EDITORIAL Universal Hepatitis B Virus Screening in Patients Receiving Immunosuppressive Therapy: A Small Step for the Oncologists, a Major Advance for Prevention of Hepatitis B Virus Reactivation he natural history of chronic hepatitis B virus (HBV) infection depends on the interaction between HBV and the host immune system. HBV reactivation is a well-recognized complication in patients with HBV infection receiving chemotherapy, recipients of bone marrow, stem cell, or solid organ transplants, and patients with autoimmune diseases receiving treatment with monoclonal antibodies (anti-CD20, antiCD52), tumor necrosis factor inhibitors, corticosteroids, or other immunosuppressive agents. Concerns about the safety of anti-CD20 antibodies in patients with underlying HBV infection have led the Food and Drug Administration to recommend that all patients treated with these agents should be screened for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc).1 HBV reactivation has not only been reported in HBsAgpositive patients but also at a lower frequency in patients who had past HBV infection (ie, HBsAg-negative, anti-HBc positive hepatitis B surface antibody positive).2 Under immunosuppression, there is a markedly enhanced viral replication as reflected by reappearance or increase of serum HBV DNA levels (ie, 1 log as compared with baseline) and anti-HBc immunoglobulin M positivity.2 In anti-HBs–positive patients who reactivate, seroreversion to HBsAg-positive status could be observed. After the withdrawal of immunosuppressive therapy, the restoration of immune function leads to a rapid immune-mediated destruction of HBV-infected hepatocytes. HBV reactivation may progress from asymptomatic hepatitis to severe hepatitis and even death from fulminant hepatic failure. Results of published studies suggest that host factors such as male sex, underlying disease such as hematologic malignancies, type of immunosuppressive therapy such as monoclonal antibodies (anti-CD20), anthracyclines, or corticosteroids, and viral factors such as baseline HBV DNA level and HBsAg positivity contribute to the risk of reactivation.3 The baseline HBV DNA level has been shown to be the best viral predictor of reactivation. The incidence of HBV reactivation is related to the HBs-Ag carrier rate and is a common clinical problem in endemic regions. However, the incidence of reactivation is difficult to evaluate because of the possible absence of HBV markers testing before and during immunosuppressive therapy, lack of standardized nomenclature and definitions of reactivation, and variation of the sensitivity and linearity of HBV DNA assays
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used across studies. In a systematic review of 14 studies of 550 HBsAg-positive patients receiving chemotherapy for hematologic or solid organ malignancies, the pooled incidences of HBV reactivation, HBV-related hepatitis, HBV-related liver failure, and HBV-related death were 37% (24%–88%), 33% (24%–88%), 13% (5%–33%), and 7% (0%–63%), respectively.4 The risk of HBV reactivation in HBsAg-negative, anti-HBc–positive patients is 5–8 times lower as compared with HBsAg-positive patients.3 Hui et al5 reported 8 cases (3.3%) of HBV reactivation of 244 HBsAg-negative lymphoma patients treated with chemotherapy. Six of these patients had low level of HBV DNA at baseline. HBV reactivation is preventable. Several nonrandomized or randomized studies and meta-analyses have shown that prophylactic antiviral therapy by using lamivudine and more recently entecavir or tenofovir is effective at preventing HBV reactivation.3,4,6,7 The pooled effect estimates of 5 randomized trials evaluating antiviral prophylaxis (lamivudine in 4 randomized controlled trials enrolling HBsAg-positive patients and entecavir in 1 randomized controlled trial enrolling HBsAg-negative, anti-HBc–positive patients) showed that prophylaxis was associated with 87% relative risk reduction of reactivation (95% confidence interval, 70%–90%).8 Antiviral prophylaxis was initiated 1 week before or at the start of chemotherapy and stopped 2–12 months after the end of chemotherapy. Furthermore, patients who received antiviral prophylaxis had less interruption of chemotherapy and lower rates of cancerrelated and all-cause mortality. Thus, HBV screening before the start of immunosuppressive therapy is a major factor to avoid HBV reactivation. HBV-naive