ERS/ECDC Statement: European Union standards for tuberculosis care, 2017 update.

The International Standards for Tuberculosis Care define the essential level of care for managing patients who have or are presumed to have tuberculosis, or are at increased risk of developing the disease. The resources and capacity in the European Union (EU) and the European Economic Area permit higher standards of care to secure quality and timely TB diagnosis, prevention and treatment. On this basis, the European Union Standards for Tuberculosis Care (ESTC) were published in 2012 as standards specifically tailored to the EU setting. Since the publication of the ESTC, new scientific evidence has become available and, therefore, the standards were reviewed and updated.A panel of international experts, led by a writing group from the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC), updated the ESTC on the basis of new published evidence. The underlying principles of these patient-centred standards remain unchanged. The second edition of the ESTC includes 21 standards in the areas of diagnosis, treatment, HIV and comorbidities, and public health and prevention.The ESTC target clinicians and public health workers, provide an easy-to-use resource and act as a guide through all the required activities to ensure optimal diagnosis, treatment and prevention of TB.

Multidrug-resistant TB in Eastern region of the EU: is the shorter regimen an exception or a rule?

WHO recently recommended the use of a shorter multidrug-resistant TB (MDR-TB) regimen under programmatic conditions. We assessed eligibility for this regimen in a cohort of 737 adult patients with MDR-TB from Latvia, Lithuania, Estonia and Bucharest city recruited in 2007 and 2009. Only 4.2% of the patients were eligible for this regimen. Ethambutol (64%), pyrazinamide resistance (58%) and previous exposure to second-line TB drugs were major reasons for non-eligibility. High-level resistance to isoniazid is expected due to widespread prevalence of katG mutations. In Eastern Europe, the use of the shorter regimen might be an exception rather than a rule.

Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance.

BACKGROUND: Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined. METHODS: Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens. RESULTS: Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from ≤1 to ≥5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome. CONCLUSIONS: Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

Decreased Time to Treatment Initiation for Multidrug-Resistant Tuberculosis Patients after Use of Xpert MTB/RIF Test, Latvia.

Few studies have examined whether the Xpert MTB/RIF test improves time to treatment initiation for persons with multidrug-resistant tuberculosis (MDR TB). We determined the impact of this test in Latvia, where it was introduced in 2010. After descriptive analyses of pulmonary MDR TB patients in Latvia during 2009-2012, time to treatment initiation was calculated, and univariate and multivariable accelerated failure time models were constructed. Univariate results showed strong evidence of an association between having rifampin-resistant TB detected by Xpert MTB/RIF and reduced time to treatment initiation versus the test not being used. A multivariable model stratifying by previous TB showed similar results. Our finding that in Latvia, time to treatment initiation was decreased for MDR TB cases that were rifampin-resistant TB by XpertMTB/RIF has implications for the use of this test in other settings with a high burden of MDR TB in which rifampin resistance is highly predictive of MDR TB.

Survival of patients with multidrug-resistant TB in Eastern Europe: what makes a difference?

BACKGROUND: The quality of care for patients with TB in Eastern Europe has improved significantly; nevertheless drug resistance rates remain high. We analysed survival in a cohort of patients with multidrug-resistant and extensively drug-resistant (MDR-/XDR-) TB from Latvia, Lithuania, Estonia and Bucharest city. METHODS: Consecutive adult new and retreatment patients with culture-confirmed pulmonary MDR-TB registered for treatment in 2009 (and in 2007 in Latvia) were enrolled; prospective survival information was collected. RESULTS: A total of 737 patients were included into the cohort. Of all MDR-TB cases, 46% were newly diagnosed; 56% of all MDR-TB cases had no additional resistance to fluoroquinolones or injectable agents, 33% had pre-XDR-TB and 11% XDR-TB. Median survival was 5.9 years in patients with MDR-TB and XDR-TB; 1.9 years in patients coinfected with HIV. Older age, male gender, alcohol abuse, retirement, co-morbidities, extrapulmonary involvement and HIV coinfection independently worsened survival. Inclusion of fluoroquinolones and injectable agents improves survival in patients with MDR-TB. Pre-XDR and XDR status did not significantly shorten survival as long as fluoroquinolones and injectable agents were part of the regimen. Moxifloxacin seems to improve survival in ofloxacin-susceptible patients when compared with older generation fluoroquinolones. CONCLUSIONS: The burden of additional resistances in patients with MDR-TB is high likely due to primary transmission of resistant strains. Social and programmatic factors including management of alcohol dependency, expansion of HIV testing and antiretroviral treatment need to be addressed in order to achieve cure and to interrupt transmission. The role of last generation fluoroquinolones and injectable agents in treatment of patients with pre-XDR and XDR-TB needs to be further investigated.

