in all disaggregated country estimates was constructed to be consistent with corresponding overall uncertainty. RESULTS: We generated disaggregated results for 216 countries. For 125 countries, incidence disaggregation was based on notifications. Of the rest, accepted samples from the prior were considered implausible in 4 countries. For 72 countries, mortality disaggregation was based on VR data; the rest were based on the CFR approach. CONCLUSIONS: While multi-stage, this approach is comparatively simple in overall logic. Disaggregated estimates have relatively larger uncertainty and should be used with caution.

Global Epidemiology of Tuberculosis and Progress Toward Meeting Global Targets - Worldwide, 2018.

Worldwide, tuberculosis (TB) is the leading cause of death from a single infectious disease agent (1), including among persons living with human immunodeficiency virus (HIV) infection (2). A World Health Organization (WHO) initiative, The End Tuberculosis Strategy, set ambitious targets for 2020-2035, including 20% reduction in TB incidence and 35% reduction in the absolute number of TB deaths by 2020 and 90% reduction in TB incidence and 95% reduction in TB deaths by 2035, compared with 2015 (3). This report evaluated global progress toward these targets based on data reported by WHO (1). Annual TB data routinely reported to WHO by 194 member states were used to estimate TB incidence and mortality overall and among persons with HIV infection, TB-preventive treatment (TPT) initiation, and drug-resistant TB for 2018 (1). In 2018, an estimated 10 million persons had incident TB, and 1.5 million TB-related deaths occurred, representing 2% and 5% declines from 2017, respectively. The number of persons with both incident and prevalent TB remained highest in the WHO South-East Asia and African regions. Decreases in the European region were on track to meet 2020 targets. Globally, among persons living with HIV, 862,000 incident TB cases occurred, and 1.8 million persons initiated TPT. Rifampicin-resistant or multidrug-resistant TB occurred among 3.4% of persons with new TB and 18% among persons who were previously treated for TB (overall, among 4.8% of persons with TB). The modest decreases in the number of persons with TB and the number of TB-related deaths were consistent with recent trends, and new and substantial progress was observed in increased TPT initiation among persons living with HIV. However, to meet the global targets for 2035, more intensive efforts are needed by public health partners to decrease TB incidence and deaths and increase the number of persons receiving TB curative and preventive treatment. Innovative approaches to case finding, scale-up of TB preventive treatment, use of newer TB treatment regimens, and prevention and control of HIV will contribute to decreasing TB.

Measuring and addressing the childhood tuberculosis reporting gaps in Pakistan: The first ever national inventory study among children.

INTRODUCTION: Tuberculosis in children may be difficult to diagnose and is often not reported to routine surveillance systems. Understanding and addressing the tuberculosis (TB) case detection and reporting gaps strengthens national routine TB surveillance systems. OBJECTIVE: The present study aimed to measure the percentage of childhood TB cases that are diagnosed but not reported to the national surveillance system in Pakistan. DESIGN: The study design was cross sectional. The study was nationwide in 12 selected districts across Pakistan, each representing a cluster. Health facilities that diagnose and treat childhood TB from all sectors were mapped and invited to participate. Lists of child TB cases were created for the study period (April-June 2016) from all study facilities and compared against the list of child TB cases notified to the national TB surveillance system for the same districts and the same period. RESULTS: All public and private health facilities were mapped across 12 sampled districts in Pakistan and those providing health services to child TB cases were included in the study. From all private health facilities, 7,125 children were found with presumptive TB during the study period. Of them, 5,258 were diagnosed with tuberculosis: 11% were bacteriologically-confirmed and 89% clinically-diagnosed; only 4% were notified to National TB Control Program. An additional 1,267 children with TB were also registered in the National TB Control Program. Underreporting was measured to be 78%. CONCLUSION: This is the first nationwide childhood TB inventory study globally and confirmed that childhood TB underreporting is very high in Pakistan. TB surveillance in the country must be strengthened to address this, with particular attention to guiding and supporting general practitioners and pediatricians to notify their TB cases.

Prevention of tuberculosis in household members: estimates of children eligible for treatment.

OBJECTIVE: To estimate of the number of children younger than 5 years who were household contacts of people with tuberculosis and were eligible for tuberculosis preventive treatment in 2017. METHODS: To estimate the number of eligible children, we obtained national values for the number of notified cases of bacteriologically confirmed pulmonary tuberculosis in 2017, the proportion of the population younger than 5 years in 2017 and average household size from published sources. We obtained global values for the number of active tuberculosis cases per household with an index case and for the prevalence of latent tuberculosis infection among children younger than 5 years who were household contacts of a tuberculosis case through systematic reviews, meta-analysis and Poisson regression models. FINDINGS: The estimated number of children younger than 5 years eligible for tuberculosis preventive treatment in 2017 globally was 1.27 million (95% uncertainty interval, UI: 1.24-1.31), which corresponded to an estimated global coverage of preventive treatment in children of 23% at best. By country, the estimated number ranged from less than one in the Bahamas, Iceland, Luxembourg and Malta to 350 000 (95% UI: 320 000-380 000) in India. Regionally, the highest estimates were for the World Health Organization (WHO) South-East Asia Region (510 000; 95% UI: 450 000-580 000) and the WHO African Region (470 000; 95% UI: 440 000-490 000). CONCLUSION: Tuberculosis preventive treatment in children was underutilized globally in 2017. Treatment should be scaled up to help eliminate the pool of tuberculosis infection and achieve the End TB Strategy targets.