patients should be immunized against HBV regardless of a lower efficacy rate to vaccination as compared with healthy subjects. There is now a consensus that HBsAg-positive patients should receive antiviral prophylaxis before immunosuppression.8–13 It is recommended that patients who have a high viral load and/or may receive lengthy and repeated cycles of immunosuppressive therapy should be treated with a high barrier to resistance antiviral, ie, entecavir or tenofovir. The use of antiviral prophylaxis is debated in anti-HBc–positive patients who are HBsAg-negative. However, prophylaxis is usually recommended in the latter group of patients with high risk factors for HBV reactivation, ie, those receiving chemotherapy for hematologic cancer or anti-CD20 antibodies therapy. Other patients are usually monitored so that antiviral therapy is initiated at the first sign of HBV reactivation. In this issue of the journal, Wi et al report the extent of HBV screening before chemotherapy and outcomes of screened patients at a tertiary oncology center between January 1, 2006 and September 30, 2011. This retrospective study was based on an electronic pharmacy
May 2015
database to identify patients who underwent chemotherapy. Testing for HBsAg for any reason at any time before the initiation of chemotherapy was considered as screening. Other HBV markers such as anti-HBc antibody or HBV DNA were not screened. Screening for HBV before chemotherapy occurred in 1279 of 8005 patients (16%), including 668 of 1805 patients (37%) with hematologic malignancies and 611 of 6200 patients (9.8%) with solid organ malignancies. In addition, 523 patients were tested after the chemotherapy was begun. There was no significant difference in the screening rates by race; however, the proportion of Asian patients was only 1.1%. In patients with hematologic malignancies, the screening level increased from 32.7% in 2006–2008 to 40.6% in 2009–2011. Factors associated with screening in the multivariate model included latter time period (odds ratio [OR], 1.26; P < .01), age (OR, 0.99; P < .01), abnormal transaminase level (OR, 3.21; P < .01), and hematologic malignancy (OR, 5.89; P < .01). Thirteen patients were found to have HBV infection (1% among tested patients), and prophylactic antiviral therapy was used in 8 of these patients. None experienced HBV reactivation. Two of the remaining 5 patients experienced HBV reactivation. Of the remaining 6203 patients (77%) never screened for HBV, 812 (13%) had a flare, of which 58 had alanine aminotransferase level 300 U/L. According to the authors, the proportion of patients in whom undiagnosed HBV infection may have been responsible for the flare appeared small. However, results for HBsAg or HBV DNA were not available; thus the real incidence of HBV reactivation is unknown. Potential explanations for the low rate of HBV reactivation in this study include a low prevalence of HBV infection, a lower risk of HBV reactivation during chemotherapy for solid tumors as compared with chemotherapy for hematologic disease, and underestimation of HBV flares because of the lack of data. HBV reactivation could be prevented by the screening of patients for HBV infection, allowing initiation of prophylactic antiviral therapy. Guidelines for HBV screening before cytotoxic or immunosuppressive therapy are controversial. The European Association for the Study of the Liver, the Asian-Pacific Association for the Study of the Liver, and the U.S. Centers for Disease Control and Prevention recommend that all candidates for chemotherapy and immunotherapy should be screened for HBsAg and anti-HBc before initiation of therapy.9–11 The American Association for the Study of Liver Diseases and the American Society of Clinical Oncology recommend screening of patients with risk factors for HBV infection.12,13 The American Gastroenterological Association guidelines on the prevention of HBV reactivation during immunosuppressive drug therapy recommend screening for HBV in patients at moderate or high risk for HBV reactivation (ie, risk of reactivation >1%) who will undergo immunosuppressive therapy.8 HBsAg-positive patients should receive antiviral prophylaxis.8–13 For patients who are anti-HBc–positive and HBsAg-negative,
