Occult HBV infection (OBI) is defined as HBV DNA detection in serum or in the liver by sensitive diagnostic tests in HBsAg-negative patients with or without serologic markers of previous viral exposure. OBI seems to be higher among subjects at high risk for HBV infection and with liver disease. OBI can be both a source of virus contamination in blood and organ donations and the reservoir for full blown hepatitis after reactivation. HBV reactivation depends on viral and host factors but these associations have not been analyzed thoroughly. In OBI, it would be best to prevent HBV reactivation which inhibits the development of hepatitis and subsequent mortality. In diverse cases with insufficient data to recommend routine prophylaxis, early identification of virologic reactivation is essential to start antiviral therapy. For retrieving articles regarding OBI, various databases, including OVID, PubMed, Scopus, and ScienceDirect, were used. 1. Introduction Hepatitis B virus (HBV) infection is a major global health problem with about 350–400 million chronically infected individuals [1]. HBV infection can induce a wide spectrum of clinical features, ranging from an inactive carrier state to fulminate hepatitis, cirrhosis, or hepatocellular carcinoma [2]. According to European Association for the Study of the Liver (EASL), about one-third of the world’s populations have serological evidence of past or present HBV infection [3]. Many of these individuals may unknowingly carry the virus for several years after recovery from acute hepatitis B without showing any clinical or biochemical evidence of liver disease, and serological markers can identify different clinical states of viral persistence [4, 5]. HBV infection is usually diagnosed when circulating hepatitis B surface antigen (HBsAg) is detected. Chronic infection is characterized by persistence of this antigen and presence of HBV DNA in serum and resolved HBV infection when patients show seropositivity for –HBc and HBs antibodies. Occult hepatitis B infection (OBI) is defined as the existence of low-level HBV DNA in the serum (<200？IU/mL), cells of the lymphatic (immune) system, and/or hepatic tissue in patients with serological markers of previous infection (anti-HBc and/or anti-HBs positive) and the absence of serum HBsAg. More than 20 percent of patients had no serologic markers because the antibody titer may become undetectable over time, leaving HBV DNA as the only marker of the infection. Thus depending on the HBV antibodies (anti-HBc and/or anti-HBs), OBI may be seropositive or seronegative [2, 3]. 2.
References
[1]
D. Lavanchy, “Hepatitis B virus epidemiology, disease burden, treatment, arid current and emerging prevention and control measures,” Journal of Viral Hepatitis, vol. 11, no. 2, pp. 97–107, 2004.
[2]
M. Torbenson and D. L. Thomas, “Occult hepatitis B,” Lancet Infectious Diseases, vol. 2, no. 8, pp. 479–486, 2002.
[3]
G. Raimondo, J. P. Allain, M. R. Brunetto et al., “Statements from the Taormina expert meeting on occult hepatitis B virus infection,” Journal of Hepatology, vol. 49, no. 4, pp. 652–657, 2008.
[4]
H. Yotsuyanagi, K. Yasuda, S. Iino et al., “Persistent viremia after recovery from self-limited acute hepatitis B,” Hepatology, vol. 27, no. 5, pp. 1377–1382, 1998.
[5]
S. Urbani, F. Fagnoni, G. Missale, and M. Franchini, “The role of anti-core antibody response in the detection of occult hepatitis B virus infection,” Clinical Chemistry and Laboratory Medicine, vol. 48, no. 1, pp. 23–29, 2010.
[6]
W. H. Gerlich, D. Glebe, and C. G. Schüttler, “Deficiencies in the standardization and sensitivity of diagnostic tests for hepatitis B virus,” Journal of Viral Hepatitis, vol. 14, no. 1, pp. 16–21, 2007.
[7]
L. Comanor and P. Holland, “Hepatitis B virus blood screening: unfinished agendas,” Vox Sanguinis, vol. 91, no. 1, pp. 1–12, 2006.
[8]
C. Bréchot, V. Thiers, D. Kremsdorf, B. Nalpas, S. Pol, and P. Paterlini-Bréchot, “Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”?” Hepatology, vol. 34, no. 1, pp. 194–203, 2001.
[9]
P. M. Mulrooney-Cousins and T. I. Michalak, “Persistent occult hepatitis B virus infection: experimental findings and clinical implications,” World Journal of Gastroenterology, vol. 13, no. 43, pp. 5682–5686, 2007.
[10]
T. I. Huo, J. C. Wu, P. C. Lee et al., “Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis,” Hepatology, vol. 28, no. 1, pp. 231–236, 1998.
[11]
G. Raimondo, T. Pollicino, I. Cacciola, and G. Squadrito, “Occult hepatitis B virus infection,” Journal of Hepatology, vol. 46, no. 1, pp. 160–170, 2007.
