Frequency of Interferon-Resistance Conferring Substitutions in Amino Acid Positions 70 and 91 of Core Protein of the Russian HCV 1b Isolates Analyzed in the T-Cell Epitopic Context

Funding Information: This study was supported by the grant of the Russian Science Foundation (Project ID 15-15-30039). Mobility and training of the researchers was supported by the grants of the Swedish Institute (TP 09272/2013 and PI 19806/2016). Publisher Copyright: © 2018 V. S. Kichatova et al.Amino acid substitutions R70Q/H and L91M in HCV subtype 1b core protein can affect the response to interferon and are associated with the development of hepatocellular carcinoma. We found that the rate of R70Q/H in HCV 1b from Russia was 31.2%, similar to that in HCV strains from Asia (34.0%), higher than that in the European (18.0%, p=0.0010), but lower than that in the US HCV 1b strains (62.8%, p<0.0001). Substitution L91M was found in 80.4% of the Russian HCV 1b isolates, higher than in Asian isolates (43.8%, p<0.0001). Thus, a significant proportion of Russian HCV 1b isolates carry the unfavorable R70Q/H and/or L91M substitution. In silico analysis of the epitopic structure of the regions of substitutions revealed that both harbor clusters of T-cell epitopes. Peptides encompassing these regions were predicted to bind to a panel of HLA class I molecules, with substitutions impairing peptide recognition by HLA I molecules of the alleles prevalent in Russia. This indicates that HCV 1b with R70Q/H and L91M substitutions may have evolved as the immune escape variants. Impairment of T-cell recognition may play a part in the negative effect of these substitutions on the response to IFN treatment.Peer reviewe

The prevalence of serological markers of viral hepatitis among labor migrants arriving in the Russian Federation

Aim. To determine of the prevalence of viral hepatitis A, E, B, C and D markers in migrant workers.Materials and methods. Blood serum samples from 1,333 migrant workers recently arrived in Russia from Uzbekistan (n = 464), Tajikistan (n = 415), Ukraine (n = 308) and Moldova (n = 146) were analyzed. Anti-HAV IgG, anti-HEV IgM and IgG, HBsAg, anti-HBV and anti-HCV were tested using commercial ELISA tests.Results. The frequency of HBsAg detection was significantly higher among migrants from Tajikistan and Uzbekistan (5,3% and 5,2%, respectively) compared to migrants from Ukraine (1,0%) and Moldova (3,4%). No anti-HDV was detected in any positive HBsAg sample. The rate of anti-HCV detection was high regardless of the country of origin: 4,5% (Uzbekistan), 4.8% (Tajikistan), 3,9% (Ukraine), 4,8% (Moldova). Anti-HEV IgG was significantly higher in migrants from Uzbekistan and Tajikistan compared to those from Ukraine and Moldova (25,4% and 43,1%, vs. 7,8% and 12,3%, respectively, p &lt;0,05). Anti-HEV IgM, indicative of current or recent infection, was detected in migrants from Uzbekistan, Tajikistan, Ukraine and Moldova with similar frequency – 3,9%, 7,8%, 5,8% and 6,8%, respectively. AntiHAV IgG positivity rate was significantly lower in migrants from Ukraine compared to those from Moldova, Uzbekistan and Tajikistan (70,1% versus 91,8%, 98,7%, 99,8%, respectively, p &lt;0,05).Conclusion. The high prevalence of hepatitis B and C serologic markers in labor migrants, as well as anti-HEV IgM, suggests a high probability of the importation of HCV, HBV and HEV in the Russian Federation. Thus, inclusion of hepatitis B, C and E testing into routine screening of labor migrants might be beneficial

Factors influencing the prevalence of resistance-associated substitutions in NS5A protein in treatment-naive patients with chronic hepatitis C

