Hepatitis B Virus Reactivation After Cytotoxic Chemotherapy: The Disease and Its Prevention

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4: REVIEW Hepatitis B Virus Reactivation After Cytotoxic Chemotherapy: The Disease and Its Prevention AYSE L. MINDIKOGLU, ARIE REGEV, and EUGENE R. SCHIFF Center for Liver Diseases, Division of Hepatology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida See CME exam on page Reactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy. In most cases, reactivations occur in patients who are carriers of HBV infection showing positive hepatitis B surface antigen (HBsAg). Reactivation also may occur in patients with resolved infection who are HBsAg negative, anti HBs positive, and anti hepatitis B core positive. HBV reactivations can lead to severe flares that may be life-threatening unless recognized and treated promptly. Physician awareness is essential because prophylactic antiviral treatment can diminish the occurrence and improve the outcome of such episodes. Patients undergoing cytotoxic therapy should be checked routinely for HBV serologic markers and serum HBV DNA levels. Patients who are HBV carriers or anti hepatitis B core positive should be monitored closely during and after the administration of cytotoxic chemotherapy. Prophylactic treatment with a nucleoside or nucleotide analogue should be considered strongly to prevent HBV reactivation in these patients. Hepatitis B remains one of the major causes of acute and chronic liver disease. It is estimated that million people have chronic hepatitis B virus (HBV) infection worldwide. HBV reactivation in patients who receive cytotoxic or immunosuppressive therapy is well documented. It generally is characterized by the reappearance of HBV DNA or hepatitis B e antigen (HBeAg) in a person who is an inactive HBV carrier or has resolved HBV infection. 1 3 The reappearance of markers of activity may be asymptomatic but often is followed by a clinical flare characterized by a substantial increase of serum transaminase levels and histologic evidence of active inflammation. Occasionally, such flares may lead to fatal hepatic failure. 4,5 According to current guidelines and treatment algorithms, the different phases and activity states of chronic HBV infection are largely defined based on 5 serologic tests and serum levels of HBV DNA determined by polymerase chain reaction (PCR) (Table 1). Case series and studies vary in the definition of HBV reactivation. Early case reports were published before testing for HBV DNA was available. As a result, HBV reactivation and flare were defined based on clinical features such as jaundice and increasing serum levels of transaminases in the absence of other causes, 6,7 or the reappearance or increase of serum levels of hepatitis B surface antigen (HBsAg) in patients with previously undetected or low levels. 8,9 Subsequent publications defined HBV reactivation based on the earlier-described criteria with the addition of the appearance or a marked increase in serum HBV DNA levels. 4,5,10,11 When present, seroconversion from anti- HBe to HBeAg positivity or the reappearance of anti hepatitis B core (HBc) immunoglobulin M is considered strong evidence for reactivation In recent studies, HBV reactivation was defined as a 10-fold or greater increase in HBV DNA level compared with the prereactivation level or the reappearance of a previously negative HBsAg on 2 consecutive tests. 11,13 There is limited information regarding the effect of prophylactic treatment on the risk of HBV reactivation in patients treated with anticancer chemotherapy. Furthermore, studies addressing this question include different patient populations consisting of inactive chronic carriers, patients with resolved HBV infection, and patients with chronic hepatitis B in the replicative state (Table 1). The outcome and survival rates are therefore reported based on mixed groups of patients. This review focuses on the cumulative experience with incidence, clinical manifestations, and prophylaxis for HBV reactivation after immunosuppressive therapy. Epidemiology The risk for HBV reactivation after cytotoxic chemotherapy varies greatly in different case series. The frequency of reactivation in HBV carriers has been reported in the range of 14% 72%. 5,14 18 This variation may be related to differences in study designs, HBV DNA assays, definitions of HBV reactivation, types of malignancy, regimens of chemotherapy, and patient populations consisting of not only inactive carriers or those with resolved hepatitis B but also patients with chronic HBV infection in the replicative phase (Table 1). Although the frequency of HBV and reactivation varies considerably between published reports, it is clear that chemotherapy administered to cancer patients who have chronic HBV infection leads to an increased risk for liver-related morbidity and mortality. 20 Abbreviations used in this paper: HBc, hepatitis B core; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction by the American Gastroenterological Association (AGA) Institute /06/$32.00 doi: /j.cgh

