vmireavizВестник медицинского института «РЕАВИЗ». Реабилитация, Врач и ЗдоровьеBulletin of the Medical Institute "REAVIZ" (REHABILITATION, DOCTOR AND HEALTH)2226-762X2782-1579РЕАВИЗ10.20340/vmi-rvz.2024.4.CLIN.4vmireaviz-1028Research ArticleКлиническая медицинаClinical medicineСовременная этиотропная терапия хронического вирусного гепатита ВModern etiotropic therapy of chronic viral hepatitis Bhttps://orcid.org/0009-0005-9395-8334БуньковаЕ. Б.Bun'kovaE. B.

Бунькова Елена Борисовна, канд. мед. наук, доцент

ул. Чапаевская, д. 227, г. Самара, 443001

Elena B. Bun'kova, Cand. Sci. (Med.), Associate Professor

227, Chapaevskaya St., Samara, 443001

bunkova27@mail.ruhttps://orcid.org/0000-0002-5732-4941БилёваН. А.BilevaN. A.

Билёва Наталья Александровна, канд. мед. наук

ул. Чапаевская, д. 227, г. Самара, 443001

Natal'ya A. Bileva, Cand. Sci. (Med.)

227, Chapaevskaya St., Samara, 443001

kosyakova1987@list.ruhttps://orcid.org/0000-0002-7269-5759БилёвА. Е.BilevA. E.

Билёв Александр Евгеньевич, д-р мед. наук, проректор по клинической работе, профессор кафедры клинической медицины

ул. Чапаевская, д. 227, г. Самара, 443001

Aleksandr E. Bilev, Dr. Sci. (Med.), Vice-Rector for Clinical Work, Professor of the Department of Clinical Medicine

227, Chapaevskaya St., Samara, 443001

bilev1956@mail.ruhttps://orcid.org/0009-0008-4591-2405СинельниковМ. И.Sinel'nikovM. I.

Синельников Михаил Исаевич, врач инфекционист, заведующий отделением

ул. Шверника, д. 1, г. Самара, 443029

Mikhail I. Sinel'nikov, Infectious disease specialist, head of department

1, Shvernika St., Samara, 443029

sinelnikovm@mail.ruМедицинский университет "Реавиз"РоссияReaviz Medical UniversityRussian FederationСамарская областная детская инфекционная больницаРоссияSamara Regional Children's Infectious Diseases HospitalRussian Federation2024181020241447686Copyright © Бунькова Е.Б., Билёва Н.А., Билёв А.Е., Синельников М.И., 20242024Бунькова Е.Б., Билёва Н.А., Билёв А.Е., Синельников М.И.Bun'kova E.B., Bileva N.A., Bilev A.E., Sinel'nikov M.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestnik.reaviz.ru/jour/article/view/1028

Хронический вирусный гепатит В представляет собой значимую проблему здравоохранения в мировом масштабе. Биологические характеристики вируса гепатита В, являющегося возбудителем данного заболевания, существенно затрудняют достижение полной элиминации вируса у большинства пациентов. В связи с этим рациональный выбор лекарственных препаратов и схем противовирусной терапии имеет решающее значение для увеличения продолжительности жизни и улучшения её качества у пациентов с хроническим вирусным гепатитом В.

Цель настоящего обзора литературы заключается в выявлении современных подходов и трендов в этиотропной терапии хронического вирусного гепатита В.

Материалы и методы

Материалы и методы. В обзоре использованы данные, опубликованные в отечественных и зарубежных научных журналах, клинических рекомендациях, нормативных документах и интернет-ресурсах.

Результаты

Результаты. В настоящее время наиболее эффективными средствами этиотропной терапии хронического вирусного гепатита В являются интерфероны (стандартный интерферон альфа, пегилированные интерфероны альфа-2а и альфа-2b), а также аналоги нуклеозидов/нуклеотидов «первой линии» (энтекавир, тенофовир) и «второй линии» (ламивудин, телбивудин, адефовир). Выбор конкретного лекарственного препарата определяется клиническим состоянием пациента, его предпочтениями, доступностью и стоимостью лечения. Несмотря на определённые ограничения современных средств этиотропной терапии хронического вирусного гепатита В, их применение позволяет значительно увеличить продолжительность жизни пациентов и улучшить её качество.

