OKÜLT HEPATİT B VİRUS ENFEKSİYONU: MOLEKÜLER MEKANİZMALAR VE KLİNİK ÖNEMİ

Year 2017, Volume: 80 Issue: 2, 71 - 81, 30.06.2017

Bülent Çakal

https://doi.org/10.18017/iuitfd.330044

Abstract

Okült Hepatitis B Virüs (HBV) infeksiyonu
(OBİ) serum HBV DNA statüsü dikkate alınmaksızın mevcut serolojik testler ile
HBV yüzey antijeni (HBsAg) negatif tespit edilen bireylerin karaciğerin de HBV
genomunun uzun süreli persistan varlığı olarak tanımlanır. OBİ virüse ve infekte
bireye ait faktörler ile çevresel faktörlerin zemininde gelişen genetik,
epigenetik ve immünolojik mekanizmaların karşılıklı etkileşimi ile şekillenen,
HBV infeksiyonunun doğal seyri içerisinde yer alan muhtemel safhalarından biri
olarak kabul edilir. OBİ klinik açıdan; okült virüsün kan transfüzyonu, doğum,
hemodiyaliz ve ortotopik karaciğer gibi organ nakli yolu ile bulaşını takiben
alıcıda tipik yeni HBV infeksiyonuna neden olabilmesi, immünsüpresyon
koşullarında OBİ reaktivasyonu ve takiben HBV ilişkili (akut ve fulminan
hepatit) karaciğer hastalıkları, kronik karaciğer hastalıklarının (KKH)
progresyonu üzerine etkisi ile özellikle hepatoselüler karsinoma (HSK) için artan bir risk faktörü olduğu yönünde hipotez
uyarınca yoğun bir tartışma ve araştırma konusudur. Buna karşın gerek HBV infeksiyonunun
bu özgün formuna neden olan gerekse ilişkili olduğu karaciğer hastalıklarının
patogenezinde rol alan moleküler mekanizmalar henüz tam olarak
aydınlatılamamıştır. Bu derlemede OBİ’nin klinik önemi, epidemiyolojik
özellikleri ve laboratuar tanısına yönelik bilimsel literatürün gözden
geçirilmesi amaçlanmıştır.

Anahtar
Kelimeler: Hepatit B virüs; okült hepatit B virüs infeksiyonu; bulaş;
reaktivasyon; kronik karaciğer hastalığı; hepatoselüler karsinoma.

Keywords

Hepatit B virüs, okült hepatit B virüs infeksiyonu, bulaş, reaktivasyon, kronik karaciğer hastalığı, hepatoselüler karsinoma

OCCULT HEPATITIS B VIRUS INFECTION: MOLECULAR MECHANISMS AND CLINICAL SIGNIFICANCE

Abstract

Occult Hepatitis B Virus (HBV) infection
(OBI) is defined as the long-lasting persistence of HBV genomes in the
hepatocytes of individuals testing negative for HBV surface antigen (HBsAg) by
currently available assays and usually for serum HBV DNA. OBI is considered as
the possible phase in the natural history of chronic HBV infection that the
host’s immune surveillance and epigenetic mechanisms are likely involved.
Clinical impact of OB is that it can be transmitted (i.e., through blood
transfusion, by liver organ
transplantation, hemodialysis and parturition) causing classic forms of
hepatitis B in newly infected individuals. The development of an
immunosuppressive status may induce OBI reactivation and development of acute
and often severe hepatitis. OBI can favor the progression of liver fibrosis.
Also OBİ infection has been hypothesized to be a significant risk factor
contributing to the progression of chronic liver diseases (CLD) with increased
risk for hepatocellular carcinoma (HCC) which may lead to an increased
progression of liver diseases. Although OBI is considered a phase in the natural
history of HBV, the molecular mechanisms leading to its occurrence and its contribution
to HCC development are yet poorly understood. In this review, it is aimed to examine
clinical importance, epidemiological aspects and laboratory diagnosis of OBI in
recent literature.

Keywords: Hepatitis B virüs;
occult hepatitis B virus infection; transmission; reactivation; chronic liver
disease; hepatocellular carcinoma.

