PASS to End TB in Europe: Accelerated efforts on prevention and systematic screening to end tuberculosis in the WHO European Region by 2030.

OBJECTIVES: Outline the objectives, methods, and initial stages of the Prevention and Systematic Screening (PASS) initiative, a complimentary element of the innovative new approach of technical assistance mechanisms of WHO and its partners to countries aligned to the Regional TB Action Plan to End TB in the European Region by 2030. DESIGN: To provide an objective and critical overview of the existing landscape on TB epidemic in the WHO European Region (the European Region) and ii) identify the strategic significance of proactive measures aimed at approaching TB pre-elimination in the Region. RESULTS: Interventions primarily include systematic screening for TB disease and treatment for TB infection (TBI). CONCLUSIONS: PASS to End TB is an exemplary initiative of how technical and funding partners are joining hands to support national health programmes to work towards global commitments to curb major public health challenges like TB.

National policies for delivering tuberculosis, HIV and hepatitis B and C virus infection services for refugees and migrants among Member States of the WHO European Region.

BACKGROUND/OBJECTIVE: Refugees and migrants to the World Health Organization (WHO) European Region are disproportionately affected by infections, including tuberculosis (TB), human immunodeficiency virus (HIV) and hepatitis B and C (HBV/HCV) compared with the host population. There are inequities in the accessibility and quality of health services available to refugees and migrants in the Region. This has consequences for health outcomes and will ultimately impact the ability to meet Regional infection elimination targets. METHODS: We reviewed academic and grey literature to identify national policies and guidelines for TB/HIV/HBV/HCV specific to refugees and migrants in the Member States of the WHO European Region and to identify: (i) evidence informing policy and (ii) barriers and facilitators to policy implementation. RESULTS: Relatively few primary national policy/guideline documents were identified which related to refugees and migrants and TB [14 of 53 Member States (26%), HIV (n = 15, 28%) and HBV/HCV (n = 3, 6%)], which often did not align with the WHO recommendations, and for some countries, violated refugees' and migrants' human rights. We found extreme heterogeneity in the implementation of the WHO- and European Centre for Disease Prevention and Control (ECDC)-advocated policies and recommendations on the prevention, diagnosis, treatment and care of TB/HIV/HBV/HCV infection among migrants across the Member States of the WHO European Region.There is great heterogeneity in implementation of WHO- and ECDC-advocated policies on the prevention, diagnosis, treatment and care of TB/HIV/HBV/HCV infection in refugees and migrants across the Member States in the Region. CONCLUSION: More transparent and accessible reporting of national policies and guidelines are required, together with the evidence base upon which these policy decisions are based. Political engagement is essential to drive the changes in national legislation to ensure equitable and universal access to the diagnosis and care for infectious diseases.

Operational Research to Inform Programmatic Approaches to the Management of Tuberculosis in Uzbekistan.

Globally, an estimated 10 million people fell ill with tuberculosis (TB) in 2019, a number that has been declining very slowly in recent years [...].

Short and long-term outcomes of video observed treatment in tuberculosis patients, the Republic of Moldova.

INTRODUCTION: The Republic of Moldova is among the 18 high priority countries for tuberculosis (TB) in Europe. This study compared adherence and short and long-term TB treatment outcomes for TB patients who experienced asynchronous Video Observed Treatment (aVOT) during three months of outpatient treatment versus Directly Observed Treatment (DOT) in operational conditions in 2016-2017 in Chisinau. METHODOLOGY: We used secondary data from the 2016-2017 Randomized Clinical Trial (RCT) that piloted the aVOT Strategy in Chisinau and data from the national TB register. Relative risk was selected as a measure of association in analysis of treatment strategies (aVOT and DOT under operational conditions) and short and long-term treatment outcomes. RESULTS: From 647 TB patients included in the study, 169 followed the treatment strategy in the RCT (83 in aVOT and 86 in DOT) and 478 were on DOT in operational conditions. Those in aVOT were more likely to have favourable short-term outcome than patients with DOT in operational conditions (RR 0.07; p < 0.001). TB recurrence as an indicator for the long-term outcome, was observed in group with DOT in operational conditions (40 cases, p = 0.006). CONCLUSIONS: This study demonstrated that the aVOT treatment strategy was associated with better adherence and both short and long-term TB treatment favourable outcomes. aVOT as a new patient-centred approach supporting TB patients on improving treatment adherence and outcomes might be recommended as an alternative to DOT strategy in the Republic of Moldova.

