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BackgroundNew, sensitive diagnostic tests facilitate identification and investigation of milder forms of tuberculosis (TB) disease. We used community-based TB testing with the Xpert MTB/RIF Ultra assay ("Ultra") to characterize individuals with previously undiagnosed TB and compare them to those from the same community who were diagnosed with TB through routine care.MethodsWe offered community-based sputum Ultra testing to adult residents of a well-defined area (population 34 000 adults) in Kampala, Uganda, via door-to-door screening and venue-based testing, then used detailed interview and laboratory testing to characterize TB-positive individuals. We compared these individuals to residents diagnosed with pulmonary TB at local health facilities and a representative sample of residents without TB (controls).ResultsOf 12 032 residents with interpretable Ultra results, 113 (940 [95% confidence interval {CI}, 780-1130] per 100 000) tested positive, including 71 (63%) positive at the lowest (trace) level. A spectrum of TB disease was observed in terms of chronic cough (93% among health facility-diagnosed cases, 77% among residents with positive community-based Ultra results at levels above trace, 33% among trace-positive community participants, and 18% among TB-negative controls), TB symptom prevalence (99%, 87%, 60%, and 38%, respectively), and C-reactive protein (75th percentile: 101 mg/L, 28 mg/L, 6 mg/L, and 4 mg/L, respectively). Community-diagnosed cases were less likely than health facility-diagnosed cases to have human immunodeficiency virus coinfection or previous TB. The specificity of Ultra was 99.4% (95% CI, 99.2%-99.5%) relative to a single spot sputum culture.ConclusionsPeople with undiagnosed prevalent TB in the community have different characteristics than those diagnosed with pulmonary TB in health facilities. Newer diagnostic tests may identify a group of people with early or very mild disease.

BackgroundClinical tuberculosis diagnosis and empiric treatment have traditionally been common among patients with negative bacteriologic test results. Increasing availability of rapid molecular diagnostic tests, including Xpert MTB/RIF and the new Xpert Ultra cartridge, may alter the role of empiric treatment.MethodsWe prospectively enrolled outpatients age > = 15 who were evaluated for pulmonary tuberculosis at three health facilities in Kampala, Uganda. Using sputum mycobacterial culture, interviews, and clinical record abstraction, we estimated the accuracy of clinical diagnosis relative to Xpert and sputum culture and assessed the contribution of clinical diagnosis to case detection.ResultsOver a period of 9 months, 99 patients were diagnosed with pulmonary tuberculosis and subsequently completed sputum culture; they were matched to 196 patients receiving negative tuberculosis evaluations in the same facilities. Xpert was included in the evaluation of 291 (99%) patients. Compared to culture, Xpert had a sensitivity of 92% (95% confidence interval 83-97%) and specificity of 95% (92-98%). Twenty patients with negative Xpert were clinically diagnosed with tuberculosis and subsequently had their culture status determined; two (10%) were culture-positive. Considering all treated patients regardless of Xpert and culture data completeness, and considering treatment initiations before a positive Xpert (N = 4) to be empiric, 26/101 (26%) tuberculosis treatment courses were started empirically. Compared to sputum smear- or Xpert-positive patients with positive cultures, empirically-treated, Xpert-negative patients with negative cultures had higher prevalence of HIV (67% versus 37%), shorter duration of cough (median 4 versus 8 weeks), and lower inflammatory markers (median CRP 7 versus 101 mg/L).ConclusionJudged against sputum culture in a routine care setting of high HIV prevalence, the accuracy of Xpert was high. Clinical judgment identified a small number of additional culture-positive cases, but with poor specificity. Although clinicians should continue to prescribe tuberculosis treatment for Xpert-negative patients whose clinical presentations strongly suggest pulmonary tuberculosis, they should also carefully consider alternative diagnoses.

New tuberculosis (TB) drugs with little existing antimicrobial resistance enable a pan-TB treatment regimen, intended for universal use without prior drug-susceptibility testing. However, widespread use of such a regimen could contribute to an increasing prevalence of antimicrobial resistance, potentially rendering the pan-TB regimen ineffective or driving clinically problematic patterns of resistance. We developed a model of multiple sequential TB patient cohorts to compare treatment outcomes between continued use of current standards of care (guided by rifampin-susceptibility testing) and a hypothetical pan-TB approach. A pan-TB regimen that met current target profiles was likely to initially outperform the standard of care; however, a rising prevalence of transmitted resistance to component drugs could make underperformance likely among subsequent cohorts. Although the pan-TB approach led to an increased prevalence of resistance to novel drugs, it was unlikely to cause accumulation of concurrent resistance to novel drugs and current first-line drugs. [ABSTRACT FROM AUTHOR]

