Admissions for hepatitis B reactivation in patients receiving immunosuppressive therapy remain unchanged from 1999 to 2014

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1 Hepatol Int (2016) 10: DOI /s ORIGINAL ARTICLE Admissions for hepatitis B reactivation in patients receiving immunosuppressive therapy remain unchanged from 1999 to 2014 Arpan Patel 1 Suna Yapali 1 Anna S. F. Lok 1,2 Received: 2 June 2015 / Accepted: 27 July 2015 / Published online: 14 August 2015 Asian Pacific Association for the Study of the Liver 2015 Abstract Background Reactivation of hepatitis B virus (HBV) replication in patients with chronic or past HBV infection receiving immunosuppressive therapy (IST) can be prevented through HBV screening and prophylactic antiviral therapy. We aimed to determine the occurrence of severe HBV reactivation secondary to IST in the era of HBV nucleos/tide analogs, the implicated IST, and outcomes. Methods We conducted a retrospective chart review of adult patients who were HBsAg? and HBV DNA? and had received IST within 90 days of admission to our hospital. Results Of 1446 patients with HBV diagnosis code admitted from 1999 to 2014, 17 had HBV reactivation, 8 of whom were admitted after Nine patients had hematologic conditions, three solid organ transplants, one hepatocellular carcinoma, and four other nonmalignant diseases. Implicated IST included chemotherapy, prednisone, antirejection therapies, budesonide, and a JAK-2 inhibitor. Three patients were screened for HBV prior to IST, but none was given antiviral prophylaxis. Six patients were initially admitted to other facilities, only two were tested for HBV, and one was started on antiviral therapy Electronic supplementary material The online version of this article (doi: /s ) contains supplementary material, which is available to authorized users. & Anna S. F. Lok aslok@med.umich.edu 1 2 Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA Division of Gastroenterology and Hepatology, University of Michigan Health System, 3912 Taubman Center, SPC 5362, Ann Arbor, MI 48109, USA prior to transfer. At admission to our hospital, all 17 were HBsAg? and HBV DNA?. Despite antiviral therapy, five patients decompensated, three died, and two had a liver transplant. Conclusion Severe HBV reactivation requiring hospital admission continues to occur because HBV screening was not performed and a prophylactic antiviral not given to those who tested positive. HBV reactivation can occur in a variety of clinical settings and in association with drugs not considered to be highly immunosuppressive. Keywords Hepatitis B virus Hepatitis Liver failure Chemotherapy Antiviral therapy Abbreviations anti-hbc Antibody to hepatitis B core antigen anti-hbs Antibody to hepatitis B surface antigen HBsAg Hepatitis B surface antigen HBV Hepatitis B virus HBeAg Hepatitis B e antigen anti-hbe Antibody to hepatitis B e antigen HIV Human immunodeficiency virus TNF Tumor necrosis factor IST Immunosuppressive therapy HCC Hepatocellular carcinoma HCV Hepatitis C virus HDV Hepatitis D virus INR International normalized ratio of prothrombin time ALT Alanine aminotransferase AST Aspartate aminotransferase TACE Transarterial chemoembolization AASLD American Association for the Study of Liver Diseases

2 140 Hepatol Int (2016) 10: EASL APASL CDC AGA ASCO Introduction European Association for the Study of the Liver The Asian Pacific Association for the Study of the Liver Centers for Disease Control and Prevention American Gastroenterological Association American Society of Clinical Oncology Reactivation of hepatitis B virus (HBV) replication in patients receiving immunosuppressive therapies (IST) was first described in the 1970s [1]. While the majority of reports of HBV reactivation were in patients who were hepatitis B surface antigen positive (HBsAg?) receiving cytotoxic therapy for cancer, HBV reactivation can occur in patients who have evidence of a past infection [HBsAg-, antibody to hepatitis B core antigen positive (anti-hbc?)] [2 4]. HBV reactivation has also been reported in a variety of clinical settings including transplant recipients receiving antirejection therapy [5] and patients receiving long-term steroids alone or in combination with other IST for rheumatologic, gastrointestinal, and dermatologic conditions [6, 7]. In recent years with the availability of many biologic agents and targeted cancer therapies, the spectrum of drugs implicated in HBV reactivation has expanded. Of these, anti-cd 20 seems to carry the greatest risk especially when used in combination with other cytotoxic agents. Tumor necrosis factor