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Background: Mass administrations of antimalarial drugs (MDA) have reduced the incidence and prevalence of P. falciparum infections in a trial in the Greater Mekong Subregion. Here we assess the impact of the MDA on P. vivax infections., Methods: Between May 2013 and July 2017, four villages in each Myanmar, Vietnam, Cambodia and Lao PDR were selected based on high prevalence of P. falciparum infections. Eight of the 16 villages were randomly assigned to receive MDA consisting of three-monthly rounds of three-day courses of dihydroartemisinin-piperaquine and, except in Cambodia, a single low-dose of primaquine. Cross-sectional surveys were conducted at quarterly intervals to detect Plasmodium infections using ultrasensitive qPCR. The difference in the cumulative incidence between the groups was assessed through a discrete time survival approach, the difference in prevalence through a difference-in-difference analysis, and the difference in the number of participants with a recurrence of P. vivax infection through a mixed-effect logistic regression., Results: 3,790 (86%) residents in the intervention villages participated in at least one MDA round, of whom 2,520 (57%) participated in three rounds. The prevalence of P. vivax infections fell from 9.31% to 0.89% at month 3 but rebounded by six months to 5.81%. There was no evidence that the intervention reduced the cumulative incidence of P.vivax infections (95% confidence interval [CI] Odds ratio (OR): 0.29 to 1.36). Similarly, there was no evidence of MDA related reduction in the number of participants with at least one recurrent infection (OR: 0.34; 95% CI: 0.08 to 1.42)., Conclusion: MDA with schizontocidal drugs had a lasting effect on P. falciparum infections but only a transient effect on the prevalence of P. vivax infections. Radical cure with an 8-aminoquinoline will be needed for the rapid elimination of vivax malaria., Competing Interests: We declare no competing of interests in any form related to employment, consultancy, patents, products in development, or marketed product, etc. None of our authors is affiliated with a commercial entity.

Introduction: To reach pre-elimination levels of tuberculosis (TB) incidence in the Netherlands, prevention of TB among immigrants through diagnosis and treatment of latent TB infection (LTBI) is needed. We studied the feasibility of a LTBI screening and treatment program among newly arriving immigrants for national implementation., Methods: We used mixed methods to evaluate the implementation of LTBI screening and treatment in five Public Health Services (PHS) among immigrants from countries with a TB incidence >50/100,000 population. We used Poisson regression models with robust variance estimators to assess factors associated with LTBI diagnosis and LTBI treatment initiation and reported reasons for not initiating or completing LTBI treatment. We interviewed five PHS teams using a semi-structured method to identify enhancing and impeding factors for LTBI screening and treatment., Results: We screened 566 immigrants; 94 (17%) were diagnosed with LTBI, of whom 49 (52%) initiated and 34 (69%) completed LTBI treatment. LTBI diagnosis was associated with male gender, higher age group, higher TB incidence in the country of origin and lower level of education. Treatment initiation was associated with PHS (ranging from 29% to 86%), lower age group, longer intended duration of stay in the Netherlands, and lower level of education. According to TB physicians, clients and their consulted physicians in the home country lacked awareness about benefits of LTBI treatment. Furthermore, TB physicians questioned the individual and public health benefit of clients who return to their country of origin within the foreseeable future., Conclusions: Doubt of physicians in both host country and country of origin about individual and public health benefits of LTBI screening and treatment of immigrants hampered treatment initiation: the high initiation proportion in one PHS shows that if TB physicians are committed, the LTBI treatment uptake can be higher., Competing Interests: Qiagen had no role in study implementation, in the analysis and reporting of the results or in the decision to publish the results. Furthermore, there are no patents, products in development, or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

[This corrects the article DOI: 10.1371/journal.pone.0192282.].