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the use of antiviral prophylaxis is debated and usually recommended in patients with high risk factors for HBV reactivation, ie, those receiving chemotherapy for hematologic cancer or anti-CD20 antibodies therapy.9 Oncologists report the absence of randomized controlled trials to determine the incidence and predictive factors for HBV reactivation in an era of low risk for HBV infection. Consequently, as reported in the present study, the level of HBV screening in chemotherapy patients in most studies is below 20%, which is far from the guidelines.14,15 The low rate of screening could be related to the uncertainty about who should be screened, the cost of testing, and the fact that oncologists do not consider HBV infection as a major issue. Absence of knowledge does not mean absence of risk. HBsAg and anti-HBc assays are sensitive, specific, and widely available worldwide at a low cost. Risk-based screening is difficult to implement and can miss infected patients who do not recognize or report risk factors. There are limited data on the cost-effectiveness of screening all patients before immunosuppressive drug therapy. However, 2 studies showed that a strategy of screening all patients was cost-effective and cost-saving in patients receiving high-risk chemotherapy.16,17 It is unknown whether universal screening is cost-effective when the risk of reactivation is low (
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Clinical Gastroenterology and Hepatology 2015;13:976–978
used across studies. In a systematic review of 14 studies of 550 HBsAg-positive patients receiving chemotherapy for hematologic or solid organ malignancies, the pooled incidences of HBV reactivation, HBV-related hepatitis, HBV-related liver failure, and HBV-related death were 37% (24%–88%), 33% (24%–88%), 13% (5%–33%), and 7% (0%–63%), respectively.4 The risk of HBV reactivation in HBsAg-negative, anti-HBc–positive patients is 5–8 times lower as compared with HBsAg-positive patients.3 Hui et al5 reported 8 cases (3.3%) of HBV reactivation of 244 HBsAg-negative lymphoma patients treated with chemotherapy. Six of these patients had low level of HBV DNA at baseline. HBV reactivation is preventable. Several nonrandomized or randomized studies and meta-analyses have shown that prophylactic antiviral therapy by using lamivudine and more recently entecavir or tenofovir is effective at preventing HBV reactivation.3,4,6,7 The pooled effect estimates of 5 randomized trials evaluating antiviral prophylaxis (lamivudine in 4 randomized controlled trials enrolling HBsAg-positive patients and entecavir in 1 randomized controlled trial enrolling HBsAg-negative, anti-HBc–positive patients) showed that prophylaxis was associated with 87% relative risk reduction of reactivation (95% confidence interval, 70%–90%).8 Antiviral prophylaxis was initiated 1 week before or at the start of chemotherapy and stopped 2–12 months after the end of chemotherapy. Furthermore, patients who received antiviral prophylaxis had less interruption of chemotherapy and lower rates of cancerrelated and all-cause mortality. Thus, HBV screening before the start of immunosuppressive therapy is a major factor to avoid HBV reactivation. HBV-naive patients should be immunized against HBV regardless of a lower efficacy rate to vaccination as compared with healthy subjects. There is now a consensus that HBsAg-positive patients should receive antiviral prophylaxis before immunosuppression.8–13 It is recommended that patients who have a high viral load and/or may receive lengthy and repeated cycles of immunosuppressive therapy should be treated with a high barrier to resistance antiviral, ie, entecavir or tenofovir. The use of antiviral prophylaxis is debated in anti-HBc–positive patients who are HBsAg-negative. However, prophylaxis is usually recommended in the latter group of patients with high risk factors for HBV reactivation, ie, those receiving chemotherapy for hematologic cancer or anti-CD20 antibodies therapy. Other patients are usually monitored so that antiviral therapy is initiated at the first sign of HBV reactivation. In this issue of the journal, Wi et al report the extent of HBV screening before chemotherapy and outcomes of screened patients at a tertiary oncology center between January 1, 2006 and September 30, 2011. This retrospective study was based on an electronic pharmacy
May 2015