alpha inhibitors (anti-tnfs) have also been reported to be associated with HBV reactivation not only in HBsAg? patients but also in HBsAg-, anti- HBc? patients. Other drugs that have been incriminated in case reports include tyrosine kinase inhibitors, m-tor inhibitors, and anti-ccr4 monoclonal antibodies [8]. Additional studies are needed to confirm the etiological association of these drugs with HBV reactivation. While many cases of HBV reactivation are subclinical and resolve spontaneously, a systematic study of HBV reactivation in HBsAg? patients receiving cytotoxic therapy found that 33.4 % of patients with HBV reactivation had clinically apparent acute hepatitis, 13 % had acute liver failure, and 5.5 % had liver-related deaths [9]. The importance of HBV reactivation lies in the potential disease severity and ease of its prevention. Abnormal liver chemistries in patients receiving IST can be caused by many conditions including sepsis, drug-induced liver injury, or tumor involvement of the liver, and an association with HBV reactivation may not be suspected unless this diagnosis is considered and tests for HBV are performed [10]. The American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), the Asian Pacific Association for the Study of the Liver (APASL), the 2008 National Institutes of Health Consensus Development Conference on Hepatitis B, the Centers for Disease Control and Prevention (CDC) in the USA, and the American Gastroenterological Association (AGA) all recommend screening patients for hepatitis B prior to beginning IST, but this is often not followed, and cases of severe HBV reactivation continue to occur [11 15]. Recommendations are also available from the National Psoriasis Foundation, American College of Rheumatology, and American Society of Clinical Oncology (ASCO), but there are variations in the recommendations of professional societies, which may contribute to the low uptake in HBV screening and antiviral prophylaxis [16 18]. We conducted this retrospective study with the aim of determining the number of cases of HBV reactivation admitted to our hospital in the last 15 years, identifying the IST that led to the reactivation, determining whether prophylactic antiviral therapy was administered and whether administration of antiviral therapy after the onset of HBV reactivation impacted outcome. Materials and methods We conducted a retrospective review of adult patients admitted to our institution between 1 June 1999 and 1 June 2014 with an ICD-9 diagnosis code for hepatitis B (070.21, , , , , , , , V02.61) after institutional review board approval of the study. Electronic health records were reviewed by two investigators (AP and SY) to identify patients who had evidence of HBV infection and who received IST within 90 days of admission. All cases that were considered to have HBV reactivation were confirmed by the senior author (ASL). Laboratory test results of interest [HBsAg, hepatitis B e antigen (HBeAg), anti-hbc, hepatitis B surface antibody (anti-hbs), hepatitis B e antibody (anti- HBe), HBV DNA, hepatitis C and D and human immunodeficiency virus antibodies (anti-hcv, anti-hdv, anti- HIV), liver panel, and international normalized ratio of prothrombin time (INR)] were queried through a search string. We chose 1999 as the start of the study period because lamivudine was first approved by the US Food and Drug Administration for treatment of hepatitis B in Patients were excluded if they did not have evidence of hepatitis B infection defined as the presence of HBsAg or detectable HBV DNA during that admission. We then identified patients who were receiving IST within 90 days of admission by performing a text search for immunosuppressive drugs (see supplement A) using the Electronic

3 Hepatol Int (2016) 10: Medical Record Search Engine (EMERSE), a program developed at the University of Michigan. Patients were further excluded if they had evidence of HDV or HIV coinfection or if they had prior liver transplantation. One patient had evidence of HCV coinfection but was included because his HCV viral load was low and he had evidence of HBsAg reverse seroconversion and HBV DNA level [66 million IU/ml. HBV reactivation was defined as follows: for patients with HBV tests prior to the start of IST: (1) HBsAg reverse seroconversion (HBsAg- to HBsAg?), (2) [1 log 10 increase in HBV DNA compared to baseline, or (3) HBV DNA undetectable at baseline became detectable; for patients with no pre-ist HBV tests: HBsAg? and HBV DNA [5 log 10 IU/ml. Liver injury was defined as ALT C100 U/l or [2 times baseline ALT. Severe liver injury was defined