Risk of Severe Acute Exacerbation of Chronic HBV Infection Cancer Patients Who Underwent Chemotherapy and Did Not Receive Anti-Viral Prophylaxis

Background Reactivation of HBV replication with an increase in serum HBV DNA and alanine aminotransferase (ALT) activity has been reported in 20–50% of hepatitis B carriers undergoing cytotoxic chemotherapy for cancer treatment. Manifestation of HBV reactivation ranges from asymptomatic self-limiting hepatitis to severe progressive hepatic failure and fatal consequences. Aim To investigate the risk of severe acute exacerbation of chronic HBV infection in HBsAg-positive cancer patients with solid tumors or hematological malignancies who underwent chemotherapy without antiviral prophylaxis. Methods A retrospective review of charts was conducted for HBsAg-positive cancer patients in our institution who underwent chemotherapy and did not receive anti-viral prophylaxis between the periods of July 2007 to January 2013. We investigate the incidence of severe acute exacerbation of chronic HBV infection if these patients with a variety of solid tumors and hematological malignancies. Results A total of 156 patients (hematological malignancies: 16; solid tumors: 140) were included. The incidence of severe acute HBV exacerbation in the patients with hematological malignancy was higher than that in solid tumors (25.0% [4/16] vs 4.3% [6/140]); P = 0.005). Additionally, patients receiving rituximab-based chemotherapy had higher acute exacerbation rate than those with non-rituximab-based chemotherapy (40.0% vs 4.1%, P = 0.001). Among the patients with solid tumors, the incidences of severe acute exacerbation of chronic HBV in hepatocellular carcinoma, colorectal cancer, lung cancer, breast cancer, gynecological cancer, urological tract cancer, head/neck cancer and other solid malignancies were 2.3%, 4.0%, 7.1%, 9.0%, 16.7%, 6.7%, 0% and 0%, respectively. Conclusion Severe acute exacerbation of chronic HBV infection may occur in HBsAg-positive patients with a variety of solid tumors who received chemotherapy without adequate anti-viral prophylaxis. Hematological malignancy and rituximab-based chemotherapy are the risk factors related to severe acute exacerbation of chronic HBV infection in HBsAg-positive cancer patients undergoing chemotherapy.


Introduction
Hepatitis B virus (HBV) infection is a global major health problem, with an estimate of 400 million chronic carriers of the HBV surface antigen (HBsAg) worldwide [1]. Chronic HBV infection is endemic in many parts of the world and in several populations, particularly in Asia, over 10% of the adult population are chronically infected with HBsAg-positive status [1][2][3]. Reactivation of HBV replication with an increase in serum HBV DNA and alanine aminotransferase (ALT) activity has been reported in 20-50% of hepatitis B carriers undergoing cytotoxic chemotherapy for cancer treatment without anti-viral prophylaxis [4][5][6][7][8][9]. A previous study has reported that the reactivation rate of HBV infection after chemotherapy was as high as 73% [10]. HBV reactivation has been reported frequently in patients diagnosed to have lymphoma or breast cancer and those who have received anticancer chemotherapy, and in this setting, the use of anthracyclines and corticosteroids as part of the chemotherapeutic combination and/or anti-emetic pre-medication were the factors shown to be associated with HBV reactivation [4,11]. Manifestation of HBV reactivation ranges from asymptomatic self-limiting hepatitis to severe progressive hepatic failure and fatal consequences [12][13].
Administering oral anti-HBV agents before chemotherapy is an effective means of reducing acute exacerbation of HBV infection and preventing fatal complications in patients with chronic HBV infection [14,15]. Both the American Association of Study in Liver Diseases (AASLD) and the European Association for the Study of Liver Disease (EASL) have recommended HBV testing before starting chemotherapy and administering oral anti-viral agents for HBsAg-positive patients [13,16]. However, the HBV infection testing rates before chemotherapy are extremely low, ranging from 14% to 31% [17][18][19]. A low HBV testing rate before chemotherapy is possibly owing to that chemotherapy is conducted by physicians from various hospital departments whose perceptions with respect to the importance of pre-chemotherapy HBV screening and HBV prophylaxis widely vary [20]. Currently, the exact severe acute exacerbation rates of chronic HBV infection in HBsAg-positive cancer patients with various solid tumors receiving chemotherapy have rarely been systemically assessed. In addition, most studies investigating flare-up of HBV infection in cancer patients receiving chemotherapy dealt with reactivation of HBV infection but not clinically significant acute exacerbation events [9].
In this study we aimed to investigate the risk of severe acute exacerbation of chronic HBV infection in HBsAg-positive cancer patients with solid tumors and hematological malignancies who underwent chemotherapy without antiviral prophylaxis in a HBV endemic area. The severe acute exacerbation rates of HBV infection in HBsAg-positive cancer patients with various solid tumors who underwent chemotherapy without HBV prophylaxis were systemically investigated.