The value of effective public tuberculosis treatment: an analysis of opportunity costs associated with multidrug resistant tuberculosis in Latvia.

BACKGROUND: A challenge to effective protection against tuberculosis is to sustain expensive and complex treatment public programs. Potential consequences of program failure include acquired drug resistance, poor patient outcomes, and potentially much higher system costs, however. In contrast, effective efforts have value illustrated by impacts they prevent. We compared the healthcare costs and treatment outcomes among multidrug-resistant tuberculosis (MDR-TB) and non MDR-TB patients in Latvia to identify benefits or costs associated with both. METHODS: We measured and compared costs, healthcare utilization, and outcomes for patients who began treatment through Latvia's TB control program in 2002 using multivariate regression analysis and negative binomial regression. RESULTS: We analyzed data for 92 MDR-TB and 54 non MDR-TB patients. Most (67%) MDR-TB patients had history of prior tuberculosis treatment. MDR-TB was associated with lower cure rates (71% vs. 91%) and greater resource utilization. MDR-TB treatment cost almost $20,000 more than non MDR-TB. CONCLUSION: Up to 2/3 of MDR-TB treated in our sample was preventable at a potential savings of over $1.3 million in healthcare resources as well as substantial individual health.

Analysis of Mycobacterium tuberculosis genetic lineages circulating in Riga and Riga region, Latvia, isolated between 2008 and 2012.

Although the number of new tuberculosis (TB) cases registered per year has decreased by 3-fold between 2001 and 2017 in Latvia, the TB incidence and rates of multidrug resistant TB in this Baltic country remain substantially higher than in most other European countries. Molecular typing methods of Mycobacterium tuberculosis (MTB) play an important role both in clinical studies of the disease and the epidemiological investigations, allowing to describe and characterize the pathogen's population structure and spread of particular genotypes. Aim of this study was to examine the prevalence of MTB lineages in Riga and Riga region of Latvia within a five-year period (2008-2012), and to evaluate the discriminatory power (DP) of spoligotyping, standard 24-locus MIRU-VNTR and IS6110-RFLP methods in this setting. The results showed that the main MTB spoligotype families were Beijing (25.3%) and LAM (24.3%), followed by T (22.1%), Ural (11.2%), Haarlem (6.6%) and X superfamily (3.4%). This distribution remained stable over the five consecutive years. 67.6% of MTB isolates were pan-susceptible, and 32.4% were resistant to any drug; multi-drug resistance was found in 5.8% of MTB strains, and 7.6% of MTB isolates were extensively drug-resistant. Drug resistance was associated with SIT1, SIT283 and SIT42 genotypes, while SIT1 and SIT42 were overrepresented among multi drug-resistant MTB strains. Overall, DP of spoligotyping method alone was 0.8953, while DP of both 24-locus MIRU-VNTR analysis and IS6110 RFLP was higher (DP = 0.9846 and 0.9927, respectively), mainly due to the improvement of the resolution for the Beijing strains. In conclusion, this work represents the first comprehensive molecular epidemiological description of TB in Latvia, highlighting the high genetic diversity of MTB strains circulating in Riga and Riga region. In combination with detailed epidemiological data this approach was helpful for the in-depth understanding of epidemiological processes in settings where the Next-Gen sequencing is not available as a routine method.

"Treatment is of primary importance, and social assistance is secondary": A qualitative study on the organisation of tuberculosis (TB) care and patients' experience of starting and staying on TB treatment in Riga, Latvia.

BACKGROUND: Vulnerable individuals with tuberculosis (TB) struggle to access and stay on treatment. While patient-related and social barriers to TB treatment adherence are well documented, less is known about how the organisation and delivery of TB care influences adherence behaviour. AIM: To examine the influence of TB service organisation and culture on patients' experience of starting and staying on treatment in Riga, Latvia. METHODS: An intervention package to support adherence to TB treatment amongst vulnerable patients in Riga, Latvia was piloted between August 2016 and March 2017. Qualitative observations (5), interviews with staff (20) and with TB patients (10) were conducted mid-way and at the end of the intervention to understand perceptions, processes, and experiences of TB care. RESULTS: The organisation of TB services is strongly influenced by a divide between medical and social aspects of TB care. Communication and care practices are geared towards addressing individual risk factors for non-adherence rather than the structural vulnerabilities that patients experience in accessing care. Support for vulnerable patients is limited because of standardised programmatic approaches, resource constraints and restricted job descriptions for non-medical staff. CONCLUSION: Providing support for vulnerable patients is challenged in this setting by the strict division between medical and social aspects of TB care, and the organisational focus on patient-related rather than systems-related barriers to access and adherence. Potential systems interventions include the introduction of multi-disciplinary approaches and teams in TB care, strengthening patient literacy at the point of treatment initiation, as well as stronger linkages with social care organisations.

Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome.