2 September 2006 HBV REACTIVATION AFTER CYTOTOXIC CHEMOTHERAPY 1077 Table 1. Terminology Used for Different Phases and Activity States of Chronic HBV Infection HBsAg Anti-HBs HBeAg Anti-HBe Anti-HBc Typical HBV DNA level by PCR (copies/ml) Resolved infection Undetectable Inactive carrier state 10 4 Replicative phase (HBeAg chronic hepatitis) 10 5 Replicative phase (HBeAg chronic hepatitis) 10 4 HBsAg, hepatitis B surface antigen; Anti-HBs, anti hepatitis B surface; anti-hbe, anti hepatitis B e; anti-hbc, anti hepatitis B core; HBV DNA, hepatitis B virus deoxyribonucleic acid; PCR, polymerase chain reaction. Patients with resolved HBV infection (HBsAg negative, anti HBs positive, anti HBc positive) are also at risk for HBV reactivation during cytotoxic chemotherapy. It is well established that individuals who cleared the surface antigen and have serologic evidence of immunity (anti-hbs) after HBV infection, still may harbor and transmit the virus. 21 Contrary to what is expected, the presence of anti-hbs, which generally is considered a protective antibody, does not eliminate the possibility of reactivation during immunosuppression. Although HBV reactivation seems to occur significantly less commonly in HBsAgnegative patients, it has been described in about 14% 20% of anti HBc-positive anti HBs-positive individuals who received chemotherapy for lymphoma. 5,18 The chemotherapy-induced reactivation inhbsag-negative patients with detectable anti- HBc and anti-hbs appears to be associated with an ongoing HBV replication by the episomal form of the virus. 22 Fulminant hepatitis also may develop in HBsAg-negative and anti HBspositive patients secondary to HBV reactivation. 23 A third important population at risk for flare is patients with chronic HBV infection in the replicative phase (Table 1). This has been shown in both HBeAg-positive patients 16 and HBeAg-negative patients (precore or core-promoter mutations). 24,25 In the latter group, chemotherapy-induced reactivation seems to carry a higher risk for fulminant hepatitis and liver failure. 24,25 Risk Factors Several factors are associated with an increased risk for HBV reactivation among HBV carriers. These include a diagnosis of lymphoma or breast cancer, male sex, young age, preexisting hepatitis, certain cytotoxic drugs (anthracyclines or vincristine), and higher HBV DNA levels based on real-time PCR measurement. 5,16,26,27 The baseline hepatic biochemical tests including alanine transaminase, total bilirubin, and albumin levels were not associated with a higher risk for HBV reactivation. A high HBV DNA level ( 10 5 copies/ml) before administration of chemotherapy was reported as the most important risk factor for HBV reactivation. 11,16 Whether steroid-free chemotherapy decreases the incidence of HBV reactivation needs to be investigated further because of conflicting reports in the literature. 28,29 In addition, transarterial chemolipiodolization is an important risk factor for HBV reactivation. In 1 study, 33.7% of hepatocellular carcinoma patients undergoing transarterial chemolipiodolization were reported to have HBV reactivation. 30 It is important to note that half of the patients who were reported to have HBV reactivation already were HBeAg positive before the chemotherapy, indicating an active HBV replication at least in some of these patients. HBV patients who were co-infected with hepatitis C virus also were found to be at higher risk for severe liver dysfunction during cytotoxic chemotherapy. 23 Pathogenesis Most episodes of chemotherapy-induced HBV reactivation are caused by a change in the balance between the immunologic response to HBV and the extent of viral proliferation. Cytotoxic therapy may suppress the normal immune function, enhance the viral replication, and, eventually, result in increased HBV DNA polymerase activity and HBV DNA and HBeAg levels, reappearance of HBsAg, and decreased HBsAb titers. 