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...

W e read with great interest the mathematical model presented by Fofana et al. (1) on the role of pyrazinamide (PZA) in the emergence of multidrug-resistant tuberculosis (MDR TB), particularly as the results of their model mirror our concerns regarding the amplification of PZA resistance during inappropriate first-line therapy and the dramatic negative consequences that this can have on the subsequent response to second-line therapy. Indeed recent data from Belarus suggest that approximately 50% of PZA resistance is acquired de novo (2). Fofana et al. (1) propose that this problem, a result of using the same important agent in first-and second-line therapy, might be circumvented by using an as-yet-unidentified new agent with characteristics similar to those of PZA in a new second-line regimen. Although considerable effort is being applied to the development of new targets for such agents (3), it is far from certain when or even if these miraculous drugs will be available for routine use. Consequently, PZA is currently a uniquely valuable agent, which we speculate will be very difficult to replace (4, 5). We therefore suggest that in settings where the a priori risk of MDR TB due to transmission is above a certain level, such as in Belarus, prescribing PZA to new patients before they have been screened for rifampin and isoniazid resistance is likely counterproductive. Screening for PZA resistance is still complicated and not in reach for many laboratories. Of course, in an ideal world, a full drug susceptibility test (DST) profile would be available for all patients before TB therapy is prescribed. Unfortunately, in reality, this is seldom the case; at best, there is a considerable delay before DST results are communicated to the physician, and at worst, DST is not performed at all until there is evidence of treatment failure, which may be between 2 and 6 months after starting the patient on first-line agents. As this scenario appears to account for 50% of the PZA resistance seen in MDR-TB cases in many settings (5), action is required now to prevent transmissible PZA-resistant mutants from becoming widely established (6, 7). Thus, we propose that, in settings with a high proportion of MDR-TB patients, PZA be withheld until there is evidence of susceptibility to other first-line agents, because of either a clinical response (acid-fast bacillus [AFB] smear conversion) or a solid laboratory diagnosis. Modeling the exact proportion of primary MDR-TB patients in whom PZA resistance was prevented, a population benefitting from this change, and discussion of the ethics of this approach would be highly informative. Delaying action Citation Anthony RM, Cynamon M, Hoffner S, Werngren J, den Hertog AL, van Soolingen D. 2017. Protecting pyrazinamide, a priority for improving outcomes in multidrug-resistant tuberculosis treatment. Antimicrob Agents Chemother 61:e00258-17. https://doi.

The TB Portals program is an international consortium of physicians, radiologists, and microbiologists from countries with a heavy burden of drug-resistant tuberculosis working with data scientists and information technology professionals. Together, we have built the TB Portals, a repository of socioeconomic/geographic, clinical, laboratory, radiological, and genomic data from patient cases of drug-resistant tuberculosis backed by shareable, physical samples. Currently, there are 1,299 total cases from five country sites (Azerbaijan, Belarus, Moldova, Georgia, and Romania), 976 (75.1%) of which are multidrug or extensively drug resistant and 38.2%, 51.9%, and 36.3% of which contain X-ray, computed tomography (CT) scan, and genomic data, respectively. The top Mycobacterium tuberculosis lineages represented among collected samples are Beijing, T1, and H3, and single nucleotide polymorphisms (SNPs) that confer resistance to isoniazid, rifampin, ofloxacin, and moxifloxacin occur the most frequently. These data and samples have promoted drug discovery efforts and research into genomics and quantitative image analysis to improve diagnostics while also serving as a valuable resource for researchers and clinical providers. The TB Portals database and associated projects are continually growing, and we invite new partners and collaborations to our initiative. The TB Portals data and their associated analytical and statistical tools are freely available at https://tbportals.niaid.nih.gov/.KEYWORDS tuberculosis, digital health, interactive portals, MDR-TB, Mycobacterium tuberculosis, query, XDR-TB, drug-resistant TB T uberculosis (TB) continues to represent a major health problem worldwide. An estimated one-third of the world's population is living with latent TB (1). In 2015, there were an estimated 10.4 million new (incident) TB cases worldwide, of which 5.9 million (56%) were among men, 3.5 million (34%) were among women, and 1.0 million (10%) were among children. People living with HIV accounted for 1.2 million (11%) of

Ongoing transmission, high levels of drug resistance, and poor diagnostic

Background In the context of WHO's End TB strategy, there is a need to focus future control efforts on those interventions and innovations that would be most effective in accelerating declines in tuberculosis burden. Using a modelling approach to link the tuberculosis care cascade to transmission, we aimed to identify which improvements in the cascade would yield the greatest effect on incidence and mortality.Methods We engaged with national tuberculosis programmes in three country settings (India, Kenya, and Moldova) as illustrative examples of settings with a large private sector (India), a high HIV burden (Kenya), and a high burden of multidrug resistance (Moldova). We collated WHO country burden estimates, routine surveillance data, and tuberculosis prevalence surveys from 2011 (for India) and 2016 (for Kenya). Linking the tuberculosis care cascade to tuberculosis transmission using a mathematical model with Bayesian melding in each setting, we examined which cascade shortfalls would have the greatest effect on incidence and mortality, and how the cascade could be used to monitor future control efforts.Findings Modelling suggests that combined measures to strengthen the care cascade could reduce cumulative tuber culosis incidence by 38% (95% Bayesian credible intervals 27-43) in India, 31% (25-41) in Kenya, and 27% (17-41) in Moldova between 2018 and 2035. For both incidence and mortality, modelling suggests that the most important cascade losses are the proportion of patients visiting the private healthcare sector in India, missed diagnosis in health care settings in Kenya, and drug sensitivity testing in Moldova. In all settings, the most influential delay is the interval before a patient's first presentation for care. In future interventions, the proportion of individuals with tuberculosis who are on highquality treatment could offer a more robust monitoring tool than routine notifications of tuberculosis.Interpretation Linked to transmission, the care cascade can be valuable, not only for improving patient outcomes but also in identifying and monitoring programmatic priorities to reduce tuberculosis incidence and mortality.