Tuberculosis is one of the most common infectious diseases worldwide. According to the approved clinical recommendations, combined anti-tuberculosis therapy with isoniazid, rifampicin, pyrazinamide and ethambutol. Isoniazid is one of the most effective anti-tuberculosis drugs for the treatment of drug-sensitive tuberculosis, however, it has a wide range of undesirable side effects, including drug-induced liver injury. The enzyme glutathione S-transferase is involved in the detoxification of toxic metabolites of isoniazid. There are a number of studies in which the role of deletion genotypes GSTM1 and GSTT1 of the enzyme glutathione S-transferase has been investigated and established, both individually and in combination to increase the frequency of undesirable adverse reactions when using drugs. However, the data obtained are ambiguous and contradictory. In this regard, we have presented an article aimed at studying the effect of polymorphic genes GSTM1 and GSTT1 on the activity of alanine aminotransferase and aspartate aminotransferase in blood serum in patients with newly diagnosed tuberculosis of the respiratory system. Preliminary results of our study showed that carrying a combination of deletion genotypes in the GSTM1 and GSTT1 genes statistically significantly increases the activity of ALT and AST in tuberculosis therapy in patients of Yakut nationality. An increase in ALT and AST levels in the blood indicates the likelihood of hepatocellular liver damage during anti-tuberculosis therapy in carriers of a combination of deletion genotypes (GSTM1(del)/GSTT1(del)) of the enzyme glutathione-S transferase.

Background. Individual sensitivity to isoniazid in tuberculosis patients is determined by the presence of N-acetyltransferase 2 (NAT2) enzyme gene allelic variants in genome. Evaluation of quantitative and qualitative alterations in peripheral blood can be used for diagnosis, disease severity estimation, or as a clue for estimation of anti-tuberculosis chemotherapy effectiveness and safety.Aim: Find associations between acetylation type and peripheral red blood cell (RBC) dynamics; determine the effect of NAT2 acetylation rate on the effectiveness and safety of treatment in patients with newly identified pulmonary tuberculosis (TB) residing in the Sakha Republic (Yakutia).Methods. This study included 146 patients with various clinical forms of newly diagnosed pulmonary TB. Oral isoniazid, rifampicin, pyrazinamide, and ethambutol were administered patients. Genotyping was performed via real time PCR.Results. Rapid and intermediate acetylators showed an increase in hemoglobin concentrations and RBC erythrocyte hemoglobin content by the end of chemotherapy (P<0.05). Incidence of anemia was lower in intermediate acetylators, compared to rapid or slow acetylators (P=0.013). Negative correlation was established between absolute RBC count and slow acetylation type (P=0.017). Patients with rapid acetylation type showed increased RBC distribution width indexes RDW-CV and RDW-SD (P<0.05).Conclusions. An adequate therapeutic effect was achieved with standard doses of anti-TB medications in patients with intermediate acetylation type. Rapid and slow acetylators required anti-TB medication dose correction. Genotyping for NAT2 gene in patients with pulmonary TB enables clinicians to choose the optimal dose of anti-TB medications, specifically, isoniazid dose.

За период наблюдения с 2010 по 2019 г. в Республике Саха (Якутия) отмечается устойчивая тенденция к снижению на 29,04% (p < 0,001) абсолютного числа впервые выявленных больных туберкулезом (ТБ) и повышение фактического охвата выполнением флюорографического (ФЛГ) обследования населения на 23,9% (p < 0,001). Увеличение доли охвата ФЛГ обследованием населения, подлежащего, но ранее не охваченного массовым профилактическим ФЛГ осмотром, за весь период наблюдения составило 51,8% (p < 0,001). Выявление больных ТБ из числа охваченных ежегодными профилактическими ФЛГ осмотрами увеличилось на 23,05% (p < 0,001), а также самообращение пациентов из числа ранее не охваченных ФЛГ обследованием снизилось на 39,5% (p < 0,05). При сравнительном анализе охвата населения плановым ФЛГ осмотром, который утверждается Министерством здравоохранения республики, и охвата фактическими ФЛГ обследованиями подлежащего населения не установлено существенных различий (p > 0,05) как на выявление больных ТБ при профилактических ФЛГ осмотрах, так и при самообращении пациентов в медицинские организации. Темп убыли выявления флюороположительных лиц в целом по республике составил 46,5% (p < 0,001). При этом выявление различной патологии органов грудной клетки (4540,50 ± 1306,91) оказалось в 14,3 раз выше, чем туберкулеза (337,87 ± 11,85). Выявление же туберкулеза (337,87 ± 11,85) и онкопатологии (226,50 ± 15,24) при проведении массовых профилактических ФЛГ осмотрах не имели существенных различий (p > 0,05). В целом выявление патологии органов грудной клетки (ОГК) при проведении массовых ФЛГ осмотров на 1000 обследований, за исключением ТБ, составило 8,20 ± 2,80 случаев, в то время как ТБ – 0,57 ± 0,90 (t = 7,90; p < 0,001). Ежегодно на ФЛГ обследование населения республики, без учета накладных расходов, в среднем было затрачено 169,9 млн руб., при обследовании флюороположительных лиц на установление заболевания ТБ – 4,7 млн руб. Таким образом, стоимость выявления одного больного ТБ без учета накладных расходов составила 545,4 тыс. руб. Профилактические ФЛГ обследования населения являются малорентабельными, но позволяют мониторировать в целом эпидемиологическую ситуацию по ТБ и своевременно принимать меры по ее стабилизации, косвенно отслеживать миграционные процессы населения.

