Advisable including glucosaminylmuramyldipeptide in Helicobacter pylori therapy: experience of ten-year investigation

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Abstract

Helicobacter pylori infection is a common bacterial infection in humans and is associated with peptic ulcer disease and chronic gastritis. The presence of natural resistance to some antibiotics in bacteria, as well as the appearance of primary and secondary resistance to antibacterial agents, complicates treatment and determines the search for new methods of therapy. The aim of this study was to evaluate the efficacy and safety of 10-year complex treatment of patients with duodenal ulcer associated with H.pylori , 136 patients (96 men, 40 women; mean age 45.8 ± 14.8 years; 18-65 years). H.pylori was determined morphologically and by rapid urease test one day before the start of therapy, after 1, 6, 12 months, 2 years, 5 and 10 years. Patients of the first group received basic therapy: omeprazole 0.02 g 2 times a day, clarithromycin 0.5 g 2 times a day, amoxicillin 1 g 2 times a day, for 10 days (OCA group 1; n = 98). Patients of the second group, in addition to the basic therapy, took 1 mg per day drug Liсopid (group 2 OСAL; n = 38). At the 1st stage of the clinical study, 130 patients completed eradication therapy. Tracking completeness was 96 %. The frequency of H.pylori eradication after per protocol treatment: OCA - 83 % (95 % CI: 75 %-91 %), OCAL - 97 % (95 % confidence interval (CI): 92 %-100 %). The incidence of adverse reactions after treatment (per protocol): OCA - 26 % (95 % CI: 17-35 %; nausea; n = 24), discontinued treatment - 5 % (95 % CI: 0.8 %-10 %; diarrhea; n = 5); OCAL - 3 % (95 % CI: 0.01 %-8 %; nausea; n = 1), all were treated. Taking the drug Liсopid 1 mg (glucosaminyl muramyl dipeptide, JSC Peptek, Russia) as part of complex therapy contributed to the elimination of H.pylori and the absence of relapses for 2 years. Observation of patients in the next 5 and 10 years also showed the advantage of including the immunomodulator in therapy: a significant 15 % decrease in H.pylori reinfection (P <0.05), a 23 % decrease in the frequency of gastrointestinal adverse reactions (P<0.01), compared with a 10-day standard triple regimen without immunomodulatory therapy with glucosaminylmuramyl dipeptide. When using several antibiotics in H.pylori eradication therapy, not only pathogenic, but also commensal microorganisms are destroyed, the waste products of which are vital and maintain immune homeostasis, including through the NOD2 receptors of innate immunity. The effectiveness of the complex therapy of H.pylori infection can be explained by the fact that the drug Liсopid compensates for the signal for innate immunity receptors that is missing due to the absence of commensals, providing an adequate immune response and preventing chronicity and recurrence of infection.

