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Prevention of immunosuppressive therapy or chemotherapy-induced reactivation of hepatitis B virus infection: Joint report of the Intractable Liver Disease Study Group of Japan and the Japanese Study Group of the Standard Antiviral Therapy for Viral Hepatitis

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... (18,19) Patients using nucleos(t)ide analogues against HBV and patients who were hepatitis B core antibody (HBcAb)positive or hepatitis B surface antibody (HBsAb)-positive despite the HBV DNA quantity being below detectable levels were monitored for HBV reactivation by measurement of the HBV DNA levels until 12 months after TACE according to the guidelines of the Japan Society of Hepatology. (20,21) Patients underwent dynamic computed tomography or magnetic resonance imaging to evaluate the efficacy of TACE at baseline and weeks 4 and 12. Efficacy of TACE was evaluated according to the guidelines of both the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (22) and the modified RECIST (mRECIST). (23) Adverse events with hospitalization or extension of hospitalization, any death, or adverse events with a risk of death were defined as serious adverse events. ...
... (9)(10)(11) In addition, no HBV reactivation was observed with appropriate management according to the guidelines of the Japan Society of Hepatology. (20,21) Our results confirmed that dexamethasone for prophylactic treatment of TACE-associated fever, anorexia, and nausea/vomiting was generally well tolerated by HCC patients including those with wellcontrolled DM or IGT and those with HBV infection. ...
Article
This randomized, double-blind, placebo-controlled trial evaluated dexamethasone efficacy at preventing fever, anorexia, and nausea/vomiting, the most frequent adverse events of transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Child-Pugh class A/B patients with HCC and no macrovascular invasion/extrahepatic metastases were randomly assigned to either a dexamethasone regimen (day 1, intravenous dexamethasone [20 mg] and granisetron [3 mg] before TACE; days 2 and 3, intravenous dexamethasone [8 mg]) or a control regimen (day 1, intravenous placebo [saline] and granisetron [3 mg]; days 2 and 3, intravenous placebo). The primary endpoint was complete response, defined as the absence of grade ≥1 fever, anorexia, or nausea/vomiting according to the Common Terminology Criteria for Adverse Events (version 4.0) and no use of rescue therapy for 120 hours after TACE. A total of 120 patients between October 2010 and June 2013 were randomly assigned to treatment groups. Overall the complete response rate was greater with the dexamethasone regimen than with the control regimen (47.5%, 95% confidence interval 34.3%-60.9%, versus 10.2%, 95% confidence interval 3.8%-20.8%; P < 0.001). Cumulative incidences of fever, anorexia, and nausea/vomiting were higher in the control regimen group compared with the dexamethasone group (P < 0.001, P < 0.001, and P = 0.095, respectively). The dexamethasone regimen was generally well tolerated by HCC patients including those with well-controlled diabetes mellitus and those with hepatitis B virus infection. Conclusion: The dexamethasone regimen was more effective than the control regimen at preventing TACE-induced fever, anorexia, and nausea/vomiting in patients with HCC. (Hepatology 2017).
... When powerful immunosuppressants and other drugs are administered to patients with occult HBV, cases have been reported in which reactivation of HBV occurs and serious hepatitis develops (de novo hepatitis) (5). When such agents are used, it has been suggested that, in addition to HBsAg measurement, anti-HBc and hepatitis B surface antibody (anti-HBs) should be measured with a highly sensitive method whenever possible, and if a patient is positive for anti-HBc or anti-HBs, an HBV-DNA assay should be performed, even if the patient is negative for HBsAg (6). Therefore, we investigated the rate of occult HBV infection in dialysis units by conducting searches for HBsAg, anti-HBc and anti-HBs in hemodialysis patients. ...
... In the present study, some patients were found to be positive for HBsAg with CLIA, even though they were negative on MAT. Before conducting immunosuppressant treatment or chemotherapy, it is recommended that highly sensitive tests (CLIA) be performed whenever possible for HBsAg, anti-HBc, and anti-HBs as a measure to prevent de novo hepatitis that occurs from reactivation of HBV (6). This would also be reasonable for HBV surveillance in dialysis units. ...
Article
Hepatitis B surface antigen is widely used in hepatitis B virus surveillance; patients who test negative for the antigen are judged to be uninfected. However, occult hepatitis B virus infection has been confirmed with hepatitis B virus DNA at low levels in the liver and peripheral blood in patients positive for hepatitis B core antibody or hepatitis B surface antibody, even if they test negative for hepatitis B surface antigen. To investigate the prevalence of occult hepatitis B virus in hemodialysis patients, we performed cross-sectional analysis of 161 hemodialysis patients in two related institutions for hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody. Hepatitis B surface antigen, hepatitis B core antibody, or hepatitis B surface antibody was present in 45 patients (28.0%). Hepatitis B virus DNA was present in six patients (3.7%), all of whom also tested positive for hepatitis B core antibody. Hepatitis B surface antibody positivity was unrelated in only one of the six patients. Four of the six patients were positive for hepatitis B surface antigen; however, two (1.3%) of these with occult hepatitis B virus infection were found to be hepatitis B surface antigen negative. Occult hepatitis B virus infection may be missed in hepatitis B virus surveillance using hepatitis B surface antigen alone; therefore, routine hepatitis B core antibody screening is necessary. Patients who test positive for hepatitis B core antibody should undergo further hepatitis B virus DNA testing to enable accurate hepatitis B virus screening.
... This alert was a suitable target to examine the potential for using clinical databases to verify the impact of distributing information to the medical community. Doctors aware of the alert when prescribing immunosuppressive agents would presumably then perform regular screening (such as HBsAg testing) and monitoring (such as HBV-DNA testing) according to Japanese HBV guidelines [6,7]. The percentage of patients tested for HBsAg or monitored for HBV-DNA would be expected to increase. ...
