Occult Hepatitis B (OBH) in Clinical Settings an association (41, 77). Furthermore, in a direct examina- tion using cassette-ligation-mediated PCR in the junc- tions between HBV DNA and human DNA, the integration of HBV DNA was identified in 10 out of 34 HCC patients, all of whom were OHB positive. Four of these integra- tions were observed in chromosome 11q (78). Altogether, clear evidence exists that OHB infection HBV maintains its pro-oncogenic properties in case of occult HBV infec- tion, possibly by integrating with the host genome, the synthesis of pro-oncogenic proteins by free intra-hepatic HBV genomes (33, 36, 47, 52, 64, 69), or by progression from through cirrhosis to hepatocellular carcinoma (73). However, to reach the conclusion that OHB plays a major role in hepatocellular transformation, additional studies on molecular pathogenesis and prospective molecular epidemiological studies are needed. 3.7. Immunosuppression Hepatitis, due to reactivation of HBV, is now a well-rec- ognized complication in patients with chronic HBV infec- tion receiving cytotoxic, corticosteroid, or immunosup- pressive therapy. In these cases reactivation of the virus may occasionally be present, leading to severe or even fulminant hepatic failure sometimes indistinguishable from de novo acute infection (34, 52, 79). Several reports have found that patients with hematological malignan- cies had a high carrier rate of overt HBV (i. e., HBsAg positivebetween23.8 and 56 %) (80, 81). Also, evidence of previous HBV infection (especially the presence of anti- HBc) varies among studies, rangingfrom37.8 % to 62.5 % (81-83) (Table 1). In this respect, HBV reactivation has been observed in two clinical settings: 1) advanced immune deficiency in patients with hematological-malignancy disorders, (such as acute leukemia, myeloproliferative disorders, lymphoproliferative disorders, and plasma cell dyscrasias,) at a prevalence of 3.3 % to 24 % (80-83); and 2) subjects who were HBsAg negative prior to chemo- therapy (alkylators, antimetabolites, antitumor antibiot- ics, corticosteroids, etc.) who underwent treatment and transplantation (bone marrow, liver, kidney, and hemato- poietic stem-cell transplantation HSCT), especially those treated with the immune suppressive rituximab (anti- CD20), alemtuzumab (anti-CD52), and infliximab (anti- TNF) (82-84). The rate of reactivation after chemotherapy has been reported to range between 3.3 % and 4 % among OHB-positive immunosuppressed patients after treat- ment (82, 83). However, there are numerous case reports of HBsAg-negative patients suffering from HBV reactiva- tion after treatment by rituximab (84, 85), alemtuzumab (86, 87), and infliximab (as a therapeutic regimen for rheumatic and Crohn’s diseases) (88, 89) , and the num- ber of these studies is increasing. HBV reactivation fol- lowing chemotherapy can resolve, persist, recur, or lead to liver failure and death. However, viral proliferation and progression of the disease increase when patients with HBV infection immune response is suppressed by Alavian S M et al. immune suppressive or cytotoxic agents. On the other hand, withdrawal of these agents leads to the immune- mediated destruction of HBV-infected hepatocytes and hepatitis flares. Such flare-ups have been attributed to changes in equilibrium due to an enhanced immuno- logical response to HBV during recovery from immune suppression (90, 91). In addition to the direct effects of immunosuppression, it has been indicated that the HBV genome contains a steroid-responsive DNA sequence that, when stimulated, results in an increase of HBsAg synthesis and HBV gene reactivation (92). 3.8. Transplantation One of the most important clinical implications of OHB is usually observed in the setting of liver transplantation. In particular, livers from donors with OHB carry a risk of HBV transmission with infection occurring in 25–95 % of the liver grafts donated from patients who are HBsAg neg- ative but anti-HBc positive. This infection route is indis- tinguishable from overt infection (9, 93-95) (Table 1). The significance of OHB in post-OLT (orthotropic liver trans- plantation) settings is controversial. Upon intrahepatic HBV DNA analysis, some patients show high levels of liver or serum HBV DNA and a high rate of reactivation (96, 97), whereas, others show low HBV-DNAHBV levels of reactiva- tion rates (93, 98, 99). However, it is postulated that most (if not all) researchers believe that OHB can be found in most recipients of livers from HBsAg-negative and anti- HBc-positive liver donors. Studies have indicated that HBV DNA remains detectable in the serum or PBMCs of patients who are anti-HBV-positive HBV DNA positive and and HBsAg- negative for several years after removal of the HBV-infected liver (99), and extra-hepatic reservoirs serv- ing as the source of reinfection (96). The majority of cases in these studies indicate that the tapering or withdrawal of immunosuppression occurred before reverse serocon- version (100). The likelihood of HBV reactivation would be minimized enormously by immunization and pre- emptive treatment with nucleos (t)ide analogue drugs as a standard strategy to prevent hepatitis B (79, 101). The need for antiviral therapy in anti-HBcAg- positive and HB- sAg- negative patients is not defined well in the literature, and the results of some studies do not support a general recommendation for preemptive use of antiviral therapy in such patients (93, 99). On the other hand, other empiri- cal findings suggest that continued treatment for at least 10 years using an antiviral agent having a high resistance barrier with little or no resistance is required to achieve viral clearance while avoiding reactivation (96, 102). How- ever, close monitoring of HBV DNA levels appears to be warranted. 4. Conclusion Additional studies in larger cohorts of patients with long-term clinical and laboratory follow-up are warrant- Hepat Mon. 2012;12(8):e6126 Published by Kowsar, © BRCGL 2012 5