Korean J Gastroenterol.  2013 Sep;62(3):154-159. 10.4166/kjg.2013.62.3.154.

Occult Hepatitis B Virus Infection in Chronic Hepatitis C

• Jang JY
• Park EJ

• KMID: 1707197
• DOI: http://doi.org/10.4166/kjg.2013.62.3.154

Abstract

Occult HBV infection is defined as the presence of HBV DNA in the liver (with or without detectable or undetectable HBV DNA in the serum) of individuals testing negative for HBsAg. Studies on occult HBV infection in hepatitis C patients have reported highly variable prevalence, because the prevalence of occult HBV infection varies depending on the hepatitis B risk factors and methodological approaches. The most reliable diagnostic approach for detecting occult HBV detection is through examination of liver DNA extracts. HCV has been suspected to strongly suppress HBV replication up to the point where it may be directly responsible for occult HBV infection development. However, more data are needed to arrive at a definitive conclusion regarding the role of HCV in inducing occult HBV infection. Occult HBV infection in chronic hepatitis C patients is a complex biological entity with possible relevant clinical implications. Influence of occult HBV infection on the clinical outcomes of chronic hepatitis C may be considered negative. However, recent studies have shown that occult HBV infection could be associated with the development of hepatocellular carcinoma and contribute to the worsening of the course of chronic liver disease over time in chronic hepatitis C patients. Nevertheless, the possible role of occult HBV infection in chronic hepatitis C is still unresolved and no firm conclusion has been made up until now. It still remains unclear how occult HBV infection affects the treatment of chronic hepatitis C. Therefore, in order to resolve current controversies and understand the pathogenic role and clinical impacts of occult HBV infection in chronic hepatitis C patients, well-designed clinical studies are needed.

Keyword

Hepatitis B virus; Occult infection; Hepatitis C, chronic

MeSH Terms

Carcinoma, Hepatocellular/complications
DNA, Viral/analysis
Hepacivirus/genetics
Hepatitis B/*complications/*diagnosis/drug therapy
Hepatitis B virus/genetics
Hepatitis C, Chronic/*complications/*diagnosis/drug therapy
Humans
Interferon-alpha/therapeutic use
Liver/virology
Liver Neoplasms/complications
DNA, Viral
Interferon-alpha

Reference

References

1. Mason A, Yoffe B, Noonan C, et al. Hepatitis B virus DNA in peripheral-blood mononuclear cells in chronic hepatitis B after HBsAg clearance. Hepatology. 1992; 16:36–41.

2. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol. 2007; 46:160–170.

3. Raimondo G, Allain JP, Brunetto MR, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008; 49:652–657.

4. Noborg U, Gusdal A, Horal P, Lindh M. Levels of viraemia in subjects with serological markers of past or chronic hepatitis B virus infection. Scand J Infect Dis. 2000; 32:249–252.

5. Paterlini P, Poussin K, Kew M, Franco D, Brechot C. Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology. 1995; 21:313–321.

6. Cacciola I, Pollicino T, Squadrito G, et al. Quantification of intrahepatic hepatitis B virus (HBV) DNA in patients with chronic HBV infection. Hepatology. 2000; 31:507–512.

7. Bréchot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Bréchot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely "occult"? Hepatology. 2001; 34:194–203.

8. Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis. 2002; 2:479–486.

9. Hu KQ. Occult hepatitis B virus infection and its clinical implications. J Viral Hepat. 2002; 9:243–257.

10. Yotsuyanagi H, Yasuda K, Iino S, et al. Persistent viremia after recovery from self-limited acute hepatitis B. Hepatology. 1998; 27:1377–1382.

11. Bläckberg J, Kidd-Ljunggren K. Occult hepatitis B virus after acute self-limited infection persisting for 30 years without sequence variation. J Hepatol. 2000; 33:992–997.

12. Liaw YF, Sheen IS, Chen TJ, Chu CM, Pao CC. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology. 1991; 13:627–631.

13. Loriot MA, Marcellin P, Walker F, et al. Persistence of hepatitis B virus DNA in serum and liver from patients with chronic hepatitis B after loss of HBsAg. J Hepatol. 1997; 27:251–258.

14. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007; 45:507–539.