Article
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Background Measures of the effectiveness of risk minimization activities are necessary for the appropriate use of drugs, and clinical databases are a low-cost method of quickly producing such results. Objective The aim of this study was to explore the secondary application of clinical databases in verifying the impact of risk minimization activities; specifically, whether such databases could be used to identify changes in hepatitis B virus testing behavior after an alert from the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Methods Patient data from December 1, 2010 to November 30, 2012 were extracted from the Medical Data Vision clinical database. The percentages of patients tested for hepatitis B virus DNA (HBV-DNA), hepatitis B surface antigen (HBsAg), and hepatitis B surface antibody (HBsAb)/hepatitis B core antibody (HBcAb) were compared 1 year before (consecutive 6-month periods A and B) and 1 year after (consecutive 6-month periods C and D) a PMDA alert regarding viral reactivation in patients receiving immunosuppressive agents. Results Data for 9866 patients in the clinical database were analyzed. After the PMDA alert, the percentage of patients tested for HBV-DNA linearly increased in periods A to D: 4.70 % (n = 262/5571), 5.78 % (n = 330/5710), 6.52 % (n = 398/6101), and 7.59 % (n = 479/6315). However, no changes were observed in the rates of HBsAg and HBcAb/HBsAb testing (around 50 and 70 %, respectively). Overall testing rates appeared to differ depending on disease and drug type. Conclusion These findings suggest that the PMDA alert was effective at recommending HBV-DNA testing. This secondary application of clinical databases may be effective for verifying the impact of risk minimization activities.
... Even though the latter is less frequently seen than the former, strict monitoring and preventive treatment are recommended by guidelines in the USA, 4 Europe, 1 Asia-Pacific 5 and Japan. [6][7][8] Because the prevalence of resolved HBV infection in Japan (23.2%) is much higher than that in Western countries, 9 all patients with rheumatoid arthritis (RA) and other rheumatic diseases (RDs) in Japan who receive immunosuppressive DMARDs, including methotrexate (MTX), leflunomide (LEF), tacrolimus (TAC), mizoribine (MZB), corticosteroids and biological DMARDs, are recommended to be screened and managed according to the guideline developed by the Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. 7 Patients with negative HBsAg results should be screened for HBsAb and HBcAb. ...
Article
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Background Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial. Objectives To investigate the incidence and risk factors for HBV reactivation in patients with RD. Methods We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded. Results Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3–182 months; median, 66 months). Conclusions The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.
... A guideline of Japanese Society of Hepatology to manage de novo hepatitis and reactivation of HBV during and after immunosuppressive drugs, was reported and became popular to use it in Japan. 10,11 Japanese guideline that prevents reactivation de novo hepatitis of HBV is widely used not only by hepatologist but also by hematologist and rheumatologist. Similar guidelines were reported from Europe and USA. ...
... The "Guideline for the Prevention of Immunosuppressive Therapy or Chemotherapy-induced Reactivation of Hepatitis B Virus Infection" was released in Japan in 2009 [3,4]. The contents of this guideline have since been incorporated into the Japan Society of Hepatology (JHS)'s "JSH Guidelines for the Management of Hepatitis B Virus Infection" [5]. ...
Article
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Screening for hepatitis B virus (HBV) infection is recommended worldwide for patients receiving systemic chemotherapy in accordance with clinical guidelines, but compliance varies by country and facility. Alert systems may be useful for promoting screening, but it is unclear how effective such systems are. In this study, we investigated HBV screening procedures and their incorporation into treatment regimens following the implementation of an alert system. An alert system was introduced at our hospital in April 2012. The rates of HBV screening in the periods before and after the introduction of the alert system (September 2010 to March 2012 and April 2012 to October 2013, respectively) were investigated. We collected data on hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and HBV-DNA testing in patients. As a result of this analysis, we developed a system in which pharmacists would intervene to check and confirm whether HBV screening had occurred in patients scheduled to begin treatment with chemotherapy. We named our project the “HBView” project, and the rate of HBV screening and the number of times pharmacists intervened was studied during specific time periods before and after the HBView project commenced (July 2013 to December 2013 and January 2014 to June 2014, respectively). After introducing the alert system, the percentage of patients tested for HBsAb/HBcAb and HBV-DNA increased significantly, from 71.6 % to 84.9 % and from 44.5 % to 69.7 %, respectively. However, the rate of compliance with HBV testing guidelines was not 100 % after interventions. The numbers of patients who were not screened but should have been before and after the introduction of HBView were 6 and 17, respectively. Two patients at risk of HBV reactivation were identified after intervention by pharmacists; their intervention thus prevented HBV reactivation. Compliance with clinical HBV screening guidelines was not sufficiently improved after the introduction of the automatic alert system; however, the HBView project proved useful in reinforcing the automatic alert system.
... These results suggest that older age groups have a greater risk of HBV reactivation. 12 With regard to HBV genotypes in Japan, approximately 30% are genotype B, and approximately 60% are genotype C. 7,13 Genotype A, which has a high probability of becoming chronic and causing horizontal transmission, 14 has tended to increase slightly over the past few years. 7 For the 23 identified HBV carriers in this study, approximately 80% were genotype C, and only 1 HBV carrier was genotype A. The phylogenetic analysis revealed that the only genotype A carrier had genotype A1, which originated in Asia, not in the USA or Europe. ...
Article
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Background & aims: Countermeasures against hepatitis B and C virus (HBV, HCV) infection at work sites in Japan have not yet been implemented. This study aimed to determine the status of viral hepatitis infection among the employees in Japan. Methods: We conducted a workplace-based cross-sectional study from 2011 to 2016 in Hiroshima. HBV and HCV markers were identified during a routine checkup of employees in 15 enterprises. The screening results were sent to employees directly and not to employers. A thorough examination of the participants who screened positive was encouraged by forwarding to them a referral letter by our research group to specialized medical institutions. Results: Of the 3,015 employees, 2,420 (80.3%) underwent hepatitis virus screening. Of these, 13.8% had been screened for hepatitis virus before this survey. The prevalence of HBsAg was 0.95% (N=23, 95% CI: 0.6-1.3%). The prevalence of anti-HBc was as high as 31.5% at age 60-69 years, and 41.5% at age 70 years and over. HCV carriers rate was 0.45% (N=11, 0.2-0.7%) and 54.5% of them had genotype 2. Thirty-four carriers were detected, and 44.1% of them were detected for the first time; 53.3% of the newly detected carriers visited medical institutions with the referral, and underwent a periodic follow-up or treatment. Conclusion: Promoting hepatitis virus screening for employees may help detect carriers who are unaware of their infection and require treatment. Submitting the results to employees with a referral letter to medical institutions at the time of positive diagnosis may be effective.
... The symptom of OLP did not become aggravated. Treatment with immunosuppressive agents, tacrolimus (Prograf ® ), mycophenolate mofetil (CellCept ® ), and prednisolone, and antiviral agents, entecavir (Baraclude ® ) as prophylaxis therapy against hepatitis B virus reactivation [19], was started. Table 1 and Figure 2 show the results of the clinical examinations. ...