18,27,31,32 Subsequent discontinuation of chemotherapy, which leads to restoration of the immune system, results in immune-mediated destruction of hepatocytes infected with HBV. 33,34 The severity of the viral replication during cytotoxic therapy and the liver damage on withdrawal of therapy seems to be associated directly with the potency of the immunosuppressive or cytotoxic therapy. 18 HBV reactivation occurs not only on withdrawal of immunosuppressive therapy, but also during persistent immunosuppression, suggesting that a direct cytopathic effect of the virus may play a role in the mechanism of HBV reactivation. 27 In addition, the glucocorticoid-responsive element of HBV that is stimulated by glucocorticoids may be important in HBV reactivation. 18,34 It has been shown that the glucocorticoid-responsive element induces replication and transcription of hepatitis HBV. 18 Clinical Manifestations Clinical manifestations of chemotherapy-induced HBV reactivation range from asymptomatic increase of serum transaminase levels to acute liver failure and death. 24,27 Serologic evidence for HBV reactivation was reported as early as 4 weeks and the median onset at 16 weeks after the first course of chemotherapy. 31 Severely affected patients may present with jaundice and can develop ascites and hepatic encephalopathy rapidly. In a prospective study, 50% of patients who developed HBV reactivation were icteric. 5 The incidence of ascites and encephalopathy was reported as 7% and 4% for HBsAg-positive and HBsAg-negative patients, respectively. 5 Liver-related mortality ranges from 5% to 22%. 5,19,35 Prevention Since 1992, 5 medications have been approved for treatment of chronic HBV infection. These include interferon alfa- 2b, lamivudine, adefovir, entecavir, and pegylated interferon alfa-2a. 1,36,37 So far, lamivudine has been used almost exclusively in clinical studies as prophylactic therapy to prevent HBV

3 1078 MINDIKOGLU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 9 Table 2. Prophylactic/Preemptive Therapy for the Prevention of Chemotherapy-Induced HBV Reactivation Study Year No. of patients and medications in prophylactic/ preemptive group Serology before chemotherapy Tumor types Type of chemotherapy Lau et al lamivudine 15 HBsAg, 4 HBeAg, 3 HBV DNA 12 NHL, 3 HL CEOP/ABVD/CHOP/COPP/others Idilman et al lamivudine 8 HBsAg, 8 HBeAg, 8 HBeAb, 1 AML, 1 HL, 3 NHL, 1 ALL, 1CLL,1MM CHOP, IDA ARA-C, ABVD, 2-CdA, hyper-cvad, fludurabine, VAD Yeo et al lamivudine 65 HBsAg, 7 HBeAg, 13 HBV DNA Dai et al lamivudine 3 HBsAg, 3 HBeAg, 3 HBeAb, 3 HBV DNA, 1 with unknown serology Leaw et al interferon, 11 lamivudine 17 NHL, 19 breast, 4 lung, 18 gastrointestinal, 4 gynecologic malignancies, 3 other cancers Steroids/anthracycline and vinca alkaloid containing regimen 4 diffuse large B-cell NHL Rituximab CHOP 24 HBsAg 24 aggressive lymphoma CEOP, BACOP, ACVB, m-bacod, BACOP-B, PACEBOM Nagamatsu lamivudine 8 HBsAg, 8 HBeAg Hepatocellular carcinoma Transhepatic arterial infusion et al 46 chemotherapy with FEM or FP regimen Hui et al lamivudine 46 HBsAg, 11 HBeAg, 35 HBeAb, 16 HBV, DNA 10 4 copies/ml 33 NHL, 2 HL, 8 AML, 3MM Steroids, anthracycline, and vinca alkaloid containing regimens NHL, non-hodgkin s lymphoma; HL, Hodgkin s lymphoma; AML, acute myeloblastic leukemia; ALL, acute lymphoblastic lymphoma; CLL, chronic lymphoblastic leukemia; MM, multiple myeloma; CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; ABVD, adriamycin, bleomycin, vinblastin, decarbazine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; COPP, cyclophosphamide, vincristine, procarbazine, prednisolone; BACOP, bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone; ACVB, doxorubicin, cyclophosphamide, vindesine, bleomycin; m-bacod, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; MACOP-B, methotrexate, doxorubicin, cyclophosphamide, prednisone, bleomycin; PACEBOM, prednisone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, methotrexate; IDA ARA-C, idarubicin, cytosine arabinoside; 2-CdA, 2-chlorodeoxyadenosine, cladribine; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; FEM, epirubicine, mytomycin-c, fluorouracil; FP, 5-fluorouracil, cysplatin. reactivation caused by immunosuppressive treatment. In most of these studies, prophylactic lamivudine administration has proven effective for the primary prevention of HBV reactivation (Table 2). In 1 nonrandomized study, a daily dose of 100 mg of lamivudine was used as a prophylactic regimen in 65 HBsAgpositive patients receiving cytotoxic chemotherapy. This group was compared to a historical control group. Twenty percent of the patients in the prophylactic lamivudine group and 19% of patients in the control group had detectable HBV DNA before the chemotherapy. 