Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab

A 59-year-old man developed acute hepatitis with reactivated hepatitis B virus (HBV) following administration of rituximab (anti-CD20 monoclonal antibody). The patient was diagnosed with malignant lymphoma in 1998, and virus marker testing indicated HBV surface antigen (HBsAg)-negative and anti-HBs antibody (anti-HBs)-positive results when chemotherapy including rituximab was started. Levels of aminotransferases were elevated, and HBsAg results turned positive. Despite therapy for late-onset hepatic failure, the patient died. Rituximab appears likely to have induced HBV reactivation in this case. Anti-viral agents should be administered for both HBsAg-positive and anti-HBs-positive patients who are scheduled to receive rituximab.     

Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B

BACKGROUND: Nucleoside analogues such as lamivudine for chronic hepatitis B have an excellent safety profile while patients are on therapy but reactivation flares occur in 19-50% of patients after stopping therapy, some of whom develop liver decompensation. AIMS: To describe and report three cases who developed fatal hepatitis B reactivation after stopping nucleoside analogue therapy. SUBJECTS AND RESULTS: Three patients are described who developed hepatitis B reactivation and liver decompensation after stopping therapy. One of the three patients was participating in a famciclovir trial and the other two were receiving lamivudine therapy for active hepatitis B infection. All three patients had documented hepatitis B flares, and all had hepatitis B virus DNA detected at that time. All patients developed decompensated liver disease despite one patient having had a prior liver biopsy showing absence of cirrhosis. Reintroduction of lamivudine therapy failed to halt progression of liver decompensation even after hepatitis B virus DNA had been demonstrated to be absent. Sequencing for lamivudine resistant mutants in two cases where serum was available failed to show evidence of mutations associated with lamivudine resistance. CONCLUSION: Hepatitis B virus reactivation, leading to decompensation and death, are possible complications of treatment withdrawal and patients should be monitored closely if therapy is ceased.     

免疫抑制治疗与乙型肝炎病毒再激活

我国是慢性HBV感染高发区,近年虽HBsAg阳性率有所下降,但在3岁以上人口中仍高达9.09%.在日常临床工作中,慢性乙型肝炎病人大多数要由传染科（或感染科）及肝病科（或消化科）医生来诊治;但是,如果慢性乙型肝炎病人患有其他系统疾病,则分别由相应的专科医生来诊治.其中血液或肿瘤科、风湿免疫科、肾病科及器官移植等专业常用的抗肿瘤化疗、免疫抑制和（或）抗排异治疗均可引起HBV的再激活（HBV reactivation）,而导致严重肝损伤甚至肝衰竭,而且原来的药物往往需要减量甚至停用而影响治疗效果.由此可见,这是一个涉及临床各个专业的实际问题.     

Fatal reactivation of hepatitis B virus following cytotoxic chemotherapy for acute myelogenous leukemia: fibrosing cholestatic hepatitis

Hepatitis B virus (HBV) is a well known pathogen that sometimes causes fulminant hepatitis in patients undergoing cytotoxic chemotherapy. Fibrosing cholestatic hepatitis (FCH) is a recently recognized unique variant of viral hepatitis, which has been occasionally reported in HBV-infected recipients of liver, renal, or bone marrow transplantation. We present here a 48-yr-old male in whom HBV was reactivated during post-remission chemotherapy for acute myelogenous leukemia, which resulted in rapidly fatal outcome. He manifested with deterioration of liver function in association with enormous replication of HBV. Liver biopsy showed marked ballooning of hepatocytes, cholestasis, and periportal fibrosis with minimum infiltrates. Immunostaining revealed that hepatocytes were strongly positive for hepatitis B surface antigen. Under the diagnosis of FCH, he was treated with lamivudine and interferon beta, which was not effective. Autopsy showed severe atrophy of the liver and marked degeneration of hepatocytes. Hematologists should be aware that FCH is a fatal complication that can develop under post-chemotherapy immunosuppressed conditions. Although there is no convincing evidence, prophylactic administration of lamivudine seems to be a reasonable strategy.     