Tuberculosis Notification Trends and Treatment Outcomes in Penitentiary and Civilian Health Care Sectors in the WHO European Region.

SETTING: Tuberculosis (TB) morbidity in penitentiary sectors is one of the major barriers to ending TB in the World Health Organization (WHO) European Region. OBJECTIVES AND DESIGN: a comparative analysis of TB notification rates during 2014-2018 and of treatment outcomes in the civilian and penitentiary sectors in the WHO European Region, with an assessment of risks of developing TB among people experience incarceration. RESULTS: in the WHO European Region, incident TB rates in inmates were 4-24 times higher than in the civilian population. In 12 eastern Europe and central Asia (EECA) countries, inmates compared to civilians had higher relative risks of developing TB (RR = 25) than in the rest of the region (RR = 11), with the highest rates reported in inmates in Azerbaijan, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation, and Ukraine. The average annual change in TB notification rates between 2014 and 2018 was -7.0% in the civilian sector and -10.9% in the penitentiary sector. A total of 15 countries achieved treatment success rates of over 85% for new penitentiary sector TB patients, the target for the WHO European Region. In 10 countries, there were no significant differences in treatment outcomes between civilian and penitentiary sectors. CONCLUSION: 42 out of 53 (79%) WHO European Region countries reported TB data for the selected time periods. Most countries in the region achieved a substantial decline in TB burden in prisons, which indicates the effectiveness of recent interventions in correctional institutions. Nevertheless, people who experience incarceration remain an at-risk population for acquiring infection, developing active disease and unfavourable treatment outcomes. Therefore, TB prevention and care practices in inmates need to be improved.

Incidence Rate and Risk Factors for Tuberculosis among People Living with HIV: A 2015-2017 Cohort from Tashkent, Uzbekistan.

People living with the human immunodeficiency virus (PLHIV) have a higher risk of developing active tuberculosis (TB) disease, and TB remains a major cause of death in PLHIV. Uzbekistan is facing a substantial TB epidemic, which increases the risk of PLHIV developing active TB. Our retrospective cohort study aimed to evaluate the incidence rate and assess the risk factors for developing active TB among PLHIV. We collected secondary data extracted from medical charts of all patients, newly diagnosed at the AIDS Center in Tashkent, during the period of 2015-2017. The incidence rate of TB among PLHIV was 5.1 (95% CI: 4.5-6.0) per 1000 person/month. Adjusted regression analysis showed three major risk factors for TB, namely, being less than 15 years old (hazard ratio (HR) 5.83; 95% CI: 3.24-10.50, p value = 0.001),low CD4 count (adjusted hazard ratio(aHR) 21.0; 95% CI: 9.25-47.7, p value < 0.001), and antiretroviral therapy (ART) interruption/not receiving ART (aHR 5.57; 95% CI: 3.46-8.97 and aHR 6.2; 95% CI: 3.75-10.24, p value < 0.001, respectively) were significantly associated with developing active TB among PLHIV. Our findings indicate that taking prescribed ART without interruptions and maintaining CD4cell counts higher than 320 cells/µL are essential to prevent the development of active TB among PLHIV.

Diagnostic Procedures, Diagnoses, and Treatment Outcomes of Patients with Presumptive Tuberculosis Pleural Effusion in Uzbekistan.