Direct-acting antivirals (DAAs) revolutionized treatment of hepatitis C virus (HCV) infection. Resistance-associated substitutions (RASs) present at the baseline impair response to DAA due to rapid selection of resistant HCV strains. NS5A is indispensable target of the current DAA treatment regimens. We evaluated prevalence of RASs in NS5A in DAA-naïve patients infected with HCV 1a (n = 19), 1b (n = 93), and 3a (n = 90) before systematic DAA application in the territory of the Russian Federation. Total proportion of strains carrying at least one RAS constituted 35.1% (71/202). In HCV 1a we detected only M28V (57.9%) attributed to a founder effect. Common RASs in HCV 1b were R30Q (7.5%), L31M (5.4%), P58S (4.4%), and Y93H (5.4%); in HCV 3a, A30S (31.0%), A30K (5.7%), S62L (8.9%), and Y93H (2.2%). Prevalence of RASs in NS5A of HCV 1b and 3a was similar to that worldwide, including countries practicing massive DAA application, i.e., it was not related to treatment. NS5A with and without RASs exhibited different co-variance networks, which could be attributed to the necessity to preserve viral fitness. Majority of RASs were localized in polymorphic regions subjected to immune pressure, with selected substitutions allowing immune escape. Altogether, this explains high prevalence of RAS in NS5A and low barrier for their appearance in DAA-inexperienced population.Fil: Kyuregyan, Karen K.. Russian Academy Of Sciences; Rusia. Russian Medical Academy Of Continuous Professional Education; Rusia. I. I. Mechnikov Research Institute For Vaccines And Sera; RusiaFil: Kichatova, Vera S.. Russian Medical Academy Of Continuous Professional Education; Rusia. Russian Academy Of Sciences; Rusia. I. I. Mechnikov Research Institute For Vaccines And Sera; RusiaFil: Karlsen, Anastasiya A.. I. I. Mechnikov Research Institute For Vaccines And Sera; Rusia. Russian Medical Academy Of Continuous Professional Education; Rusia. Russian Academy Of Sciences; RusiaFil: Isaeva, Olga V.. I. I. Mechnikov Research Institute For Vaccines And Sera; Rusia. Russian Medical Academy Of Continuous Professional Education; RusiaFil: Solonin, Sergei A.. N.V. Sklifosovsky Research Institute for Emergency Medicine; RusiaFil: Petkov, Stefan. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Isaguliants, Maria G.. Russian Academy Of Sciences; Rusia. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Mikhailov, Mikhail I.. Russian Medical Academy Of Continuous Professional Education; Rusia. I. I. Mechnikov Research Institute For Vaccines And Sera; Rusi

Гепатит Е, к 40-летию открытия вируса академиком РАМН М.С. Балаяном

2021 marks the 40th anniversary of the discovery of the hepatitis E virus by an outstanding Russian virologist, academician of the Russian Academy of Medical Sciences Mikhail Surenovich Balayan. This date is an occasion to remember this remarkable scientist and person, to analyze the current state of the problem of viral hepatitis E, to sum up the research results and to correct the prospects of scientific directions, the development of which is largely related to the basic foundations laid by M.S. Balayan.The scientific heritage of M.S. Balayan is associated with the study of poliomyelitis, hepatitis A and hepatitis E. The main contribution of Mikhail Surenovich Balayan to world science was the discovery of the hepatitis E virus. This is, in first place, associated with the significance of the results obtained and the high moral value of the experimental selfinfection with hepatitis E.The paper presents data on the study of virology, epidemiology, clinical course, diagnosis and prevention of hepatitis E. The main concepts and directions of studying hepatitis E are overviewed.В 2021 г. исполняется 40 лет с момента открытия вируса гепатита Е выдающимся отечественным вирусологом, академиком. РАМН Михаилом. Суреновичем. Балаяном. Эта дата явилась поводом вспомнить этого замечательного учёного и человека, провести анализ современного состояния проблемы вирусного гепатита Е, подвести итоги исследований и скорректировать перспективы научных направлений, развитие которых во многом связано с базовыми основами, заложенными М.С. Балаяном.Научное наследие М.С. Балаяна связано с изучением полиомиелита, гепатита А и гепатита Е. Основным вкладом Михаила Суреновича Балаяна в мировую науку явилось открытие вируса гепатита Е. Это, прежде всего, связанно со значимостью полученных результатов и высокой нравственной оценкой опыта по самозаражению гепатитом Е.В работе представлены данные по изучению вирусологии, эпидемиологии, клиники, диагностики и профилактики гепатита Е. Рассмотрены основные концепции и направления изучения гепатита Е