Keywords

Hepatitis B virüs, occult hepatitis B virus infection, transmission, reactivation, chronic liver disease, hepatocellular carcinoma

References

• 1. World Health Organization. http://www.who.int/mediacentre/factsheets/fs204/en/ erişim 12 Ocak 2015.
• 2. World Health Organization. http://www.who.int/mediacentre/factsheets/fs297/en/ erişim 12 Ocak 2015.
• 3. Shi J, Zhu L, Liu S, Xie WF. A Metaanalysis of case-control studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma in China. Br J Cancer 2005;92:607–12.
• 4. Chang MH. Cancer prevention by vaccination against hepatitis B. Recent Results. Cancer Res 2009; 181: 85-94.
• 5. Kew MC. Epidemiology of hepatocellular carcinoma. Toxicology 2002; 181–182: 35–8.
• 6. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet 2003; 62: 2089–94.
• 7. Ganem D, Prince AM. Hepatitis B virus infection natural history and clinical consequences. N Engl J Med 2004;350: 1118–29.
• 8. Fattovich G, Giustina G, Sanchez-Tapias J, Quero C, Mas A, et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol 1998; 93: 896–900.
• 9. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008; 49: 652-7.
• 10. Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis. 2002; 2: 479-86.
• 11. Pollicino T, Saitta C. Occult hepatitis B virus and hepatocellular carcinoma. World J Gastroenterol 2014; 20(20): 5951-61.
• 12. Samal J, Kandpal M, Vivekanandan P. Molecular mechanisms underlying occult hepatitis B virus infection. Clin Microbiol Rev 2012;25:142-63.
• 13. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol 2007; 46:160–70.
• 14. Fang Y, Shang QL, Liu JY, Li D, Xu WZ, Teng X, et al. Prevalence of occult hepatitis B virus infection among hepatopathy patients and healthy people in China. J Infect 2009; 58: 383–8.
• 15. Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Br_echot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”? Hepatology 2001;34: 94–203.
• 16. Ohba K, Kubo S, Tamori A, Hirohashi K, Tanaka H, Shuto T, et al. Previous or occult hepatitis B virus infection in hepatitis B surface antigen negative and anti-hepatitis C negative patients with hepatocellular carcinoma. Surg Today 2004; 34: 842–8.
• 17. Pollicino T, Saitta C, Raimondo G. Hepatocellular carcinoma: the point of view of the hepatitis B virus. Carcinogenesis 2011; 32: 1122-32.
• 18. Raimondo G, Caccamo G, Filomia R, Pollicino T. Occult HBV infection. Semin Immunopathol 2013; 35: 9-52.
• 19. Larrubia JR. Occult hepatitis B virus infection: a complex entity with relevant clinical implications. World J Gastroenterol 2011; 17: 1529-30.
• 20. Mrani S, Chemin I, Menouar K, Guillaud O, Pradat P, Borghi G, et al. Occult HBV infection may represent a major risk factor of non-response to antiviral therapy of chronic hepatitis C. J Med Virol 2007; 79: 1075–81.
• 21. De Mitri MS, Cassini R, Bernardi M. Hepatitis B virus-related hepatocarcinogenesis: molecular oncogenic potential of clear or occult infections. Eur J Cancer 2010; 46: 2178–86.
• 22. Chemin I, Trepo C. Clinical impact of occult HBV infections. J Clin Virol 2005; 34: 15–21.
• 23. De la Fuente RA, Gutiérrez ML, Garcia-Samaniego J, Fernández-Rodriguez C, Lledó JL, Castellano G. Pathogenesis of occult chronic hepatitis B virus infection. World J Gastroenterol 2011; 17: 1543-8.
• 24. Hassan ZK, Hafez MM, Mansor TM, Zekri AR. Occult HBV infection among Egyptian hepatocellular carcinoma patients. Virol. J 2011; 8: 90-5.
