Potential of Pharmacogenetic Testing in Tuberculosis Treatment
https://doi.org/10.58838/2075-1230-2025-103-6-104-116
Abstract
Pharmacogenetic testing is the most promising tool in personalized medicine aimed at enhancing effectiveness and safety of treatment, especially in complicated cases with comorbidities. The review analyzes 122 publications devoted to theoretical and applied aspects of pharmacogenetic testing in the treatment of tuberculosis patients. It considers the role of genetic polymorphisms in the response to treatment, and presents data on proteins involved in pharmacokinetics and pharmacodynamics of main anti-tuberculosis drugs and the genes encoding these proteins. The review analyzes the list of the most significant markers associated with the risk of adverse reactions during treatment of drug-sensitive and drug-resistant tuberculosis, and it characterizes prospects for their use in clinical practice. The list of references contains 56 key publications cited in the text.
About the Authors
D. A. Ivanova
Moscow Research and Clinical Center for Tuberculosis Control of the Moscow Government Department of Health; Russian Medical Academy of On-going Professional Education, Russian Ministry of Health
Russian Federation
Russian Federation
Diana A. Ivanova - Doctor of Medical Sciences, Academic Secretary, Phthisiologist, General Practitioner of City Clinical Diagnostic Center, Professor of Phthisiology Department
10 Build. 1, Stromynka St., Moscow 107014
Phone: +7 (499) 269-14-10
N. Yu. Nikolenko
Moscow Research and Clinical Center for Tuberculosis Control of the Moscow Government Department of Health
Russian Federation
Russian Federation
Nikolay Yu. Nikolenko - Candidate of Pharmacological Sciences, Researcher of Research Clinical Department
10 Build. 1, Stromynka St., Moscow 107014
Phone: +7 (499) 269-14-10
K. Yu. Galkina
Moscow Research and Clinical Center for Tuberculosis Control of the Moscow Government Department of Health
Russian Federation
Russian Federation
Kseniya Yu. Galkina - Candidate of Biological Sciences, Leading Researcher of Department of Laboratory Diagnostics of Tuberculosis and Pathomorphology
10 Build. 1, Stromynka St., Moscow 107014
Phone: +7 (499) 269-14-10
E. I. Yurovskaya
Moscow Research and Clinical Center for Tuberculosis Control of the Moscow Government Department of Health
Russian Federation
Russian Federation
Ekaterina I. Yurovskaya - Phthisiologist of Pulmonary Tuberculosis Department no. 6 of Clinic no. 2
10 Build. 1, Stromynka St., Moscow 107014
Phone: +7 (499) 269-14-10
Yu. Yu. Mitrofanova
Moscow Research and Clinical Center for Tuberculosis Control of the Moscow Government Department of Health
Russian Federation
Russian Federation
Yulia Yu. Mitrofanova - Researcher of Research Clinical Department
10 Build. 1, Stromynka St., Moscow 107014
Phone: +7 (499) 269-14-10
D. A. Kudlay
I.M. Sechenov First Moscow State Medical University
(Sechenov University), Russian Ministry of Health; Lomonosov Moscow State University; Immunology Research Institute by the Russian Federal Medical Biological Agency
Russian Federation
Russian Federation
Dmitry A. Kudlay - Correspondent Member of RAS, Doctor of Medical Sciences, Professor of Pharmacology Department of Pharmacy Institute, Leading Researcher of Laboratory of Personalized Medicine and Molecular Immunology no. 71, Immunology Research Institute by the Russian Federal Medical Biological Agency, Professor of Department of Pharmacognosy and Industrial Pharmacy, Fundamental Medicine Faculty, Lomonosov Moscow State University
8 Bd. 2, Trubetskaya St., Moscow, 119991
Phone: +7 (499) 248-05-53
References
1. Alymenko М.А., Valiev R.S., Valiev N.R., Tragira I.N., Polonikov А.V., Balobanova N.Р., Batishchev A.V., Kolomiets V.М., Mal G.S., Volkova S.N., Kozlov V.V., Suslikova E.I., Popova E.V. The effect of polymorphism of the MDR1 (ABCB1) gene on the risk of hepatotoxic reactions in patients with pulmonary tuberculosis. Antibiotics and Chemotherapy, 2023, vol. 68, no. 7-8, pp. 62-69. (In Russ.) https://doi.org/10.37489/0235-2990-2023-68-7-8-62-69
2. Zakharov A.V., Yeremeev V.V., Chumovatov N.V., Polyakova A.S., Shepelkova G.S., Komissarova O.G., Romanov V.V., Ergeshov A.E. Clinical and genetic associations of polymorphic alleles of the CYP3A4 gene in drug-resistant pulmonary TB. Vestnik TSNIIT, 2024, vol. 8, no. 4, pp. 17-30. (In Russ.) https://doi.org/10.57014/2587-6678-2024-8-4-17-30
3. Ivanova D.A., Galkina K.Yu., Borisov S.E., Safonova S.G., Kudlay D.A. Pharmacogenetic methods in assessing the risk of hepatotoxic reactions in the treatment of new tuberculosis patients. Tuberculosis and Socially Significant Diseases, 2018, vol. 6, no. 3, pp. 43-48. (In Russ.)
