gastro-jРоссийский журнал гастроэнтерологии, гепатологии, колопроктологииRussian Journal of Gastroenterology, Hepatology, Coloproctology1382-43762658-6673«Gastro» LLCgastro-j-1876Research ArticleЛЕКЦИИ И ОБЗОРЫLECTURES AND REVIEWSСкрытая инфекция вирусом гепатита ВOccult hepatitis B virus infectionИвашкинВ. Т.IvashkinV. T.ГерманЕ. Н.GermanYe. N.МаевскаяМ. В.MaevskayaM. V.200824042008182411Copyright © Ивашкин В.Т., Герман Е.Н., Маевская М.В., 20082008Ивашкин В.Т., Герман Е.Н., Маевская М.В.Ivashkin V.T., German Y.N., Maevskaya M.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gastro-j.ru/jour/article/view/1876

Цель. Представить обзор данных литературы о состоянии проблемы скрытой (латентной) инфекции вирусом гепатита В (HBV) в современном мире.Последние данные литературы. Латентная инфекция HBV – феномен, связанный главным образом с внутрипеченочным персистированием вирусной cccDNA и выраженной супрессией вирусной репликации и экспрессии вирусных антигенов. С учетом очень низкого уровня ДНК HBV для ее обнаружения требуется использовать очень чувствительные серологические и специфические методы молекулярной биологии. Торможение репликации HBV обратимо и латентная инфекция может модифицироваться в острую, которая, как правило, протекает очень тяжело. При заражении вирусом гепатита В от субъектов с латентным течением HBV­инфекции (при переливании крови или трансплантации органов и тканей) также может развиться острый гепатит. В ткани печени за счет персистирования вируса наблюдаются умеренные прогрессирующие некровоспалительные изменения, которые в течение длительного времени могут (даже при отсутствии других причин) привести к циррозу печени. Кроме того, латентная HBV­инфекция имеет онкогенные свойства, типичные для классической, «явной» инфекции, и фактически это важный фактор риска развития гепатоцеллюлярной карциномы.Заключение. Изучение вопросов, связанных с латентным течением инфекции вирусом гепатитаВ, имеет важное значение для определения тактики ведения таких пациентов. На сегодняшний день нет четких рекомендаций относительно сроков наблюдения за этими людьми, а также определенных критериев для начала противовирусной терапии, ее обоснованности, продолжительности и оценки результатов.

The aim

The aim. To present the review of literature data for state-of the art of occult (latent) hepatitis B virus (HBV) infection in the modern world.

Recent literature data

Recent literature data. A phenomenon of latent infection HBV is related  mainly to intrahepatic persistence of viral cccDNA and severe suppression of viral replication and expression of viral antigens. Taking into account very low level of DNA HBV its detection requires very sensitive serological and specific molecular biology methods. Inhibition of HBV replication is reversible and latent infection can turn into acute which, as a rule, progress very severely. At infestation by hepatitis B virus from subjects with latent course of HBV-infection (at hemotransfusion or transplantation of organs and tissues) acute hepatitis can develop as well. Due to persistence of virus moderate progressing necroinflammatory reaction in liver tissue is observed, which for a long time can (even at the absence of other causes) result in liver cirrhosis. Besides this, the latent HBV-infection has oncogenic properties, that are characteristic for classical, «manifestative» infection, and thus it is an important risk factor for hepatocellular carcinoma development.

Conclusion

Conclusion. Studying of the issues related to latent course of hepatitis B virus infection, has the important value for definition of management of such patients. At the moment there are no clear references concerning terms of follow-up, and no fixed criteria for onset of antiviral therapy, its validity, duration and evaluation of results.