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Since the identification of Helicobacter pylori in 1982, and much has been learned about this bacterium, it remains one of the most common bacterial infection in humans [1- 4]. The bacterium causes a diverse pathology of the upper gastrointestinal tract from H.pylori-induced gastroduodenitis and H.pylori-associated dyspepsia to gastroduodenal ulcer, MALT lymphoma and gastric cancer. This requires appropriate anti- Helicobacter therapy [2, 5]. H.pylori eradication is a first-line therapy for H.pylori-infected patients with dyspepsia (Kyoto Global Consensus on Helicobacter pylori; Regulation 9). H.pylori-infected patients should be offered eradication therapy unless otherwise stated (Kyoto Global Consensus on Helicobacter pylori; Regulation 17) [5]. Eradication of bacteria is also necessary to control complications and reduce the number of relapses of gastroduodenal ulcer associated with H.pylori infection. The clinical effect of successful H.pylori eradication is manifested by a sharp drop in the recurrence rate of this disease after elimination of the bacterium [6]. The presence of natural resistance to some antibiotics in bacteria, as well as the appearance of primary and secondary resistance to antibacterial agents, complicates treatment and determines the search for new methods of therapy. This is reflected in current international guidelines for H.pylori eradication, which presents not only the first-line treatment regimens, but also various other treatment regimens taking into account the clarithromycin-resistant H.pylori strains in the region (Table 1). Table 1 Recommended regimens for eradication of Helicobacter pylori (Consensus Ma-Astricht V, 2017) [2] Standard triple therapy: PPI + clarithromycin + amoxicillin (10-14 days) Standard quadrotherapy with bismuth: PPI + tetracycline + metronidazole + de-nol (10-14 days) Sequential therapy: 5-7 days - PPI + amoxicillin, then 5-7 days - PPI + clarithromycin + metronidazole / tinidazole Concomitant therapy or quadrotherapy without bismuth: PPI + amoxicillin + clarithromycin + metronidazole / tinidazole (10-14 days) Hybrid therapy: PPI + amoxicillin 14 days + from 8 to 14 days - clarithromycin + metronidazole / tinidazole First line starting circuits: standard triple therapy, standard bismuth quadrotherapy Note: PPI is a proton pump inhibitor. Таблица 1 Рекомендуемые схемы для эрадикации Helicobacter pylori (Консенсус Маастрихт V, 2017 г.) [2] Стандартная тройная терапия: ИПП + кларитромицин + амоксициллин (10-14 дней) Стандартная квадротерапия с висмутом: ИПП + тетрациклин + метронидазол + Де-нол (10-14 дней) Последовательная терапия: 5-7 дней - ИПП + амоксициллин, затем 5-7 дней - ИПП + кларитромицин + метронидазол/ тинидазол Сопутствующая терапия или квадротерапия без висмута: ИПП + амоксициллин + кларитромицин + метронидазол/тинидазол (10-14 дней) Гибридная терапия: ИПП + амоксициллин 14 дней + с 8 по 14 день - кларитромицин + метронидазол/тинидазол Стартовые схемы первой линии: стандартная тройная терапия, стандартная квадротерапия с висмутом Quadrotherapy for the CIS countries as follows: certain probiotics are effective in reducing gastrointestinal side effects caused by H.pylori Quadrotherapy for the CIS countries (taking into eradication therapy. Specific strains should only account the growth of H.pylori resistance to antibiotics be selected on the basis of proven clinical efficacy and the presence of fast metabolizers (60-70 %) in the (Consensus Maastricht V; Regulation 9). Certain population of the Russian Federation; Megraud Francis probiotics may have a beneficial effect on H.pylori “Approaches to the treatment and diagnosis of H.pylori. eradication (Consensus Maastricht V; Regulation European Register data” 2015) includes Omeprazole 10). It is believed that probiotic strains, in particular 0.02 g x 3 times a day, Amoxicillin 1.0 g x 3 times a Lactobacillus, decrease the activity of bacterial urease, day, Josamycin 1.0 g x 2 times a day, De-nol 0.24 g x the motility of H.pylori and the adhesion of H.pylori 2 times a day. The duration of therapy is 10-14 days. to gastric epithelial cells [7]. Measures to increase the effectiveness of standard The concept is formulated that the immutriple therapy taking into account the growth of nomodulating effect plays a significant role in the H.pylori