Materials and Methods Patients
We conducted a retrospective review of charts of newly diagnosed cancer patients who underwent systemic intravenous or oral chemotherapy at our institution between the periods of July 2007 to January 2013. This study was approved by Veteran General Hospital Kaohsiung (VGHKS) institutional review board, which waived informed consent requirement (VGHKS13-CT6-12) and the patient record was anonymized and de-identified prior to analysis. Patients with positive test of HBsAg at the onset of chemotherapy who did not receive antiviral prophylaxis were included for the study. Exclusion criteria included (1) local chemotherapy with intracavity instillation of cytotoxic agents, (2) cancer treatment with small molecule kinase inhibitor targeted therapy (e.g., imatinib, sorafenib) or hormone therapy alone, (3) drug or alcohol related hepatitis, and (4) patients with positive results of serum anti-HCV antibody. This study was approved by our institutional review board, which waived informed consent requirement.

Study Design
Patient charts were reviewed and data were recorded regarding age, gender, type of malignancy, tumor stage, chemotherapy agents, viral markers, HBV viral load and results of serum liver biochemical tests, creatinine level and prothrombin time from starting chemotherapy to 6 months after chemotherapy. Types of cancer were classified as hematological malignancy and solid tumor. Tumor stages were classified according to the AJCC TNM staging system. Type of chemotherapy was classified according to the presence of rituximab or not [14].
Because not all patients with HBV infection had data of HBV DNA level at baseline, the incidence of HBV reactivation could not be determined and was not included as outcome measure. Instead, main outcome measure was severe acute exacerbation of HBV infection. Severe acute exacerbation of HBV infection was defined as (1) serum alanine aminotransferase (ALT) increased beyond 10 times the upper limit of normal (ALT level ≧ 400 IU/L) during chemotherapy or 6 months following chemotherapy, (2) the presence of serum hepatitis B surface antigen at acute exacerbation, and (3) exclusion of liver injury due to superinfection or coinfection with hepatitis A, C, and D viruses, alcoholic liver disease, autoimmune hepatitis, drug hepatitis or major systemic events (e.g., shock, hypoxia, hemolytic anemia). The suspected severe acute exacerbation events were adjudicated by a hepatic injury review panel for the study according to the clinical courses, serological markers, and HBV DNA levels during acute events. Alcohol-or drug-induced liver injury was excluded by careful review of medical history and clinical course, and liver injury within 7 days following initiation of chemotherapy in the first cycle of cancer treatment was excluded for the possibility of chemotherapy agent-related hepatitis. Delayed chemotherapy treatment was defined as premature termination of treatment or delay of >8 days [9,21]. Patients with ALT ≧ 100 IU/L plus international normalized ratio (INR) ≧ 1.5, ascites, or encephalopathy were categorized as having liver decompensation [17]. Fatal HBV reactivation was defined as (1) fatal consequences due to complications of hepatic failure following severe acute exacerbation of HBV infection, and (2) exclusion of mortality caused by other major systemic diseases (e.g., acute myocardial infarct, cerebral vascular accident, and brain metastasis).

Statistical Analysis
The compared data were analyzed using a Chi-square analysis or Fisher's exact test. A value of P < 0.05 was considered significant. All statistical evaluations were performed using SPSS version 18.0 software.

Results
From July 2007 to January 2013, the charts of 3144 cancer patients undergoing chemotherapy were reviewed. A total of 156 HBsAg-positive cancer patients (hematological malignancies: 16; solid tumors: 140) were included (Fig 1). The clinical characteristics of the patients are summarized in Table 1. There were 107 (68.9%) males and 49 (31.4%) females. Most patients with hematological malignancies (81.3%) and non-HCC solid tumor had normal serum level of ALT at the onset of chemotherapy. In contrast, only 20.5% of the patients with HCC had normal ALT level before chemotherapy. None of patients with solid tumor received rituximabcontaining chemotherapy. In the hematological malignancy group, 62.5% of the patients received chemotherapy containing rituximab (Table 1). Table 2 showed the clinical outcomes of the HBsAg-positive cancer patients who received chemotherapy without antiviral prophylaxis. Severe acute exacerbation of HBV infection occurred in 25.0% (4/16) and 4.3% (6/140) of patients with hematological malignancy and solid tumor, respectively. Among the patients with solid tumors, the incidences of severe acute exacerbation of chronic HBV in HCC, colorectal cancer, lung cancer, breast cancer, gynecological cancer, urological tract cancer, head/neck cancer and other solid malignancies were 2.3%, 4.0%, 7.1%, 9.0%, 16.7%, 6.7%, 0% and 0%, respectively. Among the 16 patients with hematological malignancy, 25.0% developed liver decompensation due to severe acute exacerbation of HBV infection, and 18.7% died in fatal HBV reactivation. Additionally, delayed chemotherapy due to HBV flare up occurred in 31.3% of the patients.  Table 3 showed the univariate analysis of the clinical factors related to severe acute exacerbation of HBV infection in HBsAg-positive cancer patients who received chemotherapy without anti-viral prophylaxis. Type of malignancy and type of chemotherapy were associated with severe acute exacerbation of HBV infection. The incidences of severe acute HBV exacerbation in the patients with hematological malignancy and solid tumors were 25.0% and 4.3%, respectively. The former had higher incidence of severe acute HBV exacerbation than the latter (P = 0.005). Regarding the type of chemotherapy, rituximab-containing chemotherapy had a higher incidence of acute exacerbation than the non-rituximab-containing chemotherapy (P = 0.001). There were no significant differences with respect to age, sex, levels of ALT, AST, total bilirubin, albumin, INR, and creatinine.
In this study, all the patients receiving rituximab-based chemotherapy had hematological malignancy. Additionally, the number of cases with acute exacerbation was small. Multiple regression analysis was therefore not performed to investigate the independent risk factors predicting severe acute exacerbation of chronic HBV infection. Table 4 listed the clinical features of the ten patients who developed severe acute exacerbation of chronic HBV infection. In this study, 10 patients (lymphoma: n = 4; HCC: n = 1; lung cancer: n = 1; breast cancer: n = 1; colorectal cancer: n = 1; cervical cancer: n = 1; urological tract cancer: n = 1) developed severe acute exacerbation of HBV infection. All the severe acute exacerbation occurred after one or two cycles of chemotherapy. The median duration from initiation of chemotherapy to develop severe acute exacerbation of HBV infection was 75 days (range, 30-120 days). Fatal consequences due to severe acute exacerbation of HBV infection occurred in 4 patients.