as liver injury and total bilirubin C3.0 mg/dl or INR C1.5. Liver decompensation was defined as having severe liver injury and ascites, variceal bleeding, or encephalopathy. Prophylactic antiviral therapy was defined as administration of any of the approved nucleos(t)ide analogs for HBV prior to and up to 30 days of the start of IST and before any increase in ALT level. Results During the study period, 1446 patients with HBV diagnosis code were admitted to our hospital. Of these, 545 were HBsAg? and/or HBV DNA?, and 195 of these patients had received IST within 90 days of admission. Fifty-four patients were excluded because they had evidence of HIV or HDV coinfection or prior liver transplantation. Among the 141 patients who met our eligibility criteria, 45 had only short-term steroid use defined as less than 30 days in duration, while the other 96 received IST other than only short-term steroids. Seventeen patients had evidence of HBV reactivation, one of whom had received only shortterm steroids. Figure 1 shows the algorithm for patient selection. Admissions of the 17 patients with HBV reactivation were spread out throughout the study period with three patients admitted between 1999 and 2004, six during , and eight between 2009 and 2014 (Fig. 2). The median age of the patients was 57 years, and the range was years. Most (76 %) of the patients were males. Six patients were Caucasian, five Asian, four African American, and two of unknown race (Table 1). Nine patients had hematologic conditions, including lymphoma, multiple myeloma, myelofibrosis, and acute myelogenous leukemia. Seven of these nine patients received chemotherapy (three with concomitant steroids), one received steroids only, and the patient with myelofibrosis received a JAK-2 inhibitor only. Three patients were receiving triple antirejection therapies after a solid organ transplant that included prednisone and two of the following IST drugs: cyclosporine, sirolimus, tacrolimus, azathioprine, and mycophenolate mofetil (MMF). Two patients had rheumatologic diseases and were receiving long-term steroids, and one was also receiving azathioprine. One patient had chronic obstructive pulmonary disease (COPD) and was receiving long-term systemic steroids. One patient had hepatocellular carcinoma and had trans-arterial chemoembolization (TACE). The remaining patient was receiving budesonide only for Crohn s disease. This latter patient was a 62-year-old female noted to be HBsAg? with ALT 11 U/l at baseline; HBV DNA was not tested. She was started on budesonide as this was deemed to be safer than systemic immunosuppression given her HBV status. ALT increased to 440 U/l within 23 days, when the patient was admitted, and HBV DNA at that time was 8 log 10 IU/ml. Prior to initiation of IST, only three patients were screened for HBV; two were HBsAg? and the third HBsAg-/anti-HBc?/anti-HBs? (Fig. 3). None was tested for HBV DNA, and none was given antiviral prophylaxis. Both HBsAg? patients had normal baseline ALT, while the patient that was HBsAg-/anti-HBc? had baseline ALT of 99 U/l. One patient was found to be HBsAg? 1 year after initiation of IST in the setting of elevated ALT. After referral to hepatology clinic, the patient was found to have an HBV DNA level of 9.3 log 10 IU/ml. This patient was started on lamivudine, but this was stopped for unclear reasons 3 months prior to admission for HBV reactivation. Eleven patients were directly admitted to our institution while six were transferred from other hospitals (Fig. 3). Of the six patients that initially presented to other facilities, all but one had evidence of acute liver injury. Four had evidence of severe liver injury, and none had hepatic decompensation. Only two had HBV serologies checked at the outside hospital. Both were found to be HBsAg?. One of these two had HBV DNA [5 log10 IU/ml, ALT 104 U/l, and total bilirubin 4.7 mg/dl. This patient was started on tenofovir prior to transfer. The other patient had ALT 177 U/l, total bilirubin 12.7 mg/dl, and was not tested for HBV DNA and not started on antiviral treatment prior to transfer. On admission to our hospital, all 17 patients were found to be HBsAg? with detectable HBV DNA in serum, and 14 had HBV DNA [5 log 10 IU/ml. Eleven patients had ALT [100 U/l, and 6 had ALT [500 U/l. During the hospital admission, the mean peak ALT was 915 U/l with a median of 288 U/l and a range of U/l. The mean peak total bilirubin was 9.4 mg/dl with a median of 4.6 mg/dl and a range of mg/dl. Fourteen patients met the criteria for acute liver injury, and 11 met the criteria for severe liver injury (Fig. 3).

