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Background: Delays in seeking and accessing treatment for rifampicin-resistant tuberculosis (RR-TB) and multi-drug resistant (MDR-TB) are major impediments to TB control in high-burden, resource-limited settings., Method: We prospectively determined health-seeking behavioural patterns and associations with treatment outcomes and costs among 68 RR-TB patients attending conveniently selected facilities in a decentralised system in Harare, Zimbabwe., Results: From initial symptoms to initiation of effective treatment, patients made a median number of three health care visits (IQR 2-4 visits) at a median cost of 13% (IQR 6-31%) of their total annual household income (mean cost, US$410). Cumulatively, RR-TB patients most frequently first visited private facilities, i.e., private pharmacies (30%) and other private health care providers (24%) combined. Median patient delay was 26 days (IQR 14-42 days); median health system delay was 97 days (IQR 30-215 days) and median total delay from symptom onset to initiation of effective treatment was 132 days (IQR 51-287 days). The majority of patients (88%) attributed initial delay in seeking care to "not feeling sick enough." Total delay, total cost and number of health care visits were not associated with treatment or clinical outcomes, though our study was not adequately powered for these determinations., Conclusions: Despite the public availability of rapid molecular TB tests, patients experienced significant delays and high costs in accessing RR-TB treatment. Active case finding, integration of private health care providers and enhanced service delivery may reduce treatment delay and TB associated costs., Competing Interests: The authors have declared that no competing interests exist.

Background : Bedaquiline-containing regimens have demonstrated improved outcomes over injectable-containing regimens in the long-term treatment of multidrug-resistant tuberculosis (MDR-TB). Recently, the World Health Organization (WHO) recommended replacing injectables in the standard short-course regimen (SCR) with a bedaquiline-containing regimen. The South African national TB program similarly recommends a bedaquiline-containing regimen. Here, we investigated the cost-effectiveness of a bedaquiline-containing SCR versus an injectable-containing SCR for the treatment of MDR-TB in South Africa. Methods : A Markov model was adapted to simulate the incidence of active patients with MDR-TB. Patients could transition through eight health states: active MDR-TB, culture conversion, cure, follow-up loss, secondary MDR-TB, extensively DR-TB, end-of-life care, and death. A 5% discount was assumed on costs and outcomes. Health outcomes were expressed as disability-adjusted life years (DALYs). Results : Over a 10-year time horizon, a bedaquiline-containing SCR dominated an injectable-containing SCR, with an incremental saving of US $982 per DALY averted. A bedaquiline-containing SCR was associated with lower total costs versus an injectable-containing SCR (US $597 versus $657 million), of which US $3.2 versus $21.9 million was attributed to adverse event management. Conclusions : Replacing an injectable-containing SCR with a bedaquiline-containing SCR is cost-effective, offering a cost-saving alternative with improved patient outcomes for MDR-TB.

Background: Private healthcare is choice of point of care for 70% of Indians. Multidrug resistant tuberculosis (MDR-TB) treatment is costly and involves duration as long as 2 years., Aim: To estimate costs to patients undergoing treatment for MDR-TB., Methods: A health-economics questionnaire was administered to 50 consecutive patients who successfully completed ambulatory private treatment for MDR-TB. Direct costs included drug costs, investigations, consultation fees, travel costs, hospitalisation and invasive procedures and cost prior to presentation to us. Indirect costs included loss of income., Results: Of our cohort of 50 patients, 36 had pulmonary TB while 14 had extra-pulmonary TB (EPTB). 40 had MDR-TB and 10 had XDR-TB. There were 15 males and 35 females. Mean age was 30 years (range 16-61 years). Treatment cost for pulmonary MDR-TB averaged $5723 while it averaged $8401 for pulmonary XDR-TB and $5609 for EPTB. The major expense was due to drug costs (37%) while consultation fees were only 5%. Annual individual income for the cohort ranged from $0 to $63,000 (mean $11,430). On average, the cost of treatment ranged from 2.56% to 180.34% of the annual family income. 34/50 (68%) had total costs greater than 20% of annual family income and 39/50 (78%) had total costs greater than 10% of annual family income. The number of patients with total costs >40% of total family income was 22., Conclusion: MDR-TB in the private sector results in "catastrophic health costs". Financial and social support is essential for patients undergoing treatment for MDR-TB., (Copyright © 2018 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Growth-based drug susceptibility testing (DST) is the reference standard for diagnosing drug-resistant tuberculosis (TB), but standard time to result (TTR) is typically ≥ 3 weeks. Rapid tests can reduce that TTR to days or hours, but accuracy may be lowered. In addition to the TTR and test accuracy, the cost of a diagnostic test may affect whether it is adopted in clinical settings. We examine the cost-effectiveness of rapid diagnostics for extremely drug-resistant TB (XDR-TB) in three different high-prevalence settings., Methods: 1128 patients with confirmed TB were enrolled at clinics in Mumbai, India; Chisinau, Moldova; and Port Elizabeth, South Africa. Patient sputum samples underwent DST for first and second line TB drugs using 2 growth-based (MGIT, MODS) and 2 molecular (Pyrosequencing [PSQ], line-probe assays [LPA]) assays. TTR was the primary measure of effectiveness. Sensitivity and specificity were also evaluated. The cost to perform each test at each site was recorded and included test-specific materials, personnel, and equipment costs. Incremental cost-effectiveness ratios were calculated in terms of $/day saved. Sensitivity analyses examine the impact of batch size, equipment, and personnel costs., Results: Our prior results indicated that the LPA and PSQ returned results in a little over 1 day. Mean cost per sample without equipment or overhead was $23, $28, $33, and $41 for the MODS, MGIT, PSQ, and LPA, respectively. For diagnosing XDR-TB, MODS was the most accurate, followed by PSQ, and LPA. MODS was quicker and less costly than MGIT. PSQ and LPA were considerably faster but cost more than MODS. Batch size and personnel costs were the main drivers of cost variation., Conclusions: Multiple factors must be weighed when selecting a test for diagnosis of XDR-TB. Rapid tests can greatly improve the time required to diagnose drug-resistant TB, potentially improving treatment success, and preventing the spread of XDR-TB. Faster time to result must be weighed against the potential for reduced accuracy, and increased costs., Trial Registration: ClinicalTrials.gov Identifier: NCT02170441 .

