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\"The definitive social history of tuberculosis, from its origins as a haunting mystery to its modern reemergence that now threatens populations around the world. It killed novelist George Orwell, Eleanor Roosevelt, and millions of others - rich and poor. Desmond Tutu, Amitabh Bachchan, and Nelson Mandela survived it, just. For centuries, tuberculosis has ravaged cities and plagued the human body. In Phantom Plague, Vidya Krishnan, traces the history of tuberculosis from the slums of 19th-century New York to modern Mumbai. In a narrative spanning century, Krishnan shows how superstition and folk-remedies, made way for scientific understanding of TB, such that it was controlled and cured in the West. The cure was never available to black and brown nations. And the tuberculosis bacillus showed a remarkable ability to adapt -- so that at the very moment it could have been extinguished as a threat to humanity, it found a way back, aided by authoritarian governments, the toxic kindness of philanthropists, science denialism, and medical apartheid. Krishnan's original reporting paints a granular portrait of the post-antibiotic era as a new, aggressive, drug resistant strain of TB takes over. Phantom Plague is an urgent, riveting and fascinating narrative that deftly exposes the weakest links in our battle against this ancient foe.\"--Front jacket flap.

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide. Analysis of tuberculosis drug trials identifies features to stratify patients for longer or shorter treatment duration than the standard of care, in order to improve therapeutic outcomes.

In this randomized, controlled trial involving children with household exposure to multidrug-resistant tuberculosis, levofloxacin led to a lower incidence of tuberculosis than placebo, but the difference was not significant.

Prevention of drug-resistant tuberculosis is a global health priority. However, trials evaluating the effectiveness of treating infection among contacts of persons with drug-resistant tuberculosis are lacking. We conducted a double-blind, randomized, controlled trial comparing 6 months of daily levofloxacin (weight-based doses) with placebo to treat infection. The trial population comprised household contacts of persons with bacteriologically confirmed rifampicin-resistant or multidrug-resistant (MDR) tuberculosis in Vietnam. Contacts of any age with a positive tuberculin skin test or immunologic impairment were eligible. The primary end point was bacteriologically confirmed tuberculosis within 30 months. Secondary end points included grade 3 or 4 adverse events, death from any cause, and acquired drug resistance. Of 3948 persons screened for eligibility, 61 (1.5%) had coprevalent tuberculosis (defined as active tuberculosis disease diagnosed before randomization) and 2041 underwent randomization. Of these 2041 participants, 1995 (97.7%) completed 30 months of follow-up, had a primary end-point event, or died. Confirmed tuberculosis occurred in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% confidence interval [CI], 0.19 to 1.62); this difference was not significant. There was little difference in grade 3 or 4 adverse events between the two groups (risk difference, 1.0 percentage point; 95% CI, -0.3 to 2.4). Adverse events of any grade were reported in 306 participants (31.9%) taking levofloxacin and 125 (13.0%) taking placebo (risk difference, 18.9 percentage points; 95% CI, 14.2 to 23.6). No acquired fluoroquinolone resistance was observed. Although the incidence of tuberculosis was lower in the levofloxacin group than in the placebo group at 30 months, the difference was not significant. (Funded by the National Health and Medical Research Council of Australia; VQUIN MDR Australia New Zealand Clinical Trials Registry number, ACTRN12616000215426.).

In this phase 2 study, the addition of bedaquiline to routine therapy for multidrug-resistant tuberculosis showed significant efficacy, with accelerated sputum-culture conversion and increased culture conversion at 24 and 120 weeks. The World Health Organization (WHO) estimates that the global incidence of tuberculosis in 2012 was 8.6 million cases, with 1.3 million deaths, predominantly occurring in developing countries. 1 Although there has been some progress in reducing tuberculosis cases and deaths in the past 20 years, multidrug-resistant tuberculosis (i.e., with resistance to at least isoniazid and rifampin) remains a major challenge. The 2012 global incidence of multidrug-resistant tuberculosis was 450,000 cases. 1 Therapy for multidrug-resistant tuberculosis is a long, arduous regimen of antiquated drugs that are mainly bacteriostatic and have an unfavorable side-effect profile. 2 The WHO reports that major efforts are needed to . . .

Globally, there are more than 500,000 new infections with drug-resistant tuberculosis each year. In this trial involving patients with rifampin-resistant tuberculosis, a shorter, more intense course of treatment (9 to 11 months) was found to be noninferior to a standard 20-month regimen.

Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden. A pragmatic prospective cluster-randomised trial of Xpert for all individuals with presumptive (symptomatic) TB compared to the routine diagnostic algorithm of sputum microscopy and limited use of culture was conducted in a large TB/HIV primary care clinic. The primary outcome was the proportion of bacteriologically confirmed TB cases not initiating TB treatment by 3 mo after presentation. Secondary outcomes included time to TB treatment and mortality. Unblinded randomisation occurred on a weekly basis. Xpert and smear microscopy were performed on site. Analysis was both by intention to treat (ITT) and per protocol. Between 7 September 2010 and 28 October 2011, 1,985 participants were assigned to the Xpert (n = 982) and routine (n = 1,003) diagnostic algorithms (ITT analysis); 882 received Xpert and 1,063 routine (per protocol analysis). 13% (32/257) of individuals with bacteriologically confirmed TB (smear, culture, or Xpert) did not initiate treatment by 3 mo after presentation in the Xpert arm, compared to 25% (41/167) in the routine arm (ITT analysis, risk ratio 0.51, 95% CI 0.33-0.77, p = 0.0052). The yield of bacteriologically confirmed TB cases among patients with presumptive TB was 17% (167/1,003) with routine diagnosis and 26% (257/982) with Xpert diagnosis (ITT analysis, risk ratio 1.57, 95% CI 1.32-1.87, p<0.001). This difference in diagnosis rates resulted in a higher rate of treatment initiation in the Xpert arm: 23% (229/1,003) and 28% (277/982) in the routine and Xpert arms, respectively (ITT analysis, risk ratio 1.24, 95% CI 1.06-1.44, p = 0.013). Time to treatment initiation was improved overall (ITT analysis, hazard ratio 0.76, 95% CI 0.63-0.92, p = 0.005) and among HIV-infected participants (ITT analysis, hazard ratio 0.67, 95% CI 0.53-0.85, p = 0.001). There was no difference in 6-mo mortality with Xpert versus routine diagnosis. Study limitations included incorrect intervention allocation for a high proportion of participants and that the study was conducted in a single clinic. These data suggest that in this routine primary care setting, use of Xpert to diagnose TB increased the number of individuals with bacteriologically confirmed TB who were treated by 3 mo and reduced time to treatment initiation, particularly among HIV-infected participants. Pan African Clinical Trials Registry PACTR201010000255244. Please see later in the article for the Editors' Summary.

Background Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. Methods The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. Discussion If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. Trial registration ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

Background Clinical trials evaluating new regimens for multidrug-resistant tuberculosis (MDR-TB) are typically conducted in multiple countries because global registration of new TB drugs requires evaluation in diverse populations. The complexity of multi-site trials makes implementation challenging, especially in lower-resource settings, where the burden of MDR-TB is highest. Stakeholder engagement can improve trial implementation and outcomes. Here, we describe the Mongolia site’s stakeholder engagement during STREAM, a phase III clinical trial evaluating novel treatment regimens for MDR-TB. Main body We assessed our stakeholder engagement against the PCORI rubric. Engagement at all phases of the trial aligned well with the PCORI engagement principles of reciprocal relationships; co-learning; building partnerships; and transparency, honesty, and trust. In the planning phase, we formed a key partnership with a civil society organization to co-lead the trial, undertook stakeholder mapping, and developed an overall engagement strategy. During trial implementation, we undertook activities aimed at ensuring feasibility of the study, improving recruitment, ensuring viability of the study, and ensuring authenticity/value of stakeholder engagement. Activities, which included continuous communication with the national TB program to ensure referral of potential trial participants, implementation of a comprehensive community engagement (CE) program, delivery in collaboration with partners of psychosocial support for trial participants, capacity-building and knowledge sharing, regular communications on trial developments and progress, and community advisory board (CAB) participation in CE assessment, contributed to achieving a 98% retention rate and the highest participant recruitment across all STREAM trial sites. In the dissemination phase, CAB members worked together with the site and sponsor to ensure strategies and materials were tailored to stakeholders’ needs, including participants; communities; frontline healthworkers; and national-level stakeholders. Stakeholder participation in research and in improving routine TB care in the country has been sustained since completion of the trial. Conclusions Significant and sustainable gains can be made through stakeholder collaboration. We recommend that trial sites in lower-resourced settings take an expansive view of relevant stakeholders when planning engagement; undertake capacity-building and knowledge sharing; plan for long-term sustainability of CE; design engagement around specific objectives; tailor and optimize communication strategies; and design stakeholder engagement to involve key policy makers. Trial registration ISRCTN78372190 - Registration date is October 14, 2010 (Stage 1) and ISRCTN18148631 - Registration date is February 10, 2016 (Stage 2). 

In this report on the treatment of multidrug-resistant (MDR) tuberculosis, the authors found that delamanid, a novel anti-TB medication, led to more rapid sputum culture conversion to negative when added to a background regimen than the background regimen alone. The emergence over the past two decades of multidrug-resistant tuberculosis, or tuberculosis caused by strains of Mycobacterium tuberculosis that are resistant to isoniazid and rifampin, with or without resistance to other agents, has greatly complicated efforts to control the global tuberculosis epidemic. Approximately 440,000 cases of multidrug-resistant tuberculosis occur worldwide annually, accounting for nearly 5% of the global burden of tuberculosis. 1 Multidrug-resistant tuberculosis requires treatment with combination therapy consisting of four to six medications, including the more toxic and less potent second-line drugs, administered for up to 2 years. Cure rates are lower and mortality is higher with multidrug-resistant tuberculosis . . .