Fulminant hepatitis B virus reactivation with concomitant listeriosis after fludarabine and rituximab therapy: case report

Chronic hepatitis B infection poses a problem in patients with malignancies undergoing chemotherapy. Not uncommonly, hepatitis B virus (HBV) reactivates during or soon after chemotherapy. We report a case of a woman with acute prolymphocytic leukemia who received chemotherapy containing fludarabine and cyclophosphamide, followed by the CD 20 monoclonal antibody, rituximab. She developed fatal reactivation of hepatitis B with fulminant liver failure 3 months after completing treatment. Listeria monocytogenes was concomitantly isolated. This case indicates the importance of identifying all hepatitis B carriers and the need to closely monitor and detect reactivation early. Newer chemotherapeutic agents with potentially long-lasting effects on T cells, such as purine analogues, require extended vigilance for reactivation of HBV as well as opportunistic infections. Rituximab is increasingly used alone or in combination with other chemotherapy agents. Its possible contributory role in hepatitis B reactivation needs to be defined.     

Probable corticosteroid-induced reactivation of latent hepatitis B virus infection in an HIV-positive patient involving immune escape

We describe a patient infected with human immunodeficiency virus who possessed a serological profile suggesting a previous cleared acute hepatitis B virus (HBV) infection, including high levels of antibodies against HBV surface antigen (anti-HBs). Following the administration of inhaled glucocorticosteroids combined with protease inhibitor-based antiretroviral treatment, the patient developed an unexpected severe acute hepatitis despite persistence of anti-HBs. A genotype A2 strain emerged with 2 major mutations in the S gene, sK122R and sD144E. Molecular and biological analyses strongly suggested reactivation of a latent HBV infection. The importance and the molecular basis of these 2 epitopes in immune-escape mechanisms and host-virus interactions are discussed.     

Mechanisms of hepatitis B virus escape after immunoglobulin therapy

Passive immunoprophylaxis with hepatitis B immunoglobulin is used to reduce the risk of infection of grafts after liver transplantation and also to protect newborn children of hepatitis B virus-infected mothers. The use of hepatitis B immunoglobulin is associated with the emergence of variant viruses or escape mutants that have specific amino acid substitutions in immunodominant epitopes. Under these circumstances, high serum titres of the virus may be observed in the context of apparently protective levels of antibody to hepatitis B surface antigen. The potential impact of hepatitis B surface antigen variation on vaccination strategies remains a contentious issue. As the burden of hepatitis B virus is dramatically reduced by major vaccination programmes, a greater proportion of carriers will demonstrate hepatitis B surface antigen variation from wild-type. The degree of protection afforded by current vaccines from subsequent infection by variants of the virus is unknown. Concern is raised over the potential impact of hepatitis B surface antigen variation on hepatitis B virus polymerase inhibitor susceptibility, and the reduced sensitivity of current antigen assays for detection of hepatitis B surface antigen variants.     

Fatal liver failure caused by reactivation of lamivudine-resistant hepatitis B virus： A case report

We present a case of fetal liver failure caused by the activation of lamivudine-resistant hepatitis B virus (HBV) nine months after lamivudine treatment. A 57-year old man visited our hospital for the treatment of decompensated chronic hepatitis B. Lamivudine was started in December 2001. Subsequently, serum HBV was negative for HBV DNA with seroconversion from HBeAg to anti-HBe and improvement of liver function. However, HBV DNA and HBeAg were again detected in September 2002. He was complicated by breakthrough hepatitis and admitted to our hospital in November for severely impaired liver function. Vidarabine treatment was started and serum HBV DNA and alanine aminotransferase (ALT) decreased transiently. However, after the start of α-interferon treatment, HBV DNA level increased and liver function deteriorated. He died 1 mo after admission. An analysis of amino acid sequences in the polymerase region revealed that rtM204I/V with rtL80I/V occurred at the time of viral breakthrough. After the start of antiviral treatment, rtL180M was detected in addition to rtM204I/V and rtL80I/V, and became predominant in the terminal stage of the disease. HBV clone with a high replication capacity may be produced by antiviral treatment leading to the worsening of liver function. Antiviral therapy for patients with breakthrough hepatitis in advanced liver disease should be carefully performed.     