Extensively Drug-resistant Tuberculosis (XDR-TB) has emerged as one of the most formidable challenges to the End TB Strategy that has targeted a 95% reduction in TB deaths and 90% reduction in cases by 2035. Globally, there were an estimated 55,100 new XDR-TB cases in 2015 in 117 countries. However, only one in 30 XDR-TB cases had been reported so far. Drug susceptibility test (DST) is the mainstay for diagnosing XDR-TB, but the lack of laboratory facilities in the resource-limited endemic countries limit its uses. A few new drugs including bedaquiline and delamanid, have the potential to improve the efficiency of XDR-TB treatment, but the drugs have been included in 39 countries only. The costs of XDR-TB treatment are several folds higher than that of the MDR-TB. Despite the financing from the donors, there is an urgent need to fill the current funding gap of US$ 2 billion to ensure effective treatment and robust surveillance. In the review article we have addressed current update on XDR-TB, including surveillance, diagnosis and the interventions needed to treat and limit its spread, emphasis on extensive financial support for implementing of current recommendations to meet the goals of End TB Strategy., (Copyright © 2017 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Objective: A population-based study of 135 multidrug-resistant tuberculosis (MDR-TB) patients reported to the Centers for Disease Control and Prevention (CDC) during 2005-2007 found 73% were hospitalized. We analyzed factors associated with hospitalization., Methods: We assessed statistically significant multivariable associations with US in-patient TB diagnosis, frequency of hospitalization, length of hospital stay, and in-patient direct costs to the health care system., Results: Of 98 hospitalized patients, 83 (85%) were foreign-born. Blacks, diabetics, or smokers were more likely, and patients with disseminated disease less likely, to receive their TB diagnosis while hospitalized. Patients aged ⩾65 years, those with the acquired immune-deficiency syndrome (AIDS), or with private insurance, were hospitalized more frequently. Excluding deaths, length of stay was greater for patients aged ⩾65 years, those with extensively drug-resistant TB (XDR-TB), those residing in Texas, those with AIDS, those who were unemployed, or those who had TB resistant to all first-line medications vs. others. Average hospitalization cost per XDR-TB patient (US$285 000) was 3.5 times that per MDR-TB patient (US$81 000), in 2010 dollars. Hospitalization episode costs for MDR-TB rank third highest and those for XDR-TB highest among the principal diagnoses., Conclusions: Hospitalization was common and remains a critical care component for patients who were older, had comorbidities, or required complex management due to XDR-TB. MDR-TB in-patient costs are among the highest for any disease.

