Prevention of Acute Exacerbation of Chronic Hepatitis B Infection in Cancer Patients Receiving Chemotherapy in a Hepatitis B Virus Endemic Area Ping-I Hsu,1 Kwok-Hung Lai,1 Jin-Shiung Cheng,1 Sung-Shuo Kao,1 Yuan-Rung Li,1 Wei-Chih Sun,1 Wen-Chi Chen,1 Kung-Hung Lin,1 Chih-An Shin,1 Po-Hung Chiang,1 Yun-Da Li,1 Wei-Ting Ou,1 Hui-Chun Chen,2 and Hsien-Chung Yu1 Reactivation of hepatitis B viral (HBV) infection in cancer patients undergoing chemotherapy may cause interruption of chemotherapy and lead to liver failure and death. In our institute, a computerized order entry–based alert system was introduced in September 2011 to remind healthcare providers of HBV testing when prescribing chemotherapy. Since August 2012, an order entry–based therapeutic control system has been applied to ensure HBV prophylaxis during chemotherapy. This retrospective cohort study included cancer patients receiving chemotherapy in the Kaohsiung Veterans General Hospital from November 2009 to June 2013. The prechemotherapy HBV screening rate, HBV prophylactic rate, and severe HBV acute exacerbation rate were compared between stages with different order systems. Newly diagnosed cancer patients (n 5 2512) were included. The HBV testing rate in the screening reminder stage was higher than that in the educational stage (93.5% versus 40.2%, P < 0.001), whereas the adequate HBV prophylactic rates in the two order entry–based stages were comparable (41.1% versus 39.2%). Patients in the order entry–based therapeutic control stage had a higher HBV screening rate (99.3% versus 40.2%, P < 0.001) and a higher HBV prophylactic rate (95.8% versus 39.2%, P < 0.001) than those in the educational stage. Additionally, the severe HBV acute exacerbation rate in the therapeutic control stage was lower than those in the educational and screening reminder stages (0% versus 1.2% and 1.2%, respectively; both P < 0.01). Conclusion: A computerized order entry–based therapeutic control system can provide excellent prechemotherapy HBV screening for cancer patients undergoing chemotherapy and can effectively prevent severe acute exacerbation of HBV infection in hospitals among HBV endemic areas. (HEPATOLOGY 2015;62:387-396)
H
epatitis B viral (HBV) infection is a global health problem. Nearly 2 billion people worldwide have been infected with HBV, and 350 million people have chronic infection.1 Reactivation of HBV replication with an increase of serum HBV DNA has been reported in 20%-50% of hepatitis B carriers undergoing cytotoxic chemotherapy for cancer treatment.2,3 Reactivation of HBV may also occur in patients with resolved hepatitis B (hepatitis B surface antigen [HBsAg]-negative/antibody to hepatitis B core
antigen [anti-HBc]–positive) who receive chemotherapy containing strong immunosuppressive agents such as rituximab.4 The incidence of HBV reactivation in patients with lymphoma and resolved hepatitis B after rituximab-based therapy ranges from 1.5% to 23.8%.5-8 Reactivation of HBV infection in cancer patients receiving chemotherapy may cause interruption of chemotherapy and, in severe cases, lead to liver failure and death.9-11 Additionally, the prognosis of cancer may be compromised by disruption in anticancer treatment
Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; CI, confidence interval; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma. From the 1Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan; 2Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan Received December 20, 2014; accepted April 7, 2015. 387
388
HSU ET AL.