BACKGROUND: Conversion of sputum mycobacterial cultures from positive growth to negative growth of Mycobacterium tuberculosis in patients with pulmonary tuberculosis (TB) is considered the most important interim indicator of the efficacy of anti-TB pharmacologic treatment for multidrug-resistant disease. OBJECTIVE: To evaluate and compare time to and predictors of initial sputum culture conversion with predictors of treatment outcome for patients with multidrug-resistant TB. DESIGN: Retrospective cohort study. SETTING: Latvia. PATIENTS: All civilian patients with multidrug-resistant TB treated with the DOTS-Plus strategy between 1 January and 31 December 2000. INTERVENTION: Individualized treatment for confirmed sputum culture-positive pulmonary multidrug-resistant TB. MEASUREMENTS: Time to initial sputum culture conversion and treatment outcome. RESULTS: Among 167 patients who were sputum culture-positive at initiation of second-line therapy, 129 (77%) converted in a median time of 60 days (range, 4 to 462 days) and 38 (23%) did not convert. Independent predictors of a longer sputum culture conversion time, using an accelerated failure time regression model, included previous treatment for multidrug-resistant TB, high initial sputum culture colony count, bilateral cavitations on chest radiography, and the number of drugs the initial isolate was resistant to at treatment initiation. Treatment outcomes were statistically significantly worse for patients who did not convert their sputum culture within 2 months. LIMITATIONS: Twenty-five percent of patients missed 5 or more monthly sputum collections. CONCLUSIONS: Under program conditions in Latvia, most patients with multidrug-resistant TB achieved sputum culture conversion within 12 weeks of starting treatment. Chest radiography and sputum culture drug susceptibility testing can assist physicians in predicting which patients will convert more slowly. Sputum culture conversion is a useful and appropriate interim indicator of treatment outcome in patients with multidrug-resistant TB.

Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study.

BACKGROUND: Latvia has one of the highest rates of multidrug-resistant tuberculosis (MDRTB). Our aim was to assess treatment outcomes for the first full cohort of MDRTB patients treated under Latvia's DOTS-Plus strategy following WHO guidelines. METHODS: We retrospectively reviewed all civilian patients who began treatment with individualised treatment regimens for pulmonary MDRTB in Latvia between Jan 1, and Dec 31, 2000. We applied treatment outcome definitions for MDRTB, developed by an international expert consensus group, and assessed treatment effectiveness and risk factors associated with poor outcome. FINDINGS: Of the 204 patients assessed, 55 (27%) had been newly diagnosed with MDRTB, and 149 (73%) had earlier been treated with first-line or second-line drugs for this disease. Assessment of treatment outcomes showed that 135 (66%) patients were cured or completed therapy, 14 (7%) died, 26 (13%) defaulted, and treatment failed in 29 (14%). Of the 178 adherent patients, 135 (76%) achieved cure or treatment completion. In a multivariate Cox proportional-hazards model of these patients, independent predictors of poor outcome (death and treatment failure) included having previously received treatment for MDRTB (hazard ratio 5.7, 95% CI 1.9-16.6), the use of five or fewer drugs for 3 months or more (3.2, 1.1-9.6), resistance to ofloxacin (2.6, 1.2-5.4), and body-mass index less than 18.5 at start of treatment (2.3, 1.1-4.9). INTERPRETATION: The DOTS-Plus strategy of identifying and treating patients with MDRTB can be effectively implemented on a nationwide scale in a setting of limited resources.

Drug Susceptibility Patterns in MDR-TB Patients: Challenges for Future Regimen Design. A Cross-Sectional Study.

Globally, there is substantial concern regarding the challenges of treating complex drug resistance patterns in multidrug resistant tuberculosis cases. Utilising data from three different settings (Estonia, Latvia, Romania) we sought to contrast drug susceptibility profiles for multidrug resistant tuberculosis cases, highlight the difficulties in designing universal regimen, and inform future regimen selection. Demographic and microbiological surveillance data for multidrug resistant tuberculosis cases from 2004-13 were analysed. High levels of additional resistance to currently recommended second line drugs were seen in all settings, with extensive variability between countries. Accurate drug susceptibility testing and drug susceptibility testing data are vital to inform the development of comprehensive, flexible, multidrug resistant tuberculosis guidance.

Resistance profile and risk factors of drug resistant tuberculosis in the Baltic countries.