Tuberculosis (TB) pleural effusion (TPE) is the second most common manifestation of extrapulmonary TB (EPTB), which remains a great diagnostic challenge worldwide. In Uzbekistan, there has been no formal evaluation of the actual practices of diagnosing and treating TPE. Our cohort study therefore aimed to describe the frequency and types of different diagnostic procedures of TPE during 2017-2018 and assess the association of baseline characteristics and establish diagnostic methods with TB treatment outcomes. In total, 187 patients with presumptive TPE were assessed, and 149 had a confirmed diagnosis of TPE (other diagnoses included cancer n = 8, pneumonia n = 17, and 13 cases were unspecified). TB was bacteriologically confirmed in 22 (14.8%), cytologically confirmed in 64 (43.0%), and histologically confirmed in 16 (10.7%) patients. Hepatitis was the only co-morbidity significantly associated with unsuccessful treatment outcomes (RR 4.8; 95%CI: 1.44-15.98, p value 0.011). Multivariable regression analysis showed that drug-resistant TB was independently associated with unsuccessful TB treatment outcome. (RR 3.83; 95%CI: 1.05-14.02, p value 0.04). Multidisciplinary approaches are required to maximize the diagnostic accuracy of TPE and minimize the chances of misdiagnosis. TPE patients with co-infections and those with drug resistance should be more closely monitored to try and ensure successful TB treatment outcomes.

Operational research as an instrument to address the critical gaps for effective treatment of tuberculosis in eastern Europe and central Asia.

Editorial.

Do catastrophic costs impact treatment outcomes in people with rifampicin-resistant tuberculosis in the Republic of Moldova?

The Republic of Moldova is among the 30 Rifampicin-Resistant and/or Multidrug-Resistant (RR/MDR) Tuberculosis (TB) high burden countries in the world. Despite free TB diagnostics and treatment, TB patients face substantial economic losses and this may impact overall treatment outcomes. We assessed if there is an association between TB-related catastrophic costs and TB treatment outcomes. We conducted a cohort study using data from patient records and a survey that quantified catastrophic costs among RR/MDR-TB affected households in the Republic of Moldova in 2016. We included adult patients (age ≥18 years) with RR/MDR-TB who had been in inpatient (intensive phase) or outpatient (continuous phase) treatment for at least 2 months. Unfavourable treatment outcome, such as failure, death or lost to follow-up, was the primary outcome variable. The definition of catastrophic TB-related costs followed the World Health Organisation (WHO) guidelines: costs due to TB ≥20% of annual household income. Log-binomial regression was used to assess association between the outcome and catastrophic TB-related costs adjusting for other socio-demographic, behavioural and clinical covariates.  In total 287 RR/MDR-TB patients (78% males, mean age 42 years) were included. Of them, 30% experienced catastrophic TB-related costs. Overall, one in five patients (21%) had unfavourable treatment outcome, such as treatment failure (5%), death (8%) or lost to follow-up (8%). The experience of catastrophic TB-related costs was not associated with unfavourable treatment outcome [adjusted relative risk (aRR)=0.88, 95% CI: 0.50-1.50]. Major factors independently associated with unfavourable TB treatment outcomes were poverty (aRR=2.07; 95% CI: 1.06-4.07), urban residence (aRR=1.99; 95% CI: 1.12-3.52) and positive HIV (Human Immunodeficiency Virus) status (aRR=2.61; 95% CI: 1.31-4.89). As a result, we failed to find an association between catastrophic costs and treatment outcomes of RR/MDR-TB patients in the Republic of Moldova. However, we found that patients from poor households and urban areas were twice more likely to achieve unfavourable TB treatment outcomes disregarding whether they experienced catastrophic costs or not. Also, TB/HIV patients and urban residents were identified as the most vulnerable groups with higher risk of unfavourable treatment outcome and TB-related costs.

Factors associated with unfavourable treatment outcomes among people with rifampicin-resistant tuberculosis in Armenia, 2014-2017.