Chronic viral hepatitis B (CHB) is a significant global health problem. The biological characteristics of the hepatitis B virus, which causes this disease, significantly impede the achievement of complete virus elimination in most patients. In this regard, the rational choice of drugs and antiviral therapy regimens is crucial for increasing life expectancy and improving the quality of life in patients with CHB. The purpose of this literature review is to identify current approaches and trends in etiotropic therapy for CHB.

Materials and methods

Materials and methods. The review uses data published in domestic and foreign scientific journals, clinical guidelines, regulatory documents, and Internet resources.

Results

Results. Currently, the most effective means of etiotropic therapy for CHB are interferons (standard interferon alpha, pegylated interferons alpha-2a and alpha-2b), as well as first-line nucleoside/nucleotide analogs (entecavir, tenofovir) and second-line analogs (lamivudine, telbivudine, adefovir). The choice of a specific drug is determined by the patient's clinical condition, preferences, availability, and cost of treatment. Despite certain limitations of current etiotropic therapies for CHB, their use can significantly increase patients' life expectancy and improve their quality of life.

хронический вирусный гепатит Ввирус гепатита Винтерфероныаналоги нуклеозидов/нуклеотидовэтиотропная терапияпротивовирусная терапияChronic viral hepatitis Bhepatitis B virusinterferonsnucleoside/nucleotide analogsetiotropic therapyantiviral therapyReferencesWorld Health Organization. Hepatitis B fact sheet. 2019. Accessed September 15, 2024. http://www.who.int/mediacentre/factsheets/fs204/en/World Health Organization. Hepatitis B fact sheet. 2019. Accessed September 15, 2024. http://www.who.int/mediacentre/factsheets/fs204/en/World Health Organization. Global Progress Report on HIV, Viral Hepatitis and Sexually Transmitted Infections, 2021. Geneva: World Health Organization; 2021.World Health Organization. Global Progress Report on HIV, Viral Hepatitis and Sexually Transmitted Infections, 2021. Geneva: World Health Organization; 2021.Johannessen A, Stockdale AJ, Henrion M, et al. Diagnostic performance of non-invasive fibrosis markers for chronic hepatitis B in subSaharan Africa: a Bayesian individual patient data meta-analysis. medRxiv. Preprint posted online March 18, 2022. https://doi.org/10.1101/2022.03.18.22272415Johannessen A, Stockdale AJ, Henrion M, et al. Diagnostic performance of non-invasive fibrosis markers for chronic hepatitis B in subSaharan Africa: a Bayesian individual patient data meta-analysis. medRxiv. Preprint posted online March 18, 2022. https://doi.org/10.1101/2022.03.18.22272415Johannessen A, Pripp AH, Desalegn H, Aberra H, Gundersen SG, Berhe N. The TREAT-B score predicts disease progression in Ethiopian patients with chronic hepatitis B. Presented at: International Viral Hepatitis Elimination Workshop; December 4-5, 2020. Abstract 11.Johannessen A, Pripp AH, Desalegn H, Aberra H, Gundersen SG, Berhe N. The TREAT-B score predicts disease progression in Ethiopian patients with chronic hepatitis B. Presented at: International Viral Hepatitis Elimination Workshop; December 4-5, 2020. Abstract 11.Hsu Y-C, Chen C-Y, Chang I-W, et al. Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. Lancet Infect Dis. 2021;21(6):823-833.Hsu Y-C, Chen C-Y, Chang I-W, et al. Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. Lancet Infect Dis. 2021;21(6):823-833.Global reporting of progress towards elimination of hepatitis B and hepatitis C. Lancet. 2023;8(4):332-342. https://doi.org/10.1016/S2468-1253(22)00386-7.Global reporting of progress towards elimination of hepatitis B and hepatitis C. Lancet. 2023;8(4):332-342. https://doi.org/10.1016/S2468-1253(22)00386-7.WGO Practice Guideline. Hepatitis B. https://www.worldgastroenterology.org/guidelines/hepatitis-bWGO Practice Guideline. Hepatitis B. https://www.worldgastroenterology.org/guidelines/hepatitis-bDrafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. "Japan Society of Hepatology guidelines for the management of hepatitis B virus infection: 2019 update." Hepatology Research (50.8) 2020:892-923.Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. "Japan Society of Hepatology guidelines for the management of hepatitis B virus infection: 2019 update." Hepatology Research (50.8) 2020:892-923.Kumar, Manoj, et al. "Asian Pacific association for the study of liver (APASL) guidelines: hepatitis B virus in pregnancy." Hepatology international 16.2 (2022):211-253.Kumar, Manoj, et al. "Asian Pacific association for the study of liver (APASL) guidelines: hepatitis B virus in pregnancy." Hepatology international 16.2 (2022):211-253.Yim, H. J., Kim, J. H., Park, J. Y., Yoon, E. L., Park, H., Kwon, J. H., ... & Lee, H. W. Comparison of clinical practice guidelines for the management of chronic hepatitis B: When to start, when to change, and when to stop. Clinical and molecular hepatology. 2020;26(4):411.Yim, H. J., Kim, J. H., Park, J. Y., Yoon, E. L., Park, H., Kwon, J. H., ... & Lee, H. W. Comparison of clinical practice guidelines for the management of chronic hepatitis B: When to start, when to change, and when to stop. Clinical and molecular hepatology. 2020;26(4):411.Lim, Y. S., Ahn, S. H., Shim, J. J., Razavi, H., Razavi‐Shearer, D., & Sinn, D. H. Impact of expanding hepatitis B treatment guidelines: a modelling and economic impact analysis. Alimentary pharmacology & therapeutics. 2022;56(3):519–528.Lim, Y. S., Ahn, S. H., Shim, J. J., Razavi, H., Razavi‐Shearer, D., & Sinn, D. H. Impact of expanding hepatitis B treatment guidelines: a modelling and economic impact analysis. Alimentary pharmacology & therapeutics. 2022;56(3):519–528.World Health Organization. (2024). Consolidated guidelines on person-centred viral hepatitis strategic information: data to support the country scale-up of hepatitis prevention, diagnosis and treatment services. World Health Organization.World Health Organization. (2024). Consolidated guidelines on person-centred viral hepatitis strategic information: data to support the country scale-up of hepatitis prevention, diagnosis and treatment services. World Health Organization.Abaalkhail FA, Al-Hamoudi WK, Khathlan A, et al. SASLT practice guidelines for the management of Hepatitis B virus–An update. Saudi J Gastroenterol. 2021;27(3):115-126.Abaalkhail FA, Al-Hamoudi WK, Khathlan A, et al. SASLT practice guidelines for the management of Hepatitis B virus–An update. Saudi J Gastroenterol. 2021;27(3):115-126.Johannessen A, Gebremedhin LT, Desalegn H. New WHO hepatitis B treatment guidelines: look to Ethiopia. Lancet Glob Health. 2022;10(12):e1711-e1712.Johannessen A, Gebremedhin LT, Desalegn H. New WHO hepatitis B treatment guidelines: look to Ethiopia. Lancet Glob Health. 2022;10(12):e1711-e1712.Progress towards elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission update. Lancet. 2024;9(4):346-365.Progress towards elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission update. Lancet. 2024;9(4):346-365.Shapieva NT, Ponezheva ZhB, Makashova VV, Omarova KhG. Modern aspects of chronic hepatitis B. Lechashchiy vrach. 2019;(5):82-87.Shapieva NT, Ponezheva ZhB, Makashova VV, Omarova KhG. Modern aspects of chronic hepatitis B. Lechashchiy vrach. 2019;(5):82-87.Nguyen Thi-Hanh, Melnikova LI, Ilchenko LYu, et al. Clinical and virological characteristics of chronic hepatitis B and response to antiviral therapy. Medicine of Extreme Situations. 2023;1(25):59-67.Nguyen Thi-Hanh, Melnikova LI, Ilchenko LYu, et al. Clinical and virological characteristics of chronic hepatitis B and response to antiviral therapy. Medicine of Extreme Situations. 2023;1(25):59-67.European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-398.European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-398.Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599.Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599.Mikhailova YuV, Sterlikov SA, Gromov AV. Mortality from viral hepatitis in the Russian Federation (analytical review). Current Problems of Health Care and Medical Statistics. 2022;(1):414-437.Mikhailova YuV, Sterlikov SA, Gromov AV. Mortality from viral hepatitis in the Russian Federation (analytical review). Current Problems of Health Care and Medical Statistics. 2022;(1):414-437.Order of the Ministry of Health of Russia dated 09.11.2012 No. 786n "On approval of the standard of specialized medical care for chronic viral hepatitis B".Order of the Ministry of Health of Russia dated 09.11.2012 No. 786n "On approval of the standard of specialized medical care for chronic viral hepatitis B".Tereshkov DV, Mitsura VM. Chronic hepatitis B viral infection: clinical characteristics and antiviral therapy. Problems of Health and Ecology. 2022;19(2):82-89.Tereshkov DV, Mitsura VM. Chronic hepatitis B viral infection: clinical characteristics and antiviral therapy. Problems of Health and Ecology. 2022;19(2):82-89.Clinical guidelines "Acute hepatitis B (HBV) in adults". Moscow: NNOI; 2021:75.Clinical guidelines "Acute hepatitis B (HBV) in adults". Moscow: NNOI; 2021:75.Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol Mech Dis. 2006;1:23-61.Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol Mech Dis. 2006;1:23-61.Locarnini S, Hatzakis A, Chen D-S, Lok A. Strategies to control hepatitis B: public policy, epidemiology, vaccine and drugs. J Hepatol. 2015;62(1 Suppl):S76-S86.Locarnini S, Hatzakis A, Chen D-S, Lok A. Strategies to control hepatitis B: public policy, epidemiology, vaccine and drugs. J Hepatol. 2015;62(1 Suppl):S76-S86.Yuen M-F, Chen D-S, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4:18035.Yuen M-F, Chen D-S, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4:18035.Revill PA, Chisari FV, Block JM, et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol Hepatol. 2019;4(7):545-558.Revill PA, Chisari FV, Block JM, et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol Hepatol. 2019;4(7):545-558.Udompap P, Kim WR. Development of hepatocellular carcinoma in patients with suppressed viral replication: changes in risk over time. Clin Liver Dis. 2020;15(3):85-90.Udompap P, Kim WR. Development of hepatocellular carcinoma in patients with suppressed viral replication: changes in risk over time. Clin Liver Dis. 2020;15(3):85-90.Levrero M, Testoni B, Zoulim F. HBV cure: why, how, when? Curr Opin Virol. 2016;18:135-143.Levrero M, Testoni B, Zoulim F. HBV cure: why, how, when? Curr Opin Virol. 2016;18:135-143.Fanning GC, Zoulim F, Hou J, Bertoletti A. Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat Rev Drug Discov. 2019;18(11):827-844.Fanning GC, Zoulim F, Hou J, Bertoletti A. Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat Rev Drug Discov. 2019;18(11):827-844.Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2(10):1104-1108.Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2(10):1104-1108.Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology. 2015;479-480:672-686.Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology. 2015;479-480:672-686.Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol. 2016;64(1 Suppl):S71-S83.Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol. 2016;64(1 Suppl):S71-S83.Guidotti LG, Isogawa M, Chisari FV. Host–virus interactions in hepatitis B virus infection. Curr Opin Immunol. 2015;36:61-66.Guidotti LG, Isogawa M, Chisari FV. Host–virus interactions in hepatitis B virus infection. Curr Opin Immunol. 2015;36:61-66.Tu T, Budzinska MA, Shackel NA, Urban S. HBV DNA integration: molecular mechanisms and clinical implications. Viruses. 2017;9(4):75.Tu T, Budzinska MA, Shackel NA, Urban S. HBV DNA integration: molecular mechanisms and clinical implications. Viruses. 