database to identify patients who underwent chemotherapy. Testing for HBsAg for any reason at any time before the initiation of chemotherapy was considered as screening. Other HBV markers such as anti-HBc antibody or HBV DNA were not screened. Screening for HBV before chemotherapy occurred in 1279 of 8005 patients (16%), including 668 of 1805 patients (37%) with hematologic malignancies and 611 of 6200 patients (9.8%) with solid organ malignancies. In addition, 523 patients were tested after the chemotherapy was begun. There was no significant difference in the screening rates by race; however, the proportion of Asian patients was only 1.1%. In patients with hematologic malignancies, the screening level increased from 32.7% in 2006–2008 to 40.6% in 2009–2011. Factors associated with screening in the multivariate model included latter time period (odds ratio [OR], 1.26; P < .01), age (OR, 0.99; P < .01), abnormal transaminase level (OR, 3.21; P < .01), and hematologic malignancy (OR, 5.89; P < .01). Thirteen patients were found to have HBV infection (1% among tested patients), and prophylactic antiviral therapy was used in 8 of these patients. None experienced HBV reactivation. Two of the remaining 5 patients experienced HBV reactivation. Of the remaining 6203 patients (77%) never screened for HBV, 812 (13%) had a flare, of which 58 had alanine aminotransferase level 300 U/L. According to the authors, the proportion of patients in whom undiagnosed HBV infection may have been responsible for the flare appeared small. However, results for HBsAg or HBV DNA were not available; thus the real incidence of HBV reactivation is unknown. Potential explanations for the low rate of HBV reactivation in this study include a low prevalence of HBV infection, a lower risk of HBV reactivation during chemotherapy for solid tumors as compared with chemotherapy for hematologic disease, and underestimation of HBV flares because of the lack of data. HBV reactivation could be prevented by the screening of patients for HBV infection, allowing initiation of prophylactic antiviral therapy. Guidelines for HBV screening before cytotoxic or immunosuppressive therapy are controversial. The European Association for the Study of the Liver, the Asian-Pacific Association for the Study of the Liver, and the U.S. Centers for Disease Control and Prevention recommend that all candidates for chemotherapy and immunotherapy should be screened for HBsAg and anti-HBc before initiation of therapy.9–11 The American Association for the Study of Liver Diseases and the American Society of Clinical Oncology recommend screening of patients with risk factors for HBV infection.12,13 The American Gastroenterological Association guidelines on the prevention of HBV reactivation during immunosuppressive drug therapy recommend screening for HBV in patients at moderate or high risk for HBV reactivation (ie, risk of reactivation >1%) who will undergo immunosuppressive therapy.8 HBsAg-positive patients should receive antiviral prophylaxis.8–13 For patients who are anti-HBc–positive and HBsAg-negative,
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the use of antiviral prophylaxis is debated and usually recommended in patients with high risk factors for HBV reactivation, ie, those receiving chemotherapy for hematologic cancer or anti-CD20 antibodies therapy.9 Oncologists report the absence of randomized controlled trials to determine the incidence and predictive factors for HBV reactivation in an era of low risk for HBV infection. Consequently, as reported in the present study, the level of HBV screening in chemotherapy patients in most studies is below 20%, which is far from the guidelines.14,15 The low rate of screening could be related to the uncertainty about who should be screened, the cost of testing, and the fact that oncologists do not consider HBV infection as a major issue. Absence of knowledge does not mean absence of risk. HBsAg and anti-HBc assays are sensitive, specific, and widely available worldwide at a low cost. Risk-based screening is difficult to implement and can miss infected patients who do not recognize or report risk factors. There are limited data on the cost-effectiveness of screening all patients before immunosuppressive drug therapy. However, 2 studies showed that a strategy of screening all patients was cost-effective and cost-saving in patients receiving high-risk chemotherapy.16,17 It is unknown whether universal screening is cost-effective when the risk of reactivation is low (