4. Ivanova D.A., Yurovskaya E.I., Galkina K.Yu. Pharmacogenetic markers in the treatment of patients with multidrug-resistant tuberculosis. Pharmacogenetics and Pharmacogenomics, 2025, no. 2, pp. 23-29. (In Russ.) https://doi.org/10.37489/2588-0527-2025-2-23-29
5. Krasnova N.M., Evdokimova N.E., Egorova A.A., Filippova O.I., Alekseeva E.A., Rudykh Z.A., Chertovskykh Y.V., Vengerovskii A.I., Kravchenko A.F., Sychev D.A. Influence of the acetylation type on the incidence of isoniazid-induced hepatotoxicity in patients with newly diagnosed pulmonary tuberculosis. Antibiotics and Chemotherapy, 2020, vol. 65, no. 7-8, pp. 31-36. (In Russ.) https://doi.org/10.37489/0235-2990-2020-65-7-8-31-36
6. Krasnova N.M., Nikolaev V.M., Tatarinova O.V., Prokopyev E.S., Vengerovskii A.I., Sychev D.A. Dependence of the dosing regimen on the rate of isoniazid acetylation in patients with newly diagnosed pulmonary tuberculosis. Eksperimentalnaya i Klinicheskaya Farmakologiya, 2024, vol. 87, no. 8, pp. 20-25. (In Russ.) https://doi.org/10.30906/0869-2092-2024-87-8-20-25
7. Mozhokina G.N., Kazakov A.V., Elistratova N.A., Popov S.A. Biotransformation enzymes for xenobiotics and personalization of treatment regimens for tuberculosis patients. Tuberculosis and Lung Diseases, 2016, vol. 94, no. 4, pp. 6-12. (In Russ.) https://doi.org/10.21292/2075-1230-2016-94-4-6-12
8. Prikladnaya farmakogenetika: Monografiya. [Applied Pharmacogenetics. Monograph]. D.A Sychev, eds., Tver, OOO Izdatelstvo Triada Publ., 2021.