[12]
D. Jeantet, I. Chemin, B. Mandrand et al., “Cloning and expression of surface antigens from occult chronic hepatitis B virus infections and their recognition by commercial detection assays,” Journal of Medical Virology, vol. 73, no. 4, pp. 508–515, 2004.
[13]
S. H. Ahn, Y. N. Park, J. Y. Park et al., “Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance,” Journal of Hepatology, vol. 42, no. 2, pp. 188–194, 2005.
[14]
R. A. De la Fuente, M. L. Gutiérrez, J. Garcia-Samaniego, C. Fernández-Rodriguez, J. L. Lledó, and G. Castellano, “Pathogenesis of occult chronic hepatitis B virus infection,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1543–1548, 2011.
[15]
M. Bes, V. Vargas, M. Piron, et al., “T cell responses and viral variability in blood donation candidates with occult hepatitis B infection,” Journal of Hepatology, vol. 56, pp. 765–774, 2012.
[16]
S. Ocana, M. L. Casas, I. Buhigas, and J. L. Lledo, “Diagnostic strategy for occult hepatitis B virus infection,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1553–1557, 2011.
[17]
F. Zoulim, “New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA,” Journal of Hepatology, vol. 42, no. 3, pp. 302–308, 2005.
[18]
M. Levrero, T. Pollicino, J. Petersen, L. Belloni, G. Raimondo, and M. Dandri, “Control of cccDNA function in hepatitis B virus infection,” Journal of Hepatology, vol. 51, no. 3, pp. 581–592, 2009.
[19]
C. J. Liu, P. J. Chen, D. S. Chen, and J. H. Kao, “Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management,” Hepatology International, 2011.
[20]
J. L. Lledó, C. Fernández, M. L. Gutiérrez, and S. Oca？a, “Management of occult hepatitis B virus infection: an update for the clinician,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1563–1568, 2011.
[21]
G. Raimondo, G. Caccamo, R. Filomia, and T. Pollicino, “Occult HBV infection,” Seminars in Immunopathology, vol. 35, no. 1, pp. 39–52, 2013.
[22]
Y. Ide, Y. Ito, S. Takahashi, et al., “Hepatitis B virus reactivation in adjuvant chemotherapy for breast cancer,” Breast Cancer, 2010.
[23]
T. Matsumoto, H. Marusawa, M. Dogaki, Y. Suginoshita, and T. Inokuma, “Adalimumab-induced lethal hepatitis B virus reactivation in an HBsAg-negative patient with clinically resolved hepatitis B virus infection,” Liver International, vol. 30, no. 8, pp. 1241–1242, 2010.
[24]
M. Levast, S. Larrat, M. A. Thelu et al., “Prevalence and impact of occult hepatitis B infection in chronic hepatitis C patients treated with pegylated interferon and ribavirin,” Journal of Medical Virology, vol. 82, no. 5, pp. 747–754, 2010.
[25]
N. J. Shire, S. D. Rouster, S. D. Stanford et al., “The prevalence and significance of occult hepatitis B virus in a prospective cohort of HIV-infected patients,” Journal of Acquired Immune Deficiency Syndromes, vol. 44, no. 3, pp. 309–314, 2007.
[26]
A. S. F. Lok and B. J. McMahon, “Chronic hepatitis B,” Hepatology, vol. 45, no. 2, pp. 507–539, 2007.
[27]
D. K. Wong, F. Y. Huang, C. L. Lai et al., “Occult hepatitis B infection and HBV repli-cative activity in patients with cryptogenic cause of hepatocellular carcinoma,” Hepatology, vol. 54, pp. 829–836, 2011.
[28]
P. Toniutto, R. Minisini, C. Fabris et al., “Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression,” Clinical Transplantation, vol. 23, no. 2, pp. 184–190, 2009.
[29]
P. Bellecave, J. Gouttenoire, M. Gajer et al., “Hepatitis B and C virus coinfection: a novel model system reveals the absence of direct viral interference,” Hepatology, vol. 50, no. 1, pp. 46–55, 2009.
[30]
F. A. M. Regan, P. Hewitt, J. A. J. Barbara, and M. Contreras, “Prospective investigation of transfusion transmitted infection in recipients of over 20,000 units of blood,” British Medical Journal, vol. 320, no. 7232, pp. 403–406, 2000.
[31]
J. P. Allain, “Occult hepatitis B virus infection: implications in transfusion,” Vox Sanguinis, vol. 86, no. 2, pp. 83–91, 2004.
[32]
C. J. Liu, S. C. Lo, J. H. Kao et al., “Transmission of occult hepatitis B virus by transfusion to adult and pediatric recipients in Taiwan,” Journal of Hepatology, vol. 44, no. 1, pp. 39–46, 2006.