скрытая инфекциявирус гепатита Вмолекулы cccDNA вируса гепатита Вoccult infectionhepatitis B virushepatitis B virus cccDNA moleculesReferencesАбдурахманов Д.Т. Латентная HBV-инфекция в патогенезе хронических заболеваний печени // Рос. журн. гастроентерол. гепатол. колопроктол. – 2002. – № 6. – С. 31–37.Абдурахманов Д.Т. Латентная HBV-инфекция в патогенезе хронических заболеваний печени // Рос. журн. гастроентерол. гепатол. колопроктол. – 2002. – № 6. – С. 31–37.Апросина З.Г., Серов В.В. Патогенез хронического гепатита В // Арх. патол. – 2001. – № 2. – С. 58–62.Апросина З.Г., Серов В.В. Патогенез хронического гепатита В // Арх. патол. – 2001. – № 2. – С. 58–62.Болезни печени и желчевыводящих путей: Руководство для врачей / Под ред. В.Т. Ивашкина. – 2-е изд., испр. и доп. – М.: Изд. дом «М-Вести», 2005. – С. 103.Болезни печени и желчевыводящих путей: Руководство для врачей / Под ред. В.Т. Ивашкина. – 2-е изд., испр. и доп. – М.: Изд. дом «М-Вести», 2005. – С. 103.Маевская М.В. Лечение хронических вирусных гепатитов // Лечащий врач. – 2005. – № 2. – С. 31–37.Маевская М.В. Лечение хронических вирусных гепатитов // Лечащий врач. – 2005. – № 2. – С. 31–37.Назаренко С.А. Эволюционная биология: Материалы II Междунар. конф. «Проблема вида и видообразование». – Томск: Изд. Томского гос. ун-та, 2002. – Т. 2. – С. 82–93.Назаренко С.А. Эволюционная биология: Материалы II Междунар. конф. «Проблема вида и видообразование». – Томск: Изд. Томского гос. ун-та, 2002. – Т. 2. – С. 82–93.Berasain C, Betes M, Panizo A, et al. Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology. Gut 2000; 47:429-35.Berasain C, Betes M, Panizo A, et al. Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology. Gut 2000; 47:429-35.Besisik F, Karaca C, Akyuz F, et al. Occult HBV infection and YMDD variants in hemodialysis patients with chronic HCV infection. J Hepatol 2003; 38:506-10.Besisik F, Karaca C, Akyuz F, et al. Occult HBV infection and YMDD variants in hemodialysis patients with chronic HCV infection. J Hepatol 2003; 38:506-10.Brechot C. Pathogenesis of hepatitis B virus-related hepatocelular carcinoma: old and new paradigms. Gastroenterology 2004; 127:56-61.Brechot C. Pathogenesis of hepatitis B virus-related hepatocelular carcinoma: old and new paradigms. Gastroenterology 2004; 127:56-61.Cacciola I, Pollicino T, Squadrito G, et al. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 1999; 341:22-6.Cacciola I, Pollicino T, Squadrito G, et al. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 1999; 341:22-6.Chemin I, Trepo C. Clinical impact of occult HBV infections. J Clin Virol 2005; 34:15-21.Chemin I, Trepo C. Clinical impact of occult HBV infections. J Clin Virol 2005; 34:15-21.Chemin I, Zoulim F, Merle P, et al. High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol 2001; 34:447-54.Chemin I, Zoulim F, Merle P, et al. High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol 2001; 34:447-54.Chen SY, Kao CF, Chen CM, et al. Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein. J Biol Chem 2003; 278:591-607.Chen SY, Kao CF, Chen CM, et al. Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein. J Biol Chem 2003; 278:591-607.Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002; 123:1084-9.Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002; 123:1084-9.Chevrier MC, St-Louis M, Perreault J, et al. Detection and characterization of hepatitis B virus of anti-hepatitis B core antigen-reactive blood donors in Quebec with an in-house nucleic acid testing assay. Transfusion 2007 Oct; 47(10):1794-802.Chevrier MC, St-Louis M, Perreault J, et al. Detection and characterization of hepatitis B virus of anti-hepatitis B core antigen-reactive blood donors in Quebec with an in-house nucleic acid testing assay. Transfusion 2007 Oct; 47(10):1794-802.Dhedin N, Douvin C, Kuentz M, et al. Reverse seroconversion of hepatitis B