Concept controlling model for arresting epidemics (further on - the model) of emerging, new and re-emerging infections has been developed. Epidemic force parameters are defined: high values of contact rate of infection in acute (R-1) and chronic (R-2) forms of disease, high frequency of chronization gamma(2) with pathogen excretion, high rate of loss of natural immunity k(1), high inflow of susceptible population mu. Control targets have been identified: infected persons (detection, isolation and treatment delta), transmission mechanism (regime-restrictive measures, sanitary and hygienic procedures r), the decrease in susceptibility (vaccination, pre- and post-exposure prophylaxis lambda). Critical interdependencies between epidemic force parameters and control coefficients were studied. We obtained threshold conditions for "zero infection" asymptotic stability. In order to achieve the target result more quickly, the use of "supercritical" control levels is proposed, with the model determining the time to achieve the result. The need to affect both acute and chronic forms of infection has been proven. The model allows to solve direct and inverse problems.

IntroductionThe tuberculin skin test has significant limitations for use in individuals vaccinated with BCG. The presence in the genome of Mycobacterium tuberculosis of the RDI region, which is absent in the genome of Mycobacterium bovis BCG and most non-tuberculous mycobacteria, made it possible to develop new skin tests, which include a skin test with a recombinant tuberculosis allergen [RTA (Diaskintest®, JSC Generium, Russia)]. Diaskintest has shown high diagnostic performance in clinical trials and in conditions of high prevalence of tuberculosis infection. In 2021, the Russia was excluded from the WHO list of high TB burden countries, which makes relevant an assessment of the specificity of the RTA test under conditions of low epidemiologic risk for tuberculosis to confirm the high specificity of the test.Study objectiveTo assess the specificity of Diaskintest in the regions of the Russian Federation with low epidemiologic risk for tuberculosis.MethodsA multicenter, open-label, prospective study was conducted, which included 150 healthy volunteers aged 18–30 years old, vaccinated with BCG, who were not at risk of tuberculosis, from regions with low epidemiologic risk (Oryol region, Ryazan region, and Arkhangelsk region). During the study, 4 visits were scheduled for each participant: [Visit 0 (screening), Visit 1, Visit 2 (in 72 h) and Visit 3 (in 28 days)]. All participants, who excluded active and latent tuberculosis infection, underwent a test with RTA. To assess the safety of RTA tests, all systemic and local adverse events that occurred during 28 days were recorded. The trial was filed in the NIH clinical trials database ClinicalTrials.gov (NCT05203068).ResultsIn individuals with a negative T-SPOT.TB test, the specificity of the RTA test was 97% (95% CI: 92–99%) with a cut-off of >0 mm. The study findings confirm data 2009: 100.00 (95% CI: 94–100). When evaluating the safety of the RTA test during 28 days of follow-up, the participants did not report local and systemic adverse reactions that had a causal relationship with the RTA test.ConclusionDiaskintest is highly specific and safe, therefore it is a valuable tool as a screening test for early detection of tuberculosis.

The emergence of drug resistant Mycobacterium tuberculosis (MTB) strains has become a global public health problem, while, at the same time, there has been development of new antimicrobial agents. The main goals of this study were to determine new variants associated with drug resistance in MTB and to observe which polymorphisms emerge in MTB genomes after anti-tuberculosis treatment. We performed whole-genome sequencing of 152 MTB isolates including 70 isolates as 32 series of pre- and post-treatment MTB. Based on genotypes and phenotypic drug susceptibility, we conducted phylogenetic convergence-based genome-wide association study (GWAS) with streptomycin-, isoniazid-, rifampicin-, ethambutol-, fluoroquinolones-, and aminoglycosides-resistant MTB against susceptible ones. GWAS revealed statistically significant associations of SNPs within Rv2820c, cyp123 and indels in Rv1269c, Rv1907c, Rv1883c, Rv2407, Rv3785 genes with resistant MTB phenotypes. Comparisons of serial isolates showed that treatment induced different patterns of intra-host evolution. We found indels within Rv1435c and ppsA that were not lineage-specific. In addition, Beijing-specific polymorphisms within Rv0036c, Rv0678, Rv3433c, and dop genes were detected in post-treatment isolates. The appearance of Rv3785 frameshift insertion in 2 post-treatment strains compared to pre-treatment was also observed. We propose that the insertion within Rv3785, which was a GWAS hit, might affect cell wall biosynthesis and probably mediates a compensatory mechanism in response to treatment. These results may shed light on the mechanisms of MTB adaptation to chemotherapy and drug resistance formation.