• 25. Lalazar G, Rund D, Shouval D. Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies. Br J Haematol 2007; 136: 699-712.
• 26. Hollinger FB. Hepatitis B virus infection and transfusion medicine: science and the occult. Transfusion 2008; 48: 1001-26.
• 27. Cheung CK, Lo CM, Man K, Lau GK. Occult hepatitis B virus infection of donor and recipient origin after liver transplantation despite nucleoside analogue prophylaxis. Liver Transpl 2010; 16: 1314-23.
• 28. Allain JP, Cox L. Challenges in hepatitis B detection among blood donors. Curr Opin Hematol 2011; 18: 461-6.
• 29. Teresa Pollicino, Giovanni Raimondo. Occult Hepatitis B Infection. Journal of Hepatology 2014. 61:688–9.
• 30. Mason AL, Xu L, Guo L, Kuhns M, Perrillo RP. Molecular basis for persistent hepatitis B virus infection in the liver after clearance of serum hepatitis B surface antigen. Hepatology 1998; 27: 1736-42.
• 31. Zoulim F. New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA. J Hepatol 2005; 42: 302–8.
• 32. R. A. A. Pondé Molecular mechanisms underlying HBsAg negativity in occult HBV infection. Eur J Clin Microbiol Infect Dis. 2015; 34: 1709–31.
• 33. Conjeevaram HS, Lok AS. Occult hepatitis B virus infection: a hidden menace? Hepatology 2001; 34: 204-6.
• 34. Minuk GY, Sun DF, Uhanova J, Zhang M, Caouette S, Nicolle LE, et al. Occult hepatitis B virus infection in a North American community-based population. J Hepatol 2005; 42: 480–5.
• 35. Kim SM, Lee KS, Park CJ, Lee JY, Kim KH, Park JY, et al. Prevalence of occult HBV infection among subjects with normal serum ALT levels in Korea. J Infect 2007; 54: 185–91.
• 36. Hui CK, Sun J, Au WY, Lie AK, Yueng YH, Zhang HY, et al. Occult hepatitis B virus infection in hematopoietic stem cell donors in a hepatitis B virus endemic area. J Hepatol 2005; 42: 813–9.
• 37. Zhang Z, Zhang L, Dai Y, Jin L, Sun B, Su Q, Li X . Occult hepatitis B virus infection among people with a family history of chronic hepatitis B virus infection J Med Virol 2015; 87(11): 1890-8.
• 38. Raimondo G, Navarra G, Mondello S, Costantino L, Colloredo G, Cucinotta E, et al. Occult hepatitis B virus in liver tissue of individuals without hepatic disease. J Hepatol 2008;48: 743–6.
• 39. Stramer SL, Wend U, Candotti D, Foster GA, Hollinger FB, Dodd RY, et al. Nucleic acid testing to detect HBV infection in blood donors. N Engl J Med 2011; 364: 236–47.
• 40. Oluyinka OO, Tong HV, Bui Tien S, Fagbami AH, Adekanle O, Ojurongbe O, et al. Occult Hepatitis B Virus Infection in Nigerian Blood Donors and Hepatitis B Virus Transmission Risks. PLOS ONE 2015; 6;10(7):e0131912.
• 41. Candotti D, Lin CK, Belkhiri D, Sakuldamrongpanich T, Biswas S, Lin S, et al. Occult hepatitis B infection in blood donors from South East Asia: molecular characterisation and potential mechanisms of occurrence. Gut 2012; 61(12): 1744-53.
• 42. Song EY, Yun YM, Park MH, Seo DH. Prevalence of occult hepatitis B virus infection in a general adult population in Korea. Intervirology 2009; 52: 57–62.
• 43. Yuen MF, Lee CK, Wong DK, Fung J, Hung I, Hsu A et al. Prevalence of occult hepatitis B infection in a highly endemic area for chronic hepatitis B: a study of a large blood donor population. Gut 2010; 59(10): 1389-93.
• 44. Nna E, Mbamalu C, Ekejindu I (2014) Occult hepatitis B viral infection among blood donors in South- Eastern Nigeria. Pathog Glob Health 2014; 108: 223–8
• 45. Jutavijittum P, Andernach IE, Yousukh A, Samountry B, Samountry K, Thammavong T, et al. Occult hepatitis B infections among blood donors in Lao PDR. Vox Sang 2014; 106: 31–37.