While tuberculosis (TB) represents a significant disease burden worldwide, low-incidence countries strive to reach the WHO target of pre-elimination by 2035. Screening for TB in immigrants is an important component of the strategy to reduce the TB burden in low-incidence settings. An important option is the screening and preventive treatment of latent TB infection (LTBI). Whether this policy is worthwhile depends on the extent of transmission within the country, and introduction of new cases through import. Mathematical transmission models of TB have been used to identify key parameters in the epidemiology of TB and estimate transmission rates. An important application has also been to investigate the consequences of policy scenarios. Here, we formulate a mathematical model for TB transmission within the Netherlands to estimate the size of the pool of latent infections, and to determine the share of importation-either through immigration or travel- versus transmission within the Netherlands. We take into account importation of infections due to immigration, and travel to the country of origin, focusing on the three ethnicities most represented among foreign-born TB cases (after exclusion of those overrepresented among asylum seekers): Moroccans, Turkish and Indonesians. We fit a system of ordinary differential equations to the data from the Netherlands Tuberculosis Registry on (extra-)pulmonary TB cases from 1995-2013. We estimate that about 27% of Moroccans, 25% of Indonesians, and 16% of Turkish, are latently infected. Furthermore, we find that for all three foreign-born communities, immigration is the most important source of LTBI, but the extent of within-country transmission is much lower (about half) for the Turkish and Indonesian communities than for the Moroccan. This would imply that contact investigation would have a greater yield in the latter community than in the former. Travel remains a minor factor contributing LTBI, suggesting that targeting returning travelers might be less effective at preventing LTBI than immigrants upon entry in the country.

Background: Clinical trials that evaluate new anti-tubercular drugs and treatment regimens take years to complete due to the slow clearance of Mycobacterium tuberculosis infection and the lack of early biomarkers that predict treatment outcomes. Host Inflammation markers have been associated with tuberculosis (TB) pathogenesis. In the present study, we tested if circulating levels of C-reactive protein (CRP) and ferritin reflect mycobacterial loads and inflammation in pulmonary TB (PTB) patients undergoing anti-tuberculous therapy (ATT)., Methods: Prospective measurements of CRP and ferritin, used as readouts of systemic inflammation, were performed in cryopreserved serum samples from 165 Brazilian patients with active PTB initiating ATT. Associations between levels of these laboratory parameters with mycobacterial loads in sputum as well as with sputum conversion at day 60 of ATT were tested., Results: Circulating levels of both ferritin and CRP gradually decreased over time on ATT. At pre-treatment, concentrations of these parameters were unable to distinguish patients with positive from those with negative acid-fast bacilli (AFB) in sputum cultures. However, patients who remained with positive cultures at day 60 of ATT exhibited heightened levels of these inflammatory markers compared to those with negative cultures at that time point., Conclusions: CRP and Ferritin levels in serum may be useful to identify patients with positive cultures at day 60 of ATT.

Objective: To evaluate the performance of the Sensitire MYCOTB MIC Plate (MYCOTB) which could measure the twelve anti-tuberculosis drugs susceptibility on one 96-wells plate., Methods: A total of 140 MDR-TB strains and 60 non-MDR strains were sub-cultured and 193 strains were finally tested for drug resistance using MYCOTB and agar proportion method (APM) and another 7 strains failed of subculture. The drugs included ofloxacin (Ofx), moxifloxacin (Mfx), rifampin (RFP), amikacin (Am), rifabutin (Rfb), para-aminosalicylic acid (PAS), ethionamide (Eth), isoniazid (INH), kanamycin (Km), ethambutol (EMB), streptomycin (Sm), and cycloserine(Cs). The categorical agreement, conditional agreement, sensitivity and specificity of MYCOTB were assessed in comparison with APM. For strains with inconsistent results between MYCOTB and APM, the drug resistance related gene fragments were amplified and sequenced: gyrA for Ofx and Mfx; rpoB for RFP and Rfb; embB for EMB; rpsl for Sm; katG and the promoter region of inhA for INH, ethA and the promoter region of inhA for Eth. The sequence results were compared with results of MYCOTB and APM to analyze the consistency between sequence results and MYCOTB or APM., Results: The categorical agreement between two methods for each drug ranged from 88.6% to 100%. It was the lowest for INH (88.6%). The sensitivity and specificity of MYCOTB ranged from 71.4% to 100% and 84.3% to 100%, respectively. The sensitivity was lowest for Cs(71.4%), EMB at 10μg/ml (80.0%) and INH at 10.0μg/ml (84.6%). The specificity was lowest for Rfb (84.3%). Overall discordance between the two phenotypic methods was observed for 96 strains, of which 63 (65.6%) were found susceptible with APM and resistant with MYCOTB and the remaining 33(34.4%) strains were resistant by APM and susceptible with MYCOTB. 34/52 (65.4%) sequenced APM susceptible and MYCOTB resistant(APM-S/MYCOTB-R) strains had mutations or insertions in the amplified regions. 20/30 (66.7%) sequenced APM resistant and MYCOTB susceptible strains had mutations in the sequenced genes. MICs of twenty-nine of these thirty isolates were equal to or within 1 doubling dilution of the critical concentration., Conclusion: MYCOTB had good performance for most of tested drugs and could be used as an alternative to the more labor demanding and longer turnaround time solid culture based DST method for detection of drug susceptibility in China., Competing Interests: The authors have declared that no competing interests exist.