In a prospective study involving 5340 individuals, humoral and cellular responses revealed magnitude-dependent protection from COVID-19. Antibodies alone significantly decreased infection rates; isolated cellular response provided an intermediate level of protection. The lowest COVID-19 incidence was in the double-positive group. Background During the ongoing coronavirus disease 2019 (COVID-19) pandemic, many individuals were infected with and have cleared the virus, developing virus-specific antibodies and effector/memory T cells. An important unanswered question is what levels of T-cell and antibody responses are sufficient to protect from the infection. Methods In 5340 Moscow residents, we evaluated anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin M (IgM)/immunoglobulin G (IgG) titers and frequencies of the T cells specific to the membrane, nucleocapsid, and spike proteins of SARS-CoV-2, using interferon gamma (IFN-gamma) enzyme-linked immunosorbent spot (ELISpot) assay. Additionally, we evaluated the fractions of virus-specific CD4(+) and CD8(+) T cells using intracellular staining of IFN-gamma and interleukin 2 followed by flow cytometry. We analyzed the COVID-19 rates as a function of the assessed antibody and T-cell responses, using the Kaplan-Meier estimator method, for up to 300 days postinclusion. Results We showed that T-cell and antibody responses are closely interconnected and are commonly induced concurrently. Magnitudes of both responses inversely correlated with infection probability. Individuals positive for both responses demonstrated the highest levels of protectivity against the SARS-CoV-2 infection. A comparable level of protection was found in individuals with antibody response only, whereas the T-cell response by itself granted only intermediate protection. Conclusions We found that the contribution of the virus-specific antibodies to protection against SARS-CoV-2 infection is more pronounced than that of the T cells. The data on the virus-specific IgG titers may be instructive for making decisions in personalized healthcare and public anti-COVID-19 policies.

Abstract Background High burden of drug-resistant (DR) tuberculosis (TB) is a significant threat to national TB control programs all over the world and in the Russian Federation. Different Mycobacterium tuberculosis (MTB) genotypes are hypothesized to have specific characteristics affecting TB control programs. For example, Beijing strains are supposed to have higher mutation rates compared to strains of other genotypes and subsequently higher capability to develop drug-resistance. Results Clinical MTB isolates from HIV- and HIV+ patients from four regions of Russia were analyzed for genotypes and mutations conferring resistance to Isoniazid, Rifampicin, Ethambutol, aminoglycosides, and fluoroquinolones. Analysis of genotypes and polymorphism of genomic loci according to the HIV status of the patients – sources of MTB isolates were performed. Studied MTB isolates from HIV- TB patients belonged to 15 genotypes and from HIV + TB patients – to 6 genotypes. Beijing clinical isolates dominated in HIV- (64,7%) and HIV+ (74,4%) groups. Other isolates were of LAM (including LAM1 and LAM9), Ural, and 4 minor groups of genotypes (including 5 subclones T). The spectrum of genotypes in the HIV- group was broader than in the HIV+ group. PR of B0/W148 Beijing was significantly lower than of other Beijing genotypes in susceptible and MDR-XDR isolates. Rates of isolates belonging to non-Beijing genotypes were higher than Beijing in susceptible isolates from HIV- patients. Conclusions Beijing genotype isolates prevailed in clinical isolates of all drug susceptibility profiles both from HIV- and HIV+ patients, although B0/W148 Beijing genotype did not dominate in this study. Genome loci and mutations polymorphisms were more pronounced in clinical isolates from HIV- patients, than from HIV+.