Article
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Hepatitis C virus (HCV) infection is frequently associated with various extrahepatic manifestations, such as autoimmune features and immune complex deposit diseases. Oral lichen planus (OLP) is one such extrahepatic manifestation of HCV infection. Recently, direct-acting antivirals (DAA) have proved to be highly effective and safe for the eradication of HCV. Herein, we report a case of OLP accompanied by HCV-related hepatocellular carcinoma (HCC) that disappeared after liver transplantation and achievement of sustained virological response following interferon (IFN)-free treatment with ledipasvir (LDV) and sofosbuvir (SOF). The 50-year-old patient developed erosive OLP during IFN therapy, with hyperthyroidism at 53 years of age and HCC at 55 years. He received immunosuppressive drugs and IFN-free DAA treatment after liver transplantation at 60 years of age, which led to disappearance of the symptoms of OLP. The patient was treated safely and effectively with LDV/SOF, although it is not known whether the disappearance of OLP resulted from the eradication of HCV or the immunosuppressive therapy.
... It is therefore recommended to perform tests for not only HBs antigen but also HBs antibody and HBc antibody at screening (see 3 below). 15,16 Table 1 lists the tests that should be performed and questions that should be asked before the initiation of treatment with biologics, and Table 2 lists those that should be performed periodically after the initiation. Figure 1 shows preventive measures against tuberculosis during the treatment with biologics. ...
Article
The clinical use of adalimumab and infliximab, human anti-tumor necrosis factor (TNF)-α monoclonal antibodies, for psoriasis began in January 2010. In January 2011, ustekinumab, a human anti-interleukin-12/23p40 (IL-12/23p40) monoclonal antibody, was newly approved as the third biologic with an indication for psoriasis. While all of these biologics are expected to exhibit excellent therapeutic effect for psoriasis and to contribute to the improvement of quality of life in patients, these drugs require careful safety measures to prevent adverse drug reactions, such as serious infections. The new guidance, an English version prepared by revising the Japanese Guidance/Safety Manual for Use of Biologics for Psoriasis 2011 (in Japanese), is intended to provide up-to-date, evidence-based recommendations and safety measures on the use of biologics, and describes the optimal use of the three biologics, medical requirements for facilities for using biologics, details of safety measures against reactivation of tuberculosis and hepatitis B virus infection, and recommendable combination therapies with biologics.
... [6][7][8] In Japan, which is one of the HBV-endemic areas, 23.2% of the population has resolved HBV infection, 9 but the HBV screening rate is only 20.4%. 10 In patients with solid tumors with resolved HBV infection, it is necessary to identify a group with high risk and increase their screening rate to prevent de novo hepatitis B. Since 2012, our hospital has been conducting HBV screening in accordance with the Japanese de novo hepatitis B guidelines. 11 We conducted a retrospective study to evaluate the reactivation prevalence and risk factors in patients with resolved HBV infection. At the hospital, HBV screening was conducted according to the Japanese de novo hepatitis B guidelines. ...
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1 Background Reports of hepatitis B virus (HBV) reactivation in solid tumors are very limited, and their frequencies and risk factors were previously unknown. 2 Aim To evaluate the prevalence and risk factors of HBV reactivation in patients with solid tumors with resolved HBV infection. 3 Methods All 1088 patients with solid tumors were assessed for eligibility; 251 patients had resolved HBV infection (negative for HBs antigen and positive for anti‐HBc antibody and/or positive for anti‐HBs antibody), and HBV‐DNA was assessed for 243 of these patients in whom we analyzed the prevalence of HBV reactivation. Risk factors for HBV reactivation were exploratorily evaluated by analysis of a case–control study. 4 Results The prevalence of HBV‐DNA reactivation was 2.1% (95% confidence interval [CI], 0.3–3.9%). We did not observe any exacerbation of HBV‐DNA by early intervention. A low anti‐HBs antibody titer (<10.0 mIU/mL) and high average daily dexamethasone dose (>1.0 mg/day) were high risk factors, with odds ratios of 5.94 (95% CI, 1.15–30.6, P = 0.03) and 8.69 (95% CI, 1.27–58.8, P = 0.02), respectively. 5 Conclusion HBV reactivation in solid tumor patients was relatively rare. Therefore, risk factors that can identify targets for HBV screening must be determined in future studies.
... Thus, follow up for HBV reactivation is obviously necessary for a long period of time after completion of chemotherapy in patients with hematological malignancies, although the follow up for HBV reactivation is recommended for limited periods, such as 12 months, at least 12 months and 2-6 months, after the completion of chemotherapy by some guidelines and consensus statement. [14][15][16] Among the 24 patients who developed acute liver dysfunction at the time of the reactivation, nine patients (38%) had severe or fulminant hepatitis and seven patients (29%) died of liver failure. As previously reported, 17,18 the prognosis of patients who develop liver dysfunction as a complication of HBV reactivation remains poor. ...
... Thus early identification of virologic reactivation is essential to start antiviral therapy and prevent the occurrence of hepatitis B [19,51,65]. Serial HBV-DNA monitoring (monthly during and after chemotherapy for at least 1 year) is a reasonable strategy recommended by the latest Japanese guidelines; in this regard multicenter clinical trial in Japan is now continued [72]. With HBV-DNA NAT antiviral therapy begins when the result is >30 IU/mL and with a highly sensitive HBsAg assay (low limit of detection <0.1 ng/mL) antiviral therapy begin when the test becomes positive [20]. ...
Article
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Occult HBV infection (OBI) is defined as HBV DNA detection in serum or in the liver by sensitive diagnostic tests in HBsAg-negative patients with or without serologic markers of previous viral exposure. OBI seems to be higher among subjects at high risk for HBV infection and with liver disease. OBI can be both a source of virus contamination in blood and organ donations and the reservoir for full blown hepatitis after reactivation. HBV reactivation depends on viral and host factors but these associations have not been analyzed thoroughly. In OBI, it would be best to prevent HBV reactivation which inhibits the development of hepatitis and subsequent mortality. In diverse cases with insufficient data to recommend routine prophylaxis, early identification of virologic reactivation is essential to start antiviral therapy. For retrieving articles regarding OBI, various databases, including OVID, PubMed, Scopus, and ScienceDirect, were used.
... Guidelines for preventing HBV reactivation recommend the administration of nucleoside analogs before the start of immunosuppressive therapy in inactive carriers and at an early stage of HBV reactivation during or after immunosuppressive therapy in transiently infected patients. 29 Despite new therapeutic approaches and intensive care, the prognosis of patients without LT with both types of FH and LOHF appeared similar to that in the previous survey. In contrast, the prognosis of patients receiving LT was good in the present survey. ...