Global Epidemiology of Tuberculosis and Progress Toward Achieving Global Targets - 2017.

Worldwide, tuberculosis (TB) is the leading cause of death from a single infectious disease agent (1) and the leading cause of death among persons living with human immunodeficiency virus (HIV) infection, accounting for approximately 40% of deaths in this population (2). The United Nations' (UN) Sustainable Development Goals (3) and the World Health Organization's (WHO's) End TB Strategy (4) have defined ambitious targets for 2020-2035, including a 35% reduction in the absolute number of TB deaths and a 20% reduction in TB incidence by 2020, compared with 2015 (4). Since 2000, WHO has produced annual TB estimates for all countries (1). Global and regional disease estimates were evaluated for 2017 to determine progress toward meeting targets. In 2017, an estimated 10 million incident cases of TB and 1.57 million TB deaths occurred, representing 1.8% and 3.9% declines, respectively, from 2016. Numbers of TB cases and disease incidence were highest in the WHO South-East Asia and Africa regions, and 9% of cases occurred among persons with HIV infection. Rifampicin-resistant (RR) or multidrug-resistant (MDR) (resistance to at least both isoniazid and rifampicin) TB occurred among 3.6% and 18% of new and previously treated TB cases, respectively (5.6% among all cases). Overall progress in global TB elimination was modest in 2017, consistent with that in recent years (1); intensified efforts to improve TB diagnosis, treatment, and prevention are required to meet global targets for 2020-2035.

Incidence and prevalence of bacteriologically confirmed pulmonary tuberculosis among adolescents and young adults: a systematic review.

The burden of tuberculosis (TB) among adolescents and young adults in endemic settings is poorly characterised. This study aimed to review published and unpublished estimates of the incidence and prevalence of bacteriologically confirmed TB among young people aged 10-24 years. We searched PubMed and World Health Organization archives for publications and unpublished data from population-based epidemiologic studies reporting confirmed pulmonary TB among young people, conducted from January 2000 onwards. We identified 27 publications and unpublished data from two national surveys, representing a total of 26 studies in 19 countries. The prevalence of bacteriologically confirmed TB ranged from 45 to 799 per 100 000 in the Asia-Pacific region and from 160 to 462 per 100 000 in African settings. We did not identify any epidemiologic studies of confirmed TB among adolescents living with human immunodeficiency virus (HIV). Many studies were excluded due to absent or inadequately reported age-specific data. Adolescents and young adults living in many endemic settings appear to be at substantial risk of developing active TB. There is a pressing need to improve the routine reporting of age in epidemiologic studies of TB, and to generate high-quality epidemiologic data regarding TB among adolescents living with HIV.

The incidence of tuberculosis among adolescents and young adults: a global estimate.

Historical data show that the risk of tuberculosis increases dramatically during adolescence, and young people face unique challenges in terms of case detection and effective treatment. However, little is known about the burden of tuberculosis among young people in the modern era. This study aimed to provide the first estimates of the global and regional incidence of tuberculosis among young people aged 10-24 years.Using the World Health Organization (WHO) database of tuberculosis notifications for 2012, we estimated the burden of tuberculosis among young people by WHO region. Adjustments were made for incomplete age disaggregation and underreporting, using supplementary data from several countries representing diverse tuberculosis epidemics.We estimate that 1.78 million (uncertainty interval (UI) 1.23-3.00 million) young people developed tuberculosis in 2012, accounting for 17% of all new tuberculosis cases globally. Young people in the WHO South East Asian Region (721 000, UI 473 000-1.35 million) and the WHO African Region (534 000, UI 359 000-912 000) experienced the greatest number of tuberculosis episodes.Young people suffer a considerable burden of tuberculosis. Age-specific burden of disease estimation for this age group is complicated by incomplete age disaggregation of tuberculosis data, highlighting the importance of continued surveillance system strengthening.

The global burden of tuberculosis mortality in children: a mathematical modelling study.