Background: Short-course, rifamycin-based regimens could facilitate scale-up of tuberculosis preventive therapy (TPT), but it is unclear how stringently tuberculosis (TB) disease should be ruled out before TPT use.Methods: We developed a state-transition model of a TPT intervention among two TPT-eligible cohorts: adults newly diagnosed with HIV in South Africa (PWH) and TB household contacts in Pakistan (HHCs). We modeled two TPT regimens-4 months of rifampicin [4R] or 6 months of isoniazid [6H]-comparing each to a reference of no intervention. Before initiating TPT, TB disease was excluded either through symptom-only screening or with additional radiographic screening that could detect subclinical TB but might limit access to the TPT intervention. TPT's potential curative effects on both latent and subclinical TB were modeled, as were both acquisitions of resistance and prevention of drug-resistant disease. Although all eligible individuals received the screening and/or TPT interventions, the modeled TB outcomes comprised only those with latent or subclinical TB that would have progressed to symptomatic disease if untreated.Results: When prescribed after only symptom-based TB screening (such that individuals with subclinical TB were included among TPT recipients), 4R averted 45 active (i.e., symptomatic) TB cases (95% uncertainty range 24-79 cases or 40-89% of progressions to active TB) per 1000 PWH [17 (9-29, 43-94%) per 1000 HHCs]; 6H averted 37 (19-66, 52-73%) active TB cases among PWH [13 (7-23, 53-75%) among HHCs]. With this symptom-only screening, for each net rifampicin resistance case added by 4R, 12 (3-102) active TB cases were averted among PWH (37 [9-580] among HHCs); isoniazid-resistant TB was also reduced. Similarly, 6H after symptom-only screening increased isoniazid resistance while reducing overall and rifampicin-resistant active TB. Screening for subclinical TB before TPT eliminated this net increase in resistance to the TPT drug; however, if the screening requirement reduced TPT access by more than 10% (the estimated threshold for 4R among HHCs) to 30% (for 6H among PWH), it was likely to reduce the intervention's overall TB prevention impact.Conclusions: All modeled TPT strategies prevent TB relative to no intervention, and differences between TPT regimens or between screening approaches are small relative to uncertainty in the outcomes of any given strategy. If most TPT-eligible individuals can be screened for subclinical TB, then pairing such screening with rifamycin-based TPT maximizes active TB prevention and does not increase rifampicin resistance. Where subclinical TB cannot be routinely excluded without substantially reducing TPT access, the choice of TPT regimen requires weighing 4R's efficacy advantages (as well as its greater safety and shorter duration that we did not directly model) against the consequences of rifampicin resistance in a small fraction of recipients. [ABSTRACT FROM AUTHOR]

Background To appropriately treat tuberculosis (TB) with regimens that combine novel and older drugs, evidence-based, context-specific strategies for drug-susceptibility testing (DST) will be required. Methods We created a Markov state-transition model of 100 000 adults with TB receiving a novel, fluoroquinolone (FQ)–containing regimen. We estimated clinical outcomes and resource utilization with no FQ-DST, universal FQ-DST, or FQ-DST only for patients with rifampin-resistant TB ("targeted FQ-DST"). We considered scenarios of stronger (South Africa) and weaker (Southeast Asia) correlation of fluoroquinolone resistance with rifampin resistance, with sensitivity analysis for other setting and regimen characteristics. Results Relative to no FQ-DST, targeted FQ-DST increased cure of FQ-resistant TB by 7.5% (interquartile range [IQR], 6.7%–9.2%) in South Africa and 1.7% (IQR, 0.7%–2.5%) in Southeast Asia. However, rare FQ resistance among the more prevalent rifampin-susceptible TB accounted for 50% of FQ-resistant TB in South Africa and 83% in Southeast Asia. As a result, universal FQ-DST further increased cure of FQ-resistant TB by 3.4% (IQR, 2.3%–5.4%) in South Africa and 5.8% (IQR, 5.1%–6.3%) in Southeast Asia. With targeted FQ-DST, 1 additional patient was cured per 50 (IQR, 42–70) tests in South Africa and 44 (IQR, 37–51) in Southeast Asia. When expanding from targeted to universal FQ-DST, 1 additional cure required 3500 (IQR, 2300–5500) tests in South Africa and 410 (IQR, 370–450) in Southeast Asia. Conclusions FQ-DST improved patient outcomes and was particularly important for high-risk patient groups and less robust regimens. A universal strategy was favored in generalized epidemics of fluoroquinolone resistance. [ABSTRACT FROM AUTHOR]

A novel, shorter-course regimen for treating multidrug-resistant (MDR) tuberculosis was recently recommended by the World Health Organization. However, the most appropriate use of drug susceptibility testing (DST) to support this regimen is less clear. Implementing countries must therefore often choose between using a standardized regimen despite high levels of underlying drug resistance or require more stringent DST prior to treatment initiation. The former carries a high likelihood of exposing patients to de facto monotherapy with a critical drug class (fluoroquinolones), whereas the latter could exclude large groups of patients from their most effective treatment option. We discuss the implications of this dilemma and argue for an approach that will integrate DST into the delivery of any novel antimicrobial regimen, without excessively stringent requirements. Such guidance could make the novel MDR tuberculosis regimen available to most patients while reducing the risk of generating additional drug resistance. [ABSTRACT FROM AUTHOR]