Article
To summarize the annual nationwide survey on fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) between 2004 and 2009 in Japan. The annual survey was performed in a two-step questionnaire process to detail the clinical profile and prognosis of patients in special hospitals. Four hundred and sixty (n = 227 acute type; n = 233 subacute type) patients had FH and 28 patients had LOHF. The mean age of patients with FH and LOHF were 51.1 ± 17.0 and 58.0 ± 14.4 years, respectively. The causes of FH were hepatitis A virus in 3.0%, hepatitis B virus (HBV) in 40.2%, other viruses in 2.0%, autoimmune hepatitis in 8.3%, drug allergy-induced in 14.6% and indeterminate etiology in 29.6% of patients. HBV reactivation due to immunosuppressive therapy was observed in 6.8% of FH patients. The short-term survival rates of patients without liver transplantation (LT) were 48.7% and 24.2% for the acute and subacute type, respectively, and 13.0% for LOHF. The prognosis was poor in patients with HBV reactivation. The implementation rate for LT in FH patients was equivalent to that in the previous survey. The short-term survival rates of total patients, including LT patients, were 54.2% and 40.8% for the acute and subacute type, respectively, and 28.6% for LOHF. The demographic features and etiology of FH patients has gradually changed. HBV reactivation due to immunosuppressive therapy is problematic. Despite advances in therapeutic approaches, the prognosis of patients without LT has not improved.
... Thus, follow up for HBV reactivation is obviously necessary for a long period of time after completion of chemotherapy in patients with hematological malignancies, although the follow up for HBV reactivation is recommended for limited periods, such as 12 months, at least 12 months and 2-6 months, after the completion of chemotherapy by some guidelines and consensus statement. [14][15][16] Among the 24 patients who developed acute liver dysfunction at the time of the reactivation, nine patients (38%) had severe or fulminant hepatitis and seven patients (29%) died of liver failure. As previously reported, 17,18 the prognosis of patients who develop liver dysfunction as a complication of HBV reactivation remains poor. ...
Article
PurposeThe purpose of this multicenter cooperative study was to elucidate the clinical features of hepatitis B virus (HBV) reactivation by chemotherapeutic agents and the patient outcomes after HBV reactivation by a retrospective review of accumulated patients' medical records.Methods Records of a total of 27 patients (hematologic malignancy, 14 patients; solid tumor, 13 patients) from 11 institutions who were diagnosed between June 2005 and October 2010 as having HBV reactivation following chemotherapy were reviewed.ResultsOf the 27 patients with reactivation, 16 patients were HBsAg-positive and 11 were HBsAg-negative prior to the commencement of chemotherapy. Of the 11 patients who were HBsAg-negative prior to the chemotherapy, 10 had hematologic malignancies and 1 had a solid tumor. Of the 14 patients with hematological malignancies with HBV reactivation enrolled in the study, the reactivation occurred more than 12 months after the completion of chemotherapy in 5 patients (36%); on the other hand, none of the patients (0%) with solid tumors developed HBV reactivation more than 12 months after the completion of chemotherapy. Of the 24 patients who had acute liver dysfunction at the diagnosis of HBV reactivation, 9 (38%) had severe hepatitis and 7 (29%) died of liver failure.Conclusions Most of the patients with HBV reactivation who were HBsAg-negative prior to the chemotherapy had underlying hematologic malignancies. Furthermore, patients with hematological malignancies often developed late-onset HBV reactivation. The prognosis of patients who develop acute liver dysfunction as a complication of HBV reactivation is extremely dismal.
Article
Several case reports of hepatitis B virus reactivation after rituximab administration have been documented. We investigated the association between hepatitis B and C and 15 kinds of molecular-targeted drugs for cancer. We compared two databases, the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER) of the Pharmaceuticals and Medical Devices Agency (PMDA). Quantitative analysis involved calculating the reporting odds ratio (ROR) and 95% confidence interval (95% CI) as a measure of disproportionality. ROR is a tool that detects signals of adverse events for individual drugs, with signals detected when the lower limit of the 95% CI of ROR is > 1. We also investigated the timing of the adverse events and the age of the patients. There were 29,017,485 reports in FAERS and 2,079,653 reports in JADER. Signals were detected for rituximab-associated hepatitis B and hepatitis C, trastuzumab-associated hepatitis B, and imatinib-associated hepatitis B. In FAERS, hepatitis B often occurred within 1 month, whereas rituximab-associated hepatitis B often occurred 2-6 months after administration. In JADER, hepatitis B and rituximab-associated hepatitis B often occurred 1-3 months after administration. We conclude that signals of rituximab-associated hepatitis B and hepatitis C, trastuzumab-associated hepatitis B, and imatinib-associated hepatitis B are marked. Analyzing the timing and age of the patient at the occurrence of adverse events may suggest a relationship between drugs and these events.
Article
To evaluate the efficacy and safety of a combined regimen of bendamustine (B) and rituximab (R) in Japanese patients with relapsed/refractory (r/r) indolent B-cell non-Hodgkin lymphomas (B-NHLs) and mantle cell lymphoma (MCL). Patients aged 20-79 years with pathologically confirmed B-NHLs or MCL, which were r/r after 1-2 R-containing regimens, were included in this study. The BR regimen consisted of B (90 mg/m(2)) for two consecutive days and R (375 mg/m(2)) on day 1, 2, or 3. The course was repeated every 4 weeks for up to four cycles. Fifty-three patients were enrolled in this study and analyzed. The diagnosis included follicular lymphoma (FL) (77 %), mucosa-associated lymphoid tissue lymphoma (13 %) and others (10 %). Forty-seven (90 %) patients completed four cycles of treatment as per schedule. Best overall response rate (ORR) and complete response rate (CRR) was 94 and 71 %, respectively (for FL, ORR 95 % and CRR 80 %). The treatment was well tolerated and the primary toxicity was myelosuppression; the incidence of grade 3/4 leukopenia and neutropenia were 42 and 40 %, respectively. There were no grade 5 toxicities. The BR regimen is safe in Japanese patients with r/r indolent B-NHLs and MCL, and is effective for those with r/r indolent B-NHLs. For the evaluation of late toxicity, especially infection, longer follow-up of this cohort is needed.