BACKGROUND: Tuberculosis in children is increasingly recognised as an important component of the global tuberculosis burden, with an estimated 1 million cases in 2015. Although younger children are vulnerable to severe forms of tuberculosis disease, no age-disaggregated estimates of paediatric tuberculosis mortality exist, and tuberculosis has never been included in official estimates of under-5 child mortality. We aimed to produce a global mortality burden estimate in children using a complementary approach not dependent on vital registration data. METHODS: In this mathematical modelling study, we estimated deaths in children younger than 5 years and those aged 5-14 years for 217 countries and territories using a case-fatality-based approach. We used paediatric tuberculosis notification data and HIV and antiretroviral treatment estimates to disaggregate the WHO paediatric tuberculosis incidence estimates by age, HIV, and treatment status. We then applied systematic review evidence on corresponding case-fatality ratios. FINDINGS: We estimated that 239 000 (95% uncertainty interval [UI] 194 000-298 000) children younger than 15 years died from tuberculosis worldwide in 2015; 80% (191 000, 95% UI 132 000-257 000) of these deaths were in children younger than 5 years. More than 70% (182 000, 140 000-239 000) of deaths occurred in the WHO southeast Asia and Africa regions. We estimated that 39 000 (17%, 23 000-73 000) paediatric tuberculosis deaths worldwide were in children with HIV infections, with 31 000 (36%, 19 000-59 000) in the WHO Africa region. More than 96% (230 000, 185 000-289 000) of all tuberculosis deaths occurred in children not receiving tuberculosis treatment. INTERPRETATION: Tuberculosis is a top ten cause of death in children worldwide and a key omission from previous analyses of under-5 mortality. Almost all these deaths occur in children not on tuberculosis treatment, implying substantial scope to reduce this burden. FUNDING: UNITAID, National Institutes of Health, and National Institute for Health Research.

Global burden of drug-resistant tuberculosis in children: a mathematical modelling study.

BACKGROUND: After infection with Mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications of M tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (MDR) disease than are identified. No work has yet quantified the burden of drug-resistant infection, or accounted for other types of drug resistance or sampling uncertainty. METHODS: We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We determined drug resistance using data from the Global Project on Antituberculosis Drug Resistance Surveillance at WHO, from surveys and surveillance reported between 1988 and 2014. We combined 1000 sampled proportions for each country from a Bayesian approach with 10 000 sampled country estimates of tuberculosis disease incidence and M tuberculosis infection prevalence. We estimated the proportions of tuberculosis cases at a country level with isoniazid monoresistance, rifampicin monoresistance, multidrug resistance (MDR), fluoroquinolone-resistant multidrug resistance, second-line injectable-resistant multidrug resistance, and extensive multidrug resistance with resistance to both a fluoroquinolone and a second-line injectable (XDR). FINDINGS: We estimated that 850 000 children developed tuberculosis in 2014; 58 000 with isoniazid-monoresistant tuberculosis, 25 000 with MDR tuberculosis, and 1200 with XDR tuberculosis. We estimate 67 million children are infected with M tuberculosis; 5 million with isoniazid monoresistance, 2 million with MDR, and 100 000 with XDR. Africa and southeast Asia have the highest numbers of children with tuberculosis, but the WHO Eastern Mediterranean region, European region, and Western Pacific region also contribute substantially to the burden of drug-resistant tuberculosis because of their much higher proportions of resistance. INTERPRETATION: Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This finding has implications for approaches to empirical treatment and preventive therapy in some regions of the world. FUNDING: UNITAID.

Understanding Market Size and Reporting Gaps for Paediatric TB in Indonesia, Nigeria and Pakistan: Supporting Improved Treatment of Childhood TB in the Advent of New Medicines.

OBJECTIVE OF THE STUDY: We sought to understand gaps in reporting childhood TB cases among public and private sector health facilities (dubbed "non-NTP" facilities) outside the network of national TB control programmes, and the resulting impact of under-reporting on estimates of paediatric disease burden and market demand for new medicines. METHODOLOGY: Exploratory assessments were carried out in Indonesia, Nigeria and Pakistan, reaching a range of facility types in two selected areas of each country. Record reviews and interviews of healthcare providers were carried out to assess numbers of unreported paediatric TB cases, diagnostic pathways followed and treatment regimens prescribed. MAIN FINDINGS: A total of 985 unreported diagnosed paediatric TB cases were identified over a three month period in 2013 in Indonesia from 64 facilities, 463 in Pakistan from 35 facilities and 24 in Nigeria from 20 facilities. These represent an absolute additional annualised yield to 2013 notifications reported to WHO of 15% for Indonesia, 2% for Nigeria and 7% for Pakistan. Only 12% of all facilities provided age and sex-disaggregated data. Findings highlight the challenges of confirming childhood TB. Diagnosis patterns in Nigeria highlight a very low suspicion for childhood TB. Providers note the need for paediatric medicines aligned to WHO recommendations. CONCLUSION HOW MARKET DATA CAN SUPPORT BETTER PUBLIC HEALTH INTERVENTIONS: This study emphasises the impact of incomplete reporting on the estimation of disease burden and potential market size of paediatric TB medicines. Further studies on "hubs" (facilities treating large numbers of childhood TB cases) will improve our understanding of the epidemic, support introduction efforts for new treatments and better measure markets for new paediatric medicines.