• 46. O’Brien SF, Fearon MA, Yi QL, Fan W, Scalia V, Muntz IR, Vamvakas EC. Hepatitis B virus DNA-positive, hepatitis B surface antigen-negative blood donations intercepted by anti-hepatitis B core antigen testing: the Canadian Blood Services experience. Transfusion 2007; 47: 1809-15.
• 47. Hofer M, Joller-Jemelka HI, Grob PJ, Lüthy R, Opravil M. Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Swiss HIV Cohort Study. Eur J Clin Microbiol Infect Dis 1998; 17: 6-13.
• 48. Núñez M, Ríos P, Pérez-Olmeda M, Soriano V. Lack of ‘occult’ hepatitis B virus infection in HIV-infected patients. AIDS 2002; 16: 2099-101.
• 49. Torbenson M, Kannangai R, Astemborski J, Strathdee SA, Vlahov D, Thomas DL. High prevalence of occult hepatitis B in Baltimore injection drug users. Hepatology 2004; 39: 51–7.
• 50. Toyoda H, Hayashi K, Murakami Y, Honda T, Katano Y, Nakano I, et al. Prevalence and clinical implications of occult hepatitis B viral infection in hemophilia patients in Japan. J Med Virol 2004; 73: 195–9.
• 51. Wong DK, Huang FY, Lai CL, Poon RT, Seto WK, Fung J, et al. Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma. Hepatology 2011; 54: 829–36.
• 52. Raffa G, Maimone S, Cargnel A, Santantonio T, Antonucci G, Massari M, et al. Analysis of occult hepatitis B virus infection in liver tissue of HIV patients with chronic hepatitis C. AIDS 2007; 21: 2171–5.
• 53. Fabrizi F, Messa PG, Lunghi G, Aucella F, Bisegna S, Mangano S, et al. Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther 2005; 21: 1341–47.
• 54. Minuk GY, Sun DF, Greenberg R, Zhang M, Hawkins K, Uhanova J, et al. Occult hepatitis B virus infection in a North American adult hemodialysis patient population. Hepatology 2004; 40: 1072-77.
• 55. Chan HL, Tsang SW, Leung NW, Tse CH, Hui Y, Tam JS, et al. Occult HBV infection in cryptogenic liver cirrhosis in an area with high prevalence of HBV infection. Am J Gastroenterol 2002; 97: 1211-15.
• 56. Shetty K, HussainM, Nei L, Reddy KR, Lok AS. Prevalence and significance of occult hepatitis B in a liver transplant population with chronic hepatitis C. Liver Transpl 2008; 14: 534–40.
• 57. Allain JP, Candotti D. Diagnostic algorithm for HBV safe transfusion. Blood Transfus 2009; 7: 174–82.
• 58. Chemin I, Guillaud O, Queyron PC, Trepo C. Close monitoring of serum HBV DNA levels and liver enzymes levels is most useful in the management of patients with occult HBV infection. J Hepatol 2009; 51: 824–5.
• 59. Allain JP and Laura Cox Challenges in hepatitis B detection among blood donors Curr Opin Hematol 2011; 18: 461–6.
• 60. Komiya Y, Katayama K, Yugi H, Mizui M, Matsukura H, Tomoguri T, et al. Minimum infectious dose of hepatitis B virus in chimpanzees and difference in the dynamics of viremia between genotype A and genotype C. Transfusion 2008; 48: 286–94.
• 61. Allain JP, Belkhiri D, Vermeulen M, Crookes R, Cable R, Amiri A, et al. R) Characterization of occult hepatitis B virus strains in South African blood donors. Hepatology 2009; 49: 1868–76.
• 62. Prati D, Gerosa A, Porretti L. Occult HBV infection and blood transfusion. Journal of Hepatology 2006; 44: 818.
• 63. Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: a systematic review. J Hepatol 2010; 52: 272–9.
• 64. Coffin CS, Mulrooney-Cousins PM, van MG, Roberts JP, Michalak TI, Terrault NA. Hepatitis B virus quasispecies in hepatic and extrahepatic viral reservoirs in liver transplant recipients on prophylactic therapy. Liver Transpl 2011; 17: 955–62.