Rifampicin-Resistant/Multidrug-Resistant Tuberculosis (RR/MDR-TB) is recognized as a major public health concern globally. In Armenia, the proportion of RR/MDR-TB is increasing among all people affected with TB. We conducted a nationwide cohort study involving analysis of programmatic data to investigate the rates of and factors associated with unfavourable treatment outcomes among patients with RR/MDR-TB registered by the national TB programme from 2014 to 2017 in Armenia. We used Cox regression to identify factors associated with the outcome. Among 451 RR/MDR-TB patients, 80% were men and median age was 46 years. Of them, 53 (11.8%) had Extensively Drug-Resistant Tuberculosis (XDR-TB) and 132 (29.3%) had pre-XDR-TB. Almost half (224, 49.7%) of the patients had unfavourable treatment outcome, which included 26.8% Loss To Follow-Up (LTFU), 13.3% failures and 9.5% deaths. In multivariable analysis, people with pre-XDR-TB [adjusted Hazard Ratio [aHR] 3.13, 95% confidence intervals [CI] 2.16-4.55] and XDR-TB (aHR 4.08, 95% CI 2.45-6.79) had a higher risk of unfavourable outcomes. Patients receiving home-based treatment (71/451, 15.7%) and treatment with new drugs (172/451, 38.1%) had significantly lower risk (aHR 0.45, 95% CI 0.28-0.72 and aHR 0.26, 95% CI 0.18-0.39) of unfavourable treatment outcome.  The proportion of MDR-TB patients reaching favourable treatment outcome in Armenia was substantially lower than the recommended level (75%). The most common treatment outcome was LTFU indicating the need for further assessment of underlying determinants. Home-based treatment looks promising and future studies are required to see if expanding it to all RR/MDR-TB patients is feasible and cost-effective.

Depression and anxiety symptoms among people with rifampicin-resistant tuberculosis receiving in-patient care in the National Pulmonology Reference Institute in Romania.

Mental health comorbidities are common among tuberculosis patients, with higher prevalence among people with rifampicin-resistant/multidrug-resistant (RR/MDR) tuberculosis.  TB and depression share common risk factors adding to the overall disease burden. There is limited evidence about prevalence of depression and anxiety symptoms among tuberculosis patients in Romania. We assessed the prevalence of depression and anxiety symptoms and their evolution over the course of the treatment in RR/MDR-TB patients receiving in-patient care at the National Institute of Pneumonology (NIP) "Marius Nasta" in Romania during May-September 2020. We conducted a cohort study and used the Hospital Anxiety and Depression Scale (HADS) to assess the prevalence of depression and anxiety (defined as score≥ 8) symptoms at admission (baseline) and the second month of in-patient treatment (follow-up). Difference between baseline and follow-up depression and anxiety symptoms were assessed using McNemar test. Binary logistic regression was used to evaluate the association between sociodemographic and clinical characteristics with the presence of depression and anxiety symptoms at baseline. The cohort included 46 patients, 63% were male, mean age was 46 (±13.3) years. The prevalence of depression and anxiety in our cohort was 46% and 43% at baseline respectively, and 50% and 39%, at the follow-up respectively. About one third (7/25) of patients who had normal HADS depression score at baseline, had an increase above the threshold at the second month of treatment. No statistical difference in prevalence of depression or anxiety was found between the baseline and second month of treatment. Unadjusted analysis showed that odds of depression at baseline was lower in patients with education above 8th grade compared to patients with education below 8th grade (odds ratio=0.2, 95% confidence interval: 0.1,0.8, p=0.026). The study revealed high prevalence of depression and anxiety among RR/MDR-TB patients admitted to the NIP, underlining the necessity of evaluating the mental health of TB patients and linking them to appropriate care.

Drug-resistant tuberculosis in eastern Europe and central Asia: a time-series analysis of routine surveillance data.