The first national tuberculosis prevalence survey of Lao PDR (2010-2011).

OBJECTIVE: The objective of the study was to measure the prevalence of bacteriologically confirmed pulmonary tuberculosis (TB) in Lao PDR in 2010-2011. METHOD: A nationwide, multistage cluster-sampled cross-sectional survey was undertaken in 2010-2011. All consenting participants ≥15 years were screened for pulmonary TB with chest X-ray and symptom questionnaire. Two sputum specimens for bacteriological examination by microscopy and culture were collected from those who screened positive. Prevalence was estimated using multiple imputation and inverse probability weighting methods. RESULTS: Of 39 212 eligible participants from 50 clusters, 6290 participants provided at least one sputum sample for smear and culture. There were 237 bacteriologically confirmed pulmonary TB cases, 107 of which were smear-positive. Chest X-ray screening alone identified 230 (97.0%) cases compared with 118 (49.8%) by symptom screening alone. The estimated prevalence of smear-positive and bacteriologically confirmed TB in those ≥15 years was 278 per 100 000 (95%C.I. 199-356) and 595 per 100 000 (95%C.I. 457-733), respectively. Prevalence significantly increased with age and was higher in men than women. CONCLUSIONS: The prevalence of TB in Lao PDR is almost twice as high than previous estimates, with the greatest burden in the older population. Case detection efforts remain the primary goal of the national TB programme with case notifications being very low in comparison with the estimated number of prevalent cases. The survey observed major limitations with the diagnostic strategy of passive (symptom based) case finding that uses only direct smear microscopy for confirmation.

National tuberculosis prevalence surveys in Asia, 1990-2012: an overview of results and lessons learned.

OBJECTIVE AND METHODS: In many countries, national tuberculosis (TB) prevalence surveys are the only way to reliably measure the burden of TB disease and monitor trends. They can also provide evidence about the current performance of TB care and control and how this could be improved. We developed an inventory of Asian surveys from 1953 to 2012 and then compiled and analysed a standard set of data for all national surveys implemented between 1990 (the baseline year for 2015 global TB targets) and 2012. RESULTS: There were 21 surveys in 12 countries between 1990 and 2012; published results were available for 18. The participation rate was at least 80% and often much higher except for two surveys in Thailand. The prevalence of bacteriologically-positive TB disease among adults aged ≥15 years varied widely among countries (1.2 per 1000 population in China in 2010 to 15 per 1000 population in Cambodia in 2002), but age and sex distribution patterns were consistent with a progressive increase in rates of disease by age, and men accounting for 66-75% of prevalent cases. A high proportion of cases (40-79% across all surveys) did not report TB symptoms that met screening criteria (generally cough of 2-3 weeks or more, and blood in the sputum) and were only detected due to chest X-ray screening of all survey participants; this proportion increased over time in countries with repeat survey data. The ratio of prevalent cases to cases notified to national TB programmes was typically around two, but was as high as three in Lao PDR and Pakistan even after the internationally recommended TB control strategy had been implemented nationwide for several years. Four countries (China, Cambodia, the Republic of Korea and the Philippines demonstrated declines in smear or culture-positive pulmonary TB prevalence of approximately 50% over 10 years. CONCLUSIONS: National TB prevalence surveys in Asia show that large reductions in the prevalence of TB disease can be achieved within a decade, that men bear much more of the burden than women and that the epidemic is ageing. Comparisons among countries show that more can be achieved in TB control in some countries with existing strategies and technologies. However, with many prevalent cases not reporting classic TB symptoms, all countries face the challenge of defining and implementing strategies that will result in earlier detection and treatment of cases.

Global epidemiology of tuberculosis.

Despite the availability of effective chemotherapy, tuberculosis (TB) killed 1.3 million people in 2012. Alongside HIV, it remains a top cause of death from an infectious disease. Global targets for reductions in the epidemiological burden of TB have been set for 2015 and 2050 within the context of the Millennium Development Goals (MDGs) and by the Stop TB Partnership. Achieving these targets is the focus of national and international efforts in TB control, and showing whether or not they are achieved is of major importance to guide future and sustainable investments. This article provides a short overview of sources of data to estimate TB disease burden; presents estimates of TB incidence, prevalence, and mortality in 2012 and an assessment of progress toward the 2015 targets for reductions in these indicators based on trends since 1990 and projections up to 2015; analyzes trends in TB notifications and in the implementation of the Stop TB Strategy; and considers prospects for elimination of TB after 2015.

A four-month gatifloxacin-containing regimen for treating tuberculosis.

BACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).