Mycobacterium tuberculosis Beijing genotype associated with drug resistance is a growing public health problem worldwide. The aim of this study was the assessment of virulence for C57BL/6 mice after infection by clinical M. tuberculosis strains 267/47 and 120/26, which belong to the modern sublineages B0/W148 and Central Asia outbreak of the Beijing genotype, respectively. The sublineages were identified by the analysis of the strains' whole-genomes. The strains 267/47 and 120/26 were characterized as agents of pre-extensively drug-resistant (pre-XDR) and multidrug-resistant (MDR) tuberculosis, respectively. Both clinical strains were slow-growing in 7H9 broth compared to the M. tuberculosis H37Rv strain. The survival rates of C57BL/6 mice infected by 267/47, 120/26, and H37Rv on the 150th day postinfection were 10%, 40%, and 70%, respectively. Mycobacterial load in the lungs, spleen, and liver was higher and histopathological changes were more expressed for mice infected by the 267/47 strain compared to those infected by the 120/26 and H37Rv strains. The cytokine response in the lungs of C57BL/6 mice after infection with the 267/47, 120/26, and H37Rv strains was different. Notably, proinflammatory cytokine genes Il-1α, Il-6, Il-7, and Il-17, as well as anti-inflammatory genes Il-6 and Il-13, were downregulated after an infection caused by the 267/47 strain compared to those after infection with the H37Rv strain.

Diagnosis and treatment for pulmonary tuberculosis (TB) among children and adolescents is difficult without pathogen identification. Objective: To define the effectiveness of Mycobacteria tuberculosis (MTB) detection via broncho-alveolar lavage fluid (BALF) assay among children and adolescents with pulmonary TB. Methods: 35 patients with pulmonary TB were examined: 12 - at the age of 3-7 years, 5 - 8-13 years and 18 - 14-17 years. All of them were MTB culture negative and had negative rapid molecular tests (RMT) results for MBT from sputum samples or were unable to produce sputum. BAL from the affected area was performed via bronchoscopy. Depending on the age, the total volume of the administered saline solution varied from 15 ml (for 3-4-year-olds) to 80 ml (for 15-17-year-olds). MTB detection in BALF was performed via RMT, liquid culture testing ("BACTEC MGIT 960") and smear microscopy (SM). Results: MTB were detected in the BALF via SM in 3/35 (8.6%) patients. 4/35 (11.4%) - were MTB culture positive from BALF. The most effective method was RMT. MTB DNA was detected in 21/35 (60.0%): among aged 3-7 years - in 4/12 (33.3%), 8-13 years - in 4/5 (80%), 14-17 years - in 13/18 (72.2%). 3/21 (14,3%) (11, 15, 15 years old) children were diagnosed with multidrug-resistant TB. All 4 culture positive patients had also positive RMT results from BALF samples, in 2 cases positive results were obtained by all three methods. Conclusions: BAL improves the effectiveness of MBT detection in children and adolescents with pulmonary TB without MTB positive sputum samples by 60 % (95%CI: 43.6 -74.5) Wilson9s method) due to RMT. Depending on the age, the effectiveness ranges from 33.3% to 80%.

Rapid spread of COVID-19 pandemic made a substantial share of the world population immunised by SARS-CoV-2 antigens. Infection induces the development of virus-specific antibodies and T cells. Ample evidence on the antibody-mediated protection is contrasted by the elusive role of T cells in preventing infection. To explore the impact of T cells and to quantify the protective levels of the immune responses we conducted a large prospective study: 5,340 Moscow residents were evaluated for the antibody and cellular immune responses to SARS-CoV-2 and monitored for COVID-19 up to 300 days. The antibody and cellular responses were tightly interconnected, their magnitude inversely correlated with infection probability. Similar maximal level of protection was reached by individuals positive for both types of responses and by individuals with antibodies alone. Meanwhile, T cells in the absence of antibodies provided an intermediate level of protection. The real-world data on the protective effects of T cells have important implications for T cell immunology and development of the strategies to fight the pandemic. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04898140 ### Funding Statement The authors thank the Moscow Department of Healthcare for the help in organization of the study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Moscow City Ethics Committee of the Research Institute of the Organization of Health and Healthcare Management and performed according to the Helsinki Declaration. All participants provided their written informed consent. The study was registered on [ClinicalTrials.gov][1] (Identifier: [NCT04898140][2]). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data available within the article and supplementary materials [1]: https://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04898140&atom=%2Fmedrxiv%2Fearly%2F2021%2F10%2F06%2F2021.08.19.21262278.atom