Tuberculosis is one of the most common diseases worldwide. The pharmacokinetics of isoniazid are unpredictable and vary widely in patients taking standard doses of the drug. In order to find the optimal dose of isoniazid, therapeutic drug monitoring should be carried out, determining the equilibrium concentration of the drug in blood plasma by HPLC. The aim of this study is to determine the concentration of isoniazid in blood plasma by HPLC and calculate the pharmacokinetic parameters of isoniazid in patients with newly diagnosed pulmonary tuberculosis in the Republic of Sakha (Yakutia). We determined the equilibrium concentration of isoniazid in blood plasma by high-performance liquid chromatography in 33 patients with pulmonary tuberculosis, using a Milichrome a-02 device manufactured by CI "Econova" LLC (Russia) using a ProntoSIL 120-3-C18 AQ column. The results obtained confirm the high individual variability of pharmacokinetic parameters: the maximum equilibrium concentration of the drug, the area under the pharmacokinetic curve, the average stationary concentration of the drug, the degree of fluctuation in the concentration of isoniazid in the blood plasma of patients with tuberculosis. Individual differences in the pharmacokinetic parameters of isoniazid indicate the need for therapeutic drug monitoring when prescribing isoniazid.

The objective: to study treatment efficacy in new pulmonary tuberculosis patients depending on the genotypes of M. tuberculosis in the Republic of Sakha (Yakutia).Subjects and methods. The authors studied the clinical course and outcomes of 312 bacteriologically confirmed new pulmonary tuberculosis cases among patients admitted to hospital in 2010-2014. Molecular genetic tests included deletion analysis of RD105 and RD207 regions of DNA of the pathogen followed by MIRU-VNTR genotyping at 24 loci.Results. In the Republic of Sakha (Yakutia), the Bejing and S genotypes are of epidemic importance, these genotypes prevail among drug resistance mycobacteria. Tuberculosis caused by the Bejing genotype had multiple (MDR) and extensive drug resistance (XDR) in 30.6% of cases, its subtype CC2/W148 - in 85.3%. The S genotype was accompanied by MDR/XDR in 69.7% of cases, subtype S256 - in 78.9%. The treatment of patients was highly efficient according to the criteria of sputum conversion (92%) and cavities healing (89.4%). The lowest rates were observed in case of tuberculosis caused by the Bejing and S genotypes due to their subtypes CC2/W148 and S256. Clinical cure of new pulmonary tuberculosis caused by the Bejing genotype was achieved in 73.4% of cases, by subtype CC2/W148 - in 41.2% with a significantly higher proportion of treatment failures and lethal outcomes of tuberculosis than in other subtypes of this genotype. With the S genotype, the clinical cure was achieved in 72.7% of patients, with no significant difference in the incidence of unfavorable outcomes in patients with subtype S256.

During the COVID-19 pandemic in the Russian Federation associated with restrictions and quarantine, in order to ensure the quality and availability of tuberculosis medical care to the population of the Republic of Sakha, it became necessary to improve and search for new organizational forms of out-patient care.The objective of the study: to analyze the use of new technologies in out-patient care for tuberculosis patients in the Republic of Sakha (Yakutia) during the COVID-19 pandemic.Result: Scientific Practical Phthisiology Center introduced the following information and digital technologies to ensure the availability and quality of medical services to the population of the republic during the COVID-19 pandemic: Cloud Polyclinic, Telemedical Consultations, Radiological Information System of APK ArchiMed , Video-Controlled Treatment at Home, and Hospital at Home.All technologies have demonstrated their efficacy for remote medical consultations and contacting patients online. Based on practical experience, these technologies provided the following: improvement of medical care provided to the population through consultations, maintaining good contact with the patient, monitoring patients' well-being, and drug in-take. They assured compliance with general federal and regional anti-epidemic recommendations to prevent the spread of the new coronavirus infection.

