Hepatitis B reactivation after chemotherapy: two decades of clinical research

Abstract

Hepatitis due to hepatitis B virus reactivation after cytotoxic or immunosuppressive therapy is a serious cause of liver-related morbidity and mortality. With the characterization of the underlying pathogenesis, much progress in the management of this important clinical problem has been made in the past 2 decades. By year 2008, it is mandatory to screen for hepatitis B surface antigen status before initiating intensive chemotherapy or immunosuppressive therapy. All those who are hepatitis B surface antigen positive should be started on preemptive nucleos(t)ide analogues. However, there remains important issues, such as the type and duration of nucleos(t)ide analogue therapy, which need to be understood. As not all hepatitis B surface antigen-positive patients will suffer from HBV reactivation, it is therefore useful to identify risk factors related to HBV reactivation so that patients will not be treated unnecessarily with nucleos(t)ide analogues. To date, a high baseline level of viral replication, as reflected by high serum HBV DNA level, positive serum hepatitis B e antigen, and a high intrahepatic covalently closed circular DNA level, is the most important predictor for HBV reactivation. Recently, there has been an increased awareness of reactivation of occult hepatitis B virus, especially in hepatitis B virus endemic area, such as the Asia-Pacific region. Careful epidemiological study will be needed to clarify the impact of occult hepatitis B infection in patients treated with cytotoxic or immunosuppressive therapy. How important is the problem?Over the past 20 years of clinical practice at Queen Mary Hospital, we have seen a lot of progress in the management of hepatitis due to HBV reactivation in hepatitis B surface antigen carriers [1][2][3][4][5]. In the past, we saw patients who died of fulminant hepatic failure after being administered a few courses of cytotoxic therapy to treat their life-threatening lymphoma [6][7][8][9] and breast cancer [10][11][12] if they were also hepatitis B surface antigen positive. At that time, the literature report of this important clinical issue was scanty. The first report in the field was published by Wand et al. [13] who studied the effects of antitumor chemotherapeutic agents on hepatitis antigen (HBAg) and antibody (HBAb) in 25 patients with myeloproliferative and in 60 patients with lymphoproliferative disorders. This elegant study was performed at the time when only antigen and antibody associated with viral hepatitis could be semiquantified [14]. In those patients who had HBAg at the time of initiation of chemotherapy, bone marrow suppression by chemotherapeutic agents was associated with a marked increase in HBAg titer, which was then followed by hepatocellular damage, as manifested by an elevation in serum transaminase enzymes [13]. Since then, this important observation was further confirmed in other studies [8,15,16], with the rate of HBV reactivation ranging from 19% to 48%. Among them, one-quarter to half would be complicated, with severe hepatitis...

Clinical impact of occult hepatitis B virus infection in immunosuppressed patients

“…Reactivation of HBV infection in patients under immunosuppressive treatment is a well-known, life-threatening event described in HBsAg-positive patients (overt HBV infection) and in subjects with OBI [20,21,[42][43][44][45][46][47][48][49][50] . The reactivation of HBV infection, overt or occult, is characterized by a marked enhancement of viral replication during immunosuppressive therapy, with a wide spread of HBV to uninfected hepatocytes and a substantial increase in the HBV DNA serum level followed by the restoration of the immune function after treatment withdrawal and consequent cytotoxic-T-cell-mediated necrosis of HBVinfected hepatocytes usually responsible for a hepatic flare and in some instances for liver failure and even death [42] .…”

Non-Hodgkin’s Lymphomas

“…Treatment with rituximab alone is also a risk for hepatitis B reactivation. 67 Reactivation may result in a fulminant hepatitis, hepatic failure, and death. The median time to diagnosis of hepatitis was approximately 4 months after the initiation of rituximab, according to the package insert.…”

“…Patients positive for HBsAg are at a greater risk for hepatitis B reactivation than those positive for HBcAb. 67 In a prospective study of 100 Chinese patients undergoing chemotherapy for lymphoma, hepatitis developed in 67% of those who were HBsAg+ and 14% of those who were HBsAg-during cytotoxic therapy. 68 A retrospective study of Italian patients with lymphoma who were HBcAb+ found that 2.7% of patients treated with rituximab and chemotherapy developed viral reactivation compared with 0.8% of those treated with chemotherapy alone.…”

Hepatitis B Virus Infection in B-Cell Non-Hodgkin’s Lymphoma, and Effect of Entecavir in Prophylactic Antiviral Therapy

“…As far as our information goes, in hematologic malignancy, such as NHL and leukemia, anticancer systemic chemotherapy can induce HBV replication and reactivation of hepatitis B, which may lead to hepatitis flare and even hepatic failure [18]- [21]. Some studies have indicated that Lamivudine can reduce the incidence of HBV reactivation [22].…”