resistance to antibiotics (Recommendations mec hanism of antimicrobial action of pro-biotics [13]. of the Russian Gastroenterological Association, 2018): The origin of the immunomodulator and its influence Omeprazole 0.04 g x 2 times a day, Clarithromycin on the mucosa are the main issues [14, 15]. It is 0.5 g x 2 once a day, Amoxicillin 1.0 g x 2 times a known that glucosaminyl muramyl dipeptide (GMDP) day, De-nol 0.24 g x 2 times a day. The duration of modulate immune answer via NOD2 receptors and therapy is 10-14 days. Addition to the standard triple YB1 protein [16, 17] and is effective in the therapy therapy of probiotic strains of Bifidobacterium and of infections [18-20], allergy[21, 22], psoriasis [23], Lactobacillus [7]. correction of cytopenia [24] and microbiocenosis [25]. It is very difficult to reach H.pylori eradication. The positive effect of Licopid 10mg on the elimination In most patients, a year after successful eradication, of H.pylori was investigated earlier [26, 27] correlates reinfection of H.pylori occurs within the next 10 with another dosage of this drug - 1mg. years [8, 9]. In the Russian Federation and countries During the first stage of this randomized of Eastern Europe, H.pylori reinfection exceeds 5 % prospective comparative clinical study of the per year, in Western Europe and the USA - less than effectiveness of H. pylori elimination in standart 3 % per year [3, 10]. In order to optimize standard triple therapy with addition of GMDP 1mg was carried therapy different approaches are investigated, for out. During the second stage of this investigation the example the usage of probiotics [2, 11, 12]. frequency of relapse and reinfection of Helicobacter This is reflected in Provisions 9 and 10 of the pylori was measured. Consensus of Maastricht V [2], which are formulated Material and methods This study was approved by the Ethics Committee of the Vitebsk State Medical University (Vitebsk, Belarus) and was carried out during 2000-2020 years. Prior to the start of the study, informed consent was obtained from all patients to participate in the study and the processing of personal data. The first stage of a prospective, randomized, comparative clinical study was conducted to evaluate the efficacy and safety of H.pylori eradication during standard triple therapy with Licopid. Inclusion criteria: the presence of H.pylori- associated duodenal ulcer (DU). Exclusion criteria: patients using antibacterial drugs less than a month before the start of eradication therapy or FEGDS research. Eradication therapy was performed in 136 patients (96 men, 40 women; mean age 45.8 ± 14.8 years (mean ± SD; 18 - 65 years) with a duodenal ulcer associated with H. pylori (Table 2). Patients were divided by a randomized lottery drum method into 2 groups according to treatment protocols: omeprazole 0.04 g / day, clarithromycin 1 g / day, amoxicillin 2 g / day for 10 days (OCA; n = 98); omeprazole 0.04 g / day, clarithromycin 1 g / day, amoxicillin 2 g / day, Lycopid 0.001 g / day for 10 days (OCAL; n = 38). Patient profile Treatment Protocols Number of Patients Gender m f Age (years) Disease duration (years) Omeprazole 0.04 g / day Clarithromycin 1 g / day Amoxicillin 2 g / day 98 69 29 48,3 + 14,2 8,7 + 3,9 Omeprazole 0.04 g / day Clarithromycin 1 g / day Amoxicillin 2 g / day Lycopid 0.001 g / day 38 27 11 37,2 + 14,3 8,3 + 3,9 Total 136 96 40 45,8 + 14,8 8,6 + 4,1 Таблица 2 Характеристика пациентов Протоколы лечения Количество пациентов Пол муж жен Возраст (годы) Длительность заболевания (годы) Омепразол 0,04 г/сут Кларитромицин 1 г/сут Амоксициллин 2 г/сут 98 69 29 48,3 + 14,2 8,7 + 3,9 Омепразол 0,04 г/сут Кларитромицин 1 г/сут Амоксициллин 2 г/сут Ликопид 0,001 г/сут 38 27 11 37,2 + 14,3 8,3 + 3,9 Всего 136 96 40 45,8 + 14,8 8,6 + 4,1 Table 2 The study completed 130 patients. Six people (4.4 %) were excluded from the general group (5 people from the OCA group and 1 person from the OCAL group) due to the lack of data on the diagnosis of H.pylori or the cessation of medication. The completeness of tracking was 95.6 %. In the second stage were included 113 patients aged from 18 till 65 which successfully passed first stage (44.1 ± 13.5 years, 81 men and 32 women). Over 10 years, 11 people (9.7 %; 95 % CI: 4.215.2 %) were excluded from the general group due to the refusal of repeated endoscopic examinations