[33]
E. Cholongitas, G. V. Papatheodoridis, and A. K. Burroughs, “Liver grafts from anti-hepatitis B core positive donors: a systematic review,” Journal of Hepatology, vol. 52, no. 2, pp. 272–279, 2010.
[34]
Y. Shi, Y. H. Wu, W. Wu, et al., “Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis,” Liver International, vol. 32, pp. 231–240, 2012.
[35]
H. B. El-Serag, “Epidemiology of viral hepatitis and hepatocellular carcinoma,” Gastroenterology, vol. 142, pp. 1264–1273, 2012.
[36]
H. S. Selim, H. A. Abou-Donia, H. A. Taha, G. I. El Azab, and A. F. Bakry, “Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes,” European Journal of Internal Medicine, vol. 22, no. 2, pp. 187–190, 2011.
[37]
J. R. Larrubia, “Occult hepatitis B virus infection: a complex entity with relevant clinical implications,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1529–1530, 2011.
[38]
K. Shetty, M. Hussain, L. Nei, K. R. Reddy, and A. S. F. Lok, “Prevalence and significance of occult hepatitis B in a liver transplant population with chronic hepatitis C,” Liver Transplantation, vol. 14, no. 4, pp. 534–540, 2008.
[39]
O. Ceneli, Z. N. Ozkurt, K. Acar et al., “Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients,” World Journal of Gastroenterology, vol. 16, pp. 1765–1771, 2010.
[40]
J. -R. Larrubia, J. L. Lledó, C. Fernández, M. L. Gutiérrez, and S. Oca？a, “Management of occult hepatitis B virus infection: an update for the clinician,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1563–1568, 2011.
[41]
E. Tabor, J. H. Hoofnagle, and L. A. Smallwood, “Studies of donors who transmit posttransfusion hepatitis,” Transfusion, vol. 19, no. 6, pp. 725–731, 1979.
[42]
G. Raimondo, G. Navarra, S. Mondello et al., “Occult hepatitis B virus in liver tissue of individuals without hepatic disease,” Journal of Hepatology, vol. 48, no. 5, pp. 743–746, 2008.
[43]
C. J. Liu, D. S. Chen, and P. J. Chen, “Epidemiology of HBV infection in Asian blood donors: emphasis on occult HBV infection and the role of NAT,” Journal of Clinical Virology, vol. 36, no. 1, pp. S33–S44, 2006.
[44]
L. Covolo, T. Pollicino, G. Raimondo, and F. Donato, “Occult hepatitis B virus and the risk for chronic liver disease: a meta-analysis,” Dog Liver Disease, vol. 45, no. 3, pp. 238–244, 2013.
[45]
A. S. F. Lok, R. H. S. Liang, E. K. W. Chiu, K. L. Wong, T. K. Chan, and D. Todd, “Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: report of a prospective study,” Gastroenterology, vol. 100, no. 1, pp. 182–188, 1991.
[46]
S. P. Georgiadou, K. Zachou, E. Rigopoulou et al., “Occult hepatitis B virus infection in Greek patients with chronic hepatitis C and in patients with diverse nonviral hepatic diseases,” Journal of Viral Hepatitis, vol. 11, no. 4, pp. 358–365, 2004.
[47]
C. K. Hui, W. W. W. Cheung, H. Y. Zhang et al., “Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy,” Gastroenterology, vol. 131, no. 1, pp. 59–68, 2006.
[48]
G. Lalazar, D. Rund, and D. Shouval, “Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies,” British Journal of Haematology, vol. 136, no. 5, pp. 699–712, 2007.
[49]
Y. F. Liaw, N. Leung, J. H. Kao et al., “Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update,” Hepatology International, vol. 2, pp. 263–283, 2008.
[50]
European Association for the Study of the Liver, “EASL Clinical Practice Guidelines: management of chronic hepatitis B,” Journal of Hepatology, vol. 50, no. 2, pp. 227–242, 2009.
[51]
S. Kusumoto, Y. Tanaka, R. Ueda, and M. Mizokami, “Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy,” Journal of Gastroenterology, vol. 46, no. 1, pp. 9–16, 2011.
[52]
T. Umemura, E. Tanaka, K. Kiyosawa et al., “Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan,” Clinical Infectious Diseases, vol. 47, no. 5, pp. e52–e56, 2008.
[53]
J. H. Hoofnagle, “Reactivation of hepatitis B,” Hepatology, vol. 49, supplement 5, pp. S156–S165, 2009.
[54]
W. Yeo, P. K. Chan, S. Zhong et al., “Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors,” Journal of Medical Virology, vol. 62, pp. 299–307, 2000.