Detection of antibodies to the hepatitis E virus in domestic reindeer (<i>Rangifer tarandus</i>) in the Republic of Sakha (Yakutia)

Introduction. Although domestic pigs and wild boars are the main reservoir of zoonotic hepatitis E virus (HEV) genotypes in temperate countries, the presence of antibodies to HEV (anti-HEV) in the indigenous population of circumpolar territories, i.e. outside the habitat of wild and domestic pigs, indicates the presence of an alternative reservoir of the virus. Reindeer (Rangifer tarandus) may be a potential reservoir for HEV in the polar regions. The purpose of the study was to determine the prevalence of anti-HEV among domestic reindeer in the Republic of Sakha (Yakutia). Materials and methods. Sera from 497 domestic reindeer from the Oymyakon (n = 425) and Ust-Yansky districts (n = 72) of the Republic of Sakha (Yakutia) were tested for anti-HEV. A commercial ELISA kit DS-ELISA-ANTI-HEV-G (Diagnostic Systems-Stolitsa LLC, Russia) was used for detection of anti-HEV IgG, but a rabbit polyclonal antibody against deer IgG labeled with horseradish peroxidase (KPL, USA) at a dilution of 1 : 100 in phosphate-buffered saline were used instead of the human specific conjugate from the kit. Results. The average detection rate of anti-HEV in reindeer sera was 15.5% (95% CI: 12.6–19.0%). The detection rate of anti-HEV significantly increased with age, from 3.5% (95% CI: 1.1–9.0%) in calves aged 3–6 months to 25.0% (95% CI: 1.6 –36.5%) in deer aged 2–4 years (p 0.0001). From this age group, anti-HEV detection rates reached a plateau, not differing significantly between older age groups (p 0.05). The average anti-HEV detection rate among reindeer 2 years of age and older was 19.0% (95% CI: 15.3–23.4%). There were no statistically significant differences in the frequency of anti-HEV detection between female and male reindeer, both among adult animals and among calves. Conclusion. The observed anti-HEV detection rates among domestic reindeer in the Republic of Sakha (Yakutia) indicate that infection caused by HEV or an antigenically similar virus is common in these animals. The dynamics of antibody accumulation in the reindeer population indicates that infection apparently occurs during the first two years of life

Coverage with timely administered vaccination against hepatitis b virus and its influence on the prevalence of HBV infection in the regions of different endemicity

Funding Information: Funding: This research was funded by grant of the Russian Science Foundation (ID-20-15-00148). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Universal hepatitis B vaccination of newborns was implemented in Russia starting from 1998. From 1998 to 2019, the incidence of acute hepatitis B reduced from 43.8 to 0.57 cases per 100,000 population. Here, we assessed the timely coverage of newborns with the birth dose (HepB-BD), second dose (HepB-2nd), and three vaccine doses (HepB3) in two remote regions of Russia with low (Belgorod Oblast) and high (Yakutia) levels of hepatitis B virus (HBV) endemicity. Vaccination data were obtained from the medical records of 1000 children in Yakutia and 2182 children in Belgorod Oblast. Sera of healthy volunteers from Belgorod Oblast (n = 1754) and Yakutia (n = 1072) across all age groups were tested for serological markers of HBV to assess the infection prevalence and herd immunity. Average HepB-BD coverage was 99.2% in Yakutia and 89.4% in Belgorod Oblast (p < 0.0001) and in both regions varied significantly, from 66% to 100%, between medical centers. The principal reason for the absence of HepB-BD was parent refusal, which accounted for 63.5% of cases of non-vaccination (83/123). While timely HepB-2nd coverage was only 55.4%–64.7%: HepB3 coverage by the age of one year exceeded 90% in both study regions. HBV surface antigen (HBsAg) prevalence in the 1998–2019 birth cohort was 0.2% (95% CI: 0.01–1.3%) in Belgorod Oblast and 3.2% (95% CI: 1.9–5.2%) in Yakutia. The proportion of persons testing negative for both antibodies to HBsAg (anti-HBs) and antibodies to HBV core antigen (anti-HBc) in the 1998–2019 birth cohort was 26.2% (125/481) in Belgorod Oblast and 32.3% (162/501) in Yakutia. We also assessed the knowledge of and attitude towards vaccination among 782 students and teachers of both medical and non-medical specialties from Belgorod State University. Only 60% of medical students knew that hepatitis B is a vaccine-preventable disease. Both medical and nonmedical students, 37.8% and 31.3%, respectively, expressed concerns about safety and actual necessity of vaccination. These data indicate the need to introduce a vaccine delivery audit system, improve medical education with respect to vaccination strategies and policies, and reinforce public knowledge on the benefits of vaccination.Peer reviewe