with the diagnosis of H.pylori (8 people) or on their own desire (3 people). The completeness of tracking up to 2 years was 108 (95.6 %; 95 % CI: 91.8-99.4 %) people, from 2 to 5 years old - 104 (92.0 %; 95 % CI: 87.0 -97.0 %) of a person, from 6 to 10 years old - 102 (90.3 %; 95 % CI: 84.8-95.8 %) of a person. In a randomized trial 113 patients had the following treatment: 0.04 g omeprazole, 1.0 g clarithromycin, 2.0 g amoxicillin per day dyring 10 days (group OCA ; n=77). patients from the the second group received 0.04 g omeprazole, 1.0 g clarithromycin, 2.0 g amoxicillin and 0.001 g Lycopid per day (group OCAL ; n = 36). The tissue investigation of the duodenum was carried out by standard systematization and methods [28, 29]. To identify areas of gastric metaplasia (GM) of duodenum, an additional staining of histological sections of the mucous membrane of duodenal ulcer was performed with Chic -alcian blue (Serva) pH 1.0 and 2.5 [30]. Intestinal metaplasia and all cell- and tissuemorphologic characteristics were assessed using a visual analogue scale [31-33] according to the histological section of the Houston modification of the Sydney classification. During the histological examination of the duodenal mucosa standard indicators were taken into account [30, 34]. Diagnostics of H.pylori was carried out by Romanovsky-Giemsa stain; assessment using a standard visual-analogue scale [35] and a quick urease test (standard test systems Jatrox®-Hp-Test, Rohm Pharma, Germany; HELPIL® and AMA RUT Pro®, LLC “AMA”, Russia) [36]. For statistical processing the program «STATISTICA 10.0» and t-test were used. If the distribution of the variable was not normal, the Shapiro-Wilk test was used. The Mann-Whitney U-test was used to evaluate the differences between two independent small samples by the level of the trait, measured quantitatively. Patient age was presented as mean ± standard deviation (SD). P levels <0.05 were considered significant [37]. Results and its discussion The results of the first stage of a prospective, randomized, comparative clinical study are represented in the Table 3. The frequency of H.pylori eradication depending on the prescribed treatment (ITT) and the actual treatment received (PP): OCA - 78.6 % (95 % CI: 70.4 % -86.8 %) and 82.8 % (95 % CI: 75.1 % -90.5 %), OCAL - 94.7 % (95 % CI: 87.5 % -100 %) and 97.3 % (95 % CI: 91.7 % -100 %) respectively. The incidence of adverse reactions (PR) depending on the prescribed treatment and the actual treatment received: OCA - 24.5 % (95 % CI: 15.9 % -33.1 %) and 25.8 % (95 % CI: 16, 8-34.8 %; nausea; n = 24), discontinued treatment - 5.1 % (95 % CI: 0.7 % -9.5 %) and 5.4 % (95 % CI: 0.8 % -10.0 %; diarrhea; n = 5); OCAL - 2.6 % (95 % CI: 0.01 % -7.7 %) and 2.7 % (95 % CI: 0.01 % -7.8 %; nausea; n = 1), discontinued treatment - 0 %. Reception of Lycopid 0.001 g / day during a 10-day three-component anti-bacterial treatment significantly increased H.pylori eradication by 16.0 % (according to ITT) and 14.5 % (according to PP; respectively χ2 = 3.87; P = 0.0492 and χ2 = 4.0; P = 0.0455), with a significant decrease in PR frequency by 2.5 % (according to ITT) and 2.7 % (according to PP; respectively, χ2 = 2.38; P = 0.0115 and χ2 = 6.56; P = 0.0105) and the complete completion of the course of therapy by all patients. Table 3 Results of a prospective randomized comparative clinical study of the frequency of H. pylori eradication and adverse effects depending on the prescribed treatment (stage I). Treatment Protocols n Eradication % (95 % CI) Adverse Effects % (95 % CI) Omeprazole 0.04 g / day Clarithromycin 1 g / day Amoxicillin 2 g / day 98 98 93 ITT 78,6 (70,4-86,8) PP 82,8 (75,1-90,5) ITT 24,5 (15,9-33,1) PP 25,8 (16,8-34,8) stopped treatment ITT 5,1 (0,7-9,5) PP 5,4 (0,8 %-10,0) Omeprazole 0.04 g / day Clarithromycin 1 g / day Amoxicillin 2 g / day Lycopid 0.001 g / day 38 38 37 ITT 94,7 % (87,5-100) PP 97,3 % (91,7-100) ITT 2,6 (0,01-7,7) PP 2,7 (0,01-7,8) stopped treatment- 0 Таблица 3 Результаты проспективного рандомизированного сравнительного клинического исследования частоты эрадикации H.pylori и побочных реакций в зависимости от назначенного лечения (I этап) Протоколы лечения n Эрадикация % (95 % ДИ) Побочные реакции % (95 % ДИ) Омепразол 0,04 г/сут Кларитромицин 1 г/сут Амоксициллин 2 г/сут 98 93 ITT 78,6 (70,4-86,8) PP 82,8 (75,1-90,5) ITT 24,5 (15,9-33,1) PP 25,8 (16,8-34,8) прекратили лечение ITT 5,1 (0,7-9,5) PP 5,4 (0,8 %-10,0) Омепразол 0,04 г/сут Кларитромицин 1 г/сут Амоксициллин 2 г/сут Ликопид 0,001 г/сут 38 37 ITT 94,7 % (87,5-100) PP 97,3 % (91,7-100) ITT 2,6 (0,01-7,7) PP 2,7 (0,01-7,8) прекратили лечение - 0 After 1 months (end of stage 1 of the study) after eradication therapy, according to the morphological method and rapid urease test, H.pylori was absent in the stomach and in the sections of the mucous membrane of the mucous membrane of the duodenal bulb in all patients included in the next phase of the clinical study (table 4). Relapse of H.pylori infection 6 months after per protocol treatment: OCA - 3.9 % (95 % CI: 0.01-8.3 %; n = 3), OCAL - 0 %. Relapse of H.pylori infection 1 year after per protocol treatment: OCA - 5.2 % (95 % CI: 0.2-10.2 %; n = 4), OCAL - 0 % (Table 4). As follows from the results of the study, GMDP eliminates H.pylori during 12 and 24 months and was decreased after 5 and 10 years. Diagnosis of H. pylori after 1 months, 6 months, 1 year, 2 years, 5 years and 10 years after treatment Groups Helicobacter pylori n 1 months 6 months 1 year n 2 years n 5 years n 10 years OCA 77 - 3 4 72 9 68 13 67 23 OCAL 36 - - - 36 - 36 1 35 2 Таблица 4 Диагностика H.pylori через 1 месяца, 6 месяцев, 1 год, 2 года, 5 лет и 10 лет после лечения Группы Helicobacter pylori n 1 месяц 6 месяцев 1 год n 2 года n 5 лет n 10 лет ОКА 77 - 3 4 72 9 68 13 67 23 ОКАЛ 36 - - - 36 - 36 1 35 2 Table 4 The frequency of H.pylori reinfection 2 years after per protocol treatment: OCA - 12.5 % (95 % CI: 4.8-20.2 %; n = 9), OCAL - 0 %. The frequency of H.pylori reinfection 5 years after per protocol treatment: OCA - 19.1 % (95 % CI: 9.7-28.5 %; n = 13), OCAL - 2.8 % (95 % CI: 0 , 01-8.3 %; n = 1). The frequency of H. pylori reinfection 10 years after per protocol treatment: OCA - 34.3 % (95 % CI: 22.8-45.8 %; n = 23), OCAL - 5.7 % (95 % CI: 0, 01-13.5 %; n = 2; Table 3). Thus, in patients taking Licopid at a dose of 1 mg per day together with anti- Helicobacter pylori therapy (the OCAL group), there was no H.pylori reinfection 2 years after per protocol treatment compared to the 10-day three-component treatment protocol without Lycopid. At the second stage of the study, it was also found that patients who took Liсopid at the above dose together with three-component anti-bacterial therapy (OCAL group) had a significantly low frequency of H. pylori reinfection for 5 years (χ2 = 4.33; P = 0.0375) and 10 years (χ2 = 6.73; P = 0.0095). The choice of patients with localization of an ulcer in the duodenal bulb (duodenal ulcer) as participants in a clinical study was based on the fact that, with duodenal ulcer of onion localization, a maximum degree of contamination of H.pylori gastric mucosa was observed (99.0 %) [38] and sections of gastric metaplasia of the mucous membrane of the duodenal bulb (87.8 %) [39]. The choice of Liсopid as an immunomodulator therapy in the 10-day H.pylori eradication scheme was consistent with the concept of an “ideal” immunomodulator and was based on three main criteria, according to current scientific research data [40]: The first criterion includes the presence of N-acetyl-glucosaminyl-N-acetylmuramyl dipeptide. One of the reasons for the ineffectiveness of eradication therapy is the transition of H.pylori to metabolically inactive forms (coccoid and U-form) that are resistant to antibiotics. It was previously shown that glucosaminyl muramil dipeptide promoted the release of Mycobacterium tuberculosis from the dormant form, which, apparently, determines the effectiveness of Licopid therapy [41]. Similarly, it was previously shown that NOD1 and NOD2 receptor activation promotes the elimination of H.pylori [42, 43]. The active substence of Lycopide, N-acetylglucosaminyl-N-acetylmuramyl dipeptide (GMDP, glucosaminyl muramyl dipeptide), is the main complete repeating structural unchanged fragment of the cell wall of almost all known bacteria, a ligand of NOD2 receptors. According to the second criterion for “ideal” immunomodulator it is necessary to activate immune system through T helper 1 lymphocytes. It was shown that activation immune answer through T helper 1 lymphocytes is essential for successful treatment H. pylori [44-47]. GMDP fully complies with the second criterion - its influence on the balance T helper 1/ T helper 