Molecular epidemiological monitoring of the tuberculosis pathogen in the Arkhangelsk region

Introduction. Against the background of improvement of the main epidemiological indicators (morbidity and mortality) for tuberculosis in the Arkhangelsk region, the proportion of newly diagnosed tuberculosis patients with multidrug-resistant pathogen (MDR-TB) increased from 18.7% in 2002 to 33.8% in 2018. The purpose of this study was the genotypic characterization of Mycobacterium tuberculosis strains obtained from newly diagnosed tuberculosis patients in the Arkhangelsk region in 2018. Materials and methods. 89 M. tuberculosis strains isolated in 2018 from newly diagnosed tuberculosis patients were studied. Beijing genotype, its clusters B0/W148 and Central Asian/Russian were determined by PCR detection of the specific markers: IS6110 insertions in the dnaA-dnaN region, mutations in codons 48 of the mutT4 gene (CGG GGG) and 58 of the mutT2 gene (GGA CGA), IS6110 insertions in the Rv2664 region-Rv2665 and Rv1359-Rv1360, substitutions G A in the sigE gene. Non-Beijing strains were spoligotyped. Results. Drug resistance was detected in 41.6% (37/89), MDR — in 33.7% of strains. In 90% (27/30) of MDR strains, resistance to rifampicin and isoniazid was due to rpoB Ser531Leu and katG Ser315Thr mutations. Following M. tuberculosis genotypes were identified: Beijing (67.4%), T (14.6%), Ural (4.5%), Haarlem (4.5%), LAM (2.3%) and CAS1-Delhi (1.1%). Among the Beijing strains, clusters Central-Asian/Russian (60%; 36/60) and B0/W148 (30%; 18/60) prevailed. The majority of MDR strains belonged to the Beijing family (93.3%; 28/30), of which 64.3% (18/28) and 21.4% (6/28) belonged to clusters B0/W148 and Central-Asian/Russian, respectively. Conclusion. In heterogeneous population of the causative agent of tuberculosis in the Arkhangelsk region, the most common strains were those of the Beijing genotype; in 2018 its share increased to 67.4% (40.4% in 1998–1999). Among MDR strains, the proportion of Beijing reached 93.3%, of which more than half (64.3%) belonged to the epidemiologically and clinically significant in Russia cluster B0/W148

The impact of a line probe assay based diagnostic algorithm on time to treatment initiation and treatment outcomes for multidrug resistant TB patients in Arkhangelsk region, Russia

BACKGROUND: In the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy. STUDY AIM: The PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes. METHODS: A culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm. RESULTS: Among smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms. CONCLUSION: The results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics

Epidemiological analyses of tuberculosis in Archangelsk, Russia and implementation of a rapid assay for detection of resistance in this high burden setting

Background: Tuberculosis (TB) is a major problem in Russia, particularly regarding multidrug-resistant tuberculosis (MDR-TB). Rapid drug susceptibility testing methods are therefore needed. Objectives: To perform epidemiological analyses of TB in the Archangelsk region and to evaluate the molecular method GenoType®MTBDRplus in this type of setting. Materials and methods: Clinical and microbiological data of all TB patients in Archangelsk were collected in 2010. Smear-positive sputa were analysed by MTBDRplus and Bactec MGIT 960. Results: The number of TB cases was 812 (incidence 65/105) and among these patients, 151 cases were registered in the penitentiary system (incidence 1162/105). Most patients were men, 94% had pulmonary TB and 22% were relapses. Out of all cases, 341 (42%) were smear positive and thus contagious and 176 (22%) had MDR-TB, among which one had extensively drug resistant tuberculosis (XDR-TB). Furthermore, two TB patients had strains being resistant to rifampicin, but susceptible to isoniazid. The number of cases being both contagious and MDR-TB was 128 representing 15.8% of all TB cases (incidence 10.2/105). Among these 128 TB patients 37 were relapses representing 25.7% of all the relapse cases. The results of MTBDRplus and Bactec MGIT analyses corresponded in 98.8%. Conclusions: In Archangelsk many TB patients had contagious MDR-TB thus being hazardous in society and relapsing pulmonary TB was common. The TB situation in the prisons was particularly severe. The analyses showed furthermore that MTBDRplus is of major value in this setting

Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received 3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs

Роль биомаркеров мочи в диагностике туберкулеза легких (обзор)

Диагностика туберкулеза на основе анализа мокроты имеет ограничения для отдельных категорий пациентов (пожилые люди, дети, лица, живущие с ВИЧ). Альтернативным методом может быть ускоренный поиск биомаркеров заболевания в моче, при котором возможно получение большего объема материала неинвазивным путем. Проведен поиск публикаций на английском языке в базах данных PubMed и Cochrane Library, опубликованных с 2010 по 2021 год, с использованием терминов tuberculosis + urine + biomarkers. Работы, посвященные анализу липоарабиноманнана в моче, исключены из данного обзора в связи с изученностью темы. В рассмотренных публикациях представлено более 30 биомаркеров мочи, используемых для диагностики туберкулеза и оценки эффективности противотуберкулезной терапии. Активно продолжает изучаться экстракция микобактериальной трансренальной ДНК из мочи, но чувствительность и специфичность диагностики зависят от метода экстракции и ВИЧ-статуса пациента. Биомаркер туберкулеза IP-10, вероятно, является неспецифическим маркером воспаления, однако его уровень коррелирует с ВИЧ-статусом и может быть полезен для оценки ответа на противотуберкулезное лечение. Показан потенциал метаболомных биомаркеров и биосигнатур в оценке активности туберкулезного процесса и дифференциальной диагностике туберкулеза с другими респираторными заболеваниями. Количество достоверных биомаркеров для прогнозирования результатов лечения туберкулеза ограничено. В многочисленных нецелевых исследованиях масс-спектроскопический анализ использовался для выявления метаболомных и протеомных биомаркеров в моче. Представленные работы отличались по дизайну и методам исследования, лишь некоторые публикации содержали анализ специфичности и чувствительности рассматриваемых методов диагностики. В будущем комбинация биомаркеров хозяина и патогена может повысить чувствительность и специфичность диагностики туберкулеза

The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region, Russia

BackgroundIn the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy.Study aimThe PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes.MethodsA culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm.ResultsAmong smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms.ConclusionThe results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics

Treatment outcomes after 20 months of MDR-TB treatment comparing patients diagnosed based on different diagnostics in the LPA-based and culture-based algorithms (p = 0.003, Fisher’s exact test on the 6-by-2 table to evaluate whether the distribution in in treatment outcomes differed between culture-based and LPA-based algorithms.

<p>Treatment success was more common with the LPA-based algorithm, while lost to follow-up and all-cause mortality were more common with the culture-based algorithm).</p

Sputum and culture conversion rates at 2 and 6 months of treatment (<i>p</i>-values calculated for difference between proportions).

<p>Sputum and culture conversion rates at 2 and 6 months of treatment (<i>p</i>-values calculated for difference between proportions).</p

Data MDR-TB patients in culture-based and LPA-based algorithm.

<p>Data MDR-TB patients in culture-based and LPA-based algorithm.</p