Hepatitis viruses under immunosuppressive agents

Abstract

Clinical and experimental studies have shown that T cell-mediated immune mechanisms are involved in the pathogenesis of hepatitis B virus (HBV) and hepatitis C virus infection. Immunosuppressants may impair T cell function and thereby reduce immune-mediated hepatocytolysis and virus clearance. In addition, corticosteroid may activate the glucocorticoid responsive element in the HBV genome to enhance HBV replication and gene expression. These combined effects result in an increase of viraemia in association with a decrease of serum aminotransferase and hepatic necroinflammation. In acute infection, use of immunosuppressants will increase the incidence of chronic evolution. In chronic infection, withdrawal of immunosuppressants will be followed by a clinical flare due to a rebound of immune attack to hepatocytes with increased viral load. This may lead to a subsequent decrease of the viraemia. Therefore, short-term use of immunosuppressant before antiviral therapy may be beneficial in the treatment of chronic viral hepatitis. However, the clinical rebound may be extremely severe and lead to hepatitis failure; thus, the patients should be monitored closely upon tapering and after the withdrawal of immunosuppressants. Long-term use of immunosuppressants in patients with hepatitis virus infection is usually deleterious, particularly in patients after organ transplantation. These findings suggest that clinicians should be cautious in the use of immunosuppressants in patients with hepatitis virus infection.

Hepatitis B reactivation after chemotherapy: two decades of clinical research

“…In the transplant setting, steroids, azathioprine, cyclosporine, and tacrolimus (FK 506) are commonly used to prevent graft rejection. In vitro, corticosteroid increases HBV DNA and RNA production by stimulating HBV transcription [70,71], by binding to the glucocorticoid responsive element (GRE), and augmenting the HBV enhancer I. In addition, the use of rituximab can effectively remove or suppress anti-HBs producing B cells and cause reactivation of HBV even in HBV immune patients.…”

“…Among the chemotherapeutic agents used, corticosteroids and anthracyclines [1][2][3][4][5][6][7] are most frequently associated with HBV reactivation. The HBV DNA contains a glucocorticoid-responsive element that facilitates replication [70,71], while anthracyclines have been shown in vitro to stimulate HBV DNA secretion [99]. Hence, ''steroid free'' chemotherapy has been proposed to minimize the risk of HBV reactivation.…”

“…This is exemplified in patients treated with BMT, where there is a higher incidence of HBV reactivation when compared with the more commonly used, standard dose of chemotherapy [1][2][3][4][5]. Also, patients with gastrointestinal malignancies who undergo cytotoxic chemotherapy, mainly consisting of less-immunosuppressive agents (fluorouracil and folinic acid), have a lower risk of developing viral reactivation [71], and in HBV-infected patients with hepatocellular carcinoma, the incidence of HBV reactivation appears to correlate with the level of immunosuppression of the anticancer therapy administered; viral reactivation was reported in 40, 25, and 2% of patients who underwent systemic chemotherapy, transatrial chemotherapy, and percutaneous ethanol injection or surgical resection, respectively, in descending order of immunosuppressive effects [58,89,101].…”

Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy

“…Second, patients with gastrointestinal malignancies who undergo cytotoxic chemotherapy, mainly consisting of less-immunosuppressive agents (fluorouracil and folinic acid), have a lower risk of developing viral reactivation. 89 Third, in HBVrelated patients with hepatocellular carcinoma, the incidence of HBV reactivation appears to correlate with the level of immunosuppression of the anticancer therapy administered; viral reactivation was reported in 40%, 25%, and 2% of patients who underwent systemic chemotherapy, transarterial chemotherapy, and percutaneous ethanol injection or surgical resection, respectively, in descending order of immunosuppressive effects. 20,24,76 Although the duration of chemotherapy has not been proven to be an associating factor, 18 Kumagai et al 16 have reported that patients who were on second or third line of chemotherapy had a higher incidence of HBV reactivation.…”

“…Among the former, corticosteroids and anthracyclines have been most frequently associated with the condition. 10,18,85-87 HBV DNA contains a glucocorticoid responsive element that has been reported to facilitate HBV replication, 88,89 while anthracycline has been demonstrated in vitro to stimulate HBV DNA secretion from HepG2-derived 2.2.15 cells in a dosedependent manner. 90 Both anthracyclines and corticosteroids are commonly used as part of the anticancer treatment and antiemetic premedication for patients who have hematological and breast malignancies.…”