РАСПРОСТРАНЕННОСТЬ СЕРОЛОГИЧЕСКИХ МАРКЕРОВ ВИРУСНЫХ ГЕПАТИТОВ СРЕДИ ТРУДОВЫХ МИГРАНТОВ, ПРИБЫВАЮщИХ В РОССИйСКУЮ ФЕДЕРАЦИЮ

Aim. To determine of the prevalence of viral hepatitis A, E, B, C and D markers in migrant workers.Materials and methods. Blood serum samples from 1,333 migrant workers recently arrived in Russia from Uzbekistan (n = 464), Tajikistan (n = 415), Ukraine (n = 308) and Moldova (n = 146) were analyzed. Anti-HAV IgG, anti-HEV IgM and IgG, HBsAg, anti-HBV and anti-HCV were tested using commercial ELISA tests.Results. The frequency of HBsAg detection was significantly higher among migrants from Tajikistan and Uzbekistan (5,3% and 5,2%, respectively) compared to migrants from Ukraine (1,0%) and Moldova (3,4%). No anti-HDV was detected in any positive HBsAg sample. The rate of anti-HCV detection was high regardless of the country of origin: 4,5% (Uzbekistan), 4.8% (Tajikistan), 3,9% (Ukraine), 4,8% (Moldova). Anti-HEV IgG was significantly higher in migrants from Uzbekistan and Tajikistan compared to those from Ukraine and Moldova (25,4% and 43,1%, vs. 7,8% and 12,3%, respectively, p &lt;0,05). Anti-HEV IgM, indicative of current or recent infection, was detected in migrants from Uzbekistan, Tajikistan, Ukraine and Moldova with similar frequency – 3,9%, 7,8%, 5,8% and 6,8%, respectively. AntiHAV IgG positivity rate was significantly lower in migrants from Ukraine compared to those from Moldova, Uzbekistan and Tajikistan (70,1% versus 91,8%, 98,7%, 99,8%, respectively, p &lt;0,05).Conclusion. The high prevalence of hepatitis B and C serologic markers in labor migrants, as well as anti-HEV IgM, suggests a high probability of the importation of HCV, HBV and HEV in the Russian Federation. Thus, inclusion of hepatitis B, C and E testing into routine screening of labor migrants might be beneficial. Цель. Определение распространенности маркеров вирусных гепатитов А, Е, В, С и D среди рабочих мигрантов, недавно прибывших в Российскую Федерацию.Материалы и методы. Исследованы образцы сыворотки крови от 1333 трудовых мигрантов, недавно прибывших в РФ из Узбекистана (n=464), Таджикистана (n=415), Украины (n=308) и Молдовы (n=146). Анти-ВГА IgG, анти-ВГЕ IgM и IgG, HBsAg, анти-ВГD и анти-ВГС определяли с помощью коммерческих ИФА-тестов.Результаты. Частота выявления HBsAg была достоверно выше среди мигрантов из Таджикистана и Узбекистана (5,3% и 5,2% соответственно) по сравнению с мигрантами из Украины (1,0%) и Молдовы (3,4%). Ни в одном позитивном по HBsAg образце не были выявлены анти-ВГD. Частота выявления анти-ВГС среди трудовых мигрантов была высокой, независимо от страны происхождения: 4,5% (Узбекистан), 4,8% (Таджикистан), 3,9% (Украина), 4,8% (Молдова). Анти-ВГЕ IgG достоверно чаще выявляли среди мигрантов из Узбекистана и Таджикистана по сравнению с мигрантами из Украины и Молдовы (25,4% и 43,1% против 7,8% и 12,3% соответственно, p&lt;0,05). Анти-ВГЕ IgM, свидетельствующие о текущей или недавно перенесенной инфекции, выявляли среди мигрантов из Узбекистана, Таджикистана, Украины и Молдовы с примерно одинаковой частотой – 3,9%, 7,8%, 5,8% и 6,8% соответственно. Серопозитивные по анти-ВГА IgG лица достоверно реже встречались среди мигрантов из Украины по сравнению с лицами, прибывшими из Молдовы, Узбекистана и Таджикистана (70,1% против 91,8%, 98,7%, 99,8% соответственно, p&lt;0,05).Заключение. Высокая частота выявления маркеров гепатитов В и С у трудовых мигрантов, а также анти-ВГЕ IgM, позволяет предполагать высокую вероятность завоза ВГС, ВГВ и ВГЕ в РФ, что делает необходимым включение в алгоритм обследования трудовых мигрантов маркеров гепатитов В, С и Е.