Background: Tuberculosis (TB) prevalence surveys offer a unique opportunity to study health seeking behaviour at the population level because they identify individuals with symptoms that should ideally prompt a health consultation., Objective: To assess the health-seeking behaviour among individuals who were presumptive TB cases in a national population based TB prevalence survey., Methods: A cross sectional survey was conducted between 2013 and 2014 among 66 survey clusters in Zambia. Clusters were census supervisory areas (CSAs). Participants (presumptive TB cases) were individuals aged 15 years and above; having either cough, fever or chest pain for 2 weeks or more; and/or having an abnormal or inconclusive chest x-ray image. All survey participants were interviewed about symptoms and had a chest X-ray taken. An in-depth interview was conducted to collect information on health seeking behaviour and previous TB treatment., Results: Of the 6,708 participants, the majority reported at least a history of chest pain (3,426; 51.1%) followed by cough (2,405; 35.9%), and fever (1,030; 15.4%) for two weeks or more. Only 34.9% (2,340) had sought care for their symptoms, mainly (92%) at government health facilities. Of those who sought care, 13.9% (326) and 12.1% (283) had chest x-ray and sputum examinations, respectively. Those ever treated for TB were 9.6% (644); while 1.7% (114) was currently on treatment. The average time (in weeks) from onset of symptoms to first care-seeking was 3 for the presumptive TB cases. Males, urban dwellers and individuals in the highest wealth quintile were less likely to seek care for their symptoms. The likelihood of having ever been treated for TB was highest among males, urban dwellers; respondents aged 35-64 years, individuals in the highest wealth quintile, or HIV positive., Conclusion: Some presumptive TB patients delay care-seeking for their symptoms. The health system misses opportunities to diagnose TB among those who seek care. Improving health-seeking behaviour among males, urban dwellers and those with a higher social economic status; and addressing health care lapses in TB case detection is required if TB is to be effectively controlled in Zambia., Competing Interests: The authors have declared that no competing interests exist.

Introduction: There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey., Methods: Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings., Results: Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR-TB patients were also top priorities in their respective categories. Results were internally consistent and robust., Discussion: Priorities retained from the 2008 research agenda include shorter MDR-TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data., Conclusion: There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.

Background: A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa., Method: An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015-2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds., Results: It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618)., Conclusion: The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa.

Introduction: The impact on treatment outcomes of XpertMTB/RIF, a molecular-based test that provides rapid diagnosis of tuberculosis (TB) and rifampicin resistance with high accuracy, has not been reported despite its adoption in a few countries. We here report treatment outcomes in a step-wedged cluster randomized trial for patients diagnosed with XpertMTB/RIF compared to patients diagnosed with sputum smear examination in public health facilities in Brazil., Methods: Treatment outcome data were added to the trial database of patients diagnosed from 4 February to 4 October 2012, and crosschecked with data from the national mortality and the drug-resistant TB registers. Treatment outcomes in the intervention (n=2232) and baseline (n=1856) arms were compared using a multilevel regression model., Results: Unfavourable outcomes were frequent in both arms, mainly due to loss to follow-up (16%). Overall unfavourable outcomes were not reduced in the intervention arm (29.6% versus 31.7%, OR=0.93; 95%CI=0.79-1.08). However, the overall TB-attributed death rate was lower in the intervention arm (2.3% vs. 3.8%). Adjusted for HIV status, age group and city, the intervention resulted in a 35% decrease in TB-attributed deaths (OR=0.65, 95%CI=0.44-0.97)., Conclusions: The proportion of patients successfully treated did not increase with Xpert MTB/RIF implementation, with high loss to follow-up rates in both arms. We did observe a 35% reduction in TB-related mortality, which we hypothesize may be explained by less advanced disease among the smear-negative patients diagnosed by Xpert. In conclusion, XpertMTB/RIF introduction did not improve TB treatment outcomes in Brazil., Trial Registration: clinicaltrials.gov NCT01363765.