• 65. Toniutto P, Minisini R, Fabris C, De FT, Marangoni F, Burlone M, et al. Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression. Clin Transplant 2011; 23: 184–90.
• 66. Sagnelli E, Pisaturo M, Martini S, Filippini P, Sagnelli C, Coppola N. Clinical impact of occult hepatitis B virus infection in immunosuppressed patients. World J Hepatol 2014; 6: 384-93.
• 67. Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009; 27: 605–11.
• 68. Pei SN, Chen CH, Lee CM, Wang MC, Ma MC, Hu TH, et al. Reactivation of hepatitis B virus following rituximabbased regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol 2010; 89: 255–62.
• 69. Ritchie D, Piekarz RL, Blombery P, Karai LJ, Pittaluga S, Jaffe ES, et al. Reactivation of DNA viruses in association with histone deacetylase inhibitor therapy: a case series report. Haematologica 2009; 94: 1618–22.
• 70. Onozawa M, Hashino S, Izumiyama K, Kahata K, Chuma M, Mori A, et al. Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection. Transplantation 2005; 79: 616–9.
• 71. Vigano M, Vener C, Lampertico P, Annaloro C, Pichoud C, Zoulim F, et al. Risk of hepatitis B surface antigen seroreversion after allogeneic hematopoietic SCT. Bone Marrow Transplant 2011; 46: 125–31.
• 72. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2012; 57: 167–185.
• 73. Covolo L, Pollicino T, Raimondo G, Donato F. Occult hepatiti B virus and risk for chronic liver disease: A meta-analysis. Dig Liv Dis 2013; 45: 238–44.
• 74. Shi Y, Wu YH, Wu W, Zhang WJ, Yang J, Chen Z. Association between occult hepatitis B virus infection and the risk of hepatocellular carcinoma: a meta-analysis. Liver Int 2012; 32: 231–40.
• 75. Squadrito G, Spinella R, Raimondo G. The clinical significance of occult HBV infection Annals of Gastroenterology 2014; 27: 15-9.
• 76. Murakami Y, Saigo K, Takashima H, Minami M, Okanoue T, Bréchot C, Paterlini-Bréchot P. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 2005; 54: 1162–8.
• 77. Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Craxi A, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004; 126: 102-10.
• 78. Wong DK, Yuen MF, Poon RT, Yuen JC, Fung J, Lai CL. Quantification of hepatitis B virus covalently closed circular DNA in patients with hepatocellular carcinoma. J Hepatol 2006; 45: 553-9.
• 79. Sheu JC, Huang GT, Shih LN, Lee WC, Chou HC, Wang JT, et al. Hepatitis C and B viruses in hepatitis B surface antigen-negative hepatocellular carcinoma. Gastroenterology 1992; 103: 1322-1327.
• 80. Paterlini P, Driss F, Nalpas B, Pisi E, Franco D, Berthelot P, et al. Persistence of hepatitis B and hepatitis C viral genomes in primary liver cancers from HBsAg-negative patients: a study of a low-endemic area. Hepatology 1993; 17: 20-9.
• 81. 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 1997; 25:226-8.
• 82. Bläckberg J, Kidd-Ljunggren K. Occult hepatitis B virus after acute self-limited infection persisting for 30 years without sequence variation. J Hepatol 2000; 33: 992-7.
• 83. Yuki N, Nagaoka T, Yamashiro M, Mochizuki K, Kaneko A, Yamamoto K, et al. Long-term histologic and virologic outcomes of acute self-limited hepatitis B. Hepatology 2003; 37: 1172-9.
• 84. Mulrooney-Cousins PM, Michalak TI. Persistent occult hepatitis B virus infection: experimental findings and clinical implications. World J Gastroenterol 2007; 13: 5682-6.