Treatment failure and resistance amplification are common among patients with rifampin-resistant tuberculosis (TB). Drug susceptibility testing (DST) for second-line drugs is recommended for these patients, but logistical difficulties have impeded widespread implementation of second-line DST in many settings. To provide a quantitative perspective on the decision to scale up second-line DST, we synthesize literature on the prevalence of second-line drug resistance, the expected clinical and epidemiologic benefits of using second-line DST to ensure that patients with rifampin-resistant TB receive effective regimens, and the costs of implementing (or not implementing) second-line DST for all individuals diagnosed with rifampin-resistant TB. We conclude that, in most settings, second-line DST could substantially improve treatment outcomes for patients with rifampin-resistant TB, reduce transmission of drug-resistant TB, prevent amplification of drug resistance, and be affordable or even cost-saving. Given the large investment made in each patient treated for rifampin-resistant TB, these payoffs would come at relatively small incremental cost. These anticipated benefits likely justify addressing the real challenges faced in implementing second-line DST in most high-burden settings. [ABSTRACT FROM AUTHOR]

Summary Background Multidrug-resistant (MDR) tuberculosis can be acquired through de-novo mutation during tuberculosis treatment or through transmission from other individuals with active MDR tuberculosis. Understanding the balance between these two mechanisms is essential when allocating resources for MDR tuberculosis. We aimed to create a dynamic transmission model of an MDR tuberculosis epidemic to estimate the contributions of treatment-related acquisition and person-to-person transmission of resistance to incident MDR tuberculosis cases. Methods In this modelling analysis, we constructed a dynamic transmission model of an MDR tuberculosis epidemic, allowing for both treatment-related acquisition and person-to-person transmission of resistance. We used national tuberculosis notification data to inform Bayesian estimates of the proportion of each country's 2013 MDR tuberculosis incidence that resulted from MDR transmission rather than treatment-related MDR acquisition. Findings Global estimates of 3·5% MDR tuberculosis prevalence among new tuberculosis notifications and 20·5% among re-treatment notifications translate into an estimate that resistance transmission rather than acquisition accounts for a median 95·9% (95% uncertainty range [UR] 68·0–99·6) of all incident MDR tuberculosis, and 61·3% (16·5–95·2) of incident MDR tuberculosis in previously treated individuals. The estimated proportion of MDR tuberculosis resulting from transmission varied substantially with different countries' notification data—ranging from 48% (95% UR 30–75) in Bangladesh to 99% (91–100) in Uzbekistan. Estimates were most sensitive to estimates of the transmissibility of MDR strains, the probability of acquiring MDR during tuberculosis treatment, and the responsiveness of MDR tuberculosis to first-line treatment. Interpretation Notifications of MDR prevalence from most high-burden settings are consistent with most incident MDR tuberculosis resulting from transmission rather than new treatment-related acquisition of resistance. Merely improving the treatment of drug-susceptible tuberculosis is unlikely to greatly reduce future MDR tuberculosis incidence. Improved diagnosis and treatment of MDR tuberculosis—including new tests and drug regimens—should be highly prioritised. Funding National Institutes of Health and the Bill & Melinda Gates Foundation. [ABSTRACT FROM AUTHOR]

Whether multidrug-resistant tuberculosis (MDR-TB) is less transmissible than drug-susceptible (DS-)TB on a population level is uncertain. Even in the absence of a genetic fitness cost, the transmission potential of individuals with MDR-TB may vary by infectiousness, frequency of contact, or duration of disease. We used a compartmental model to project the progression of MDR-TB epidemics in South Africa and Vietnam under alternative assumptions about the relative transmission efficiency of MDR-TB. Specifically, we considered three scenarios: consistently lower transmission efficiency for MDR-TB than for DS-TB; equal transmission efficiency; and an initial deficit in the transmission efficiency of MDR-TB that closes over time. We calibrated these scenarios with data from drug resistance surveys and projected epidemic trends to 2040. The incidence of MDR-TB was projected to expand in most scenarios, but the degree of expansion depended greatly on the future transmission efficiency of MDR-TB. For example, by 2040, we projected absolute MDR-TB incidence to account for 5% (IQR: 4–9%) of incident TB in South Africa and 14% (IQR: 9–26%) in Vietnam assuming consistently lower MDR-TB transmission efficiency, versus 15% (IQR: 8–27%)and 41% (IQR: 23–62%), respectively, assuming shrinking transmission efficiency deficits. Given future uncertainty, specific responses to halt MDR-TB transmission should be prioritized. [ABSTRACT FROM AUTHOR]

Background: Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy.Methods: A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy.Results: Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 ± 1% to 67 ± 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 ± 1% and cure of all TB from 87.3 ± 0.1% to 89.5 ± 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa's high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation.Conclusions: Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context. [ABSTRACT FROM AUTHOR]