Background: High costs are a limitation to scaling up the Xpert MTB/RIF assay (Xpert) for the diagnosis of tuberculosis in resource-constrained settings. A triaging strategy in which a sensitive but not necessarily highly specific rapid test is used to select patients for Xpert may result in a more affordable diagnostic algorithm. To inform the selection and development of particular diagnostics as a triage test we explored combinations of sensitivity, specificity and cost at which a hypothetical triage test will improve affordability of the Xpert assay., Methods: In a decision analytical model parameterized for Uganda, India and South Africa, we compared a diagnostic algorithm in which a cohort of patients with presumptive TB received Xpert to a triage algorithm whereby only those with a positive triage test were tested by Xpert., Findings: A triage test with sensitivity equal to Xpert, 75% specificity, and costs of US$5 per patient tested reduced total diagnostic costs by 42% in the Uganda setting, and by 34% and 39% respectively in the India and South Africa settings. When exploring triage algorithms with lower sensitivity, the use of an example triage test with 95% sensitivity relative to Xpert, 75% specificity and test costs $5 resulted in similar cost reduction, and was cost-effective by the WHO willingness-to-pay threshold compared to Xpert for all in Uganda, but not in India and South Africa. The gain in affordability of the examined triage algorithms increased with decreasing prevalence of tuberculosis among the cohort., Conclusions: A triage test strategy could potentially improve the affordability of Xpert for TB diagnosis, particularly in low-income countries and with enhanced case-finding. Tests and markers with lower accuracy than desired of a diagnostic test may fall within the ranges of sensitivity, specificity and cost required for triage tests and be developed as such.

Background: Adherence to treatment and sputum smear conversion after 2 months of treatment are thought to be important for successful outcome of tuberculosis (TB) treatment., Methods: Retrospective cohort study of new adult TB patients diagnosed in the first quarter of 2007 at 48 clinics in Rwanda. Data were abstracted from TB registers and individual treatment charts. Logistic regression analysis was done to examine associations between baseline demographic and clinical factors and three outcomes adherence, sputum smear conversion at two months, and death., Results: Out of 725 eligible patients the treatment chart was retrieved for 581 (80%). Fifty-six (10%) of these patients took <90% of doses (defined as poor adherence). Baseline demographic characteristics were not associated with adherence to TB treatment, but adherence was lower among HIV patients not taking antiretroviral therapy (ART); p = 0.03). Sputum smear results around 2 months after start of treatment were available for 220 of 311 initially sputum-smear-positive pulmonary TB (PTB+) patients (71%); 175 (80%) had achieved sputum smear conversion. In multivariable analysis, baseline sputum smear grade (odds ratio [OR] = 2.7, 95% Confidence interval [CI] 1.1-6.6 comparing smear 3+ against 1+) and HIV infection (OR 3.0, 95%CI 1.3-6.7) were independent predictors for non-conversion at 2 months. Sixty-nine of 574 patients (12%) with known TB treatment outcomes had died. Besides other known determinants, poor adherence had an independent, strong effect on mortality (OR 3.4, 95%CI 1.4-7.8)., Conclusion: HIV infection is an important independent predictor of failure of sputum smear conversion at 2 months among PTB+ patients. Poor adherence to TB treatment is an important independent determinant of mortality.

Background: High levels of defaulting from treatment challenge tuberculosis control in many African cities. We assessed defaulting from tuberculosis treatment in an African urban setting., Methods: An observational study among adult patients with smear-positive pulmonary tuberculosis receiving treatment at urban primary care clinics in Kampala, Uganda. Defaulting was defined as having missed two consecutive monthly clinic visits while not being reported to have died or continued treatment elsewhere. Defaulting patients were actively followed-up and interviewed. We assessed proportions of patients abandoning treatment with and without the information obtained through active follow-up and we examined associated factors through multivariable logistic regression., Results: Between April 2007 and April 2008, 270 adults aged ≥15 years were included; 54 patients (20%) were recorded as treatment defaulters. On active follow-up vital status was established of 28/54 (52%) patients. Of these, 19 (68%) had completely stopped treatment, one (4%) had died and eight (29%) had continued treatment elsewhere. Extrapolating this to all defaulters meant that 14% rather than 20% of all patients had truly abandoned treatment. Daily consumption of alcohol, recorded at the start of treatment, predicted defaulting (adjusted odds ratio [OR(adj)] 4.4, 95%CI 1.8-13.5), as did change of residence during treatment (OR(adj) 8.7, 95%CI 1.8-41.5); 32% of patients abandoning treatment had changed residence., Conclusions: A high proportion of tuberculosis patients in primary care clinics in Kampala abandon treatment. Assessing change of residence during scheduled clinic appointments may serve as an early warning signal that the patient may default and needs adherence counseling.