during the course of hepatitis, with a delay in treatment cycles and premature termination of chemotherapy.4 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.12-14 The American Association for the Study of Liver Diseases has recommended that all persons at high risk for HBV be screened for prior HBV infection before chemotherapy.15 The guidelines of the European Association for the Study of the Liver also advise HBV testing before starting chemotherapy.16 The US Centers for Disease Control and Prevention has recommended that all patients be screened for HBV infection before administration of any immunosuppression.17 Despite differences regarding which patients should be screened, all guidelines indicate that some form of systemic screening is needed to identify patients at risk for reactivation. However, HBV infection testing rates before chemotherapy are extremely low in non-HBV endemic countries. For example, the HBV screening rate before the onset of chemotherapy at the MD Anderson Cancer Center in the United States was only 17%,18 and the HBV infection testing rates before chemotherapy ranged from 14% to 31% in Canada.19 Additionally, HBV infection testing rates prior to chemotherapy are quite low in HBV endemic countries. For instance, only 17% of patients received prechemotherapy HBV testing at the West China Hospital.20 A low HBV testing rate before chemotherapy is partially owing to the fact that chemotherapy is conducted by physicians from various hospital departments whose perceptions with respect to the importance of prechemotherapy HBV screening vary widely.21 To improve HBV prophylaxis in patients receiving chemotherapy, an education program concerning HBV prophylaxis for healthcare providers in our institute was begun in November 2009. A computerized order entry–based alert system (e-REMINDER) and a therapeutic control system (e-CONTROL) were developed to notify healthcare providers of prechemotherapy HBV testing and prophylaxis when prescribing chemotherapy agents in 2011 and 2012, respectively. The aims of this study were (1) to compare the prechemotherapy HBV screening rate and HBV prophylactic
HEPATOLOGY, August 2015
rate in the educational, order entry–based screening reminder, and order entry–based therapeutic control stages in a high endemic area of HBV infection and (2) to assess the rates of severe acute exacerbation of HBV infection across the three time periods.
Patients and Methods Patient Identification. To prevent an acute flareup of HBV among chemotherapy patients, the hepatologists in our hospital adopted an educational strategy in November 2009 and went to the major medical departments to educate the physicians on how to perform prechemotherapy HBV testing and HBV prophylaxis. In September 2011, a computerized order entry–based alert system (e-REMINDER) was developed to remind physicians to test for HBV infection before chemotherapy and to administer oral anti-HBV medications for HBV carriers whenever they prescribed chemotherapy agents.22 Subsequently, an order entry– based therapeutic control system (e-CONTROL) was developed to ensure the safety of chemotherapy, in August 2012. In this retrospective cohort study, we used the hospital cancer registry, pharmacy, and patient account databases. We reviewed the cancer registry to identify newly diagnosed cancer patients registered from November 1, 2009, to June 30, 2013. Inpatients who had a new diagnosis of cancer and had undergone their first systemic intravenous or oral chemotherapy at the Kaohsiung Veterans General Hospital were included. Exclusion criteria included (1) local chemotherapy with intracavity instillation of cytotoxic agents and (2) cancer treatment with hormone therapy alone. This study was approved by our institutional review board, which waived the informed consent requirement. Methods and Definitions. Patient charts were reviewed, and data were recorded regarding age, gender, type of malignancy, tumor stage, chemotherapy agents, department administering chemotherapy, HBV testing (HBsAg and anti-HBc) within 2 years prior to chemotherapy, and anti-HBV medications administered during chemotherapy. Types of cancer were classified as hematological malignancies, hepatocellular carcinoma (HCC), and solid tumors other than HCC.
Address reprint requests to: Hsien-Chung Yu, M.D., Division of Gastroenterology, Department of Internal Medicine, Kaoshiung Veterans General Hospital, 386 Ta Chung 1st Road, Kaohsiung 813, Taiwan, R.O.C. E-mail: [email protected]; tel: 1886-7-3462074; fax: 1886-7-3468237. C 2015 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27843 Potential conflict of interest: Nothing to report.
HEPATOLOGY, Vol. 62, No. 2, 2015
Fig. 1. Road map for prechemotherapy HBV screening in the order entry–based screening reminder stage.
We specified HCC patients because of the etiological relationship between HBV infection and HCC. Tumor stages were classified according to the American Joint Committee on Cancer’s TNM staging system. Type of chemotherapy was classified as regimens with or without rituximab. In Taiwan, the costs of HBV tests are covered by the National Heath Insurance. Nucleos (t)ide analogues were reimbursed for HBsAg-positive cancer patients undergoing chemotherapy within a time frame between 1 week prior to the start of chemotherapy and 6 months after completion of chemotherapy. We therefore stopped nucleos(t)ide analogues 6 months following completion of chemotherapy. The study periods were classified into three stages: the educational (November 2009-August 2011), order entry–based screening reminder (September 2011-July 2012), and order entry–based therapeutic control stages (August 2012-June 2013). In the educational stage, two hepatologists (H.-C.Y. and P.-I.H.) went to the major medical departments to provide education on HBV prophylaxis during chemotherapy with lectures. The contents of the standard lecture slides included the causes of HBV reactivation during chemotherapy, levels of reactivation risk, morbidity and mortality associated with HBV reactivation, benefits of antiviral prophylaxis during chemotherapy, and methods of
HSU ET AL.
