Global tuberculosis targets and milestones set for 2016-2035: definition and rationale.

BACKGROUND: Global tuberculosis (TB) targets were set as part of the World Health Organization's End TB Strategy (2016-2035) and the Sustainable Development Goals (2016-2030). OBJECTIVE: To define and explain the rationale for these targets. DESIGN: Scenarios for plausible reductions in TB deaths and cases were developed using empirical evidence from best-performing countries and modelling of the scale-up of under-used interventions and hypothetical TB vaccines. Results were discussed at consultations in 2012 and 2013. A final proposal was presented to the World Health Assembly in 2014 and unanimously endorsed by all Member States. RESULTS: The 2030 targets are a 90% reduction in TB deaths and 80% reduction in TB incidence compared with 2015 levels. The 2035 targets are for reductions of 95% and 90%, respectively. A third target-that no TB-affected households experience catastrophic costs due to the disease by 2020-was also agreed. CONCLUSION: The global TB targets and milestones set for the period 2016-2035 are ambitious. Achieving them requires concerted action on several fronts, but two things are fundamental: 1) progress towards universal health coverage to ensure that everyone with TB can access high-quality treatment; and 2) substantial investment in research and development for new tools to prevent TB disease among the approximately 1.7 billion people infected

The global tuberculosis epidemic and progress in care, prevention, and research: an overview in year 3 of the End TB era

Summary Tuberculosis is the number one cause of death from infectious disease globally and drug-resistant forms of the disease are a major risk to global health security. On the occasion of World Tuberculosis Day (March 24, 2018), we provide an up-to-date review of the status of the tuberculosis epidemic, recommended diagnostics, drug treatments and vaccines, progress in delivery of care and prevention, progress in research and development, and actions needed to accelerate progress. This Review is presented in the context of the UN Sustainable Development Goals and WHO's End TB Strategy, which share the aim of ending the global tuberculosis epidemic. In 2016, globally there were an estimated 10·4 million new cases of tuberculosis, and 600 000 new cases with resistance to rifampicin (the most powerful first-line drug). All countries and age groups are affected by tuberculosis, but most cases (90%) in 2016 were in adults, and almost two-thirds were accounted for by seven countries: India, Indonesia, China, Philippines, Pakistan, South Africa, and Nigeria. The sex ratio (male to female) was 1·9 and 10% of patients with newly diagnosed tuberculosis were also HIV-positive. There were 1·7 million deaths from tuberculosis in 2016, including 0·4 million deaths among people co-infected with HIV (officially classified as deaths caused by HIV/AIDS). Progress in care and prevention means that the global mortality rate (deaths per 100 000 people per year) is decreasing by 3·4% per year and incidence (new cases per 100 000 people per year) is decreasing by 1·9% per year. From 2000 to 2016, the annual global number of tuberculosis deaths decreased by 24% and the mortality rate declined by 37%. Worldwide, an estimated 53 million deaths were averted through successful treatment. Nonetheless, major gaps in care and prevention remain. For example, the 6·3 million new cases of tuberculosis reported globally in 2016 represented only 61% of the estimated incidence; only one in five of the estimated number of people with drug-resistant tuberculosis was enrolled in treatment. Pipelines for new diagnostics, drugs, and vaccines are progressing, but slowly. Actions needed to accelerate progress towards global milestones and targets for reductions in the burden of tuberculosis disease set for 2020, 2025, 2030, and 2035 include closing coverage gaps in testing, reporting of cases, and overall access to health care, especially in countries that account for the largest share of the global gap; multisectoral efforts to reduce prevalence of major risk factors for infection and disease; and increased investment in research and development

CJCheck Stage 1: development and testing of a checklist for reporting community juries – Delphi process and analysis of studies published in 1996–2015

Background Opportunities for community members to actively participate in policy development are increasing. Community/citizen's juries (CJs) are a deliberative democratic process aimed to illicit informed community perspectives on difficult topics. But how comprehensive these processes are reported in peer-reviewed literature is unknown. Adequate reporting of methodology enables others to judge process quality, compare outcomes, facilitate critical reflection and potentially repeat a process. We aimed to identify important elements for reporting CJs, to develop an initial checklist and to review published health and health policy CJs to examine reporting standards. Design Using the literature and expertise from CJ researchers and policy advisors, a list of important CJ reporting items was suggested and further refined. We then reviewed published CJs within the health literature and used the checklist to assess the comprehensiveness of reporting. Results CJCheck was developed and examined reporting of CJ planning, juror information, procedures and scheduling. We screened 1711 studies and extracted data from 38. No studies fully reported the checklist items. The item most consistently reported was juror numbers (92%, 35/38), while least reported was the availability of expert presentations (5%, 2/38). Recruitment strategies were described in 66% of studies (25/38); however, the frequency and timing of deliberations was inadequately described (29%, 11/38). Conclusions Currently CJ publications in health and health policy literature are inadequately reported, hampering their use in policy making. We propose broadening the CJCheck by creating a reporting standards template in collaboration with international CJ researchers, policy advisors and consumer representatives to ensure standardized, systematic and transparent reporting.RT was supported by a NHMRC Screening and Test Evaluation Program (STEP) Grant (#633033). RS was supported by a Bond University Vice Chancellor’s Research Grant Scheme. CD, SMC and LR received funding support from NHMRC Project Grant (#1023197). CD received funding support from a NHMRC Project Grant (#1083079). SMC is funded through NHMRC Career Development Fellowship (#1032963). JMS was funded by an Australian National Preventive Health Agency Fellowship (20STR2013F) and an NHMRC Capacity Building Grant (565501)