Article
With hepatitis B virus reactivation, it is crucial to identify patients with high-risk of contracting fatal hepatitis and initiate a prophylactic antiviral treatment. Since April 2016, our institution has introduced a systematic program to encourage prophylactic action for all patients using immunosuppressive agents. High-risk patients were identified in a data warehouse of our electronic medical chart system by applying an in-house software. An alert message was sent to the attending doctor in one of three ways. Strategy 1 was a direct message on paper from the pharmacist monitoring chemotherapy regimens or an on-screen notification two weeks after prescriptions of other immunosuppressants. Strategy 2 was an on-screen notification to remind the risk of prescription followed by a message on paper after two weeks. Strategy 3 was an on-screen notification only. The number of doctors who followed all steps in the guideline within four weeks of prescription were calculated. Rates of successful completion for each strategy were then compared using Ryan's multiple range test. The completion rates were 35.2% (n = 193), 72.6% (n = 449), 66.6% (n = 413), and 50.0% (n = 50) in no program and Strategies 1 through 3, respectively. They were significantly different in all combinations (P < 0.01 or P < 0.05) excluding the comparisons between no program and Strategy 3 or between Strategies 1 and 2. It is suggested that alerting doctors on paper is an effective measure to promote prophylactic action, while the efficacy of on-screen notifications was limited even when shown during prescription.
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The case of a 72-year-old female who identified a lymph node enlargement in the left axilla is reported in the present study. A lymph node biopsy revealed a metastatic adenocarcinoma of the axillary lymph node. Following various assessments, the patient was diagnosed with occult breast cancer and lymph node metastases, for which treatment was initiated. Trastuzumab monotherapy was administered as the patient was elderly, positive for the hepatitis B virus and exhibited the following immunostaining/immunohistochemical analysis results: Estrogen receptor (ER) negative (-), progesterone receptor (PgR) negative (-) and human epidermal growth factor receptor 2 (HER2) positive (3+). Breast ultrasonography was performed 10 months after the initial trastuzumab administration and the left axillary lymph node enlargement had reduced in size and severity. However, a skin rash (erythema) was observed encompassing the left breast and extending into the axilla. As determined by the result of a skin biopsy of this area, the patient was diagnosed with occult breast cancer with cutaneous metastases. The immunohistochemical analysis results obtained from the skin biopsy were similar to those obtained from the lymph nodes: ER (-), PgR (-) and HER2 (3+). Therefore, the patient was switched from trastuzumab to lapatinib monotherapy. The erythema completely disappeared after two months of treatment. At present (34 months following lapatinib monotherapy initiation) no new lesions or severe side-effects have been observed.
Article
We report a female patient withacute hepatitis B due to horizontal transmission of hepatitis B virus from her husband, who suffered fromde novo hepatitis B. A 48-year-old man underwent peripheral blood stem cell transplantation(PBSCT) for adult T cell leukemia/lymphoma (ATLL). Nine months after the initial treatment, he was referred to our hospital because of jaundice.Laboratory datashowedelevatedserum aminotransferase levels and hepatitis B surface antigen (HBsAg) positivity. We diagnosed de novo hepatitis B because a pre-PBSCT serum sample was negative for HBsAg and positive for anti-hepatitis Bcore antibody (HBcAb). His liver function improved with entecavir therapy. Two months after his diagnosis of hepatitis B, his 31-year-old wife was admitted with fever and appetiteloss. She was diagnosed with acute hepatitis B because of increased serum aminotransferase levels and HBsAg and anti-HBc immunoglobulin M positivity. Sequencing of HBV DNA inthe serum obtained from both patientsshowed99.9% homology.Therefore, we diagnosed her acute hepatitis B as due to horizontal transmission of de novo hepatitis Bfrom her husband. HBV derived from de novo hepatitis B should be considered a potential source of infection, although intrafamilial transmission ofde novo hepatitis Bis rare.
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Reactivation of hepatitis B virus (HBV) has recently been reported as a fatal complication in patients undergoing cytotoxic chemotherapy. We herein describe a case of reactivation in a 76-year-old man who had undergone pelvic exenteration for colorectal cancer (CRC). He was treated with a modified FOLFOX6 chemotherapy regimen after the operation. Thirteen months later, his laboratory data showed severe liver dysfunction. His hepatitis B surface antigen (HBsAg) test was positive, and his HBV-DNA level was elevated. We diagnosed the patient with HBV reactivation as his HBsAg test was negative before starting chemotherapy. His liver dysfunction improved after administration of entecavir. This is the first report describing HBV reactivation following chemotherapy for an HBsAg-negative CRC patient.
Article
Despite increasing reports of hepatitis B virus (HBV) reactivation in hematological malignancies, its incidence, and risk factors are still obscure. The aim of this study was to clarify the frequency and risk factors of HBV reactivation in hepatitis B surface antigen (HBsAg) undetectable patients with malignant lymphoma or multiple myeloma, during or after chemotherapy. A total of 109 patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma were enrolled in this study. Anti-hepatitis B surface (anti-HBs) and anti-hepatitis B core (anti-HBc) were checked before treatment, and HBV DNA in sera was quantified monthly during and after chemotherapy. Out of 109 patients, 42 (38.5%) had anti-HBs and 59 (54.1%) had anti-HBc. Among the 59 anti-HBc positive patients, four patients (4/59, 6.8%) showed HBV reactivation during 20.5 median follow-up months. In all four patients with HBV reactivation, peripheral lymphocyte counts before chemotherapy were lower than those without HBV reactivation (P = 0.033). HBV reactivation occurred during and after chemotherapy containing rituximab for non-Hodgkin lymphoma. Four patients, who had HBV reactivation, did not develop de novo hepatitis due to HBV reactivation and were able to undergo chemotherapy against malignant lymphoma as scheduled. Monitoring of HBV DNA in sera is useful for the early diagnosis of HBV reactivation, and preemptive therapy is an useful alternative to prevent hepatitis due to HBV reactivation. Patients must be monitored periodically for HBV-DNA levels during and after chemotherapy. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
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Recent findings suggest that reactivation of hepatitis B (HB) virus (HBV) in renal transplantation recipients with a past HBV infection is an important cause of morbidity and mortality. In the present study, we reviewed the clinical and virologic courses of past HBV infections in recipients following renal transplantation. We retrospectively analyzed pretransplant HB surface antigen (HBsAg), HB core antibody (HBcAb), HB surface antibody (HBsAb), and HBV deoxyribonucleic acid (DNA) levels in 147 patients who underwent renal transplantation at our institution between September 2000 and November 2011. Thirty-four (23.1%) of the patients were diagnosed with a past HBV infection. The mean age of patients with a past HBV infection was significantly older than that of those without (48.4 vs 41.1 years, P = .002), while the duration of hemodialysis (HD) was significantly longer (138 vs 79.5 months, P = .027) and ratio of cadaveric transplantation procedures was higher (41.2% vs 21.2%, P = .035). During the follow-up period after renal transplantation, HBsAg was negative, HBV DNA was undetectable, and serum alanine aminotransferase level was normal in all patients. There were no statistically differences for graft and patient survival, and serum creatinine level between patients with and without a past HBV infection. Our results indicate that a past HBV infection is significantly associated with older age, longer duration of HD, and cadaveric transplantation. However, no HBV reactivation occurred in our previously infected patients, and the presence of HBcAb or HBsAb positivity did not influence graft or patient survival or renal function following renal transplantation.