389
HBV screening and prophylaxis in chemotherapy patients. No pretests or posttests were conducted to assess the knowledge of the attendees. Overall, seven lectures were administered to the chemotherapy prescribers during the period between 2009 and 2011. Thirty of the 39 physicians (76.9%) who prescribed chemotherapy attended the education programs. In the order entry–based screening reminder stage, the hospital computer checked patients’ data on HBsAg within 2 years prior to chemotherapy whenever the physicians prescribed chemotherapy agents (Fig. 1). If no data on HBsAg were available, the computer system reminded the doctor to check HBsAg and antiHBc. If HBsAg data were available and displayed positive results, the system reminded the physicians to prescribe anti-HBV medications. The recommendation in the e-REMINDER stage was a soft reminder. If the patients receiving chemotherapy had no prior HBsAg testing, an alert message box reminding the doctors to check HBsAg and anti-HBc was automatically shown on the computer screen. The doctors could select the “agree to screen” button in the message box to test HBsAg and anti-HBc or just close the box and ignore the reminder. If the doctors selected the “agree to screen” button, an order to test serum HBsAg and antiHBc was automatically printed out from the computers. Because the databank of the e-REMINDER system in our hospital could not detect testing results outside the hospital, the reminder system only checked the HBsAg data of patients who had been examined within the past 2 years in our hospital. For patients who had prior testing outside the hospital, it was still recommended that HBsAg and anti-HBc be checked before chemotherapy. Patients who had a prior test with a negative HBsAg result could be prescribed chemotherapy agents directly, and no additional message for anti-HBc testing was advised. In the order entry–based therapeutic control stage, the hospital computer system controlled both prechemotherapy HBV screening and prophylaxis (Fig. 2). Whenever the physicians prescribed chemotherapy agents, the hospital computer checked the patient’s data on HBsAg within 2 years prior to chemotherapy. If HBsAg data were unavailable, the computer system requested the physicians to check HBsAg and antiHBc, and chemotherapy was not allowed. If HBsAg data were available and showed negative results, the physicians could prescribe chemotherapy agents directly. If HBsAg data displayed positive results, the system requested the physicians to prescribe anti-HBV medications. No chemotherapy was allowed if antiHBV medications were not prescribed. In this system,
390
HSU ET AL.
dispensing was allowed if data on HBsAg, but not anti-HBc, were available. Because some cancer patients with chronic hepatitis B had received oral anti-HBV therapy at other hospitals and our computer system could not censor the anti-HBV medications prescribed elsewhere, a computer function to waive these patients from the therapeutic control system was established and controlled by the staff in the Department of Gastroenterology and Hepatology. Outcome Measures. The laboratory results database was searched for evidence of HBsAg and antiHBc testing (Ortho-Clinical Diagnostics, Rochester, NY) prior to chemotherapy. Adequate screening was defined as (1) screening for HBsAg in patients receiving chemotherapy without rituximab or (2) screening for HBsAg and anti-HBc in patients receiving with rituximab-containing chemotherapy. Resolved hepatitis B was defined as HBsAg–/anti-HBc1 (regardless of antibody to HBsAg status). Because not all patients with HBV infection had data on HBV DNA level at baseline, the incidence of HBV reactivation could not be determined and was not included as an outcome measure. Instead, we described clinical outcomes of severe acute exacerbation in HBsAg-positive patients and liver decompensation related to severe acute exacerbation of HBV infection. Severe acute exacerbation in HBsAg-positive patients 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 HBsAg in the serum, 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. Drug-induced liver injury was excluded by careful review of the 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. Additionally, liver function impairment induced by liver metastasis was excluded according to image studies (e.g., liver sonography, abdominal computed tomography). Only severe acute exacerbation events confirmed by the adjudication committee were included in the analysis. Liver decompensation
HEPATOLOGY, August 2015
Fig. 2. Road map for prechemotherapy HBV screening and prophylaxis in the order entry–based therapeutic control stage.
related to severe acute exacerbation of HBV was defined as severe acute exacerbation of HBV infection with the development of hepatic encephalopathy, serum total bilirubin level exceeding 2 mg/dL, or an international normalized ratio of prothrombin time more than 1.5. 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). The causes of death were confirmed by the adjudication committee of the study. Statistical Analysis. Primary outcomes were (1) frequency of adequate HBV screening before chemotherapy and (2) frequency of HBV prophylaxis during the first cycle of chemotherapy in cancer patients with positive results of HBsAg testing within 2 years prior
HEPATOLOGY, Vol. 62, No. 2, 2015
HSU ET AL.