[55]
P. Papamichalis, A. Alexiou, M. Boulbou, G. N. Dalekos, and E. I. Rigopoulou, “Reactivation of resolved hepatitis B virus infection after immunosuppression: is it time to adopt pre-emptive therapy?” Clinics and Research in Hepatology and Gastroenterology, vol. 36, no. 1, pp. 84–93, 2012.
[56]
M. Watanabe, A. Shibuya, Y. Tsunoda et al., “Re-appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection,” Liver International, vol. 31, no. 3, pp. 340–347, 2011.
[57]
J. E. Uhm, K. Kim, T. K. Lim et al., “Changes in serologic markers of hepatitis B following autologous hematopoietic stem cell transplantation,” Biology of Blood and Marrow Transplantation, vol. 13, no. 4, pp. 463–468, 2007.
[58]
T. Sera, Y. Hiasa, K. Michitaka et al., “Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by Rituximab,” Internal Medicine, vol. 45, no. 11, pp. 721–724, 2006.
[59]
A. Kn？ll, M. Pietrzyk, M. Loss, W. A. Goetz, and W. Jilg, “Solid-organ transplantation in HBsAg-negative patients with antibodies to HBV core antigen: Low risk of HBV reactivation,” Transplantation, vol. 79, no. 11, pp. 1631–1633, 2005.
[60]
M. F. Abdelmalek, T. M. Pasha, N. N. Zein, D. H. Persing, R. H. Wiesner, and D. D. Douglas, “Subclinical reactivation of hepatitis B virus in liver transplant recipients with past exposure,” Liver Transplantation, vol. 9, no. 12, pp. 1253–1257, 2003.
[61]
R. A. de la Fuente, M. L. Gutiérrez, J. Garcia-Samaniego, C. Fernández-Rodriguez, J. L. Lledó, and G. Castellano, “Pathogenesis of occult chronic hepatitis B virus infection,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1543–1548, 2011.
[62]
N. Shinkai, Y. Tanaka, E. Orito et al., “Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection,” Hepatology Research, vol. 36, no. 4, pp. 272–276, 2006.
[63]
P. Borentain, P. Colson, D. Coso et al., “Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer.,” Journal of Viral Hepatitis, vol. 17, no. 11, pp. 807–815, 2010.
[64]
R. Loomba, A. Rowley, R. Wesley et al., “Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy,” Annals of Internal Medicine, vol. 148, no. 7, pp. 519–528, 2008.
[65]
M. L. Manzano-Alonso and G. Castellano-Tortajada, “Reactivation of hepatitis B virus infection after cytotoxic chemotherapy or immunosuppressive therapy,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1531–1537, 2011.
[66]
W. Yeo, P. K. S. Chan, W. M. Ho et al., “Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy,” Journal of Clinical Oncology, vol. 22, no. 5, pp. 927–934, 2004.
[67]
W. Yeo and P. J. Johnson, “Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy,” Hepatology, vol. 43, no. 2, pp. 209–220, 2006.
[68]
F. B. Hollinger and G. Sood, “Occult hepatitis B virus infection: a covert operation,” Journal of Viral Hepatitis, vol. 17, no. 1, pp. 1–15, 2010.
[69]
A. S. F. Lok and B. J. McMahon, “Chronic hepatitis B: update 2009,” Hepatology, vol. 50, no. 3, pp. 661–662, 2009.
[70]
M. L. Manzano-Alonso and G. Castellano-Tortajada, “Reactivation of hepatitis B virus infection after cytotoxic chemotherapy or immunosuppressive therapy,” World Journal of Gastroenterology, vol. 17, no. 12, pp. 1531–1537, 2011.
[71]
E. B. Kim, D. S. Kim, S. J. Park, Y. Park, K. H. Rho, and S. J. Kim, “Hepatitis B virus reactivation in a surface antigen-negative and antibodypositive patient after rituximab plus CHOP chemotherapy,” Cancer Research and Treatment, vol. 40, pp. 36–38, 2008.
[72]
H. Tsubouchi, H. Kumada, K. Kiyosawa et al., “Prevention of immunosuppressive therapy or chemotherapy-induced reactivation of hepatitis B virus infection—Joint report of the Intractable Liver Diseases Study Group of Japan and the Japanese Study Group of the Standard Antiviral Therapy for Viral Hepatitis,” Acta Hepatologica Japonica, vol. 50, no. 1, pp. 38–42, 2009.
[73]
D. Candotti and J. P. Allain, “Transfusion-transmitted hepatitis B virus infection,” Journal of Hepatology, vol. 51, no. 4, pp. 798–809, 2009.