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A 58-year-old man was diagnosed as a hepatitis B virus (HBV) carrier approximately 30 years ago. He was diagnosed with renal cell carcinoma when he was 57 years old. Radical nephrectomy was performed, and everolimus was administered to treat his lung metastasis. After beginning the everolimus, intermittent fever, general fatigue, and jaundice developed. He was admitted under a diagnosis of flare (acute exacerbation) of chronic B hepatitis due to HBV reactivation. Despite intensive care, he died of hepatic failure and fungus infection. The autopsy findings were compatible with hepatic failure due to HBV reactivation by everolimus. Antiviral prophylaxis must be taken into consideration before beginning immunosuppressive therapy such as everolimus in HBV carriers.
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Docetaxel plus cyclophosphamide (TC) therapy is standard adjuvant chemotherapy for breast cancer. In TC therapy, rash frequently occurs and results in decreased quality of life for patients. In this study, we performed a retrospective analysis of the efficacy of dexamethasone (Dex) for reducing rash associated with TC therapy. Forty-two patients treated with TC therapy at our hospital between April 2012 and March 2014 were examined. The patients were classified into a low Dex group (n = 17), who were administered Dex (6.6 mg) before chemotherapy, and a high Dex group (n = 25), who were administered Dex (13.2 mg) before chemotherapy. On Days 2-4, both groups were orally administered Dex (4 mg/day). The incidence of rash in the low Dex group was Grade 1: 29.4%, Grade 2: 41.2%, Grade 3: 11.8%; the incidence of rash in the high Dex group was Grade 1: 56.0%, and Grade 2: 16.0%. The incidence of rash in the high Dex group was significantly lower than that in the low Dex group (P = 0.031). In both groups, rash appeared frequently in the first course (no significant difference). No difference was observed considering other adverse events between the two groups. Additionally, no other adverse events caused by Dex were observed, including consumption of a sleeping pill, treatment for gastric ulcer, marked worsening of diabetes mellitus, or reactivated hepatitis B virus. Our investigation suggests that administration of increased Dex doses before chemotherapy with TC is effective in reducing rash.
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抄録 症例は75歳,男性.特発性膜性腎症に対し免疫抑制療法を施行されていた.治療開始11カ月後に肝障害が出現し当科入院.膜性腎症診断時のHBs抗原陰性,HBs抗体陰性,HBc抗体陽性であり既往感染例と考えられたが,肝障害出現時にHBs抗原陽転化を認めたため,de novo B型肝炎と診断した.HBV-DNAは9.1 logcopies/mLと上昇しており,核酸アナログ製剤の内服を開始した.以後,トランスアミナーゼ,HBV-DNAともに漸減し,重症化・劇症化することなく経過した.de novo B型肝炎の基礎疾患として本症例のような腎疾患の報告は少なく,文献的考察を加えて報告する.
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Reactivation of hepatitis B virus (HBV) has been reported in patients undergoing systemic chemotherapy or other immunosuppressive therapy, and prophylaxis of HBV reactivation is essential. The Japanese guidelines for HBV reactivation were published in 2009, but there have been some reports that the HBV screening prevalence was low. Therefore, we investigated the preventive measure of HBV reactivation in chemotherapy patients using the Plan-Do-Check-Act (PDCA) cycle and conducted a retrospective survey to clarify the efficacy of this measure. During the period from January 2015 to January 2016, HBV screening was defined as hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody. We compared screening rates before and after starting this measure (January 4, 2015 to July 12, 2015 and July 13, 2015 to January 22, 2016, respectively). Of 440 new patients who received chemotherapy, HBV screening rates before and after starting this measure significantly increased from 24.9% to 79.2%. After starting this measure, we have carried out 6 cycles of the PDCA cycle. The HBV screening rates of each cycle were 63.3%, 65.7%, 82.1%, 86.7%, 87.9%, and 92.6%, respectively. Since the third cycle, ward-pharmacists have checked HBV screening, and the HBV screening rate has been maintained at 80% or more. Despite the HBV screening rate not reaching 100%, these results suggest that the preventive measures of HBV reactivation using the PDCA cycle are highly effective for increasing the HBV screening rate.
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Background: The prophylaxis for hepatitis B virus (HBV) reactivation assumes that hepatic injury after reactivation is often rapidly progressive and can evoke fulminant hepatitis. The incidence and prognosis of reactivation in patients with rheumatoid arthritis (RA) may be different from those receiving organ transplantation and cancer chemotherapy. This study aimed to investigate the incidence, risk factors, and clinical course of HBV reactivation and develop a scoring system for risk stratification in RA patients with resolved infection. Methods: HBV DNA was measured using real-time polymerase chain reaction, and patient data were collected for 4 years in RA patients with resolved HBV infection who were treated with steroids or synthetic or biologic immunosuppressive drugs. Results: Among 1127 patients, HBV DNA was detected in 57 patients (1.65/100 person-years); none of the reactivated patients exhibited worsening of hepatic function. Multivariate logistical analysis revealed that age > 70 years and HB core antibody (HBcAb) positivity alone were independent risk factors for HBV reactivation. HBV DNA ≥ 2.1 log copies/mL was observed in 15 patients (0.43/100 person-years); seven patients were treated with nucleic acid analogs (NAAs), whereas the remaining eight were observed without treatment. Among reactivated cases, 15 cases changed to HBV DNA-negative status spontaneously, whereas 24 cases remained HBV DNA positive < 2.1 log copies/mL during the observation period. We designed the following scoring system: HBV reactivation risk score = 1 × (age > 70 years) + 2 × (HBcAb positivity alone) + 1 × (treatment other than methotrexate monotherapy). This revealed that patients with the highest score had an odds ratio of 13.01 for HBV reactivation, compared to those with the lowest score. Conclusions: Rapid progression and poor outcomes after HBV reactivation were not frequent in RA patients with resolved infection. Our new risk scoring system might be useful for screening and optimization of prophylactic treatment by distinguishing patients with significantly lower reactivation risk.