391
Fig. 3. Patient disposition.
to chemotherapy. Secondary outcomes were (1) frequency of severe acute exacerbation of HBV infection and (2) frequency of liver decompensation related to severe acute exacerbation of HBV. Only the events confirmed by the hepatic injury review panel were included in the analysis. The outcomes were analyzed by the chi-squared test with Yates correction or Fisher’s exact test for categorical data. The Student t test was employed for comparison of continuous variables. We used SPSS software (version 10.1; Chicago, IL) for all statistical calculations. A P value
H
epatitis B viral (HBV) infection is a global health problem. Nearly 2 billion people worldwide have been infected with HBV, and 350 million people have chronic infection.1 Reactivation of HBV replication with an increase of serum HBV DNA has been reported in 20%-50% of hepatitis B carriers undergoing cytotoxic chemotherapy for cancer treatment.2,3 Reactivation of HBV may also occur in patients with resolved hepatitis B (hepatitis B surface antigen [HBsAg]-negative/antibody to hepatitis B core
antigen [anti-HBc]–positive) who receive chemotherapy containing strong immunosuppressive agents such as rituximab.4 The incidence of HBV reactivation in patients with lymphoma and resolved hepatitis B after rituximab-based therapy ranges from 1.5% to 23.8%.5-8 Reactivation of HBV infection in cancer patients receiving chemotherapy may cause interruption of chemotherapy and, in severe cases, lead to liver failure and death.9-11 Additionally, the prognosis of cancer may be compromised by disruption in anticancer treatment
Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; CI, confidence interval; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma. From the 1Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan; 2Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan Received December 20, 2014; accepted April 7, 2015. 387
388
HSU ET AL.
during the course of hepatitis, with a delay in treatment cycles and premature termination of chemotherapy.4 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.12-14 The American Association for the Study of Liver Diseases has recommended that all persons at high risk for HBV be screened for prior HBV infection before chemotherapy.15 The guidelines of the European Association for the Study of the Liver also advise HBV testing before starting chemotherapy.16 The US Centers for Disease Control and Prevention has recommended that all patients be screened for HBV infection before administration of any immunosuppression.17 Despite differences regarding which patients should be screened, all guidelines indicate that some form of systemic screening is needed to identify patients at risk for reactivation. However, HBV infection testing rates before chemotherapy are extremely low in non-HBV endemic countries. For example, the HBV screening rate before the onset of chemotherapy at the MD Anderson Cancer Center in the United States was only 17%,18 and the HBV infection testing rates before chemotherapy ranged from 14% to 31% in Canada.19 Additionally, HBV infection testing rates prior to chemotherapy are quite low in HBV endemic countries. For instance, only 17% of patients received prechemotherapy HBV testing at the West China Hospital.20 A low HBV testing rate before chemotherapy is partially owing to the fact that chemotherapy is conducted by physicians from various hospital departments whose perceptions with respect to the importance of prechemotherapy HBV screening vary widely.21 To improve HBV prophylaxis in patients receiving chemotherapy, an education program concerning HBV prophylaxis for healthcare providers in our institute was begun in November 2009. A computerized order entry–based alert system (e-REMINDER) and a therapeutic control system (e-CONTROL) were developed to notify healthcare providers of prechemotherapy HBV testing and prophylaxis when prescribing chemotherapy agents in 2011 and 2012, respectively. The aims of this study were (1) to compare the prechemotherapy HBV screening rate and HBV prophylactic
HEPATOLOGY, August 2015
rate in the educational, order entry–based screening reminder, and order entry–based therapeutic control stages in a high endemic area of HBV infection and (2) to assess the rates of severe acute exacerbation of HBV infection across the three time periods.