Species diversity of non-tuberculous mycobacteria isolated from HIV-positive and HIV-negative patients Introduction: The incidence of mycobacteriosis is growing due to an increase in the number of immunocompromised patients, including those with HIV infection. The species diversity of non-tuberculous mycobacteria (NTM) in patients with different HIV statuses is not well understood. Aims and Objectives: Compare species diversity of NTM in HIV-positive (HIV+) and HIV-negative (HIV-) patients. Methods: We conducted a retrospective study of NTM infections at the National Center for Phthisiopulmonology and Infectious Diseases in 2018-2019. All patients were divided into two groups: HIV+ (54 patients) and HIV- (85 patients). Both groups of patients had isolated NTM and mycobacteriosis was diagnosed. NTM isolates were obtained using MGIT and FX systems (BD, USA). Identification was carried out using MALDI-TOF MS (Bruker, Germany). Results: The Mycobacterium avium complex (MAC) prevailed in both groups, beeing more common in HIV+ patients than in HIV- patients: 98.1% versus 60.0% (p <0.001). Of the causative agents of MAC infection, M. avium predominates in both groups, but is most often found in HIV+ group: in 96.3% versus 40.0% (p <0.001). M. intracellulare was less common: 1.9% versus 20.0% (p <0.001). The following most common species were also identified in HIV- groups: M. abscessus (11.8%), M. kansasii (10.6%), M.lentiflavum and M.fortuitum (3.5%) Conclusion: In group with HIV+, the main species of NTM is M.avium. In patients with HIV -, the NTM spectrum is more diverse

Application of next-generation sequencing to detect MTB resistance to first- and second-line anti-TB drugs Introduction: Drug resistance (DR) in Mycobacterium tuberculosis (MTB) is a global challenge in TB Control worldwide. Phenotypic drug susceptibility testing (DST) is sometimes inconsistent and usually takes about a month. Next-generation sequencing (NGS) is a novel approach to detecting key DR-associated mutations of MTB. Aims and Objectives: evaluating the sensitivity and specificity of NGS for detecting MTB DR compared to phenotype-based methods. Methods: 47 MTB isolates were randomly selected from the laboratory collection. The phenotypic DST was studied in the MGIT system at critical concentrations for first- and second-line anti-TB drugs. Extracted genomic DNA was prepared and then whole genome sequencing was performed using MGISEQ-200RS (BGI, China). DR was evaluated through SNP identification in resistance-associated genes (rpsL, rRNA, katG, inhA, rpoB, embB, pncA, rpsA, gyrA, gyrB, rrs, eis). Results: NGS has been shown to be a highly sensitive method for detecting mutations associated with resistance to isoniazid, rifampicin, ofloxacin, levofloxacin and moxifloxacin (100%) and streptomycin (96,7%). Sensitivity values to ethambutol and kanamycin were lower (87.5% and 88.9%). Low sensitivity was observed for pyrazinamide (29.4%), amikacin and capreomycin (60.0%). Specificity was more than 90% for all anti-TB drugs. Conclusion: NGS allows detecting DR to a wide range of anti-TB drugs with high sensitivity and specificity. This research is still ongoing.