after allogeneic bone marrow transplantation: a retrospective study of 37 patients with pretransplant anti-HBs and anti-HBc. Transplantation 1998; 66:616-9.Dhedin N, Douvin C, Kuentz M, et al. Reverse seroconversion of hepatitis B after allogeneic bone marrow transplantation: a retrospective study of 37 patients with pretransplant anti-HBs and anti-HBc. Transplantation 1998; 66:616-9.Dickson RC, Everhart JE, Lake JR, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology 1997; 113:1668-74.Dickson RC, Everhart JE, Lake JR, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology 1997; 113:1668-74.Donato F, Gelatti U, Limina RM, Fattovich G. Souther Europe as an example of interaction between various enviror mental factors: a systematic review of the epidemiologic evidence. Oncogene 2006; 25:3756-70.Donato F, Gelatti U, Limina RM, Fattovich G. Souther Europe as an example of interaction between various enviror mental factors: a systematic review of the epidemiologic evidence. Oncogene 2006; 25:3756-70.Fabrizi F, Messa PG, Lunghi G, et al. Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther 2005; 21:1341-7.Fabrizi F, Messa PG, Lunghi G, et al. Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther 2005; 21:1341-7.Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl J Med 2004; 350:1118-29.Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl J Med 2004; 350:1118-29.Guidotti LG, Chisari FV. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 2001; 19:65-91.Guidotti LG, Chisari FV. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 2001; 19:65-91.Guidotti LG, Rochford R, Chung J, et al. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999; 284:825-9.Guidotti LG, Rochford R, Chung J, et al. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999; 284:825-9.Hass M, Hannoun C, Kalinina T, et al. Functional analysis of hepatitis B virus reactivating in hepatitis B surface antigen-negative individuals. Hepatology (Baltimore, MD) 2005; 42:93-103.Hass M, Hannoun C, Kalinina T, et al. Functional analysis of hepatitis B virus reactivating in hepatitis B surface antigen-negative individuals. Hepatology (Baltimore, MD) 2005; 42:93-103.Hilleman MR. Overview of the pathogenesis, prophylaxis and therapeusis of viral hepatitis B, with focus on reduction to practical applications. Vaccine 2001; 19:1837-48.Hilleman MR. Overview of the pathogenesis, prophylaxis and therapeusis of viral hepatitis B, with focus on reduction to practical applications. Vaccine 2001; 19:1837-48.Hou J, Karayiannis P, Walters J, et al. A unique insertion in the S gene of surface antigen-negative hepatitis B virus Chinese carriers. Hepatology (Baltimore, MD) 1995; 21:273-8.Hou J, Karayiannis P, Walters J, et al. A unique insertion in the S gene of surface antigen-negative hepatitis B virus Chinese carriers. Hepatology (Baltimore, MD) 1995; 21:273-8.Hussain M, Soldevila-Pico C, Emre S, et al.; NIH HBV-OLT Study Group. Presence of intrahepatic (total and ccc) HBV DNA is not predictive of HBV recurrence after liver transplantation. Liver Transpl. 2007 Aug; 13(8):1137-44.Hussain M, Soldevila-Pico C, Emre S, et al.; NIH HBV-OLT Study Group. Presence of intrahepatic (total and ccc) HBV DNA is not predictive of HBV recurrence after liver transplantation. Liver Transpl. 2007 Aug; 13(8):1137-44.Iannitto E, Minardi V, Calvaruso G, et al. Hepatitis B virus reactivation and ale-mtuzumab therapy. Eur J Haematol 2005; 74:254-8.Iannitto E, Minardi V, Calvaruso G, et al. Hepatitis B virus reactivation and ale-mtuzumab therapy. Eur J Haematol 2005; 74:254-8.Jeantet D, Chemin I, Mandrand B, et al. Cloning and expression of surface antigens from occult chronic hepatitis B virus infections and their recognition by commercial detection assays. J Med Virol 2004; 73:508-15.Jeantet D, Chemin I, Mandrand B, et al. Cloning and expression of surface antigens from occult chronic hepatitis B virus infections and their recognition by commercial detection assays. J Med Virol 2004; 73:508-15.Kawatani T, Suou T, Tajima F, et al. Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies. Eur J Haematol 2001; 67:45-50.Kawatani T, Suou T, Tajima F, et al. Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies. Eur J Haematol 2001; 67:45-50.Lok ASF, Liang RHS, Chiu EKW, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterolgy 1991; 100:182-8.Lok ASF, Liang RHS, Chiu EKW, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterolgy 1991; 100:182-8.Marcellin P, Giostra E, Martinot-Peignoux M, et al. Redevelopment of hepatitis B surface antigen after renal transplantation. Gastroenterology 1991; 100:1432-4.Marcellin P, Giostra E, Martinot-Peignoux M, et al. Redevelopment of hepatitis B surface antigen after renal transplantation. Gastroenterology 1991; 100:1432-4.Marion PI. In Ground squirrel hepatitis virus. In: McLachlan A, editor. Molecular biology of hepatitis B virus. Boca Raton, Florida: CRC Press; 1991. p. 39-51.Marion PI. In Ground squirrel hepatitis virus. In: McLachlan A, editor. Molecular biology of hepatitis B virus. Boca Raton, Florida: CRC Press; 1991. p. 39-51.Marusawa H, Uemoto S, Hijikata M, et al. Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology (Baltimore, MD) 2000; 31:488-95.Marusawa H, Uemoto S, Hijikata M, et al. Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology (Baltimore, MD) 2000; 31:488-95.Mc Clary H, Koch R, Chisari FV, Guidotti LG. Inhibition of hepatitis B virus replication during schistosoma mansoni infection in transgenic mice. J Exp Med 2000; 192:289-94.Mc Clary H, Koch R, Chisari FV, Guidotti LG. Inhibition of hepatitis B virus replication during schistosoma mansoni infection in transgenic mice. J Exp Med 2000; 192:289-94.Michalak TI, Mulrooney PM, Coffin CS. Low doses of hepadnavirus induce infection of the lymphatic system that does not engage the liver. J Virol 2004; 78:1730-8.Michalak TI, Mulrooney PM, Coffin CS. Low doses of hepadnavirus induce infection of the lymphatic system that does not engage the liver. J Virol 2004; 78:1730-8.Michalak TI, Pardoe IU, Coffin CS, et al. Occult lifelong persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis. Hepatology (Baltimore, MD) 1999; 29:928-38.Michalak TI, Pardoe IU, Coffin CS, et al. Occult lifelong persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis. Hepatology (Baltimore, MD) 1999; 29:928-38.Minuk GY, Sun DF, Greenberg R, et al. Occult hepatitis B virus infection in a North American adult hemodialysis patient population. Hepatology (Baltimore, MD) 2004; 40:1072-7.Minuk GY, Sun DF, Greenberg R, et al. Occult hepatitis B virus infection in a North American adult hemodialysis patient population. Hepatology (Baltimore, MD) 2004; 40:1072-7.Patrick Yachimski, Raymond T. Chung. Hepatitis B virus infection in liver transplant candidates and recipients // Medscape General Medicine. 2005; 7(2):20.Patrick Yachimski, Raymond T. Chung. Hepatitis B virus infection in liver transplant candidates and recipients // Medscape General Medicine. 2005; 7(2):20.Pollicino T, Belloni L, Raffa G, et al. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology 2006; 130:823-37.Pollicino T, Belloni L, Raffa G, et al. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology 2006; 130:823-37.Raimondo G. Occult hepatitis B virus infection. J Hepatol (46) 2007; 160-70.Raimondo G. Occult hepatitis B virus infection. J Hepatol (46) 2007; 160-70.Regan FA, Hewitt P, Barbara JA, Contreras M. Pro­spective investigation of transfusion transmitted infection in recipients of over 20 000 units of blood. TTI Study Group. BMJ (Clinical research ed) 2000; 320:403-6.Regan FA, Hewitt P, Barbara JA, Contreras M. Pro­spective investigation of transfusion transmitted infection in recipients of over 20 000 units of blood. TTI Study Group. BMJ (Clinical research ed) 2000; 320:403-6.