Hepatitis B caused by a hepatitis B surface antigen escape mutant

Amino acid substitutions within the S gene involving the major antigenic a determinant of the hepatitis B virus (HBV) surface antigen (HBsAg) have been detected in cases of failure of immunization against the virus. Our report showed development of clinical hepatitis in presence of antibody to HBsAg in a healthy individual. A single amino acid substitution (G145R) within the a determinant of the HBsAg was determined by sequencing of the isolated HBV strain. Lamivudine treatment efficiently cleared the peripheral HBV DNA, HBsAg, and hepatitis B e antigen. In conclusion, the immune escape mutant in the S gene can cause hepatitis despite pre-existing naturally acquired immunity.     

Fatal hepatitis B reactivation after autologous bone marrow transplantation

We report a fatal case of hepatitis B reactivation following autologous bone marrow transplantation for acute lymphocytic leukaemia. The presence of antibodies to HBs and HBc at presentation indicated previous infection with hepatitis B; these antibodies disappeared during the course of treatment for leukaemia. HBsAg was first detected in serum 5 weeks post-transplant; liver function tests began to deteriorate 8 weeks later, when HBeAg was first detected. The hepatitis followed a fulminant course, and the patient died 10 days later, in the 15th week following transplant.     

Fatal hepatic failure caused by chemotherapy-induced reactivation of hepatitis B virus in a patient with hematologic malignancy

A patient with hematologic malignancy and hepatitis B virus (HBV) infection received chemotherapy containing a glucocorticoid. The patient developed severe hepatitis after chemotherapy and, despite achieving complete remission of the malignancy, died of hepatic failure. We carried out a retrospective study of changes in the serological markers of HBV in this patient. Both serum hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) were negative on admission. During the course of chemotherapy, HBsAg gradually became positive, but no liver dysfunction was apparent until after completion of the chemotherapy. The patient showed no initial evidence of being a latent HBV carrier. Therefore, we believe that screening for HBsAg is insufficient for detecting latent HBV carriers, and that investigation for hepatitis B core antibody (HBcAb) is essential.     

拉米夫定预防化疗诱发乙型肝炎病毒再活动的初步研究

我国是乙型肝炎病毒(HBV)感染的高发区，在各种肿瘤患者中并发HBV感染亦属多见。肿瘤患者在接受化疗时，我们多关注抗肿瘤药物对肝脏的影响，而对HBV再活化很少顾及。现报道16例肿瘤伴HBV感染者，化疗后HBV再活化对预后的影响及拉米夫定阻止HBV再活化作用。     

Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers

Viral reactivation in hepatitis B surface antigen (HBsAg) carriers undergoing immunosuppressive therapy is well documented. To evaluate the role of lamivudine prophylaxis in Hepatitis B virus (HBV) carriers treated with immunosuppression for nonhepatic disorders, we reviewed our experience between 1997 and 2000 at Hadassah University Hospital (Jerusalem, Israel). Controls were patients who were HBV carriers and who, between 1990 and 1995, were treated for hematological malignancies but were not treated with lamivudine. Eighteen HBsAg-positive patients were treated with immunosuppression. Fourteen were males, with a mean age of 48 years. Eleven patients had lymphoma; 2 had colonic adenocarcinoma; and 5 had cryoglobulinemia, enophthalmitis, vasculitis, malignant histocytosis, or ulcerative colitis. Fourteen patients were treated with chemotherapy, and 4 with prolonged high-dose corticosteroids. All patients were HBsAg-positive; 4 had hepatitis B e antigen, and 10 had HBV DNA by polymerase chain reaction. Lamivudine was administered to 13 patients in the treatment group 1 to 60 days (mean, 15 days) before immunosuppressive treatment and continued 0.5 to 24 months (mean, 7 months) following initiation of immunosuppression. Mean follow-up after lamivudine administration was 21 months. Three patients died of lymphoma complications and 10 (77%) survived. None of the patients had clinical or serological evidence of HBV reactivation during or after lamivudine prophylaxis. Of 6 patients who presented with liver function test disturbances, 5 improved during combined lamivudine and immunosuppression treatment. At the end of follow-up, HBV DNA became undetectable in 2 of 10 patients. In 2 patients, seroconversion from HBsAg to anti-HBs was observed. In contrast, 2 of 5 control patients had HBV reactivation. Lamivudine prophylaxis in HBsAg carriers receiving immunosuppressive therapy may prevent HBV reactivation and hepatic failure.