Introduction: DR and HIV are the major challenges for worldwide eradication of tuberculosis (TB). Aims: To determine MTB DR mutations, prevalent in HIV+ and HIV- individuals; to identify MTB clonal lines evolutionary successful with respect to DR mutations. Methods: MTB cultures were isolated from symptomatic patients (93 HIV+ and 267 HIV-) before the onset of TB treatment and subjected to biochip hybridisation. Results: Latter DR mutations were statistically significant prevalent in HIV+ as compared to HIV- individuals: -S531L rpoB (rifampicin resistance), -M306V embB (etambutol resistance), -‘S531L rpoB + S315T(1) katG’ (isoniazid resistance), -‘S531L rpoB + S315T(1) katG + M306V embB’. The prevalence in HIV- individuals of S315T(1) katG not combined with S531L rpoB was statistically significant. The prevalence in HIV+ patients of the MDR marker ‘S531L rpoB + S315T(1) katG’ was demonstrated for all genotypes; its proportion amounted to 100% in B0/W148 genotype. Two distinct evolutionary successful MDR clonal lines originating in Chelyabinsk were discovered: 1) Beijing genotype with the marker ‘S531L rpoB + S315T(1) katG + M306V embB’; spread to Kemerovo, Leningrad, Stavropol, and Nizhnii Novgorod regions; 8 out of 19 (42%) cultures were XDR; 2) B0/W148 genotype with the marker ‘S531L rpoB + S315T(1) katG + N296H embB’, spread to Kemerovo, Leningrad, Nizhnii Novgorod, and Moscow regions; 2 out of 12 (17%) cultures were XDR. Conclusion: MTB passage through HIV+ patients induces new MDR (and potentially XDR) clonal lines, which retain tropism to HIV+ patients even after passage through HIV- individuals.

Introduction: Time to detection (TtD) of Mycobacteria tuberculosis (MT) on liquid media is the valuable tool to assess the bacterial load in the sample, long times corresponding to oligobacillarity, short times - to dangerous conditions with massive bacterial overload [Diacon AH, et al., 2010; Visser M.E. et al., 2012]. Aim: To study Ttd dependence on clinical picture of TB and molecular genetic MT variability. Methods: 351 positive liquid MT cultures were studied, all from different TB patients, in 6 regions of Russia (Central, South, Ural, Siberia). 339 isolated from sputum (19 - induced), 9 - pleural effusion, 3 - bronco-alveolar lavage. All cultures were genotyped and typed for mutations of resistance. 9 patient/culture characteristics were studied by the dispersion analysis in the univariate general linear model. Results: Modelling excluded 6 parameters (gender, age, HIV status, CD4, MDR genotype) and included 3: clinical form, presence/absence of lung destruction and MT genotype. Estimated marginal means of TtD were: caseous pneumonia 6.6 days [95%CI 2.2;11.1], disseminated pulmonary TB 9.3 [7.6; 11.1], infiltrative pulmonary TB 13.2 [12.1; 14.3], extrapulmonary TB 18.0 [13.9; 22.0]. In case of cavitary TB TtD was 9.0 [6.8;11.2], noncavitary TB 13.8 [11.6; 16.0]. For genotypes LAM and Ural TtD was 15.5 [12.6; 18.4], Beijing 9.6 [7.6; 11.7], B0/W148 9.0 [5.9; 12.1]. Conclusions: Shortest TtD, corresponding to biggest bacterial loads, were found in caseous pneumonia, disseminated and cavitary TB.Genotype B0/W148 demonstrated TtD less than 10 days, even in noncavitary TB, that corresponds to its high virulence.

Secondary pulmonary mycoses etiology agent species diversity in patients with tuberculosis and in patients with HIV infection Introduction: In recent years, there has been an increase in the incidence of mycoses. TB and HIV patients are at risk of developing secondary mycoses, the study of the etiology of pathogens is highly demanded. Aims and Objectives: To define of the prevailing classes and species of fungi in TB and HIV patients. Methods: A retrospective analysis of the documentation of in-patients with TB without HIV (N=67) and HIV patients with AIDS (N=121, in 4 patients AIDS was manifested by TB) was carried out. Fungi were diagnosed in etiology specific sites: BAL, biopsy specimens, pleural fluid. Fluorescence microscopy (Calcofluor White with Evans blue), culture studies (Czapek Dox Agar) and PCR-RT were used. Results: In TB patients mold fungi predominate (64.2%), yeast fungi (26.9%) and P.jirovecii (8.9%) were less common. In HIV-infected patients yeast fungi (57.0%) and P.jirovecii were the leaders (29.8%), molds were less common (13.2%). The difference in the distribution is statistically significant (χ2=43.5; p<0.001). In both groups A. fumigatus prevails in molds (46.5% and 17.6%), C. albicans prevails in yeasts (66.7% and 63.8%). Conclusion: In TB patients without HIV mold fungi are most often found, in patients with HIV infection - yeast fungi are the leaders. In both groups A. fumigatus was most common in molds, C. albicans in yeasts.