9. Stepanova N.A. Personalizirovannyye podkhody k povysheniyu effektivnosti i bezopasnosti farmakoterapii tuberkuleza organov dykhaniya. Avtoref. diss. dokt. med. nauk. [Personalized approaches to improving the effectiveness and safety of pharmacotherapy of respiratory tuberculosis. Synopsis of Doct. Diss.]. Moscow, 2022. Available: https://critub.ru/wp-content/uploads/AvtoreferatStepanovaNA-na-sajt.pdf Accessed September 27, 2025
10. Tyulkova T.E., Tkachuk A.P., Akmalova K.A., Abdullaev Sh.P., Mirzaev K.B., Sychev D.A., Manuylov V.A. Genetic polymorphisms affect the metabolism of antituberculosis drugs. Pharmacogenetics and Pharmacogenomics, 2024, no. 2, pp. 37-45. (In Russ.) https://doi.org/10.37489/2588-0527-2024-2-37-45
11. Yunusbaeva M.M., Borodina L.Ya., Bilalov F.S., Sharipov R.A., Yunusbaev B.B. A study of the influence of CYP3A5, CYP2B6 and NAT2 gene polymorphism on the effectiveness of treatment for multidrug-resistant tuberculosis Pharmacogenetics and Pharmacogenomics, 2020, no. 2, pp. 26-27. (In Russ.) https://doi.org/10.37489/2588-0527-2020-2-26-27
12. Ahmad J., Dellinger A., Nicoletti P., Barnhart H.X., Ghabril M., Fontana R.J. et al. Clinical and HLA associations of fluoroquinolone-induced liver injury: results from the drug-induced liver injury network. The American Journal of Gastroenterology, 2025, no. 10, pp. 14309. https://doi.org/10.14309/ajg.0000000000003457
13. Ahmed S., Zhou Z., Zhou J., Chen S.Q. Pharmacogenomics of drug metabolizing enzymes and transporters: relevance to precision medicine. Genomics, Proteomics & Bioinformatics, 2016, vol. 14, no. 5, pp. 298-313. https://doi.org/10.1016/j.gpb.2016.03.008.
14. Allegra S., Di Paolo A., Cusato J., Fatiguso G., Arrigoni E., Danesi R., Corcione S., D'Avolio A. Different underlying mechanism might explain the absence of a significant difference in area under the concentration-time curve of linezolid for different ABCB1 genotypes. Therapeutic Drug Monitoring, 2019, vol. 41, no. 2, pp. 254-255. https://doi.org/10.1097/FTD.0000000000000596
15. Araujo-Mariz C., Militão de Albuquerque M.F.P., Lopes E.P., Ximenes R.A.A., Lacerda H.R., Miranda-Filho D.B., Lustosa-Martins B.B., Pastor A.F.P., Acioli-Santos B. Hepatotoxicity during TB treatment in people with HIV/AIDS related to NAT2 polymorphisms in Pernambuco, Northeast Brazil. Annals of Hepatology, 2020, vol. 19, no. 2, pp. 153-160. https:// doi.org/10.1016/j.aohep.2019.09.008
16. Azuma J., Ohno M., Kubota R., Yokota S., Nagai T., Tsuyuguchi K., Okuda Y., Takashima T., Kamimura S., Fujio Y., Kawase I. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy. European Journal of Clinical Pharmacology, 2013, vol. 69, no. 5, pp. 1091-1101. https:// doi.org/10.1007/s00228-012-1429-9
17. Barliana M.I., Afifah N.N., Yunivita V., Ruslami R. Genetic polymorphism related to ethambutol outcomes and susceptibility to toxicity. Frontiers in Genetics, 2023, no. 14, pp. 1118102. https://doi.org/10.3389/fgene.2023.1118102
18. Cai Y., Yi J., Zhou C., Shen X. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PLoS One, 2012, vol. 7, no. 10, pp. e47769. https://doi.org/10.1371/journal.pone.0047769
19. Cheli S., Fusi M., De Silvestri A., Bonini I., Clementi E., Cattaneo D., Montrasio C., Baldelli S. In linezolid underexposure, pharmacogenetics matters: The role of CYP3A5. Biomedicine & Pharmacotherapy, 2021, no. 139, pp. 111631. https://doi.org/10.1016/j.biopha.2021.111631
20. Clinical Pharmacogenomics (ClinPgx). Available: https://www.clinpgx.org/ Accessed September 30, 2025