BACKGROUND: Among all WHO regions, the WHO European Region has the highest proportion of drug-resistant tuberculosis among new and retreated cases. The 18 high-priority countries in eastern Europe and central Asia account for 85% of the tuberculosis incidence and more than 90% of drug-resistant tuberculosis cases emerging in the region. We aimed to analyse time-series trends in notification rates of drug-resistant tuberculosis among new tuberculosis cases in the 18 high-priority countries in the WHO European Region. METHODS: We used country data stored in WHO's global tuberculosis database. For each country, we calculated annual notification rates per 100 000 population of new tuberculosis cases and of drug-resistant tuberculosis among new cases reported from Jan 1, 2000, to Dec 31, 2017. We computed annual percentage changes of notification rates and identified time-points of significant change in trends using the joinpoint regression method. FINDINGS: All 17 countries with data (no data available from Turkmenistan) showed a significant decline in new tuberculosis notification rates in the most recent years since the last joinpoint if one was identified. Notification rates of drug-resistant tuberculosis showed diverse trends, with substantial year-to-year variation. In the most recent years, notification rates of drug-resistant tuberculosis among new tuberculosis cases were decreasing in two countries (Estonia and Latvia), increasing in eight countries (Azerbaijan, Kyrgyzstan, Moldova [Republic of Moldova], Romania, Russia [Russian Federation], Tajikistan, Ukraine, and Uzbekistan), and stable in seven countries (Armenia, Belarus, Bulgaria, Georgia, Kazakhstan, Lithuania, and Turkey). INTERPRETATION: Our findings suggest that countries in the WHO European Region are more successful in controlling drug-susceptible tuberculosis than drug-resistant forms, and as a result, the proportion of drug-resistant strains among newly notified patients with tuberculosis is increasing in many settings. Two countries showed that it is possible to decrease incidence of both drug-susceptible and drug-resistant tuberculosis. If no additional efforts are made in prevention and care of patients with drug-resistant tuberculosis, further decline of the tuberculosis burden will be halted. Further studies are needed to investigate the success stories and document the most effective interventions to reach the target to end tuberculosis by 2030. FUNDING: United States Agency for International Development.

Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.

BACKGROUND: In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. METHODS: Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. FINDINGS: Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87-94) for rpoB (rifampicin resistance), 86% (74-93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39-68) for pncA (pyrazinamide resistance), 85% (77-91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81-92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. INTERPRETATION: Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Determinants of site of tuberculosis disease: An analysis of European surveillance data from 2003 to 2014.

BACKGROUND: We explored host-related factors associated with the site of tuberculosis (TB) disease using variables routinely collected by the 31 EU/EEA countries for national surveillance. METHODS: Logistic regression models were fitted to case-based surveillance data reported to the European Centre for Disease Prevention and Control for TB cases notified from 2003 to 2014. Missing data on HIV infection and on susceptibility to isoniazid and rifampicin for many patients precluded the inclusion of these variables in the analysis. Records from Finland, Lithuania, Spain and the United Kingdom were excluded for lack of exact details of disease localisation; other records without one or more variable (e.g. previous treatment history, geographical origin) or who had mixed pulmonary and extrapulmonary disease or more than one form of extrapulmonary disease were also removed (total exclusion = 38% of 913,637 notifications). RESULTS: 564,916 TB cases reported by 27 EU/EEA countries had exclusive pulmonary (PTB; 83%) or extrapulmonary (EPTB; 17%) disease. EPTB was associated with age <15 years (aOR: 5.50), female sex (aOR: 1.60), no previous TB treatment (aOR: 3.10), and geographic origin (aOR range: 0.52-3.74). Origin from the Indian subcontinent or Africa was most strongly associated with lymphatic, osteo-articular and peritoneal/digestive localization (aOR>3.7), and age <15 years with lymphatic (aOR: 17.96) and central nervous system disease (aOR: 11.41). CONCLUSIONS: Awareness of host-related determinants of site of TB is useful for diagnosis. The predilection for EPTB among patients originating from countries outside Europe may reflect strain preferences for disease localization, geographic/ethnic differences in disease manifestation and other factors, like HIV.

Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project.

BACKGROUND: Pyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available. METHODS: In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system. FINDINGS: Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0-42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0-16·6% for ofloxacin, to 0·5-12·4% for levofloxacin, and 0·9-14·6% for moxifloxacin when tested at 0·5 µg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 µg/mL was low in all countries. INTERPRETATION: Although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.