Implementing the global plan to stop TB, 2011-2015 - optimizing allocations and the global fund's contribution: A scenario projections study

Background: The Global Plan to Stop TB estimates funding required in low- and middle-income countries to achieve TB control targets set by the Stop TB Partnership within the context of the Millennium Development Goals. We estimate the contribution and impact of Global Fund investments under various scenarios of allocations across interventions and regions. Methodology/Principal Findings: Using Global Plan assumptions on expected cases and mortality, we estimate treatment costs and mortality impact for diagnosis and treatment for drug-sensitive and multidrug-resistant TB (MDR-TB), including antiretroviral treatment (ART) during DOTS for HIV-co-infected patients, for four country groups, overall and for the Global Fund investments. In 2015, China and India account for 24% of funding need, Eastern Europe and Central Asia (EECA) for 33%, sub-Saharan Africa (SSA) for 20%, and other low- and middle-income countries for 24%. Scale-up of MDR-TB treatment, especially in EECA, drives an increasing global TB funding need - an essential investment to contain the mortality burden associated with MDR-TB and future disease costs. Funding needs rise fastest in SSA, reflecting increasing coverage need of improved TB/HIV management, which saves most lives per dollar spent in the short term. The Global Fund is expected to finance 8-12% of Global Plan implementation costs annually. Lives saved through Global Fund TB support within the available funding envelope could increase 37% if allocations shifted from current regional demand patterns to a prioritized scale-up of improved TB/HIV treatment and secondly DOTS, both mainly in Africa - with EECA region, which has disproportionately high per-patient costs, funded from alternative resources. Conclusions/Significance: These findings, alongside country funding gaps, domestic funding and implementation capacity and equity considerations, should inform strategies and policies for international donors, national governments and disease control programs to implement a more optimal investment approach focusing on highest-impact populations and interventions

Transmission modeling to infer tuberculosis incidence prevalence and mortality in settings with generalized HIV epidemics

Tuberculosis (TB) killed more people globally than any other single pathogen over the past decade. Where surveillance is weak, estimating TB burden estimates uses modeling. In many African countries, increases in HIV prevalence and antiretroviral therapy have driven dynamic TB epidemics, complicating estimation of burden, trends, and potential intervention impact. We therefore develop a novel age-structured TB transmission model incorporating evolving demographic, HIV and antiretroviral therapy effects, and calibrate to TB prevalence and notification data from 12 African countries. We use Bayesian methods to include uncertainty for all TB model parameters, and estimate age-specific annual risks of TB infection, finding up to 16.0%/year in adults, and the proportion of TB incidence from recent (re)infection, finding a mean across countries of 34%. Rapid reduction of the unacceptably high burden of TB in high HIV prevalence settings will require interventions addressing progression as well as transmission

Improving the quality of modelling evidence used for tuberculosis policy evaluation.

Mathematical modelling is commonly used to evaluate policy options for tuberculosis (TB) control in high-burden countries. Although major policy and funding decisions are made based on these analyses, there is concern about the variability of results produced using modelled policy analyses. We discuss new guidance for country-level TB policy modelling. The guidance was developed by the TB Modelling and Analysis Consortium in collaboration with the World Health Organization Global TB Programme, with input from a range of TB stakeholders (funders, modelling groups, country TB programme staff and subject matter experts). The guidance describes principles for country-level TB modelling, as well as good practices for operationalising the principles. The principles cover technical concerns such as model design, parameterisation and validation, as well as approaches for incorporating modelling into country-led policy making and budgeting. For modellers, this guidance suggests approaches to improve the quality and relevance of modelling undertaken to support country-level planning. For non-modellers, this guidance describes considerations for engaging modelling technical assistance, contributing to a modelling exercise and reviewing the results of modelled analyses. If routinely adopted, this guidance should improve the reliability, transparency and usefulness of modelling for country-level TB policy making. However, this guidance will not address all challenges facing modelling, and ongoing work is needed to improve the empirical evidence base for TB policy evaluation and develop stronger mechanisms for validating models. Increasing country ownership of the modelling process remains a challenge, requiring sustained engagement and capacity building