ЛЕКАРСТВЕННО-РЕЗИСТЕНТНЫЕ ВАРИАНТЫ ВГС СУБТИПА 1B, ЦИРКУЛИРУЮЩИЕ НА ТЕРРИТОРИИ РОССИЙСКОЙ ФЕДЕРАЦИИ: АНАЛИЗ АМИНОКИСЛОТНЫХ МУТАЦИЙ В БЕЛКАХ NS5A И CORE

Aim. To determine the prevalence of amino acid substitutions in hepatitis C virus NS5a and core proteins which are associated with resistance to direct-acting antivirals and interferon in genotype 1b (HCV-1b) strains circulating in Russia. Materials and methods. Nucleotide sequences of NS5a (n=93) and core (n=30) of HCV-1b were obtained using direct sequencing of respective amplified genome fragments. The search for resistance associated substitutions was performed for amino acid positions 28, 29, 30, 31, 32, 58, 62, 92, 93 of NS5a, and 70 and 91 amino acid positions of core proteins, respectively. Results. The total proportion of HCV-1b strains carrying resistance associated substitutions in NS5a was 22,6% (21/93). The total detection rate of L31M and Y93H substitutions that are associated with resistance to the majority of NS5a inhibitors was 10,8%. Less clinically significant substitutions L28M, R30Q, P58S/T, A92T were detected too. The proportion of infections caused by HCV-1b strains that are potentially resistant both to interferon and NS5a inhibitors was 10% (10/30). Conclusion. Testing of HCV-1b infected patients for background resistance profile could be a useful tool to prevent the choosing of initially ineffective treatment regimen.Цель: определение распространенности штаммов вируса гепатита С субтипа 1b (ВГС-1b) на территории Российской Федерации, несущих аминокислотные мутации в белках NS5a и core, ассоциированные с лекарственной резистентностью к ингибиторам NS5a и препаратам интерферона соответственно. Материалы и методы: определение нуклеотидной последовательности белка NS5a (n=93), а также белка core (n=30) ВГС-1b проводилось методом прямого секвенирования амплифицированных фрагментов генома. Поиск мутаций, ассоциированных с лекарственной резистентностью, проводился в аминокислотных позициях 28, 29, 30, 31, 32, 58, 62, 92, 93 белка NS5a и аминокислотных позициях 70 и 91 белка core ВГС-1b. Результаты: 22,6% (21/93) исследованных изолятов ВГС-1b несли мутации, ассоциированные с лекарственной резистентностью к ингибиторам NS5a. В 10,8% последовательностей были выявлены замены L31M и Y93H, связанные с устойчивостью к большинству ингибиторов NS5a, а также менее значимые с клинической точки зрения замены L28M, R30Q, P58S/T, A92T. Доля лиц, инфицированных штаммами ВГС-1b, потенциально резистентными одновременно к препаратам интерферона и ингибиторам NS5a, составила 10% (10/30). Заключение: полученные данные свидетельствуют в пользу целесообразности предварительного исследования профиля резистентности ВГС-1b перед назначением терапии для предотвращения выбора заведомо неэффективного препарата