Drug-resistant tuberculosis (TB) has increased at an alarming rate in the WHO European Region. Of the 27 countries worldwide with a high burden of multidrug resistant-TB (MDR-TB), 15 are in the European Region. An estimated 78,000 new cases of MDR-TB occur annually in the Region, of which approximately 10% are extensively drug-resistant (XDR)-TB. In response, the WHO Regional Office for Europe developed a Consolidated Action Plan to Prevent and Combat Multidrug- and Extensively Drug-resistant Tuberculosis (2011-2015). Our objective was to analyse the cost-effectiveness of implementing the plan, with the expected achievements of diagnosing 85% of estimated MDR-TB cases and treating at least 75% successfully. A transmission model, using epidemiological data reported to WHO was developed to calculate expected achievements. WHO-CHOICE database was used for cost analyses. The highly cost-effective plan is expected to prevent the emergence of 250,000 new MDR-TB and 13,000 XDR-TB patients respectively, saving US$7 billion and 120,000 lives. The plan and accompanying Resolution were fully endorsed by the sixty-first session of the WHO Regional Committee for Europe in 2011. Member States need to continuously improve health system performance and address TB determinants. Research and development of new medicines, tools and patient-friendly services are also crucial., (Copyright © 2015. Published by Elsevier Ltd.)

Data on availability and cost of anti-tuberculosis (TB) drugs in relation to affordability at national level are scarce. We performed a cross-sectional study on availability and cost of anti-TB drugs at major TB-reference centres in 37 European countries. Costs of standardised treatment regimens used for pan-sensitive TB, multidrug-resistant (MDR) TB, pre-extensively drug-resistant (XDR) TB, and XDR-TB were compared using a purchasing power analysis. Affordability was evaluated in relation to monthly national gross domestic products per capita (GDP). At least one second-line injectable and either moxifloxacin or levofloxacin were available in all countries. Linezolid and clofazimine were available in 79% and 46% of the countries, respectively. Drug cost for XDR-TB was three-times more expensive than those for MDR-TB. The average price of treatment for pan-sensitive TB represented a maximum of 8.5% of the monthly GDP across countries, while for standard MDR-TB treatment this was <30% in only six countries and more than 100% in four countries. Treatment of XDR-TB represented more than 100% of a month's GDP in all countries where the regimen was available. High cost and limited availability of drugs for treatment of drug-resistant TB, particularly beyond resistance to first-line drugs, are a major impediment to successful TB control in Europe., (Copyright ©ERS 2015.)

Background: We conducted a first baseline survey in Jilin Province of China to determine the proportion of drug-resistant tuberculosis (TB), and to analyze risk factors associated with the emergence of drug-resistance., Methodology/principal Findings: Thirty counties in Jilin Province were randomly selected as survey sites using a stratified cluster sampling method. People enrolled in the survey were new and re-treated, smear-positive pulmonary TB patients newly enrolled in local TB control and prevention institutions during the survey period. Sputum samples were collected, and the susceptibility of bacterial strains to anti-TB drugs was analyzed by proportion method. Based on the survey results, we estimated the number of drug-resistant TB patients and analyzed the risk factors associated with the emergence of drug resistance. Of 1,174 new TB patients and 597 re-treated TB patients, 8.6% and 23.2% were multi-drug resistant (MDR)-TB patients, respectively. Approximately 12% of MDR-TB patients were extensively drug-resistant. We estimate that approximately 1,290 new MDR-TB cases develop in Jilin Province every year. Of these, 810 cases would be new patients, and 480 cases would involve re-treated patients. Risk factors associated with MDR-TB include employment status, educational background, and income level., Conclusions/significance: Jilin Province remains one of the highest-burden areas in China for drug-resistant TB. The higher number of MDR-TB among new cases suggested that the transmission of drug-resistant strains in Jilin is an urgent problem in the MDR-TB control and prevention system of Jilin Province. Improving the treatment compliance of TB patients and the quality of medical care in public health institutions is urgently needed.

Background: Drug-resistant tuberculosis (DR-TB) remains a threat to global public health, owing to the complexity and delay of diagnosis and treatment. The Global Consortium for Drug-resistant Tuberculosis Diagnostics (GCDD) was formed to develop and evaluate assays designed to rapidly detect DR-TB, so that appropriate treatment might begin more quickly. This paper describes the methodology employed in a prospective cohort study for head-to-head assessment of three different rapid diagnostic tools., Methods: Subjects at risk of DR-TB were enrolled from three countries. Data were gathered from a combination of patient interviews, chart reviews, and laboratory testing from each site's reference laboratory. The primary outcome of interest was reduction in time from specimen arrival in the laboratory to results of rapid drug susceptibility tests, as compared with current standard mycobacterial growth indicator tube (MGIT) drug susceptibility tests., Results: Successful implementation of the trial in diverse multinational populations is explained, in addition to challenges encountered and recommendations for future studies with similar aims or populations., Conclusions: The GCDD study was a head-to-head study of multiple rapid diagnostic assays aimed at improving accuracy and precision of diagnostics and reducing overall time to detection of DR-TB. By conducting a large prospective study, which captured epidemiological, clinical, and biological data, we have produced a high-quality unique dataset, which will be beneficial for analyzing study aims as well as answering future DR-TB research questions. Reduction in detection time for XDR-TB would be a major public health success as it would allow for improved treatment and more successful patient outcomes. Executing successful trials is critical in assessment of these reductions in highly variable populations., Trial Registration: ClinicalTrials.gov NCT02170441.