15. Levast M, Larrat S, Thelu MA, et al. Prevalence and impact of occult hepatitis B infection in chronic hepatitis C patients treated with pegylated interferon and ribavirin. J Med Virol. 2010; 82:747–754.

16. González S, Navas S, Madejón A, et al. Hepatitis B and D genomes in hepatitis B surface antigen negative patients with chronic hepatitis C. J Med Virol. 1995; 45:168–173.

17. Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med. 1999; 341:22–26.

18. Fukuda R, Ishimura N, Niigaki M, et al. Serologically silent hepatitis B virus coinfection in patients with hepatitis C virus-associated chronic liver disease: clinical and virological significance. J Med Virol. 1999; 58:201–207.

19. Uchida T, Kaneita Y, Gotoh K, et al. Hepatitis C virus is frequently coinfected with serum marker-negative hepatitis B virus: probable replication promotion of the former by the latter as demonstrated by in vitro cotransfection. J Med Virol. 1997; 52:399–405.

20. Zignego AL, Fontana R, Puliti S, et al. Impaired response to alpha interferon in patients with an inapparent hepatitis B and hepatitis C virus coinfection. Arch Virol. 1997; 142:535–544.

21. Kazemi-Shirazi L, Petermann D, Müller C. Hepatitis B virus DNA in sera and liver tissue of HBsAg negative patients with chronic hepatitis C. J Hepatol. 2000; 33:785–790.

22. Jang JY, Jeong SW, Cheon SR, et al. Clinical significance of occult hepatitis B virus infection in chronic hepatitis C patients. Korean J Hepatol. 2011; 17:206–212.

23. Sagnelli E, Imparato M, Coppola N, et al. Diagnosis and clinical impact of occult hepatitis B infection in patients with biopsy proven chronic hepatitis C: a multicenter study. J Med Virol. 2008; 80:1547–1553.

24. Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol. 2008; 23:512–520.

25. 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.

26. Schüttler CG, Fiedler N, Schmidt K, Repp R, Gerlich WH, Schaefer S. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol. 2002; 37:855–862.

27. Bellecave P, Gouttenoire J, Gajer M, et al. Hepatitis B and C virus coinfection: a novel model system reveals the absence of direct viral interference. Hepatology. 2009; 50:46–55.

28. Eyre NS, Phillips RJ, Bowden S, et al. Hepatitis B virus and hepatitis C virus interaction in Huh-7 cells. J Hepatol. 2009; 51:446–457.

29. Jardi R, Rodriguez F, Buti M, et al. Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology. 2001; 34:404–410.

30. Sheen IS, Liaw YF, Chu CM, Pao CC. Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection. J Infect Dis. 1992; 165:831–834.

31. Pontisso P, Gerotto M, Ruvoletto MG, et al. Hepatitis C genotypes in patients with dual hepatitis B and C virus infection. J Med Virol. 1996; 48:157–160.

32. Zarski JP, Bohn B, Bastie A, et al. Characteristics of patients with dual infection by hepatitis B and C viruses. J Hepatol. 1998; 28:27–33.

33. Crockett SD, Keeffe EB. Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection. Ann Clin Microbiol Antimicrob. 2005; 4:13.

34. Fernandez-Rodriguez CM, Gutierrez ML, Lledó JL, Casas ML. Influence of occult hepatitis B virus infection in chronic hepatitis C outcomes. World J Gastroenterol. 2011; 17:1558–1562.

35. Mimms LT, Mosley JW, Hollinger FB, et al. Effect of concurrent acute infection with hepatitis C virus on acute hepatitis B virus infection. BMJ. 1993; 307:1095–1097.

36. Liaw YF. Hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. J Gastroenterol. 2002; 37(Suppl 13):65–68.

37. Conjeevaram HS, Lok AS. Occult hepatitis B virus infection: a hidden menace? Hepatology. 2001; 34:204–206.

38. 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.

39. Kang SY, Kim MH, Lee WI. The prevalence of "anti-HBc alone" and HBV DNA detection among anti-HBc alone in Korea. J Med Virol. 2010; 82:1508–1514.