Клинико-эпидемиологическая характеристика гепатитов В и дельта в Республике Дагестан

Aim: The analysis of the incidence of hepatitis B in the Republic of Dagestan (RD) and clinical and epidemiological characteristics of HBV/HDV coinfection in the region.Materials and Methods. The dynamics of the hepatitis B incidence rates and the coverage of vaccination against this infection in the RD in 2008-2022 were analyzed based on the data from of the statistical forms of Rospotrebnadzor. The clinical and epidemiological characteristics of delta hepatitis were analyzed in 371 patients under dispensary observation at the Republican Center for Infectious Diseases named after S.-А.М. Magomedov.Results. Over the past 10 years, the incidence of CHB in the RD has increased more than 4.5 times, from 1.4 per 100 thousand population in 2008 to 6.7 per 100 thousand population in 2022. A decrease in the rates of hepatitis B child immunization in the RD is observed since 2009. Hepatitis B vaccination coverage rates in adult population fell sharply after 2010, both in the RD and in the Russian Federation  on average. The frequency of HDV co-infection in persons infected with HBV in the RD is 13.8%, but reaches 15% in some regions of the republic, indicating the moderate level   of endemicity. Patients with HBV/HDV coinfection are predominantly males aged 25–45 years with advanced fibrosis or cirrhosis. All cases of HDV infection in the RD are caused by viral genotype 1.Conclusions. The obtained results testify to the significance of the problem of hepatitis B and delta in the RD. The number of identified patients and, accordingly, the rate of co-infection, apparently, will increase with the expansion of screening for markers of HDV infection, when patients who were registered as HBsAg carriers will be examined according to the patient routing guidelines. The late diagnosis of delta hepatitis in RD and the limited possibilities of antiviral therapy are another significant issues.Цель: анализ заболеваемости гепатитом В в Республике Дагестан и клинико-эпидемиологическая характеристика ко-инфекции HBV/HDV в регионе.Материалы и методы: проведен анализ динамики заболеваемости гепатитом В и охвата вакцинацией против этой инфекции в Республике Дагестан в 2008–2022 гг. по материалам форм статистического учета Роспотребнадзора. Проанализированы клинико-эпидемиологические  характеристики  гепатита   дельта  у 371 пациента, находящихся на диспансерном наблюдении в Республиканском центре инфекционных болезней им. С.-А.М. Магомедова.Результаты: за последние 14 лет заболеваемость хроническим гепатитом В в Республике Дагестан увеличилась более чем в 4,5 раза, с 1,4 на 100 тыс. населения в 2008 г. до 6,7 на 100 тыс. населения в 2022 г. Результаты анализа охвата вакцинацией против гепатита В свидетельствуют о снижении уровня иммунизации детского населения в Республике Дагестан после 2009 г. Показатели охвата вакцинацией против гепатита В взрослого населения резко упали после 2010 г., как в Республике Дагестан, так и в Российской Федерации в среднем. Частота ко-инфекции HDV у лиц, инфицированных HBV, в Республике Дагестан составляет 13,8%, но достигает 15% в отдельных районах республики, что позволяет отнести ее к регионам с умеренной эндемичностью. Среди пациентов с ко-инфекцией HBV/HDV преобладают мужчины в возрасте 25–45 лет, с продвинутыми стадиями фиброза или циррозом. Во всех случаях HDV-инфекция была вызвана 1 генотипом вируса.Заключение:  полученные  результаты  свидетельствуют о значимости проблемы гепатитов В и дельта в Республике Дагестан. Количество выявленных больных и, соответственно, показатель частоты ко-инфекции, повидимому, будут увеличиваться при расширении скрининга на маркеры HDV-инфекции, когда пациенты, находившиеся на диспансерном учете как носители HВsAg, будут обследованы по алгоритму согласно приказу о маршрутизации. Не меньшей проблемой является поздняя диагностика гепатита дельта в Республике Дагестан и ограниченные возможности противовирусной терапии