Comparison of susceptibility testing results of MAC isolated from HIV-positive and HIV-negative patients Introduction: Mycobacterium avium complex (MAC) are common pathogens of mycobacteriosis. Comparison of susceptibility testing results of MAС isolated from HIV-positive and HIV-negative patients is relevant. Aims and Objectives: Compare drug sensitivity of MAC isolates in HIV-positive (HIV +) and HIV-negative (HIV-) patients. Methods: We conducted a retrospective study of MAC infection at the National Center for Phthisiopulmonology and Infectious Diseases in 2018-2019. All patients were divided into two groups: HIV + (53 patients) and HIV- (27 patients). MAC was isolated in all patients. Identification was carried out using software Sepsityper MBT module and Mycobacterium library version 6 containing 952 MSPs (main spectra)178 genus MALDI-TOF MS (Bruker Daltonic, Germany). Drug sensitivity tests were performed for clarithromycin, moxifloxacin, amikacin, linezolid, were carried out using in broth microdilution. Interpretation of the results was carried out in accordance with CLSI M 62-1ed; 2018. Results: In patients with HIV + and HIV- drug susceptibility, MAC most often persists for clarithromycin (96.2% and 96.3%) and moxifloxacin (54.7% and 74.1%). Drug resistance of MAC was most often observed to linezolid (67.9% and 51.9%) and to amikacin (39.6% and 40.7%). Conclusion: In patients with HIV + and HIV- differences in the results of drug sensitivity of MAС were not detected.

Introduction: Multidrug-resistant tuberculosis (MDR-TB) is one of the global challenges in TB Control. In the Russian Federation, TB incidence, prevalence and death rates have been decreasing since 2010. Nevertheless the burden of MDR-TB and co-infection (HIV-TB) remains. Aims: To study drug resistance among new TB cases in HIV-positive patients (Pts) in comparison with HIV-negative pts. Methods: Multicentral study was performed in 6 Russian regions with high prevalence of HIV in 2018. A representative random sample of cultures from new TB cases, obtained before the onset of treatment, from each region was made. Thus we collected 150 cultures from HIV negative cases and 53 from HIV positive. Drug sensittivity testing (DST) was performed on liquid media to H; R; E; Z, Ofx, Lfx, Mfx, Km, Am, Сm. Results: Total drug resistance (DR) was prevalent in HIV-positive pts in comparison with HIV-negative [60.4% vs 50.7%, OR = 1.445, 95% CI 0.764-4.2731]. Proportion of MDR-TB appeared to be 1.8 times significantly higher [45.3% vs 25.2%, OR = 2.439, 95% CI 1.268-4.692]. XDR-TB was prevalent in HIV-positive patients also as a tendency [33.0% vs 18.4%, OR = 2.214, 95% CI 0.680-7.208]. Conclusions: MDR-TB tuberculosis in comparison with HIV-negative pts. MDR TB was found 1.8 times more often among HIV-positive new TB pts. The causes of this phenomenon are to be investigated. We continue our research in the direction of estimation bacterial density in HIV+ and HIV- and MDR-TB clonal distribution in HIV affected areas.