38 Lamivudine was started within 7 days before the initiation of chemotherapy and discontinued 8 weeks after the. In the prophylactic lamivudine group, HBV reactivation was significantly less frequent in the group who received prophylactic lamivudine compared with historical controls (4.6% vs 24.4%). In a recent randomized trial, a 100-mg daily dose of lamivudine was given to 30 HBsAg-positive lymphoma patients preemptively starting 1 week before chemotherapy or only when there was serologic evidence of HBV reactivation. 31 Twenty percent of the patients in the early preemptive lamivudine group and 33% of patients in the control group had detectable HBV DNA before chemotherapy. In the absence of HBV reactivation, the early preemptive treatment was discontinued 6 weeks or later after the. There was no HBV reactivation in the early preemptive lamivudine group, whereas 53% of the patients who did not receive early preemptive lamivudine had HBV reactivation. HBV reactivation free survival in patients who received early pre-emptive lamivudine therapy was reported as significantly longer than in patients who were treated only after reactivation. Idilman et al 34 conducted a cohort study consisting of 18 inactive chronic HBV carriers. Eight patients were started on a daily dose of 100 mg prophylactic lamivudine on the same day as chemotherapy and continued for a year after the discontinuation of chemotherapy. No HBV reactivation was observed in patients who received prophylactic lamivudine in contrast to 50% HBV reactivation in patients who did not receive prophylactic lamivudine therapy. Despite these encouraging results, the optimal time to start and discontinue lamivudine prophylaxis in patients undergoing chemotherapy remains to be determined. One of the major concerns with early initiation and longterm lamivudine therapy exceeding 6 months duration is the emergence of lamivudine-resistant mutant strains (YMDD mu-

4 September 2006 HBV REACTIVATION AFTER CYTOTOXIC CHEMOTHERAPY 1079 Table 2. Continued Time to initiation of prophylactic/preemptive therapy Duration of prophylactic/preemptive therapy Dose of lamivudine/interferon Outcome 1 week before chemotherapy Continued minimum 6 weeks after and until white blood cell count normalized At the initiation of chemotherapy Within 7 days before the initiation of chemotherapy Continued 1 year after discontinuation of chemotherapy Continued 8 weeks after 100 mg/day No HBV reactivation in lamivudine group 100 mg/day No HBV reactivation in lamivudine group, 50% survival in lamivudine group without HBV reactivation 100 mg/day HBV reactivation in 4.6% of patients in lamivudine group 1 week before chemotherapy Continued 4 weeks after 100 mg/day Delayed HBV reactivation in all patients At the initiation of chemotherapy Average period was 28 days before chemotherapy Continued 4 8 weeks after 1 week before chemotherapy Continued months after 13 received SC alfa-interferon 3 10/U 3 times wk, 11 received lamivudine 100 mg/day No clinical hepatitis, 100% survival in lamivudine group, 54% survival in interferon group without reactivation Throughout chemotherapy 100 mg/day No hepatitis B exacerbation during the chemotherapy, HBeAg seroconversion occurred in 3 patients 100 mg/day HBV reactivation in 23.9% of patients tation), which may occur in up to 32% of patients at 1 year. 31,38,39 However, YMDD mutation has been described in a relatively low percentage (1.6%) of patients receiving lamivudine prophylaxis during cytotoxic chemotherapy. 40 The use of lamivudine also may be associated with acute flares of HBV on discontinuation of therapy. A flare of hepatitis after lamivudine withdrawal was reported in as many as 20% of patients. 41 In a prospective study of 4 HBsAg-positive lymphoma patients who received prophylactic lamivudine therapy until 4 weeks after the discontinuation of chemotherapy, HBV flare occurred 5 and 7 months after the discontinuation of lamivudine. 