Article
Hepatitis B arising from hepatitis B virus (HBV) reactivation following chemotherapy or hematopoietic stem cell transplantation has a high risk of mortality. In January 2013, we began checking the HBV screening results of all patients scheduled to undergo chemotherapy. Furthermore, it has been reported that hepatitis B following HBV reactivation may develop even after chemotherapy has been completed. As yet, pharmacists have not been involved in preventive measures against HBV reactivation after the completion of chemotherapy. To address this, we constructed a HBV test confirmation system. In November 2013, we began checking the intervals and results of HBV-DNA tests in the 12 months following the completion of chemotherapy in patients with resolved HBV (hepatitis B surface antigen (HBs-Ag) negative and hepatitis B surface antibody (HBs-Ab) positive and/or hepatitis B core antibody (HBc-Ab) positive). We compared the implementation rate of HBV marker testing before and after initiating our approach. The implementation rate of blood testing for HBs-Ab/HBc-Ab in all patients scheduled to undergo chemotherapy rose significantly to 91%/95%, respectively, from 27%/27% (P < 0.001). In addition, the implementation rate of HBV-DNA testing after the completion of rituximab-steroid combination therapy in patients with resolved HBV rose significantly to 69% from 27% (P < 0.001). The rate after hematopoietic stem cell transplantation rose to 64% from 25%. In conclusion, such an approach by pharmacists is useful as a preventive measure against hepatitis B arising from HBV reactivation.
Article
Hepatitis B virus (HBV) reactivation can be triggered by immunosuppressive chemotherapy. HLA class II molecules may play a role in HBV reactivation. Genetic polymorphism and mRNA expression of HLA class II were examined in patients with latent HBV infection treated with immunosuppressive therapies. Subjects with resolved HBV infection who had undergone treatment with immunosuppressive chemotherapies were retrospectively enrolled (n = 42) and divided into reactivated (n = 9) and non-reactivated groups (n = 33). Patients were genotyped for 17 single nucleotide polymorphisms (SNPs) within HLA class II DPA1 and DPB1, and mRNA expression levels of HLA class II genes were assessed. The frequency of the AA genotype of rs872956, a SNP in HLA-DPB1, was significantly higher in the reactivated group than in the non-reactivated group (55.6% vs. 12.1% , p < 0.05). The frequencies of the T allele and non-AA genotypes (AT/TT) of rs3116996 (located in DPB1) were significantly higher in the reactivated group (T allele frequency: 16.7% vs. 0.0% [p < 0.01], non-AA genotype frequency: 22.2% vs. 0.0% [p < 0.05]). Multivariate logistic regression identified the AA genotype of rs872956 as an independent protective factor against HBV reactivation (odds ratio [OR] = 18.1, 95% confidence interval [CI] = 2.6–126.7, p < 0.01). mRNA expression of HLA-DPB1 was lower in the HBV reactivated group than in the non-reactivated group (median 276.1 ± 165.6/β-actin vs. 371.4 ± 407.5/β-actin [p < 0.05]). These results suggest the involvement of HLA class II molecules in HBV reactivation after treatment with immunomodulatory agents. This article is protected by copyright. All rights reserved
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Objectives: This study aimed to investigate the frequency of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) and to verify the guidelines relating to HBV reactivation in Japan. Methods: We retrospectively investigated 1,351 RA patients who were treated with antirheumatic drugs at our hospital. Results: Fifty patients (3.7%; 50/1351) were determined to be HBV carriers and 360 patients (26.7%; 360/1351) had resolved infections. HBV reactivation occurred in 6 cases (1.7%: 6/360) with resolved infections, of whom, 2 cases (0.6%; 2/360) developed de novo HBV infections. Eleven of the patients who were HBV carriers received a nucleoside analogue (NA) prophylactically. In all of the cases, the HBV-DNA levels became undetectable and the patients’ liver function normalized. Sixteen patients, who had lower titers of the HBV surface antigen and undetectable HBV-DNA levels, did not show HBV reactivation in the absence of NA therapy. Conclusions: The results from this study suggest that HBV reactivation might not be so frequent among RA patients, and that reliable indicators for prescribing a NA should be clarified for RA patients.
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A 68-year-old man with occult hepatitis B virus (HBV) infection was diagnosed with malignant lymphoma and achieved complete remission after treatment with a chemotherapy regimen including rituximab for 5 months. Entecavir (ETV) was also used during and after chemotherapy and was ended at 14 months after chemotherapy. However, reactivation of HBV was observed in blood tests, which showed not only elevation of HBV-DNA but also HBsAg and HBeAg, at 27 months after the end of chemotherapy. After restarting ETV, the HBV-DNA levels immediately subsided. In addition, anti-HBs became and remained positive at 31 months after chemotherapy. ETV was re-discontinued at 36 months after chemotherapy.
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A hepatologist have three major roles in a liver transplantation in Japan: pretransplant evaluation for liver transplant recipients and living donors; management of recurrent liver diseases after transplantation; and research based on new aspects of liver transplantation. All roles are performed in collaboration with medical staff personnel in many clinical departments. This collaboration results in the improvement of prognosis after a liver transplantation and the development of hepatology.
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Although herpes simplex virus (HSV) infection manifests with a range of symptoms, progression to fulminant hepatitis is rare. We describe herein our experience treating a patient with HSV that developed into fulminant hepatitis and virus-associated hemophagocytic syndrome (VAHS). The patient was a 26-year-old woman who initially presented to another hospital with chief complaints of fever and general malaise, and was immediately admitted based on a diagnosis of acute hepatitis. Hepatic dysfunction failed to improve, so she was then referred to our hospital and admitted to our Department of Gastroenterological Medicine for further care and was then transferred to the intensive care unit the following day for systemic care. Fulminant hepatitis, hemophagocytic syndrome (HPS), and disseminated intravascular coagulation were diagnosed based on the findings of physical examination and hematology on admission, and she was started on plasma exchange, high-dose steroid therapy, and immunosuppressive therapy. HSV was subsequently identified as the underlying cause based on the results of virus antibody testing and liver biopsy immunostaining, and antiviral drugs were added to the treatment regimen. The patient responded to treatment and was released from the ICU 13 days after admission. While fulminant HSV hepatitis is rare, delays in treatment can adversely impact patient prognosis. Early biopsy should therefore be considered in the event of fulminant hepatitis of HSV.