The Effect of Tuberculosis on Mortality in HIV Positive People: A Meta-Analysis

Tuberculosis is a leading cause of death in people living with HIV (PLWH). We conducted a meta analysis to assess the effect of tuberculosis on mortality in people living with HIV. Meta-analysis of cohort studies assessing the effect of tuberculosis on mortality in PLWH. To identify eligible studies we systematically searched electronic databases (until December 2008), performed manual searches of citations from relevant articles, and reviewed conference proceedings. Multivariate hazard ratios (HR) of mortality in PLWH with and without tuberculosis, estimated in individual cohort studies, were pooled using random effect weighting according to "Der Simonian Laird method" if the p-value of the heterogeneity test was <0.05. Fifteen cohort studies were systematically retrieved. Pooled overall analysis of these 15 studies estimating the effect of tuberculosis on mortality in PLWH showed a Hazard Ratio (HR) of 1.8 (95% confidence interval (CI): 1.4-2.3). Subanalysis of 8 studies in which the cohort was not exposed to highly active antiretroviral therapy (HAART) showed an HR of 2.6 (95% CI: 1.8-3.6). Subanalysis of 6 studies showed that tuberculosis did not show an effect on mortality in PLWH exposed to HAART: HR 1.1 (95% CI: 0.9-1.3). These results provide an indication of the magnitude of benefit to an individual that could have been expected if tuberculosis had been prevented. It emphasizes the need for additional studies assessing the effect of preventing tuberculosis or early diagnosis and treatment of tuberculosis in PLWH on reducing mortality. Furthermore, the results of the subgroup analyses in cohorts largely exposed to HAART provide additional support to WHO's revised guidelines, which include promoting the initiation of HAART for PLWH co-infected with tuberculosis. The causal effect of tuberculosis on mortality in PLWH exposed to HAART needs to be further evaluated once the results of more cohort studies become availabl

Heightened Vulnerability to MDR-TB Epidemics after Controlling Drug-Susceptible TB

Prior infection with one strain TB has been linked with diminished likelihood of re-infection by a new strain. This paper attempts to determine the role of declining prevalence of drug-susceptible TB in enabling future epidemics of MDR-TB.A computer simulation of MDR-TB epidemics was developed using an agent-based model platform programmed in NetLogo (See http://mdr.tbtools.org/). Eighty-one scenarios were created, varying levels of treatment quality, diagnostic accuracy, microbial fitness cost, and the degree of immunogenicity elicited by drug-susceptible TB. Outcome measures were the number of independent MDR-TB cases per trial and the proportion of trials resulting in MDR-TB epidemics for a 500 year period after drug therapy for TB is introduced.MDR-TB epidemics propagated more extensively after TB prevalence had fallen. At a case detection rate of 75%, improving therapeutic compliance from 50% to 75% can reduce the probability of an epidemic from 45% to 15%. Paradoxically, improving the case-detection rate from 50% to 75% when compliance with DOT is constant at 75% increases the probability of MDR-TB epidemics from 3% to 45%.The ability of MDR-TB to spread depends on the prevalence of drug-susceptible TB. Immunologic protection conferred by exposure to drug-susceptible TB can be a crucial factor that prevents MDR-TB epidemics when TB treatment is poor. Any single population that successfully reduces its burden of drug-susceptible TB will have reduced herd immunity to externally or internally introduced strains of MDR-TB and can experience heightened vulnerability to an epidemic. Since countries with good TB control may be more vulnerable, their self interest dictates greater promotion of case detection and DOTS implementation in countries with poor control to control their risk of MDR-TB

Factors Associated with the Performance of a Blood-Based Interferon-γ Release Assay in Diagnosing Tuberculosis

Background: Indeterminate results are a recognised limitation of interferon-γ release assays (IGRA) in the diagnosis of latent tuberculosis (TB) infection (LTBI) and TB disease, especially in children. We investigated whether age and common co-morbidities were associated with IGRA performance in an unselected cohort of resettled refugees. Methods: A retrospective cross-sectional study of refugees presenting for their post-resettlement health assessment during 2006 and 2007. Refugees were investigated for prevalent infectious diseases, including TB, and for common nutritional deficiencies and haematological abnormalities as part of standard clinical screening protocols. Tuberculosis screening was performed by IGRA; QuantiFERON-TB Gold in 2006 and QuantiFERON-TBGold In-Tube in 2007. Results: Complete data were available on 1130 refugees, of whom 573 (51%) were children less than 17 years and 1041 (92%) were from sub-Saharan Africa. All individuals were HIV negative. A definitive IGRA result was obtained in 1004 (89%) refugees, 264 (26%) of which were positive; 256 (97%) had LTBI and 8 (3%) had TB disease. An indeterminate IGRA result was obtained in 126 (11%) refugees (all failed positive mitogen control). In multivariate analysis, younger age (linear OR = 0.93 [95% CI 0.91-0.95],