40. Rodríguez-Iñigo E, Bartolomé J, Ortiz-Movilla N, et al. Hepatitis C virus (HCV) and hepatitis B virus (HBV) can coinfect the same hepatocyte in the liver of patients with chronic HCV and occult HBV infection. J Virol. 2005; 79:15578–15581.

41. Samal J, Kandpal M, Vivekanandan P. Molecular mechanisms underlying occult hepatitis B virus infection. Clin Microbiol Rev. 2012; 25:142–163.

42. Dumoulin FL, von dem Bussche A, Li J, et al. Hepatitis C virus NS2 protein inhibits gene expression from different cellular and viral promoters in hepatic and nonhepatic cell lines. Virology. 2003; 305:260–266.

43. Said ZN, ElSayed MH, El-Bishbishi IA, et al. High prevalence of occult hepatitis B in hepatitis C-infected Egyptian children with haematological disorders and malignancies. Liver Int. 2009; 29:518–524.

44. Nirei K, Kaneko M, Moriyama M, Arakawa Y. The clinical features of chronic hepatitis C are not affected by the coexistence of hepatitis B virus DNA in patients negative for hepatitis B surface antigen. Intervirology. 2000; 43:95–101.

45. Matsuoka S, Nirei K, Tamura A, et al. Influence of occult hepatitis B virus coinfection on the incidence of fibrosis and hepatocellular carcinoma in chronic hepatitis C. Intervirology. 2008; 51:352–361.

46. Kannangai R, Vivekanandan P, Netski D, et al. Liver enzyme flares and occult hepatitis B in persons with chronic hepatitis C infection. J Clin Virol. 2007; 39:101–105.

47. Chemin I, Guillaud O, Queyron PC, Trépo 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; 51:824–825.

48. Selim HS, Abou-Donia HA, Taha HA, El Azab GI, Bakry AF. Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes. Eur J Intern Med. 2011; 22:187–190.

49. Mrani S, Chemin I, Menouar K, 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; 79:1075–1081.

50. Sagnelli E, Coppola N, Scolastico C, Mogavero AR, Filippini P, Piccinino F. HCV genotype and "silent" HBV coinfection: two main risk factors for a more severe liver disease. J Med Virol. 2001; 64:350–355.

51. Hui CK, Lau E, Wu H, et al. Fibrosis progression in chronic hepatitis C patients with occult hepatitis B coinfection. J Clin Virol. 2006; 35:185–192.

52. Pollicino T, Squadrito G, Cerenzia G, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology. 2004; 126:102–110.

53. Adachi S, Shibuya A, Miura Y, Takeuchi A, Nakazawa T, Saigenji K. Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus. Scand J Gastroenterol. 2008; 43:849–856.

54. Miura Y, Shibuya A, Adachi S, et al. Occult hepatitis B virus infection as a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C in whom viral eradication fails. Hepatol Res. 2008; 38:546–556.

55. Shi Y, Wu YH, Wu W, Zhang WJ, Yang J, Chen Z. Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a metaanalysis. Liver Int. 2012; 32:231–240.

56. Wong DK, Huang FY, Lai CL, et al. Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma. Hepatology. 2011; 54:829–836.

57. Squadrito G, Pollicino T, Cacciola I, et al. Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients. Cancer. 2006; 106:1326–1330.

58. Ikeda K, Marusawa H, Osaki Y, et al. Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: a prospective study. Ann Intern Med. 2007; 146:649–656.

59. Tamori A, Hayashi T, Shinzaki M, et al. Frequent detection of hepatitis B virus DNA in hepatocellular carcinoma of patients with sustained virologic response for hepatitis C virus. J Med Virol. 2009; 81:1009–1014.

60. Toyoda H, Kumada T, Kiriyama S, et al. Prevalence of low-level hepatitis B viremia in patients with HBV surface antigen-ne-gative hepatocellular carcinoma with and without hepatitis C virus infection in Japan: analysis by COBAS TaqMan real-time PCR. Intervirology. 2007; 50:241–244.

61. Fukuda R, Ishimura N, Hamamoto S, et al. Coinfection by serologically-silent hepatitis B virus may contribute to poor interferon response in patients with chronic hepatitis C by downregulation of type-I interferon receptor gene expression in the liver. J Med Virol. 2001; 63:220–227.