Identification of growing tuberculosis incidence clusters in a region with a decrease in tuberculosis prevalence in Moscow (2000-2019).

Background: The control of tuberculosis (TB) may benefit from a prospective identification of areas where the incidence may increase in addition to the traditionally identified foci of high incidence. We aimed to identify residential areas with growing tuberculosis incidence rates and assess their significance and stability. Methods: We analysed the changes in TB incidence rates using case data georeferenced with spatial granularity to apartment buildings in the territory of Moscow from 2000 to 2019. We identified sparsely distributed areas with significant increases in the incidence rate inside residential areas. We tested the stability of found growth areas to case underreporting via stochastic modelling. Results: For 21 350 cases with smear- or culture-positive pulmonary TB among residents from 2000 to 2019, we identified 52 small-scale clusters of growing incidence rate responsible for 1% of all registered cases. We tested clusters of disease growth for underreporting and found them to be relatively unstable to resampling with case drop-out, but their spatial displacement was small. Territories with a stable increase in TB incidence rate were identified and compared to the rest of the city, which is characterised by a significant decrease in incidence. Conclusions: Identified areas with a tendency for an increase in the TB incidence rate may be important targets for disease control services.

Reduced susceptibility and resistance to bedaquiline in clinical M. tuberculosis isolates.

OBJECTIVES: Bedaquiline is an effective drug used to treat MDR and XDR tuberculosis, providing high cure rates in complex therapy. Mutations in the mmpR (rv0678) and atpE genes are associated with reduced susceptibility to bedaquiline and have been identified in both in vitro selected strains and clinical isolates. However, the phenotypic criteria used to detect bedaquiline resistance have yet to be established due to the collection of few clinical isolates from patients receiving bedaquiline-containing treatment regimens. METHODS: One hundred eighty-two clinical isolates from 74 patients receiving bedaquiline and 163 isolates from 107 patients not exposed to bedaquiline were analysed. The bedaquiline MICs were tested using serial dilutions on 7H11 agar plates and the Bactec MGIT 960 system. The mmpR and atpE genes were sequenced by Sanger sequencing. RESULTS: The 7H11 agar method allowed for rapid discrimination between mutated and wild-type isolates and between exposed and non-exposed isolates. Seventy-three percent of bedaquiline-exposed isolates, as well as 91% of isolates with mutations, had an elevated bedaquiline MIC (≥ 0.12 mg/L on 7H11 media) compared to the reference isolates (89% had an MIC ≤ 0.03 mg/L). Previously reported in vitro-selected mutants (E61D and A63P) and novel AtpE substitutions (G25S and D28G) were observed in the clinical isolates. Substitutions in codon 63 of AtpE were likely associated with a higher bedaquiline MIC. Five new cases of pre-existing reduced susceptibility to bedaquiline, accompanied by mmpR mutations in most isolates, without a history of bedaquiline treatment were identified. CONCLUSIONS: Bedaquiline treatment leads to an elevated bedaquiline MIC and the acquisition of mmpR and atpE gene mutations in tuberculosis strains. The standardisation of bedaquiline phenotypic susceptibility testing is urgently needed based on observed discrepancies between our study and previous studies and differences in solid and liquid media MIC determinations.

Small-scale stable clusters of elevated tuberculosis incidence in Moscow, 2000-2015: Discovery and spatiotemporal analysis.

OBJECTIVES: To find residential areas with high incidence rate of tuberculosis in Moscow using spatio-temporal analysis of incidence data. METHODS: We analyzed the spatial patterns of residence locations of smear or culture positive patients with pulmonary tuberculosis in Moscow. To identify clusters with high local incidence rates, the neighborhoods of detected cases were studied. We assessed the spatial and temporal stability of clusters. RESULTS: For 19033 cases diagnosed with smear or culture positive pulmonary tuberculosis among residents of Moscow in 2000-2015 we identified 18 small-scale clusters of increased incidence rate responsible for 3% of all registered cases identified on a territory inhabited by only 1% of the population. Locations of clusters were sufficiently stable in space throughout the whole period. The local incidence rate inside clusters was significantly (3-4 times) higher than the city average during the whole observation period. The presence of clusters was associated with the incidence rate in the surrounding area. Socio-demographic characteristics of patients in clusters were not significantly different from the average characteristics of patients in the city. CONCLUSIONS: The detected small-scale clusters of increased incidence may be used to target active case finding for tuberculosis. The causes and mechanisms of cluster formation and stability need further study.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study.

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

Outcomes of patients with drug-resistant-tuberculosis treated with bedaquiline-containing regimens and undergoing adjunctive surgery.