4 142 Hepatol Int (2016) 10: Fig. 1 Algorithm for patient selection Fifteen patients (including the patient who was started on tenofovir prior to transfer) were started on antiviral therapy a median of 4 (range 1 60) days after admission. Nine patients were started on entecavir, four on lamivudine, and two on tenofovir. One patient who did not receive antiviral therapy had advanced HCC and chose hospice care. The other patient had HBV DNA [5 log 10 IU/ml. Antiviral therapy was planned but a repeat test 1 month later showed the patient to be HBsAg- despite continuing IST. Multiple subsequent HBsAg and HBV DNA tests in the following months were negative. Despite the administration of antiviral therapy, five patients decompensated and three died: two patients from liver failure and one of complications related to liver transplant (Fig. 3). Two patients with decompensation survived but one required a liver transplant. Table 2 shows that all the patients who decompensated had high bilirubin and INR compared to two of ten who were successfully rescued with antiviral therapy. Of the 14 patients that survived, 13 were followed at our clinics. Six patients had resolution of HBV reactivation defined as return of ALT to baseline or normal and HBV DNA to undetectable, and/or HBsAg loss for patients who were initially HBsAg positive (two patients). Three did not have enough follow-up to comment on resolution, two died a few months later from an unrelated cause, and two had

5 Hepatol Int (2016) 10: Fig. 2 Temporal trend of hospital admissions for HBV reactivation Table 1 Baseline characteristics of the 17 patients with HBV reactivation Characteristics Gender, male 13 (76) Median age, years 57 (range 37 75) Race Caucasian 6 (35) Asian 5 (29) Black 4 (24) Unknown 2 (12) Direct admission 11 (65) Underlying disease Hematologic 9 (53) Solid organ transplant 3 (18) SLE, sarcoidosis 2 (12) COPD 1 (6) HCC 1 (6) Crohn s 1 (6) IST Chemotherapy ± steroid 8 (47) Steroid? other IST 4 (24) Steroid only 4 (24) JAK-2 inhibitor only 1 (6) Data expressed as number (%) unless indicated otherwise SLE systemic lupus erythematosus, COPD chronic obstructive pulmonary disease, HCC hepatocellular carcinoma, IST immunosuppressive therapy marked reduction in HBV DNA but not to undetectable levels at the most recent follow-up, both at 1 month after discharge. Discussion In this retrospective review of a single-center experience in the US, we found 17 patients admitted to our hospital for HBV reactivation secondary to IST between 1999 and 2014 with no indication of a decline over the 15-year study period. Of note, five (29.4 %) patients had hepatic decompensation and three (17.6 %) died. Continued occurrence of severe HBV reactivation due to IST is troubling even though this complication can be prevented. HBV screening is the first step in preventing HBV reactivation. Our study revealed only three (17.6 %) patients were screened for HBV prior to initiation of IST, and none was tested for HBV DNA or administered prophylactic antiviral therapy even though two were HBsAg? and the third HBsAg-/anti-HBc?. Furthermore, only two of six patients initially admitted to an outside hospital had HBV serologies checked, and although both were found to be HBsAg?, only one was started on antiviral therapy prior to transfer to our hospital. The low screening rate might be related to discrepancies among various guidelines regarding which patients should be screened, lack of awareness of HBV reactivation and guideline recommendations, and

6 144 Hepatol Int (2016) 10: Fig. 3 Management and Outcome of Patients with Evidence of HBV reactivation failure to recognize that HBV reactivation can occur in nononcologic settings and in association with medications that may not be considered to be immunosuppressive. Several studies have demonstrated the cost-effectiveness of universal screening strategies for hepatitis B among patients who are potential candidates for IST, even in patients who are not HBsAg? [16 19]. While the most compelling studies demonstrating the cost-effectiveness of universal screening have been performed among high-risk patients receiving chemotherapies and anti-cd20 agents, there is also evidence to support screening among patients who are at lower risk for reactivation [16, 18, 20]. Nevertheless, controversy remains concerning whether it is more cost-effective to conduct universal versus targeted screening in patients who will be receiving IST with low or moderate risk of HBV reactivation, particularly in countries with low prevalence of HBV infection. The AGA, CDC, AASLD, EASL, APASL, and National Psoriasis Foundation all recommend screening patients for hepatitis B prior to initiation of IST by testing for HBsAg and anti-hbc ± anti-hbs [21 23]. The Japanese Society of Hepatology recommends additional testing for HBV DNA to help tailor therapy in patients who are HBsAg- [24]. In contrast, the ASCO guideline previously stated that there is insufficient evidence to recommend routine screening for all patients undergoing IST. Their 2015 update again states that there is insufficient evidence for universal screening for hepatitis B prior to initiation of IST