Discussion
While HBV reactivation is a recognized complication in HBsAg-positive cancer patients undergoing chemotherapy, the exact frequency of severe acute exacerbation of HBV infection in these patients remains unclear. The current study showed the incidences of severe acute exacerbation of chronic HBV in HBsAg-positive patients with lymphoma, HCC, colorectal cancer, lung cancer, breast cancer, gynecological cancer, urological tract cancer, head/neck cancer and other solid malignancies were 25.0%, 2.3%, 4.0%, 7.1%, 9.0%, 16.7%, 20%, 0% and 0%, respectively. The mortality rate in the patients with severe acute exacerbation of HBV infection was 28.0% though all of them receiving antiviral therapy following HBV flare up. Our data suggest that pre-chemotherapy HBV screening and prophylaxis are indicated for patients with lymphoma and a variety of solid tumors including HCC, urological, gynecological, breast, colorectal, and lung cancers.
Rituximab is a chimeric mouse human anti-CD20 monoclonal antibody that can reduce B cell numbers and antibody levels. It is widely used as a single agent or in combination with chemotherapy in the management of CD20+ lymphomas, such as DLBCL and follicular lymphoma, and is a well known immunosuppressant associated with HBV reactivation. HBV reactivation may also occur in patients with resolved hepatitis B (HBsAg-negative/hepatitis B core antibody [anti-HBc]-positive) who receive rituximab. The incidence of HBV reactivation in patients with lymphoma and resolved hepatitis B after rituximab-based therapy ranges from 1.5% to 23.8% [29,30]. Therefore, screening for HBsAg & anti-HBc is strongly recommended for patients receiving with rituximab-containing chemotherapy, and antiviral prophylaxis should be considered in both HBsAg-positive cancer patients and those with resolved hepatitis B undergoing rituximab-containing chemotherapy.
Administering oral anti-HBV agents before chemotherapy is an effective means of reducing HBV reactivation and preventing fatal complications in patients with chronic HBV infection [14,15]. One of our recent studies also demonstrated that none (0%) of the 208 HBsAg-positive patients receiving HBV prophylaxis by oral anti-viral agents in our hospital from November 2009 to June 2013 developed severe acute exacerbation of HBV infection [31]. A meta-analysis by Lenna et al showed that patients given lamivudine prophylaxis reduced 87%, 70%, and 92% of HBV reactivation, reactivation related mortality, and chemotherapy disruptions, respectively [32]. Many clinical guidelines, including the American Association of Study in Liver Diseases (AASLD), European Association for the Study of Liver Disease (EASL) and United States Center for Disease Control and Prevention (CDC) therefore recommend the use of prophylactic antiviral agents for HBsAg-positive cancer patients undergoing cytotoxic chemotherapy [13,16,33].
Despite its contributions, this retrospective study has several limitations. Firstly, the numbers of HBsAg-positive patients in a variety of solid tumors were small. Secondly, it was a retrospective study. Therefore, some factors might influence physicians' decisions to perform prechemotherapy screening and anti-viral prophylaxis or not. Thirdly, it was a single-institute study in an HBV endemic area. Nonetheless, it provided the incidence of severe acute exacerbation of HBV infection in hematological malignancy and a variety of solid tumors in HBsAg carriers who underwent chemotherapy without adequate HBV prophylaxis.
In conclusion, severe acute exacerbation of chronic HBV infection may occur in HBsAgpositive patients with a variety of solid tumors who received chemotherapy without adequate anti-viral prophylaxis. Hematological malignancy and rituximab-based chemotherapy are the risk factors related to severe acute exacerbation of chronic HBV infection in HBsAg-positive cancer patients undergoing chemotherapy.
Supporting Information S1 Data. Underlying participant-level data are provided in a supporting information file. (XLS)