Objectives: 4220 new cases of tuberculosis (TB) were reported in Germany in 2012; of those, 65 cases were multidrug-resistant TB (MDR-TB) or extensively multidrug-resistant TB (XDR-TB) cases. However, there is only limited information on the economic consequences of drug resistance patterns on the treatment costs of MDR-and XDR-TB patients., Methods: On the basis of drug susceptibility of the single MDR-TB/XDR-TB strains the direct medical costs of suitable therapies were calculated according to the current guidelines of the World Health Organization (WHO) and those of the German Central Committee against Tuberculosis. These costs were combined with hospital and outpatients monitoring costs and followed the most recent German invoicing system and health statistics. Total drug and monitoring costs and were determined by Monte-Carlo simulation comprising all different options., Results: According to this, the mean drug costs were €51,113.22 (range €19,586.14 to €94,767.90). The weighted costs for hospitalization were €26,000.76 per patient compared to only €2,192.13 for primary outpatients; the total treatment costs of MDR-TB amounted to €64,429.23. These are joined by the costs due to loss of productivity, varying between €17,721.60 and €44,304. From a societal perspective, the total cost per MDR-TB/XDR-TB case reach an amount between €82,150 and €108,733 per case, respectively., Conclusion: Cost analyses based on strain resistance patterns allow more reliable estimates of the real costs of treating MDR-TB/XDR-TB than do methods that ignore this factor. Advantageously, they demonstrate the economic impact of drug-resistant TB in low-incidence countries. Costs of productivity loss is of new importance because of the length of MDR-XDR therapy, but its true share of total costs has still to be determined., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases., Objective: To evaluate the potential cost-effectiveness of rapid DST for SLDs., Design: We constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST., Results: For rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries., Conclusion: Rapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Without better vaccines it is unlikely that tuberculosis (TB) will ever be eliminated. An investment of ∼ €560 million is considered necessary to develop a new, effective vaccine in the European Union (EU). However, less is known about the costs of TB disease in the EU. We performed a systematic review of literature and institutional websites addressing the 27 EU members to summarise cost data. We searched MEDLINE, EMBASE and Cochrane bibliographies for relevant articles. Combining direct and indirect costs, we arrived at an average per-TB case costs in the original EU-15 states plus Cyprus, Malta and Slovenia of €10 282 for drug-susceptible TB, €57 213 for multidrug resistant (MDR)-TB and €170 744 for extensively drug resistant (XDR)-TB. In the remaining new EU states, costs amounted to €3427 for drug-susceptible TB and €24 166 for MDR-TB/XDR-TB. For the 70 340 susceptible TB cases, 1488 MDR-TB and 136 XDR-TB cases notified in 2011 costs of €536 890 315 accumulated in 2012. In the same year, the 103 104 disability-adjusted life years caused by these cases, when stated in monetary terms, amounted to a total of €5 361 408 000. Thus, the resulting economic burden of TB in the EU clearly outweighs the cost of investing in more efficient vaccines against TB.

Linezolid is identified as an effective drug with which to treat patients failing multidrug-resistant (MDR)-tuberculosis (TB) treatment. However, cost and safety are the concerns. In India, the average price of a 600-mg pill of linezolid is less than one US dollar, much cheaper than most of the third-line drugs. A prospective study of 29 MDR-TB treatment failure patients (16 with laboratory-proven extensively drug-resistant (XDR)-TB and the remaining 13 with MDR-TB with resistance to any quinolone but sensitive to injectables) was carried out in Delhi, India. All patients received daily unsupervised therapy with linezolid, one injectable agent, one fluoroquinolone and two or more other drugs. Patients received a median of six anti-mycobacterial agents. Besides linezolid, capreomycin, moxifloxacin, levofloxacin and amoxycillin-clavulanic acid were used in 41.4%, 58.6%, 41.4%, and 79.3% of patients. Out of a total of 29 patients, 89.7% patients achieved sputum smear and culture conversion; 72.4% showed interim favourable outcome; 10.3% died, 6.8% failed and 10.3% patients defaulted. Linezolid had to be stopped in three (10.3%) patients due to adverse reactions. The outcome of treatment of 16 XDR-TB patients was comparable to the other 13 MDR-TB patients. Linezolid is an effective, cheap and relatively safe drug for patients failing MDR-TB treatment, including those with confirmed XDR-TB.