Patients and Methods Patient Identification. To prevent an acute flareup of HBV among chemotherapy patients, the hepatologists in our hospital adopted an educational strategy in November 2009 and went to the major medical departments to educate the physicians on how to perform prechemotherapy HBV testing and HBV prophylaxis. In September 2011, a computerized order entry–based alert system (e-REMINDER) was developed to remind physicians to test for HBV infection before chemotherapy and to administer oral anti-HBV medications for HBV carriers whenever they prescribed chemotherapy agents.22 Subsequently, an order entry– based therapeutic control system (e-CONTROL) was developed to ensure the safety of chemotherapy, in August 2012. In this retrospective cohort study, we used the hospital cancer registry, pharmacy, and patient account databases. We reviewed the cancer registry to identify newly diagnosed cancer patients registered from November 1, 2009, to June 30, 2013. Inpatients who had a new diagnosis of cancer and had undergone their first systemic intravenous or oral chemotherapy at the Kaohsiung Veterans General Hospital were included. Exclusion criteria included (1) local chemotherapy with intracavity instillation of cytotoxic agents and (2) cancer treatment with hormone therapy alone. This study was approved by our institutional review board, which waived the informed consent requirement. Methods and Definitions. Patient charts were reviewed, and data were recorded regarding age, gender, type of malignancy, tumor stage, chemotherapy agents, department administering chemotherapy, HBV testing (HBsAg and anti-HBc) within 2 years prior to chemotherapy, and anti-HBV medications administered during chemotherapy. Types of cancer were classified as hematological malignancies, hepatocellular carcinoma (HCC), and solid tumors other than HCC.
Address reprint requests to: Hsien-Chung Yu, M.D., Division of Gastroenterology, Department of Internal Medicine, Kaoshiung Veterans General Hospital, 386 Ta Chung 1st Road, Kaohsiung 813, Taiwan, R.O.C. E-mail: [email protected]; tel: 1886-7-3462074; fax: 1886-7-3468237. C 2015 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27843 Potential conflict of interest: Nothing to report.
HEPATOLOGY, Vol. 62, No. 2, 2015
Fig. 1. Road map for prechemotherapy HBV screening in the order entry–based screening reminder stage.
We specified HCC patients because of the etiological relationship between HBV infection and HCC. Tumor stages were classified according to the American Joint Committee on Cancer’s TNM staging system. Type of chemotherapy was classified as regimens with or without rituximab. In Taiwan, the costs of HBV tests are covered by the National Heath Insurance. Nucleos (t)ide analogues were reimbursed for HBsAg-positive cancer patients undergoing chemotherapy within a time frame between 1 week prior to the start of chemotherapy and 6 months after completion of chemotherapy. We therefore stopped nucleos(t)ide analogues 6 months following completion of chemotherapy. The study periods were classified into three stages: the educational (November 2009-August 2011), order entry–based screening reminder (September 2011-July 2012), and order entry–based therapeutic control stages (August 2012-June 2013). In the educational stage, two hepatologists (H.-C.Y. and P.-I.H.) went to the major medical departments to provide education on HBV prophylaxis during chemotherapy with lectures. The contents of the standard lecture slides included the causes of HBV reactivation during chemotherapy, levels of reactivation risk, morbidity and mortality associated with HBV reactivation, benefits of antiviral prophylaxis during chemotherapy, and methods of
HSU ET AL.