Introduction: Molecular genetic methods (MGM) provide rapid detection of Mycobacterium tuberculosis (MTB) DNA and DST. It is critical important for TB and HIV co-infected patients due to acute and severe TB manifestation. Aims: To study efficiency of MTB DNA detection (MTBD) by MGM among new TB cases with HIV positive (HIV+) and HIV negative (HIV-) status. Methods: 9 TB hospitals from different Russian regions were randomly selected and 433 new TB cases, detected in 2018, were included in study: 115 HIV+, 318 HIV- patients. We used real-time PCR (Amplitub-qPCR) for MTBD. Detection rate was defined as the proportion of cases, verified by PCR to all included TB cases. Results: Clinical manifestations of TB were: pulmonary tuberculosis without cavity (PTB) (235 cases), PTB with cavity (PTBC) (175 cases), extrapulmonary TB (EPTB) (23 cases). Proportion of TB clinical manifestations in HIV+ patients: EPTB (5.2%) <PTBC (27.0%) <PTB (67.8%) Proportion of TB clinical manifestations in HIV- patients: EPTB (5.3%) <PTBC (45.3%) <PTB (49.4%) Table. The efficiency of MTBD depending on HIV-status and clinical manifestations (%). Conclusion: The efficiency of MTBD by used PCR systems comprised 73.7%. There was high efficiency of MTBD for new TB cases with HIV+ and HIV- status. The efficiency of MTBD for new EPTB cases with HIV- was fairly high – 58.8%.

Introduction: Patients with isoniazid-resistance and rifampicin-sensitivity pulmonary tuberculosis (Hr-TB) can have resistance to other anti-TB drugs. Incorrect treatment may increase the resistance of mycobacteria TB (MBT) and develop multidrug and extensively drug-resistant TB. In the Russian Federation (RF), levofloxacin (Lfx) and capreomycin (Cm) are key drugs for treatment of Hr-TB, with addition of three 1st-line anti-TB drugs. Objective: To determine the effect of additional drug resistance (DR) of MBT in patients with Hr-TB on the efficacy of chemotherapy. Methods: We studied MTB drug resistance (DR) in 1379 Hr-TB patients started treatment in 2015 from 18 regions of the Russian Federation. All patients were distributed into 4 groups: group 1- DR to Lfx and Cm - 23/1379, group 2 – DR to Lfx and drug sensitivity (DS) to Cm - 56/1379, group 3 - DS to Lfx and DR to Cm - 41/1379, group 4 - DS to Lfx and Cm -1259/1379. Unfavorable outcome was registed in patients with culture positive at the 5th month of chemotherapy. Results: Significance of additional DR of MBT in Hr-TB patients was defined. Statistically significant differences were revealed between 1 and 4 groups. In the case of MBT sensitivity to fluoroquinolone and polypeptide, an unfavorable outcome was determined in 12.8% (162/1259), while in the case of resistance to fluoroquinolones and polypeptide in 34.7% (8/23) (OR=3.44;p<0,05) [95% CI 1.4 – 8.43]. Conclusion: DR simultaneously to both TB-drugs (Lfx, Cm) is a predictor of unfavorable outcome in Hr-TB cases, compared to the preserved sensitivity to both TB-drugs.

Introduction: Study of Regional mycobacterium tuberculosis (MBT) Drug Resistance (DR) allows to adopt treatment strategy in regions with high burden of XDR-TB. Aims and Objectives: To assess the frequency and spectrum of DR to first and second line drugs in the Ural regions. Methods: Multicenter trial in the six regions (Kurgan, Sverdlovsk, Tyumen, Chelyabinsk, Khanty-Mansiysk and Yamalo-Nenets) of the Ural was conducted in 2018. Totally 3.953 new TB cases patients and 1650 retreatment TB cases were registered. 1931 new TB cases and 1650 retreatment (relapse and chronic TB patients) have culture confirmation of TB. DST results for H; R; E; Z, Ofx, Lfx, Mfx, Km, Am, Cm were available for 1,852 new TB cases and 943 retreatment TB cases. Results: Among new TB cases: DR-TB was detected in 56.6% [95%CI 53.6-59.5], including Z and E resistance respectively in 9.1% [95%CI 7.5-9.8] and 25.0% [95%CI 22.5-27.6]. MDR-TB in 30.6% [95%CI 27.9-33.4] cases. Pre-XDR-TB with resistance to SLD injectable was found in 6.5% [95%CI 4.1-9.5] and pre-XDR-TB with resistance to Fq in 9.0% [95%CI 6.2-12.3] out of new MDR-TB cases. XDR TB was found in 12.2% [95%CI 8.9-15.9] out of MDR-TB cases. Among retreatment cases: DR-TB was detected in 83.5% [95%CI 80.2-86.5], MDR-TB in 45.6%, [95% CI 41.4-49.8]. Pre-XDR-TB with resistance to SLD injectable was found in 9.1% [95%CI 5.8-12.9] and with resistance to Fq in 7.4% [95%CI 4.5-11.0] out of new MDR-TB cases. XDR TB was found in 19.0% [95% CI 909-18.5] out of MDR-TB cases. Conclusions: In the Ural regions there is distribution of MDR strains with high level DR to first and second line drugs including XDR TB among new TB cases and retreatment cases in 12.2% and 19.0% respectively.