• 85. Wong D. K.-H., Fung J., Lee C.-K., Seto W.-K., Leung J.,. Yuen M.-F et.al. Intrahepatic hepatitis B virus replication and liver histology in subjects with occult hepatitis B infection. Clin Microbiol Infect 2016; 22: 290.
• 86. Kannangai R, Vivekanandan P, Netski D, Mehta S, Kirk GD, Thomas DL, et al. Liver enzyme flares and occult hepatitis B in persons with chronic hepatitis C infection. J Clin Virol 2007; 39: 101–5.
• 87. Raimondo G, Pollicino T, Squadrito G. What is the clinical impact of occult hepatitis B virus infection? Lancet 2005; 365: 638-40.
• 88. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 2004; 127: 56–61.
• 89. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56.
• 90. Kao JH, Chen PJ, Lai MY, Chen DS. Occult hepatitis B virüs infection and clinical outcomes of patients with chronic hepatitis C. J. Clin. Microbiol 2002, 40: 4068–71.
• 91. Koike K, Shimotouno K, Okada S, Okamoto H, Hayashi N, Ueda K, et al. Survey of hepatitis B virus coinfection in hepatitis C virus-infected patients suffering from chronic hepatitis and hepatocellular carcinoma in Japan. Jpn J Cancer Res 1999; 90: 1270-2.
• 92. Yotsuyanagi H, Hashidume K, Suzuki M, Maeyama S, Takayama T, Uchikoshi T. Role of hepatitis B virus in hepatocarcinogenesis in alcoholics. Alcohol Clin Exp Res 2004; 28: 181-5.
• 93. Chung HT, Lai CL, Wu PC, Lok AS. Synergism of chronicalcoholism and hepatitis B infection in liver disease. J Gastroenterol Hepatol 1989; 4: 11-6.
• 94. Lok AS, Everhart JE, Di Bisceglie AM, Kim HY, Hussain M,Morgan TR. Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C. Hepatology 2011; 54: 434-42.
• 95. 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.
• 96. Fwu CW, Chien YC, Kirk GD, Nelson KE, You SL, Kuo HS, Feinleib M, Chen CJ. Hepatitis B virus infection and hepatocellular carcinoma among parous Taiwanese women: nationwide cohort study. J Natl Cancer Inst 2009; 101: 1019-27.
• 97. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004; 126: 1750-8.
• 98. Korba BE, Wells FV, Baldwin B, Cote PJ, Tennant BC, Popper H, et al. Hepatocellular carcinoma in woodchuck hepatitis virusinfected woodchucks: presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infections. Hepatology 1989; 9: 461–70
• 99. Marion,P.I. In: McLachlan,A. (ed) Molecular Biology of Hepatitis B Virus. CRC Press, Boca Raton, FL, 1991; 39–51.
• 100. Michalak TI, Pardoe IU, Coffin CS, Churchill ND, Freake DS, Smith P, et al. Occult lifelong persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis. Hepatology 1999; 29: 928-38.
• 101. Transy C, Fourel G, Robinson WS, Tiollais P, Marion PL, Buendia MA. Frequent amplification of c-myc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus. Proc Natl Acad Sci U S A 1992; 89: 3874-8.
• 102. Tanaka M, Tanaka H, Tsukuma H, Ioka A, Oshima A, Nakahara T. Risk factors for intrahepatic cholangiocarcinoma: a possible role of hepatitis B virus. J Viral Hepat 2010; 17: 742–8.
• 103. Perumal V, Wang J, Thuluvath P, Choti M, Torbenson M. Hepatitis C and hepatitis B nucleic acids are present in intrahepatic cholangiocarcinomas from the United States. Hum Pathol 2006; 37: 1211–6.
• 104. Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens. N Engl J Med 1981; 305: 1067–73.
• 105. Gozuacik D, Murakami Y, Saigo K, Chami M, Mugnier C, Lagorce D, et al. Identification of human cancer-related genes by naturally occurring Hepatitis B Virus DNA tagging. Oncogene 2001; 20: 6233-40.
• 106. Makvandi M. Update on occult hepatitis B virus infection. World J Gastroenterol 2016; 22(39): 8720-87.