21. Fernandes D.C., Santos N.P., Moraes M.R., Braga A.C., Silva C.A., Ribeiro-dos-Santos A., Santos S. Association of the CYP2B6 gene with anti-tuberculosis drug-induced hepatotoxicity in a Brazilian Amazon population. International Journal of Infectious Diseases, 2015, no. 33, pp. 28-31. https://doi.org/10.1016/j.ijid.2014.04.011
22. Garrabou G., Soriano À., Pinós T., Casanova-Mollà J., Pacheu-Grau D., Morén C. et al. Influence of mitochondrial genetics on the mitochondrial toxicity of linezolid in blood cells and skin nerve fibers. Antimicrobial Agents and Chemotherapy, 2017, vol. 61, no. 9, pp. e00542-17. https://doi.org/10.1128/AAC.00542-17
23. Haas D.W., Abdelwahab M.T., van Beek S.W., Baker P., Maartens G., Bradford Y. et al. Pharmacogenetics of between-individual variability in plasma clearance of bedaquiline and clofazimine in South Africa. The Journal of Infectious Diseases, 2022, vol. 226, no. 1, pp. 147-156. https://doi.org/10.1093/infdis/jiac024
24. Headriawan A., Pramono A.A., Sukadi A. et al. NAT2 Gene rs1041983 is associated with anti-tuberculosis drug induced hepatotoxicity among pediatric tuberculosis in Bandung, Indonesia. The Application of Clinical Genetics, 2021, no. 14, pp. 297-303. https://doi.org/10.2147/TACG.S303668
25. Hoa P.Q., Kim H.K., Jang T.W., Seo H., Oh J.Y., Kim H.C. et al. Population pharmacokinetic model of rifampicin for personalized tuberculosis pharmacotherapy: Effects of SLCO1B1 polymorphisms on drug exposure. International Journal of Antimicrobial Agents, 2024, vol. 63, no. 2, pp. 107034. https://doi.org/10.1016/j.ijantimicag.2023.107034
26. Hussain Z., Zhu J., Ma X. Metabolism and hepatotoxicity of pyrazinamide, an antituberculosis drug. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 2021, vol. 49, no. 8, pp. 679-682. https://doi.org/10.1124/dmd.121.000389
27. Jiang M., Yang J., Yang L., Wang L, Wang T., Han S. et al. An association study of HLA with levofloxacin-induced severe cutaneous adverse drug reactions in Han Chinese. iScience, 2023, vol. 26, no. 8, pp. е107391. https://doi.org/10.1016/j.isci.2023.107391
28. Kivrane A., Ulanova V., Grinberga S., Sevostjanovs E., Viksna A., Ozere I., Bogdanova I., Zolovs M., Ranka R. Exploring variability in rifampicin plasma exposure and development of anti-tuberculosis drug-induced liver injury among patients with pulmonary tuberculosis from the pharmacogenetic perspective. Pharmaceutics, 2024, vol. 16, no. 3, pp. 388. https://doi.org/10.3390/pharmaceutics16030388
29. Lopez-Medina A.I., Campos-Staffico A.M., Chahal C.A., Volkers I., Jacoby J.P., Berenfeld O., Luzum J.A. Genetic risk factors for drug-induced long QT syndrome: findings from a large real-world case-control study. Pharmacogenomics, 2024, vol. 25, no. 3, pp. 117-131. https://doi.org/ 10.2217/pgs-2023-0229
30. Mackay E., Platt G., Peloquin C.A., Brooks M.B., Coit J.M., Velásquez G.E. et al. Impact of pharmacogenetics on pharmacokinetics of first-line antituberculosis drugs in the HIRIF Trial. The Journal of Infectious Diseases, 2025, vol. 232, no. 2, pp. 258-265. https://doi.org/10.1093/infdis/jiaf195
31. Mahajan R., Tyagi A.K. Pharmacogenomic insights into tuberculosis treatment shows the NAT2 genetic variants linked to hepatotoxicity risk: a systematic review and meta-analysis. BMC Genomics Data, 2024, vol. 25, no. 1, pp. 103. https://doi.org/10.1186/s12863-024-01286-y
32. Manca A., Calcagno A., D'Avolio A., Cusato J. Pharmacogenetics of first-line antitubercular drugs: an update. Therapeutic Drug Monitoring, 2025, no. 2. Online ahead of print. https://doi.org/10.1097/FTD.0000000000001378
33. McDermott J.H., Wolf J., Hoshitsuki K., Huddart R., Caudle K.E., Whirl-Carrillo M. et al. clinical pharmacogenetics implementation consortium guideline for the use of aminoglycosides based on MT-RNR1 genotype. Clin. Pharmacol. Ther., 2022, vol. 111, no. 2, pp. 366-372. https://doi.org/10.1002/cpt.2309