Introduction. Liver damage can be a dangerous side effect of using isoniazid. Individual susceptibility to isoniazid in humans is dependent on the presence of N-acetyltransferase 2 allelic variants in genome. It was imperative to assess the effect of genetically determined isoniazid acetylation rate in terms of risk of developing isoniazid-induced hepatotoxicity, as well as prevention of potential hepatopathy, and improvement of tuberculosis chemotherapy safety. Aim. To study the effect of acetylation type on the incidence of isoniazid hepatotoxicity in residents of the Sakha Republic (Yakutia) with newly diagnosed pulmonary tuberculosis. Methods. The study included 112 patients with newly diagnosed pulmonary tuberculosis. Genotyping was performed using real-time polymerase chain reaction. The following single nucleotide polymorphisms were studied: rs1801280, rs1799930, rs1799931, rs1799929, rs1208, rs1041983. Hepatotoxicity was determined based on the results of clinical laboratory monitoring and using the criteria developed by the European Association for the Study of the Liver (2019). Results. Hepatotoxic reactions developed more often in slow acetylators (43.2%), compared to fast acetylators (20.7%) and intermediate acetylators (10.9%); p=0.002. Serum alanine aminotransferase activity was 5 or more times above the upper limit of normal activity in 37.8% of slow acetylators, and in 8.7% of intermediate acetylators; p=0.001. Clinical manifestations of isoniazid hepatotoxicity were observed more often in slow acetylators (29.7%), than in fast acetylators (3.4%); p=0.000. Conclusion. Slow acetylation type ought to be considered an important risk factor for developing isoniazid hepatotoxicity in patients with pulmonary tuberculosis.

e key reasons for development of drug-resistant M. tuberculosis are prescription of inadequate chemotherapy regimens, early discontinuation and/or interruptions of chemotherapy, lack in both range and amounts of necessary drugs, use of the drugs of substandard quality. is article highlights basic principles of rational chemotherapy for TB, including adherence to clinical guidelines, prescription of drugs with due regard to information in package lea ets.

Ethnic differences in allele frequencies and genotype distribution for polymorphic variants of NAT2 gene (NAT2*5, NAT2*6, NAT2*7) were studied among ethnic Yakuts and Russians with newly diagnosed pulmonary tuberculosis. This is the first study to establish allele and genotype frequencies for polymorphic variants of NAT2 gene (NAT2*5, *6, *7) among ethnic Yakuts and Russians, who permanently reside in the Sakha Republic (Yakutia). Prevalence of NAT2*5, *6, *7 polymorphisms among Yakuts and Russians was determined, and ethnic differences were shown in allele frequencies and genotype distribution of NAT2 polymorphic variants: rs1801280 (341T>C), rs1799930 (590G>A), and rs1799931 (857G>A).

Goal: reconstruction of epidemic transmission of Beijing genotype of Mycobacterium tuberculosi s on the territory with limited migration based on the comparative study of 153 isolates isolated from patients of different generations in theSakhaRepublic (Yakutia). Materials and methods. The structure of Mycobacterium tuberculosis population was described and analyzed through MIRU-VNTR-genotyping, subtyping of the parts of RD105/RD207 genome, pattern classification as per clonal pattern of Merker M. et al (2015), and phylogenetic simulation. Results. It was found out that highly transmissive subtypes of Beijing genotype having a high potential of developing drug resistance was confidently more prevalent (χ2 = 8.3, p < 0.01) among younger people (born after 1990) compared to the older generation (born before 1959). It was also found out that during previous five decades a certain shift occurred in the structure of M. tuberculosis population. Conclusion. The obtained data confirm the hypothesis that epidemic sybtypes ofBeijing genotype were brought to the territory of theSakhaRepublic (Yakutia) fairly recently (approximately fifty years ago) compared to the other regions ofRussia.