2017;9(4):75.Summers J, Jilbert AR, Yang W, et al. Hepatocyte turnover during resolution of a transient hepadnaviral infection. Proc Natl Acad Sci U S A. 2003;100(20):11652-11659.Summers J, Jilbert AR, Yang W, et al. Hepatocyte turnover during resolution of a transient hepadnaviral infection. Proc Natl Acad Sci U S A. 2003;100(20):11652-11659.Wooddell CI, Yuen M-F, Chan HL-Y, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med. 2017;9(409):eaan0241.Wooddell CI, Yuen M-F, Chan HL-Y, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med. 2017;9(409):eaan0241.Simon TG, Ma Y, Ludvigsson JF, et al. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med. 2020;382(11):1018-1028.Simon TG, Ma Y, Ludvigsson JF, et al. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med. 2020;382(11):1018-1028.Sitia G, Aiolfi R, Di Lucia P, et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A. 2012;109(32):E2165.Sitia G, Aiolfi R, Di Lucia P, et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A. 2012;109(32):E2165.Iannacone M, Sitia G, Narvaiza I, Ruggeri ZM, Guidotti LG. Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus. Clin Vaccine Immunol. 2007;14(11):1532-1535.Iannacone M, Sitia G, Narvaiza I, Ruggeri ZM, Guidotti LG. Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus. Clin Vaccine Immunol. 2007;14(11):1532-1535.Asabe S, Wieland SF, Chattopadhyay PK, et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol. 2009;83(19):9652-9662.Asabe S, Wieland SF, Chattopadhyay PK, et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol. 2009;83(19):9652-9662.Wisse E, Jacobs F, Topal B, Frederik P, De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocytedirected gene transfer. Gene Ther. 2008;15(17):1193-1199.Wisse E, Jacobs F, Topal B, Frederik P, De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocytedirected gene transfer. Gene Ther. 2008;15(17):1193-1199.Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89(4):1269-1339.Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89(4):1269-1339.Whalley SA, Murray JM, Brown D, et al. Kinetics of acute hepatitis B virus infection in humans. J Exp Med. 2001;193(7):847-854.Whalley SA, Murray JM, Brown D, et al. Kinetics of acute hepatitis B virus infection in humans. J Exp Med. 2001;193(7):847-854.Wieland SF, Spangenberg HC, Thimme R, Purcell RH, Chisari FV. Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. Proc Natl Acad Sci U S A. 2004;101(7):2129-2134.Wieland SF, Spangenberg HC, Thimme R, Purcell RH, Chisari FV. Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. Proc Natl Acad Sci U S A. 2004;101(7):2129-2134.Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101(17):6669-6674.Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101(17):6669-6674.Suslov A, Boldanova T, Wang X, Wieland S, Heim MH. Hepatitis B virus does not interfere with innate immune responses in the human liver. Gastroenterology. 2018;154(6):1778-1790.Suslov A, Boldanova T, Wang X, Wieland S, Heim MH. Hepatitis B virus does not interfere with innate immune responses in the human liver. Gastroenterology. 2018;154(6):1778-1790.Tsui LV, Guidotti LG, Ishikawa T, Chisari FV. Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes. Proc Natl Acad Sci U S A. 1995;92(26):12398-12402.Tsui LV, Guidotti LG, Ishikawa T, Chisari FV. Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes. Proc Natl Acad Sci U S A. 1995;92(26):12398-12402.Heise T, Guidotti LG, Cavanaugh VJ, Chisari FV. Hepatitis B virus RNA-binding proteins associated with cytokine-induced clearance of viral RNA from the liver of transgenic mice. J Virol. 1999;73(1):474-481.Heise T, Guidotti LG, Cavanaugh VJ, Chisari FV. Hepatitis B virus RNA-binding proteins associated with cytokine-induced clearance of viral RNA from the liver of transgenic mice. J Virol. 1999;73(1):474-481.Heise T, Guidotti LG, Chisari FV. La autoantigen specifically recognizes a predicted stem-loop in hepatitis B virus RNA. J Virol. 1999;73(7):5767-5776.Heise T, Guidotti LG, Chisari FV. La autoantigen specifically recognizes a predicted stem-loop in hepatitis B virus RNA. J Virol. 1999;73(7):5767-5776.Wieland SF, Guidotti LG, Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. J Virol. 2000;74(9):4165-4173.Wieland SF, Guidotti LG, Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. J Virol. 