34. Naidoo A., Ramsuran V., Chirehwa M., Denti P., McIlleron H., Naidoo K. et al. Effect of genetic variation in UGT1A and ABCB1 on moxifloxacin pharmacokinetics in South African patients with tuberculosis. Pharmacogenomics, 2018, vol. 19, no. 1, pp. 17-29. https://doi.org/10.2217/pgs-2017-0144
35. Oelofse C., Ndong Sima C.A.A., Möller M., Uren C. Pharmacogenetics as part of recommended precision medicine for tuberculosis treatment in African populations: Could it be a reality? Clinical and Translational Science, 2023, vol. 16, no. 7, pp. 1101-1112. https://doi.org/10.1111/cts.13520
36. Pasipanodya J.G., Srivastava S., Gumbo T. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy. Clinical Infection Diseases, 2012, vol. 55, no. 2, pp. 169-177. https://doi.org/ 10.1093/cid/cis353
37. Peng W., Zhao Z.Z., Jiao L., Wu T., Chen H., Zhang C.Y. et al. Prospective study of ALDH1A1 gene polymorphisms associated with antituberculosis drug-induced liver injury in western Chinese Han population. Microbiol. Immunol., 2021, vol. 65, no. 4, pp. 143-153. https://doi.org/ 10.1111/1348-0421.12877
38. Petros Z., Lee M.M., Takahashi A., Zhang Y., Yimer G., Habtewold A., Amogne W., Aderaye G., Schuppe-Koistinen I., Mushiroda T., Makonnen E., Kubo M., Aklillu E. Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity. BMC Genomics, 2016, vol. 17, no. 1, pp. 755. https://doi.org/10.1186/s12864-016-3078-3
39. Rens N.E., Uyl-de Groot C.A., Goldhaber-Fiebert J.D., Croda J., Andrews J.R. Cost-effectiveness of a pharmacogenomic test for stratified isoniazid dosing in treatment of active tuberculosis. Clinical Infection Diseases, 2020, no. 71, pp. 3136-3143. https://doi.org/10.1093/cid/ciz1212
40. Richardson M., Kirkham J., Dwan K., Sloan D.J., Davies G., Jorgensen A.L. NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis. International Journal Tuberculosis and Lung Disease, 2019, vol. 23, no. 3, pp. 293-305. https://doi.org/10.5588/ijtld.18.0324
41. Santoso S.B., Pribadi P., Irham L.M. Isoniazid-induced liver injury risk level in different variants of N-acetyltransferase 2 (NAT2) polymorphisms: a literature review. Pharmacia, 2023, vol. 70, no. 4, pp. 973-981. https://doi.org/10.3897/pharmacia.70.e109869
42. Schiuma M., Dinegro S., Battini V., Torre A., Covizzi A., Civati A. et al. NAT2 acetylation status predicts hepatotoxicity during antituberculosis therapy: cumulative risk analysis of a multiethnic cohort. International Journal of Molecular Sciences, 2025, vol. 26, no. 8, pp. 3881. https://doi.org/10.3390/ijms26083881
43. Sherwin K.B.S, de Kock L., Diacon A.H., Werely C.J., Xia H., Rosenkranz B., van der Merwe L., Donald P.R. N-Acetyltransferase genotypes and the pharmacokinetics and tolerability of para-aminosalicylic acid in patients with drug-resistant pulmonary tuberculosis. Antimicrob. Agents Chemother., 2015, vol. 59, no. 7, pp. 4129-4138. https://doi.org/10.1128/aac.04049-14
44. Sileshi T., Makonnen E., Telele N.F., Barclay V., Zumla A., Aklillu E. Variability in plasma rifampicin concentrations and role of SLCO1B1, ABCB1, AADAC2 and CES2 genotypes in Ethiopian patients with tuberculosis. Infect. Dis. (Lond.), 2024, vol. 56, no. 4, pp. 308-319. https://doi.org/10.1080/23744235.2024.2309348
45. Spahn C., Toda N., Groat B., Aimer O., Rogers S., Oni-Orisan A., Monte A., Hakooz N. and the Pharmacogenomics Global Research Network Publications Committee. Transforming pharmacovigilance with pharmacogenomics: toward personalized risk management. Clinical Pharmacology & Therapeutics, 2025, vol. 18, no. 6, pp. 1286-1296. https://doi.org/10.1002/cpt.70095.