The population structure of Mycobacterium tuberculosis is typically clonal therefore genotypic lineages can be unequivocally identified by characteristic markers such as mutations or genomic deletions. In addition, drug resistance is mainly mediated by mutations. These issues make multiplexed detection of selected mutations potentially a very powerful tool to characterise Mycobacterium tuberculosis. We used Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for dispersed mutations, which can be successfully applied to Mycobacterium tuberculosis as was previously shown. Here we selected 47 discriminative and informative markers and designed MLPA probes accordingly to allow analysis with a liquid bead array and robust reader (Luminex MAGPIX technology). To validate the bead-based MLPA, we screened a panel of 88 selected strains, previously characterised by other methods with the developed multiplex assay using automated positive and negative calling. In total 3059 characteristics were screened and 3034 (99.2%) were consistent with previous molecular characterizations, of which 2056 (67.2%) were directly supported by other molecular methods, and 978 (32.0%) were consistent with but not directly supported by previous molecular characterizations. Results directly conflicting or inconsistent with previous methods, were obtained for 25 (0.8%) of the characteristics tested. Here we report the validation of the bead-based MLPA and demonstrate its potential to simultaneously identify a range of drug resistance markers, discriminate the species within the Mycobacterium tuberculosis complex, determine the genetic lineage and detect and identify the clinically most relevant non-tuberculous mycobacterial species. The detection of multiple genetic markers in clinically derived Mycobacterium tuberculosis strains with a multiplex assay could reduce the number of TB-dedicated screening methods needed for full characterization. Additionally, as a proportion of the markers screened are specific to certain Mycobacterium tuberculosis lineages each profile can be checked for internal consistency. Strain characterization can allow selection of appropriate treatment and thereby improve treatment outcome and patient management.

Background: Early detection and treatment of tuberculosis cases are the hallmark of successful tuberculosis control. We conducted a cross-sectional study at public primary health facilities in Kampala city, Uganda to quantify diagnostic delay among pulmonary tuberculosis (PTB) patients, assess associated factors, and describe trajectories of patients' health care seeking., Methodology/principal Findings: Semi-structured interviews with new smear-positive PTB patients (≥ 15 years) registered for treatment. Between April 2007 and April 2008, 253 patients were studied. The median total delay was 8 weeks (IQR 4-12), median patient delay was 4 weeks (inter-quartile range [IQR] 1-8) and median health service delay was 4 weeks (IQR 2-8). Long total delay (>14 weeks) was observed for 61/253 (24.1%) of patients, long health service delay (>6 weeks) for 71/242 (29.3%) and long patient delay (>8 weeks) for 47/242 (19.4%). Patients who knew that TB was curable were less likely to have long total delay (adjusted Odds Ratio [aOR] 0.28; 95%CI 0.11-0.73) and long patient delay (aOR 0.36; 95%CI 0.13-0.97). Being female (aOR 1.98; 95%CI 1.06-3.71), staying for more than 5 years at current residence (aOR 2.24 95%CI 1.18-4.27) and having been tested for HIV before (aOR 3.72; 95%CI 1.42-9.75) was associated with long health service delay. Health service delay contributed 50% of the total delay. Ninety-one percent (231) of patients had visited one or more health care providers before they were diagnosed, for an average (median) of 4 visits (range 1-30). All but four patients had systemic symptoms by the time the diagnosis of TB was made., Conclusions/significance: Diagnostic delay among tuberculosis patients in Kampala is common and long. This reflects patients waiting too long before seeking care and health services waiting until systemic symptoms are present before examining sputum smears; this results in missed opportunities for diagnosis.