The rates of multi- and extensively drug-resistant tuberculosis (X/MDRTB) in the Baltic countries are the highest within the European Union hampering recent achievements of national TB control programmes. We included all consecutive culture-confirmed X/MDRTB patients registered for treatment in 2009 in Latvia, Lithuania and Estonia into this multicenter case-control study. Cases were compared with randomly selected controls with non-MDRTB registered for treatment in the same year across these sites. Of 495 MDRTB patients, 243 (49.7%) showed resistance to at least one second-line drug, 206 (42.1%) had pre-XDRTB (i.e. MDRTB with additional resistance to a second-line injectable or fluoroquinolones) and 64 (13.1%) had XDRTB. Younger age, male gender and known contact with an MDRTB case were associated with increased risk of primary infection with X/MDRTB strains. Previous treatment and alcohol abuse were strong predictors for MDRTB acquisition; defaults and failures in the past triggered XDRTB development. All patients received appropriate therapy; less than half of the patients were fully adherent. An erroneous treatment strategy is unlikely to drive resistance development. Increasing patients' compliance, addressing issues of social support, rapid detection of drug resistance and improving infection control is crucial for prevention of further spread of X/MDRTB and achieving higher cure rates.

Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies.

BACKGROUND: Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. METHODS: We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. FINDINGS: We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p<0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment. INTERPRETATION: Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. FUNDING: US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.

Predictors of poor outcomes among patients treated for multidrug-resistant tuberculosis at DOTS-plus projects.

The Objective of this analysis was to identify predictors of death, failure, and default among MDR-TB patients treated with second-line drugs in DOTS-plus projects in Estonia, Latvia, Philippines, Russia, and Peru, 2000-2004. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using multivariable regression. Of 1768 patients, treatment outcomes were: cure/completed - 1156 (65%), died - 200 (11%), default - 241 (14%), failure - 118 (7%). Independent predictors of death included: age>45 years (RR = 1.90 (95%CI 1.29-2.80), HIV infection (RR = 4.22 (2.65-6.72)), extrapulmonary disease (RR = 1.54 (1.04-2.26)), BMI<18.5 (RR = 2.71 (1.91-3.85)), previous use of fluoroquinolones (RR = 1.91 (1.31-2.78)), resistance to any thioamide (RR = 1.59 (1.14-2.22)), baseline positive smear (RR = 2.22 (1.60-3.10)), no culture conversion by 3rd month of treatment (RR = 1.69 (1.19-2.41)); failure: cavitary disease (RR = 1.73 (1.07-2.80)), resistance to any fluoroquinolone (RR = 2.73 (1.71-4.37)) and any thioamide (RR = 1.62 (1.12-2.34)), and no culture conversion by 3rd month (RR = 5.84 (3.02-11.27)); default: unemployment (RR = 1.50 (1.12-2.01)), homelessness (RR = 1.52 (1.00-2.31)), imprisonment (RR = 1.86 (1.42-2.45)), alcohol abuse (RR = 1.60 (1.18-2.16)), and baseline positive smear (RR = 1.35 (1.07-1.71)). Patients with biomedical risk factors for treatment failure or death should receive heightened medical attention. To prevent treatment default, management of patients who are unemployed, homeless, alcoholic, or have a prison history requires extra measures to insure treatment completion.

Mortality from HIV and TB coinfections is higher in Eastern Europe than in Western Europe and Argentina.

BACKGROUND AND OBJECTIVES: Tuberculosis (TB) is a leading cause of death in HIV-infected patients worldwide. We aimed to study clinical characteristics and outcome of 1075 consecutive patients diagnosed with HIV/TB from 2004 to 2006 in Europe and Argentina. METHODS: One-year mortality was assessed in patients stratified according to region of residence, and factors associated with death were evaluated in multivariable Cox models. RESULTS: At TB diagnosis, patients in Eastern Europe had less advanced immunodeficiency, whereas a greater proportion had a history of intravenous drug use, coinfection with hepatitis C, disseminated TB, and infection with drug-resistant TB (P < 0.0001). In Eastern Europe, fewer patients initiated TB treatment containing at least rifamycin, isoniazid, and pyrazinamide or combination antiretroviral therapy (P < 0.0001). Mortality at 1 year was 27% in Eastern Europe, compared with 7, 9 and 11% in Central/Northern Europe, Southern Europe, and Argentina, respectively (P < 0.0001). In a multivariable model, the adjusted relative hazard of death was significantly lower in each of the other regions compared with Eastern Europe: 0.34 (95% confidence interval 0.17-0.65), 0.28 (0.14-0.57), 0.34 (0.15-0.77) in Argentina, Southern Europe and Central/Northern Europe, respectively. Factors significantly associated with increased mortality were CD4 cell count less than 200 cells/microl [2.31 (1.56-3.45)], prior AIDS [1.74 (1.22-2.47)], disseminated TB [2.00 (1.38-2.85)], initiation of TB treatment not including rifamycin, isoniazid and pyrazinamide [1.68 (1.20-2.36)], and rifamycin resistance [2.10 (1.29-3.41)]. Adjusting for these known confounders did not explain the increased mortality seen in Eastern Europe. CONCLUSION: The poor outcome of patients with HIV/TB in Eastern Europe deserves further study and urgent public health attention.