2 shift towards T helper 1 has been proven [21, 22, 48]. By the third criterion an “ideal” immunomodulator has a bacterial, probiotic origin. According to Regulation 9 of Working Group 5 (Consensus Maastricht V) [2] and based on 14 meta-analyzes of RCTs (2007-2019) [49- 62], which combined 259 RCTs with 41727 patients, the addition of Lactobacillus strains optimizes therapy and decreases adverse effects. These meta-analyzes found that specific strains of Lactobacillus or several probiotic strains increase eradication of H.pylori by 8.1 % and reduce the number of adverse reactions when using the probiotic 14 days before eradication therapy or during eradication therapy. Bifidobacterium and Saccharomyces boulardii did not affect the level of eradication during anti- Helicobacter therapy [58, 62]. The use of specific strains of probiotics (Lactobacillus bulgaricus, Lactobacillus acidophilus, Lactobacillus casei DN-114001, Lactobacillus gasseri, and Bifidobacterium infantis 2036) during eradication therapy can be considered as an option to increase the level of H.pylori eradication, especially when the antibiotic is not effective [63, 68]. The effect of probiotics on the reduction of adverse reactions during eradication therapy has been proven [62]. A significant increase in the eradication of H.pylori by 17 % was found using mainly specific strains of Lactobacillus. When multicomponent probiotics were used as adjuvant therapy, eradication increased by only 2.8 % [54]. Monotherapy with probiotics using specific strains of Lactobacillus led to significant (P <0.001), compared with placebo, eradication of H.pylori in 16 % of patients, using multicomponent probiotics (which included Lactobacillus strains) in 14 % of patients [63]. Interestingly, that GMDP was for identified the first time as a fragment of Lactobacillus bulgaricus cell wall [64] and thus its beneficial effect in H.pylori therapy is consistent with the data of the above studies. Based on the data obtained, it can be concluded that therapy with the immunomodulator Liсopid in a 10-day H.pylori eradication scheme demonstrated an encouraging result. GMDP maintaines the long term (2, 5 and 10 years) eradication of H.pylori in 100 %, 98 % and in 95 % of cases. The reinfection of H.pylori after 5 years of the treatment is observed in 32 %-91,4 % cases [8, 9, 65]. Thus, the method for optimizing H. pylori therapy proposed in this research is in demand and has practical significance. Conclusions GMDP at a dose of 0.001 g per day during 10-day three-component anti-Helicobacter therapy significantly increased H.pylori eradication by 16 % (according to ITT; χ2 = 3, 87; P = 0.0492) and by 14.5 % (according to PP; χ2 = 4.0; P = 0.0455), with a significant decrease in the frequency of adverse reactions from the gastrointestinal tract by 2.5 % (according to ITT; χ2 = 2.38; P = 0.0115) and 2.7 % (according to PP; χ2 = 6.56; P = 0.0105) and the completion of the course of therapy by all patients. GMDP maintain the absence of H.pylori in 100 % during 2 years, in 98 % after 5 years and in 95 % after 10 years after treatment. Triple antibiotic eradication therapy of H. pylori, eliminates both pathogenic and commensal microorganisms, the waste products of which are vital and maintain immune homeostasis, including via NOD2 receptors of innate immunity. The success of the complex H.pylori eradication treatment can be explained by the compensatory effect of the GMDP for the missing signal from commensals for innate immunity receptors, providing an adequate immune response and preventing chronicity and recurrence of the infection.

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About the authors

M. R Konorev

Vitebsk State Medical University

Author for correspondence.
Email: svgur@mail.ru
Vitebsk, Belarus

S. V Guryanova

Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry RAS; Peoples’ Friendship University of Russia (RUDN University)

Email: svgur@mail.ru
Moscow, Russian Federation

E. N Tyshevich

Vitebsk State Medical University

Email: svgur@mail.ru
Vitebsk, Belarus

R. A Pavlyukov

Vitebsk State Medical University

Email: svgur@mail.ru
Vitebsk, Belarus

O. Yu Borisova

Moscow Research Institute of Epidemiology and Microbiology named after G.N. Gabrichevsky

Email: svgur@mail.ru
Moscow, Russian Federation

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