2000;74(9):4165-4173.Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. J Immunol. 2002;169(9):5188-5195.Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. J Immunol. 2002;169(9):5188-5195.Vilarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci U S A. 2007;104(46):18187-18192.Vilarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci U S A. 2007;104(46):18187-18192.Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005;79(11):7269-7272.Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005;79(11):7269-7272.Suslov A, Wieland S, Menne S. Modulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B. Curr Opin Virol. 2018;30:9-17.Suslov A, Wieland S, Menne S. Modulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B. Curr Opin Virol. 2018;30:9-17.Iwasaki A. A virological view of innate immune recognition. Annu Rev Microbiol. 2012;66:177-196.Iwasaki A. A virological view of innate immune recognition. Annu Rev Microbiol. 2012;66:177-196.Webster GJ, Reignat S, Maini MK, et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology. 2000;32(5):1117-1124.Webster GJ, Reignat S, Maini MK, et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology. 2000;32(5):1117-1124.Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77(1):68-76.Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77(1):68-76.Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996;4(1):25-36.Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996;4(1):25-36.Wong YC, Tay SS, McCaughan GW, Bowen DG, Bertolino P. Immune outcomes in the liver: is CD8 T cell fate determined by the environment? J Hepatol. 2015;63(4):1005-1014.Wong YC, Tay SS, McCaughan GW, Bowen DG, Bertolino P. Immune outcomes in the liver: is CD8 T cell fate determined by the environment? J Hepatol. 2015;63(4):1005-1014.Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV. CD40 activation rescues antiviral CD8⁺ T cells from PD-1-mediated exhaustion. PLoS Pathog. 2013;9(7):e1003490.Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV. CD40 activation rescues antiviral CD8⁺ T cells from PD-1-mediated exhaustion. PLoS Pathog. 2013;9(7):e1003490.Bénéchet AP, De Simone G, Di Lucia P, et al. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature. 2019;574(7777):200-205.Bénéchet AP, De Simone G, Di Lucia P, et al. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature. 2019;574(7777):200-205.Pol JG, Caudana P, Paillet J, Piaggio E, Kroemer G. Effects of interleukin-2 in immunostimulation and immunosuppression. J Exp Med. 2020;217(1):e20191247.Pol JG, Caudana P, Paillet J, Piaggio E, Kroemer G. Effects of interleukin-2 in immunostimulation and immunosuppression. J Exp Med. 2020;217(1):e20191247.Kuipery A, Gehring AJ, Isogawa M. Mechanisms of HBV immune evasion. Antiviral Res. 2020;179:104816.Kuipery A, Gehring AJ, Isogawa M. Mechanisms of HBV immune evasion. Antiviral Res. 2020;179:104816.Fisicaro P, Barili V, Montanini B, et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat Med. 2017;23(3):327-336.Fisicaro P, Barili V, Montanini B, et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat Med. 2017;23(3):327-336.Wieland SF. The chimpanzee model for hepatitis B virus infection. Cold Spring Harb Perspect Med. 2015;5(6):a021469.Wieland SF. The chimpanzee model for hepatitis B virus infection. Cold Spring Harb Perspect Med. 2015;5(6):a021469.Tian Y, Kuo CF, Akbari O, Ou JH. Maternal-derived hepatitis B virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission. Immunity. 2016;44(5):1204-1214.Tian Y, Kuo CF, Akbari O, Ou JH. Maternal-derived hepatitis B virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission. Immunity. 2016;44(5):1204-1214.Publicover J, Gaggar A, Nishimura S, et al. Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B. J Clin Invest. 2013;123(9):3728-3739.Publicover J, Gaggar A, Nishimura S, et al. Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B. J Clin Invest. 2013;123(9):3728-3739.

The authors declare that there are no conflicts of interest present.