389
HBV screening and prophylaxis in chemotherapy patients. No pretests or posttests were conducted to assess the knowledge of the attendees. Overall, seven lectures were administered to the chemotherapy prescribers during the period between 2009 and 2011. Thirty of the 39 physicians (76.9%) who prescribed chemotherapy attended the education programs. In the order entry–based screening reminder stage, the hospital computer checked patients’ data on HBsAg within 2 years prior to chemotherapy whenever the physicians prescribed chemotherapy agents (Fig. 1). If no data on HBsAg were available, the computer system reminded the doctor to check HBsAg and antiHBc. If HBsAg data were available and displayed positive results, the system reminded the physicians to prescribe anti-HBV medications. The recommendation in the e-REMINDER stage was a soft reminder. If the patients receiving chemotherapy had no prior HBsAg testing, an alert message box reminding the doctors to check HBsAg and anti-HBc was automatically shown on the computer screen. The doctors could select the “agree to screen” button in the message box to test HBsAg and anti-HBc or just close the box and ignore the reminder. If the doctors selected the “agree to screen” button, an order to test serum HBsAg and antiHBc was automatically printed out from the computers. Because the databank of the e-REMINDER system in our hospital could not detect testing results outside the hospital, the reminder system only checked the HBsAg data of patients who had been examined within the past 2 years in our hospital. For patients who had prior testing outside the hospital, it was still recommended that HBsAg and anti-HBc be checked before chemotherapy. Patients who had a prior test with a negative HBsAg result could be prescribed chemotherapy agents directly, and no additional message for anti-HBc testing was advised. In the order entry–based therapeutic control stage, the hospital computer system controlled both prechemotherapy HBV screening and prophylaxis (Fig. 2). Whenever the physicians prescribed chemotherapy agents, the hospital computer checked the patient’s data on HBsAg within 2 years prior to chemotherapy. If HBsAg data were unavailable, the computer system requested the physicians to check HBsAg and antiHBc, and chemotherapy was not allowed. If HBsAg data were available and showed negative results, the physicians could prescribe chemotherapy agents directly. If HBsAg data displayed positive results, the system requested the physicians to prescribe anti-HBV medications. No chemotherapy was allowed if antiHBV medications were not prescribed. In this system,
390
HSU ET AL.
dispensing was allowed if data on HBsAg, but not anti-HBc, were available. Because some cancer patients with chronic hepatitis B had received oral anti-HBV therapy at other hospitals and our computer system could not censor the anti-HBV medications prescribed elsewhere, a computer function to waive these patients from the therapeutic control system was established and controlled by the staff in the Department of Gastroenterology and Hepatology. Outcome Measures. The laboratory results database was searched for evidence of HBsAg and antiHBc testing (Ortho-Clinical Diagnostics, Rochester, NY) prior to chemotherapy. Adequate screening was defined as (1) screening for HBsAg in patients receiving chemotherapy without rituximab or (2) screening for HBsAg and anti-HBc in patients receiving with rituximab-containing chemotherapy. Resolved hepatitis B was defined as HBsAg–/anti-HBc1 (regardless of antibody to HBsAg status). Because not all patients with HBV infection had data on HBV DNA level at baseline, the incidence of HBV reactivation could not be determined and was not included as an outcome measure. Instead, we described clinical outcomes of severe acute exacerbation in HBsAg-positive patients and liver decompensation related to severe acute exacerbation of HBV infection. Severe acute exacerbation in HBsAg-positive patients 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 HBsAg in the serum, 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. Drug-induced liver injury was excluded by careful review of the 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. Additionally, liver function impairment induced by liver metastasis was excluded according to image studies (e.g., liver sonography, abdominal computed tomography). Only severe acute exacerbation events confirmed by the adjudication committee were included in the analysis. Liver decompensation
HEPATOLOGY, August 2015
Fig. 2. Road map for prechemotherapy HBV screening and prophylaxis in the order entry–based therapeutic control stage.
related to severe acute exacerbation of HBV was defined as severe acute exacerbation of HBV infection with the development of hepatic encephalopathy, serum total bilirubin level exceeding 2 mg/dL, or an international normalized ratio of prothrombin time more than 1.5. 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). The causes of death were confirmed by the adjudication committee of the study. Statistical Analysis. Primary outcomes were (1) frequency of adequate HBV screening before chemotherapy and (2) frequency of HBV prophylaxis during the first cycle of chemotherapy in cancer patients with positive results of HBsAg testing within 2 years prior
HEPATOLOGY, Vol. 62, No. 2, 2015
HSU ET AL.
391
Fig. 3. Patient disposition.
to chemotherapy. Secondary outcomes were (1) frequency of severe acute exacerbation of HBV infection and (2) frequency of liver decompensation related to severe acute exacerbation of HBV. Only the events confirmed by the hepatic injury review panel were included in the analysis. The outcomes were analyzed by the chi-squared test with Yates correction or Fisher’s exact test for categorical data. The Student t test was employed for comparison of continuous variables. We used SPSS software (version 10.1; Chicago, IL) for all statistical calculations. A P value