7 Hepatol Int (2016) 10: Table 2 Clinical features and laboratory data immediately before initiation of antiviral therapy Patient no. Outcome ALT (U/l) INR Bilirubin (mg/dl) 1 Death Death Death [8.0 a 4 Decompensated [8.0 a HBV DNA (log 10 IU/ml) 5 Decompensated [8.23 a 6 Rescued Rescued Rescued Rescued Rescued 137 NA 0.9 [8.23 a 11 Rescued Rescued Rescued Rescued Rescued a Multiple assays were limited by the upper range of detection [25]. Despite current recommendations national surveys show an adoption rate of screening between 13 and 19 % [26, 27]. Chemotherapy, high-dose steroids, and more recently biologics such as anti-cd 20 and anti-tnf have been incriminated in causing HBV reactivation in multiple studies. Our study identified two patients who experienced HBV reactivation after receiving treatment that is not generally considered to be immunosuppressive: budesonide, which has a high affinity for the glucocorticoid receptor and low systemic activity due to its extensive firstpass metabolism in the liver, and JAK-2 inhibitor, which has a specific cytokine signaling pathway, thereby not targeting ubiquitously expressed molecules as traditional IST does. Our findings confirm concerns that the scope of HBV reactivation due to IST is expanding. Whereas steroids, chemotherapy, and antirejection therapies were the cause of HBV reactivation in patients admitted in earlier eras, the incriminated ISTs among the eight patients admitted between 2009 and 2014 included chemotherapy, steroids (budesonide), steroids? chemotherapy? anti- CD20 [2], steroids? antirejection therapies, antirejection therapies? chemotherapy, experimental JAK-2 inhibitor, and chemotherapy? anti-cd20. Thus, more studies are needed to determine which medical conditions and which drugs or biologics might cause HBV reactivation. Such information must be readily available to all physicians, not just oncologists, rheumatologists, gastroenterologists, and dermatologists, as new drugs or biologics are added to the list. This will require concerted effort of multiple professional societies to develop and disseminate consensus recommendations that are evidence based. Our study highlights the importance of preventing HBV reactivation. Two-thirds of our patients had severe liver injury, and despite administration of antiviral therapy after a median of 4 days upon arrival at our hospital, 29 % had hepatic decompensation and 18 % died. In contrast, studies of prophylactic antivirals administered before or concurrently with the start of IST compared to no prophylaxis showed a relative risk of for HBV reactivation and HBV-related hepatitis and for HBV-related death [9]. An alternative strategy to prophylactic antiviral therapy is on-demand antiviral therapy in which patients are closely monitored and antiviral therapy initiated at the first sign of HBV DNA or ALT increase. However, the ondemand approach has been shown to be inferior to prophylactic antiviral therapy in randomized controlled trials in high-risk settings, and the frequency of monitoring adopted in clinical studies may not be feasible in clinical practice [2, 28, 29]. There are several limitations to our study. First, its retrospective nature made it difficult to be certain we identified all cases of HBV reactivation during the study period even though we used automated text search and lab queries to help us screen through all patients with ICD codes of hepatitis B. Second, the lack of baseline HBV testing forced us to rely on multiple definitions for HBV reactivation. Liver injury in patients receiving IST can be due to multiple causes, and it is possible that liver injury in a few of our patients might have been due to other causes. For example, the patient who inadvertently stopped lamivudine might have experienced liver injury from viral relapse because of discontinuation of antiviral therapy. Third, our experience at a tertiary academic center cannot be generalized to other clinical settings.

8 146 Hepatol Int (2016) 10: In summary, our study showed that HBV reactivation continues to occur in patients receiving IST largely because of the lack of HBV screening and the lack of timely administration of antiviral therapy. Our experience showed that antiviral therapy administered after the onset of severe liver injury may not reverse its course, and liver failure and death can ensue. Our findings also indicate that HBV reactivation can be caused by many ISTs and also drugs that are not generally considered to be immunosuppressive. Consensus recommendations from multiple professional societies are urgently needed to guide physicians from all disciplines to prevent HBV reactivation. Compliance with ethical standards Conflict of interest Arpan Patel and Suna Yapali have nothing to disclose. Anna Lok has received research grants from Bristol-Myers Squibb and Gilead Sciences and has served on advisory board of Gilead Science. 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