Article
A 63-year-old female and a 63-year-old male with resolved HBV infection suffered a relapse of malignant lymphoma. After bendamustine hydrochloride monotherapy, HBV reactivation occurred. Entecavir treatment was commenced immediately, with tests for HBV DNA negative without development of hepatitis. Regular monitoring of HBV DNA based on the guidelines from the Japan Society of Hepatology was useful.
Article
Recently, the high mortality rate resulting from the reactivation of hepatitis B virus (HBV) through the use of immunosuppressive therapy or chemotherapy for fulminant hepatitis patients has been recognized as one of the most critical medical issues. On May 19, 2014, we started a collaborative drug therapy management (HBV-CDTM) project to establish a preventive procedure that can be used to avoid HBV reactivation. Before starting the project, the project protocol developed by the commission of chemotherapy was approved by the Director of Iwakuni Clinical Center. We decided to manage the HBV screening demonstrated in the hepatitis B treatment guidelines in collaboration with pharmacists, doctors and medical technologists. To fill in clinical records when conducting HBV-CDTM, we used the “eXChart” of the electronic clinical record system “HOPE/EGMAIN-GX” to simplify tasks, information sharing among medical staff members with different duties and collection of electronic clinical data. From May 19, 2014 to January 31, 2015, we applied HBV-CDTM to 211 patients in total, and found three patients (1.4%) were hepatitis B surface antigen (HBsAg)-positive, and 75 patients (35.5%) were hepatitis B core antibody positive and/or hepatitis B surface antibody-positive despite being HBsAg-negative. We extracted 78 high-risk patients of HBV reactivation through HBV-CDTM. In addition, the operation rate of HBV screening examination after the introduction of HBV-CDTM rose to 98.6% from that of 3.2% before introduction. Through the HBV-CDTM project, we concluded that the introduction of HBV-CDTM enabled reduction of doctors' loads and enhanced the preventive procedure against HBV reactivation.
Article
Reactivation of hepatitis B virus (HBV) and de novo HBV hepatitis in patients with rheumatic diseases given intensive and long-term immunosuppressive therapy with or without biological disease-modifying antirheumatic drugs is of great concern, especially in regions where the virus is endemic, including Japan. To ascertain a better benefit-risk balance for immunosuppressive therapy for patients with rheumatic diseases, the Japan College of Rheumatology developed this proposal. All patients with rheumatic diseases commencing immunosuppressive therapy should be screened for hepatitis B surface antigen (HBsAg); those who are negative for HBsAg should be screened for hepatitis B core antibody (HBcAb) and hepatitis B surface antibody (HBsAb) as well. HBV carriers and serum HBV DNA positive patients with resolved infection should receive nucleoside analog as soon as possible, prior to commencing immunosuppressive therapy. For serum HBV DNA negative patients with resolved infection, careful monthly monitoring using serum levels of aspartate and alanine aminotransferases and HBV DNA is recommended during and at least 12 months after withdrawal of immunosuppressive therapy. If serum HBV DNA becomes positive, patients should receive nucleoside analog treatment as soon as possible, while ongoing immunosuppressive therapy should be continued to avoid severe or fulminant hepatitis development. To facilitate proper management of patients with HBV infection, collaboration between rheumatologists and hepatologists is strongly encouraged.
Article
Glucocorticoids have been shown to influence the severity of hepatitis B virus–related chronic hepatitis in human. However, very little is known about the effects of glucocorticoids on hepatitis B virus replication in vitro. In this report, we used a welldifferentiated human hepatoma cell line, Hep3B, transfected with hepatitis B virus complementary DNA as a model to show that a glucocorticoid analog, dexamethasone, can directly stimulate the production of HBsAg and HBeAg. Elevation of 3.5-kb pregenomic RNA and all other viral RNAs in the transfected Hep3B cells after dexamethasone treatment supports the hypothesis that glucocorticoids directly stimulate hepatitis B virus gene expression in vitro. The concentration of dexamethasone for its half-maximal stimulatory activity toward HBsAg, HBeAg and all viral transcripts was approximately 10–8 mol/L, close to the affinity of glucocorticoid receptors to [3H]triamcinolone acetonide in Hep3B cells ( ± 10–8 mol/L). Specific glucocorticoid antagonist RU38486 completely blocked dexamethasone-induced HBV gene expression, suggesting that the stimulatory effect of dexamethasone was mediated through specific glucocorticoid receptors. (HEPATOLOGY 1992;16:13–18.)
Article
Hepatitis virus infection through virus reactivation has a high risk of mortality in patients with hematological malignancies receiving chemotherapy. We examined the incidence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and severe liver dysfunction (alanine aminotransferase >ten times the normal upper limit and total bilirubin >5 mg/dl) during chemotherapy in 268 patients with hematological malignancies. Eight patients (3.0%) were infected with HBV and 22 patients (8.2%) were infected with HCV. One patient (0.4%) was infected with both HBV and HCV. HBV- or HCV-infected patients showed severe liver dysfunction at a significantly higher incidence than non-infected patients (11/31 (35.5%) vs. 0/237 (0%), p<0.0001). Furthermore, the incidence of severe liver dysfunction in HBV-infected patients was significantly higher than in HCV-infected patients (6/8 (75.0%) vs. 4/22 (18.2%), p<0.01). Three of eight HBV-infected patients were initially negative for hepatitis B surface antigen (HBsAg) by latex agglutination and became positive for HBsAg during chemotherapy. Furthermore, all three patients developed severe liver dysfunction and two developed fatal fulminant hepatitis. From an examination of the original stock of serum samples before chemotherapy, two patients were found to be positive for HBV-DNA by polymerase chain reaction (PCR). Although post-transfusion HBV infection was suspected in the one remaining patient, the cause of HBV infection could not be clarified due to the impossibility of examination in blood donors. Since HBV-infected patients develop severe liver dysfunction at a higher incidence than either patients not infected with virus or HCV-infected patients before chemotherapy for hematological malignancies, it is recommended that HBV-DNA should be tested by PCR to detect HBV marker-negative carriers and liver function tests should be carefully monitored.
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