Introduction: Tuberculosis (TB) and infection, caused by Mycobacterium avium complex (MAC), are the main opportunistic diseases in late presentation of HIV-infection Aims and Objectives: To determine clinical and laboratory signs of MAC infection to improve the diagnosis and treatment of HIV patients Methods: Among treated in 2018 in HIV-unit - 9 patients we diagnosed to have MAC infection, 15 - pulmonary TB, 1 - M. kansasii infection. The proportion of MAC and TB was 17 % (24 from 144 admitted patients). Verification of MAC and TB was made by molecular genetic methods and/or culture (MGM/CL) Results: MGM/CL for MAC was positive from: blood, urine and feces - 5 patients (including 3 in combination with sputum and liquid bronchoalveolar lavage (S/LBAL)) -1st group, S/LBAL solely - 4 patients - 2nd group. All from the 1st group had fever more than 380 Celsius with duration more than 1 month. Among the 2nd group only 1 had fever. Association of fever and positive MGM/CL from blood, urine, feces (1st group substrates) was strong and significant (Pearson contingency coefficient C=0.620, Fisher exact=0.048; p<0.05). This allowed us to describe “the septic form” of MAC disease in HIV patients. 1 patient had MAC infection with hectic temperature, positive MGM from sputum, positive CL from blood, sputum and LBAL, and absence of lung, mediastinal and abdominal lymph node lesions on CT scan Contrary to MAC TB patients had positive MGM/CL from S/LBAL, lymph node puncture and pleural effusion, but not blood, urine and feces. 8 (53%) were febrile Conclusion: Febrile HIV late presenters should be suspected for “the septic form” of MAC disease; blood, urine and feces being obligatory tested by MGM/CL

Introduction: Drug-resistant TB requires special approach to treatment, based on MTB drugs susceptibility data. Choice of cost -effective study method is important for practical healthcare. Goal and objectives: The goal was to assess cost effectiveness of the drug sensitivity of MTB study using cultural methods on liquid (MGIT system) and solid media in the Russian population. Methods: The analysis was performed by minimizing costs by modeling based on the National epidemiological and statistical data, taking into account social perspective. Direct costs of the cultural studies to identify MTB and determine its sensitivity to ten first and second-line anti-TB drugs, hospitalization and treatment of patients were assessed. While assessing indirect costs we considered average wages and proportion of working patients. Results: Given the assumptions made, the use of liquid media (MGIT system) made it possible to reduce duration of hospitalization by 25 days, treatment costs in an intensive phase by 9.6% (41.1 thousand. rub. / patient), all direct medical costs for an intensive phase - by 6.3% (27.5 thousand rub. / patient.). Indirect costs were reduced at the same time by 14.3% (14.9 thousand. rub. / patient). The total cost was reduced by 7.8% (42.4 thousand. rub. / patient). Conclusions: The use of liquid media provided faster adequate TB treatment assignment compared with solid media culture, reduced duration of hospitalization and costs caused by the disease. Increase in MDR-TB patients entails economic benefits of liquid media usage.