The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

SUMMARY Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis . Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampinresistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided. Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

growing political momentum to definitively address tuberculosis, could all make ending the pandemic within a generation more feasible than ever before. Moving forward with bold, comprehensive strategies Globally, the priority must be to deliver person-centred and family-centred services to all individuals with tuberculosis who present to care. This approach means ensuring that high-quality diagnostics, treatment, and prevention modalities are available to all, wherever they seek care. Improving quality of tuberculosis care in the private sector is crucial to end tuberculosis in high incidence countries such as India, the country with the highest tuberculosis burden. Modelling shows that optimising private sector engagement in India could avert 8 million deaths from tuberculosis between 2019 and 2045 (appendix p 3). In high drug-resistant tuberculosis burden countries, access to rapid drug susceptibility testing (DST) and second-line drugs is essential to success. In Moldova, where more than 25% of all tuberculosis cases are drug-resistant, improving access to DST and second-line drugs would reduce mortality from drug-resistant tuberculosis by 44% in the coming generation (appendix p 3). Secondly, tuberculosis programme budgets must increase to enable reaching these people and populations at high risk of tuberculosis. In Kenya, for example, where the proportions of HIV and tuberculosis coinfection are high, scaling up access to both antiretroviral therapy and tuberculosis preventive therapy can help save an additional 3 million lives over the next generation (appendix p 3). However, ultimately, the fight against tuberculosis will not be won unless countries also ensure that everyone, not just high-risk groups, can access essential health Key messages The Commission recommends five priority investments to achieve a tuberculosis-free world within a generation. These investments are designed to fulfil the mandate of the UN High Level Meeting on tuberculosis. In addition, they answer the question of how countries with high-burden tuberculosis and their development partners should target their future investments to ensure that ending tuberculosis is achievable. Invest first to ensure that high quality rapid diagnostics and treatment are provided to all individuals receiving care for tuberculosis, wherever they seek care This priority includes rapid drug susceptibility testing and second-line treatment for resistant forms of tuberculosis. Achieving universal, high-quality person-centred and family-centred care-including sustained improvement in the performance of private sector providers-usually should be the top policy and budget priority. Reach people and populations at high risk for tuberculosis (such as household and other close contacts of people with tuberculosis, and people with HIV) and bring them into care Active case-finding and treatment in high-risk populations demands adequate resources to reach and care for these populations. At the same time, reaching certain high-risk populations, such as people co-infec...

OBJECTIVE-To determine whether interferon-gamma release assays (IGRAs) improve the identification of HIV-infected individuals who could benefit from LTBI therapy. DESIGN-Systematic review and meta-analysis.METHODS-We searched multiple databases through May2010 for studies evaluating the performance of the newest commercial IGRAs (QuantiFERON-Gold In-tube [QFT-GIT] and T-SPOT. TB [TSPOT])in HIV-infected individuals. We assessed the quality of all studies included in the review, summarized results in pre-specified sub-groups using forest plots, and where appropriate, calculated pooled estimates using random effects models. RESULTS-The search identified 37 studies that included 5736 HIV-infected individuals. In3 longitudinal studies, the risk of active TB was higher in HIV-infected individuals with positive versus negative IGRA results. However, the risk difference was not statistically significant in the 2 studies that reported IGRA results according to manufacturer-recommended criteria. In persons with active TB(a surrogate reference standard for LTBI), pooled sensitivity estimates were heterogeneous, but higher for TSPOT (72%, 95% CI 62-81%) than for QFT-GIT (61%, 95% CI 41-75%). However, neither IGRA was consistently more sensitive than the tuberculin skin test (TST) in head-to-head comparisons. While TSPOT appeared to be less affected by immunosuppression than QFT-GIT and TST, overall, differences between the three tests were small or inconclusive.CONCLUSIONS-Current evidence suggests that IGRAs perform similarly to the TST at identifying HIV-infected individuals with LTBI. Given that both tests have modest predictive value and sub-optimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistical considerations.

In low- and middle-income countries, neither the tuberculin skin test nor IGRAs have value for active tuberculosis diagnosis in adults, especially in the context of HIV coinfection.

Interventional researchers face many design challenges when assessing intervention implementation in real-world settings. Intervention implementation requires holding fast on internal validity needs while incorporating external validity considerations (such as uptake by diverse subpopulations, acceptability, cost, and sustainability). Quasi-experimental designs (QEDs) are increasingly employed to achieve a balance between internal and external validity. Although these designs are often referred to and summarized in terms of logistical benefits, there is still uncertainty about (a) selecting from among various QEDs and (b) developing strategies to strengthen the internal and external validity of QEDs. We focus here on commonly used QEDs (prepost designs with nonequivalent control groups, interrupted time series, and stepped-wedge designs) and discuss several variants that maximize internal and external validity at the design, execution and implementation, and analysis stages.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.