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; 10:1104-8.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; 10:1104-8.Sagnelli E, Coppola N, Scolastico C, et al. Isolated anti-HBc in chronic hepatitis C predicts a poor response to interferon treatment. J Med Virol 2001; 65:681-7.Sagnelli E, Coppola N, Scolastico C, et al. Isolated anti-HBc in chronic hepatitis C predicts a poor response to interferon treatment. J Med Virol 2001; 65:681-7.Samuel D, Forns X, Berenguer M, et al. Report of the monothematic EASL conference on liver transplantation for viral hepatitis (Paris, France, January 12-14, 2006). J Hepatol 2006; 45:127-43.Samuel D, Forns X, Berenguer M, et al. Report of the monothematic EASL conference on liver transplantation for viral hepatitis (Paris, France, January 12-14, 2006). J Hepatol 2006; 45:127-43.Schuttler CG, Fiedler N, Schmidt K, et al. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol 2002; 37:855-62.Schuttler CG, Fiedler N, Schmidt K, et al. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol 2002; 37:855-62.Sera T, Hiasa Y, Michitaka K, et al. Anti-HBs-positive li­ver failure due to hepatitis B virus reactivation induced by rituximab. Internal Med (Tokyo, Japan) 2006; 45:721-4.Sera T, Hiasa Y, Michitaka K, et al. Anti-HBs-positive li­ver failure due to hepatitis B virus reactivation induced by rituximab. Internal Med (Tokyo, Japan) 2006; 45:721-4.Torbenson M, Kannangai R, Astemborski J, et al. High prevalence of occult hepatitis B in Baltimore injection drug users. Hepatology (Baltimore, MD) 2004; 39:51-7.Torbenson M, Kannangai R, Astemborski J, et al. High prevalence of occult hepatitis B in Baltimore injection drug users. Hepatology (Baltimore, MD) 2004; 39:51-7.Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002; 2:479-86.Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002; 2:479-86.Toyoda H, Hayashi K, Murakami Y, et al. Prevalence and clinical implications of occult hepatitis B viral infection in hemophilia patients in Japan. J Med Virol 2004; 73:195-9.Toyoda H, Hayashi K, Murakami Y, et al. Prevalence and clinical implications of occult hepatitis B viral infection in hemophilia patients in Japan. J Med Virol 2004; 73:195-9.Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology (Baltimore, MD) 2006; 44:675-84.Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology (Baltimore, MD) 2006; 44:675-84.Yoshiba M, Sekiyama K, Sugata F, et al. Post-trans­fusion fulminant hepatitis B after screening for hepatitis B virus core antibody. Lancet 1992; 339:253-4.Yoshiba M, Sekiyama K, Sugata F, et al. Post-trans­fusion fulminant hepatitis B after screening for hepatitis B virus core antibody. Lancet 1992; 339:253-4.Yu MC, Yuan JM, Ross RK, Govindarajan S. Presen­ce of antibodies to the hepatitis B surface antigen is associated with an excess risk for hepatocellular carcinoma among non-Asians in Los Angeles County, California. Hepatology (Baltimore, MD) 1997; 25:226-8.Yu MC, Yuan JM, Ross RK, Govindarajan S. Presen­ce of antibodies to the hepatitis B surface antigen is associated with an excess risk for hepatocellular carcinoma among non-Asians in Los Angeles County, California. Hepatology (Baltimore, MD) 1997; 25:226-8.Yuki N, Nagaoka T, Yamashiro M, et al. Long-term histo­logic and virologic outcomes of acute self-limited hepatitis B. Hepatology (Baltimore, MD) 2003; 37:1172-9.Yuki N, Nagaoka T, Yamashiro M, et al. Long-term histo­logic and virologic outcomes of acute self-limited hepatitis B. Hepatology (Baltimore, MD) 2003; 37:1172-9.Zoulim F. New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA. J Hepatol 2005; 42:302-8.Zoulim F. New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA. J Hepatol 2005; 42:302-8.

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