46. Sundell J., Bienvenu E., Birgersson S., Äbelö A., Ashton M. Population pharmacokinetics and pharmacogenetics of ethambutol in adult patients coinfected with tuberculosis and HIV. Antimicrob. Agents Chemother., 2020, vol. 64, no. 2, pp. e01583-19. https://doi.org/10.1128/AAC.01583-19
47. Tarazjani A.D., Jouabadi S.M., Jouabadi S.M., Naderi E., Sturkenboom M., Ahmadizar F. Genetic polymorphism and risk of anti-tuberculosis drug-induced liver injury (AT-DILI): a systematic review and meta-analysis. 2025. Available: https://www.medrxiv.org/collection/pharmacology-andtherapeutics?page=2 Accessed November 21, 2025
48. Ulanova V., Kivrane A., Viksna A., Pahirko L., Freimane L., Sadovska D. et al. Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships. Front. Pharmacol., 2024, no. 15, pp. 1332752. https://doi.org/10.3389/fphar.2024.1332752.
49. Verma R., da Silva K.E., Rockwood N., Wasmann R.E., Yende N., Song T., Kim E., Denti P., Wilkinson R.J., Andrews J.R. A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing. American Journal of Respiratory and Critical Care Medicine, 2024, vol. 209, no. 12, pp. 1486-1496. https://doi.org/10.1164/rccm.202309-1583OC.
50. VigiAccess. Available: https://www.vigiaccess.org/ Accessed November 21, 2025
51. Weiner M., Gelfond J., Johnson-Pais T.L., Engle M., Peloquin C.A., Johnson J.L., Sizemore E.E., Mac Kenzie W.R. Elevated plasma moxifloxacin concentrations and SLCO1B1 g.-11187G>A polymorphism in adults with pulmonary tuberculosis. Antimicrobial Agents and Chemotherapy, 2018, vol. 62, no. 5, pp. e01802 01817.
52. WHO, Global Tuberculosis Report 2024. Geneva, World Health Organization. 2024, pp. 1-68. Available: https://worldhealthorg.shinyapps.io/tb_profiles/ Accessed October 21, 2025
53. Yang S., Hwang S.J., Park J.Y., Chung E.K., Lee J.I. Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis. BMJ Open, 2019, vol. 9, no. 8, pp. e027940. https://doi.org/ 0.1136/bmjopen-2018-027940
54. Zhang M., Wang S., Wilffert B., Tong R., van Soolingen D., van den Hof S., Alffenaar J.W. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis. Br. J. Clin. Pharmacol., 2018, vol. 84, no. 12, pp. 2747-2760. https://doi.org/10.1111/bcp.13722
55. Zhang X.H., Xie Y., Xu Q.G., Cao K., Xu K., Jin Z.B., Li Y., Wei S.H. Mitochondrial mutations in ethambutol-induced optic neuropathy. Front. Cell Dev. Biol., 2021, no. 9, pp. 754676. https://doi.org/10.3389/fcell.2021.754676
56. Zou J., Chen S., Rao W., Fu L, Zhang J., Liao Y. et al. Population pharmacokinetic modeling of bedaquiline among multidrug-resistant pulmonary tuberculosis patients from China. Antimicrob. Agents Chemother., 2022, vol. 66, no. 10, pp. e0081122. https://doi.org/10.1128/aac.00811-22
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For citations:
Ivanova D.A., Nikolenko N.Yu., Galkina K.Yu., Yurovskaya E.I., Mitrofanova Yu.Yu., Kudlay D.A. Potential of Pharmacogenetic Testing in Tuberculosis Treatment. Tuberculosis and Lung Diseases. 2025;103(6):104-116. (In Russ.) https://doi.org/10.58838/2075-1230-2025-103-6-104-116
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