OBJECTIVES: No study evaluated the contribution of adjunctive surgery in bedaquiline-treated patients. This study describes treatment outcomes and complications in a cohort of drug-resistant pulmonary tuberculosis (TB) cases treated with bedaquiline-containing regimens undergoing surgery. METHODS: This retrospective observational study recruited patients treated for TB in 12 centres in 9 countries between January 2007 and March 2015. Patients who had surgical indications in a bedaquiline-treated programme-based cohort were selected and surgery-related information was collected. Patient characteristics and surgical indications were described together with type of operation, surgical complications, bacteriological conversion rates, and treatment outcomes. Treatment outcomes were evaluated according to the time of surgery. RESULTS: 57 bedaquiline-exposed cases resistant to a median of 7 drugs had indication for surgery (52 retreatments; 50 extensively drug-resistant (XDR) or pre XDR-TB). Sixty percent of cases initiated bedaquiline treatment following surgery, while 36.4% underwent the bedaquiline regimen before surgery and completed it after the operation. At treatment completion 90% culture-converted with 69.1% achieving treatment success; 21.8% had unfavourable outcomes (20.0% treatment failure, 1.8% lost to follow-up), and 9.1% were still undergoing treatment. CONCLUSIONS: The study results suggest that bedaquiline and surgery can be safely and effectively combined in selected cases with a specific indication.

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study.

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

Examination of bedaquiline- and linezolid-resistant Mycobacterium tuberculosis isolates from the Moscow region.

Objectives: To study the isolates with acquired resistance to bedaquiline and linezolid that were obtained from patients enrolled in a clinical study of a novel therapy regimen for drug-resistant TB in Moscow, Russia. Methods: Linezolid resistance was detected using MGIT 960 with a critical concentration of 1 mg/L. The MIC of bedaquiline was determined using the proportion method. To identify genetic determinants of resistance, sequencing of the mmpR ( Rv0678 ), atpE , atpC , pepQ , Rv1979c , rrl , rplC and rplD loci was performed. Results: A total of 85 isolates from 27 patients with acquired resistance to linezolid and reduced susceptibility to bedaquiline (MIC ≥0.06 mg/L) were tested. Most mutations associated with a high MIC of bedaquiline were found in the mmpR gene. We identified for the first time two patients whose clinical isolates had substitutions D28N and A63V in AtpE, which had previously been found only in in vitro -selected strains. Several patients had isolates with elevated MICs of bedaquiline prior to treatment; four of them also bore mutations in mmpR , indicating the presence of some hidden factors in bedaquiline resistance acquisition. The C154R substitution in ribosomal protein L3 was the most frequent in the linezolid-resistant strains. Mutations in the 23S rRNA gene (g2294a and g2814t) associated with linezolid resistance were also found in two isolates. Heteroresistance was identified in ∼40% of samples, which reflects the complex nature of resistance acquisition. Conclusions: The introduction of novel drugs into treatment must be accompanied by continuous phenotypic susceptibility testing and the analysis of genetic determinants of resistance.

Treatment interruptions among patients with tuberculosis in Russian TB hospitals.

OBJECTIVE: To evaluate risk factors for in-patient treatment interruptions (TIs) in Russian tuberculosis (TB) hospitals. METHODS: The regional case-based registers for all TB patients registered in the main regional TB hospitals were analyzed for the period 1993-2002. Multivariable analysis of risk factors for TIs was performed using logistic regression. The prediction rule was developed based on the final multivariable model coefficients obtained from analysis of the largest (Lipetsk) database. RESULTS: During the study period, 18-50% of new cases and 36-56% of retreatment cases had interrupted in-patient treatment. In multivariate analysis, independent predictors of treatment interruption included: male gender (odds ratios (ORs) 1.5-2.3), age group 25-50 years (ORs 1.5-1.7), alcohol abuse (ORs 1.8-4.0), imprisonment history (ORs 1.3-2.5), unemployment (ORs 1.1-2.8), being a retreatment case (ORs 1.3-2.5), and having severe forms of TB (1.4-4.0); factors protective from interruption included urban residence (ORs 0.7-0.9) and having concomitant diseases (ORs 0.6-0.8). Based on the Lipeck model, new TB cases from the four regions were divided into low, high, and very high risk groups. Proportions of TI were approximately 20-35% in the low risk group, approximately 60-75% in the high risk group, and approximately 75-85% in the very high risk group (except Orel). CONCLUSIONS: We have described the independent predictors of patient TI, and a predictive rule for the in-patient TB treatment phase interruptions has been developed. Treatment interruption is a significant obstacle in the success of the National Tuberculosis Control Program in Russia. Interventions targeted at the high risk groups should be implemented in order to prevent in-patient treatment interruption.