Background. The retrospective assessment of key indicator levels and their trends at the start point of new strategy realization for tuberculosis control in Russia is an important predictor of the global program implementation to reduce the burden of this infection. Materials and methods. We analyzed incidence, prevalence and mortality among general and children population in Russian federal districts, in European and Asian regions, and in countries having a common border with Russia. Results. Presented material confirms the wide spread of tuberculosis in Russia, where the average annual incidence rate for 2005-2015 was 71.9 ± 2.5 0/0000, which attributes Russia to average-burden country. The most important characteristic of the studied period was a stable decreasing tendency of the key TB indicatorsformed by 2015. However, enormously uneven distribution of TB incidence, prevalence and mortality in some federal districts reveals different starting points of the regions. Relatively favorable territories include Central and Crimean Federal Districts, and the most unfavorable are Siberian and Far Eastern Federal Districts. The TB incidence significantly increases from West to East. Revealed unfavorable increasing tendency of children TB in combination with the trend described above indicates active transmission of TB infection in the Asian part of Russia. We also revealed the likelihood of mutual influence of migratory exchanges of Russian border regions and neighboring countries, which most strongly manifests on territories with low and medium TB incidence rates.

The population structure of Mycobacterium tuberculosis from Republic of Sakha (Yakutia) was studied using 24-loci MIRU-VNTR genotyping. Most of the studied 199 strains isolated from 199 pulmonary tuberculosis patients (34.2% or 68 of 199 strains) belonged to the Beijing genotype. Multiple drug resistant and extensively drug resistant (MDR/XDR) isolates were predominant (χ2 = 15.5; p < 0.001) among representatives of the CC2/W148 subtype of the Beijing genotype (9.5% or 19 of 199 isolates). Strains of the genotype S (15.6% or 31 of 199 isolates) were the second most common genotype after Beijing. Most of the strains of S genotype had an identical profile, 233325153325141344222372. Among non-Beijing isolates, representatives of the S genotype included the most significant proportion of MDR or XDR ((χ2 = 59.8; p < 0.001). Isolates of Ural genotype were the third most common (10% or 20 of 199 isolates). The strains belonging to LAM genotype (8.5% or 17 of 199) were genetically heterogeneous. Minor genotypes T and Haarlem were also highly heterogeneous. The epidemic spread of MBT isolates belonging to S genotype and CC2/W148 of the Beijing genotype in Yakutia was reconstructed based on a phylogenetic model. The probable time of origin was estimated using the scale proposed by M. Merker et al. (2015). It was shown that isolates of the CC2/W148 subtype divided into four phylogenetic sublineages and were introduced in the recent historical period (the 20th century). Phylogenetic relationships between 30 MIRU-VNTR profiles of S genotype representatives from Yakutia and 31 reference S-profiles profiles from Europe and Canada were studied. Profiles of the isolates of S-genotype from Yakutia formed compact phylogenetic group. It suggested that these strains have been evolving in Yakutia. It was revealed that the ancestral genotype S was imported onto the territory of Yakutia 300–600 years ago.

Aim. Complex evaluation of epidemiologic situation for tuberculosis on the territory of the Far Eastern Federal District (FEFD) and the Republic of Sakha (Yakutia). Materials and methods. Data (morbidity, prevalence, mortality, genotypes of Mycobacterium tuberculosis), characterizing, epidemiologic situation for tuberculosis from 2002 - 2014 were used. Results. The highest parameters of tuberculosis morbidity from all the regions of Russian Federation were registered in FEFD, and from all the territories of the region the highest levels were registered in Primorsky Region and Jewish Autonomous Region (166.3±6.2 %ooo and 166.1±4,8 °/oooo, respectively), and lowest - in Magadan Region and Yakutia (76.0±2.1 °/oooo and 78.6±1,9 70000, respectively). In the regions, located in the arctic zone of the Republic of Yakutia, epidemiologic situation is characterized as non-welfare. Moreover, the highest parameters of moibidity for tuberculosis were registered among low-number peoples of the north. Conclusion. Integral evaluation of the main epidemiologic parameters allows to conduct a more in-depth comparative evaluation of the epidemiologic situation. Taking into account such an approach, in the FEFD the most non-welfare situation was established to be registered in Primorsky Region, and in Yakutia the most welfare occurs. Monitoring of the circulation of genotypes of Mycobacterium tuberculosis allows to assume a possibility of displacement of genotype S by more aggressive (transmissive) subtypes of Beijing genotype.

The authors proved high informative content of the computed tomography (CT), on the basis of the study of diagnostic informative content of radiographic research methods used in the survey of children and adolescents on primary pulmonary tuberculosis. CT diagnostic significance indicators exceed informative content of traditional radiographic techniques (radiography and linear tomography) in 2-2.5 times. A comparative assessment of radiation doses received during conventional radiological methods and CT is given. The authors revealed the dependence of the received radiation dose from the age, the highest radiation burden falls on young children and adolescents. In the result of the research, a high radiation dose at linear tomography at low diagnostic informative content was defined, thus indicating the need to abandon this method at testing children and adolescents to primary tuberculosis, in favor of CT.