42 In another recent study, 46 HBsAg-positive patients were treated with pre-emptive lamivudine throughout the chemotherapy, starting 1 week before the initiation of chemotherapy and ending 3 to 3.4 months after its completion. 40 The total duration of lamivudine treatment ranged from 6.2 to 31.5 months. Despite these extended periods of treatment, HBV reactivation occurred after the withdrawal of lamivudine in 11 of 46 patients (23.9%), leading to liver failure in 3 patients. The reactivation rate after lamivudine withdrawal was significantly higher in patients with high prechemotherapy HBV DNA levels ( 10 4 copies/ml) compared with those who had low prechemotherapy HBV DNA levels ( 10 4 copies/ml) (50% vs 10%). HBV reactivation was more frequent in HBeAg-positive patients compared to HBeAgnegative patients (45.5% vs 17.1%). These observations suggest that patients with higher HBV DNA levels ( 10 4 copies/ml) or positive HBeAg before chemotherapy may require a longer duration of pre-emptive lamivudine treatment after the completion of chemotherapy. 40 However, there is no evidence to support the use of specific preventive treatments in different HBV populations. Interferon has not been shown to be effective in the prevention of chemotherapy-induced HBV reactivation because of its delayed effect. 18 However, despite its disadvantages, successful treatment with alfa interferon in combination with lamivudine was reported in a lamivudine-resistant HBV carrier who had HBV reactivation 1 month after the completion of chemotherapy. 43 Adefovir dipivoxil, an adenosine analogue, has been used as pre-emptive therapy in combination with lamivudine in patients who had developed YMDD mutation during lamivudine monotherapy 40 and to prevent emergence of YMDD mutation. 44 Adefovir dipivoxil may be considered in lamivudine-resistant patients and as a first agent in the prophylaxis of HBV recurrence. 40,44 Although no data exist regarding entecavir, a nucleoside analogue recently approved by the Food and Drug Administration, it may prove to be effective for primary prophylaxis and in lamivudine- and adefovir-resistant cases. Conclusions and Recommendations Every patient undergoing cytotoxic chemotherapy should be checked for HBsAg and total HBcAb before the initiation of treatment. HBeAg, anti-hbe, and serum HBV DNA levels should be tested in all HBsAg-positive patients. HBV DNA should be tested by HBV PCR assay with a detection limit of 10 2 copies/ml or less and should be monitored throughout the immunosuppressive therapy. Although there still are controversies regarding the timing for initiation and discontinua-

5 1080 MINDIKOGLU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 9 tion of prophylactic antiviral treatment because of the limited number of large controlled studies, prophylactic therapy is highly recommended in HBsAg-positive patients to avoid reactivation. Although the prevalence and natural history of reactivation are different in the different groups of HBV patients, there are insufficient data to support particular regimens in different groups. Most of the studies addressing preventive therapy deal with mixed populations and do not address specific patient groups. We recommend initiating prophylactic therapy at least 1 week before the initiation of chemotherapy and discontinuing the treatment at least 6 months after the resolution of the immunocompromised state. The anti-hbv treatment can be discontinued only if there is no biochemical or serologic evidence (disappearance of HBeAg, appearance of HBeAb, and a decrease in HBV DNA levels by PCR to 10 4 copies/ml) to suggest HBV reactivation (increase in HBV DNA level or reappearance of HBeAg as discussed before). Antiviral treatment may be deferred in HBsAg-negative HBcAb-positive patients until HBV DNA becomes detectable during or after chemotherapy. Serum transaminase levels should be monitored throughout the immunosuppressive treatment and every 6 months after the discontinuation. Although there is no clear evidence in the literature to support a specific interval, we recommend checking hepatic biochemical tests at least once a month during cytotoxic chemotherapy in HBV patients. HBV serology and HBV DNA should be checked at least once every 2 months during treatment. Patients who have active liver disease owing to hepatitis B should be treated indefinitely or until seroconversion occurs (disappearance of HBeAg, appearance of anti-hbe, and a decrease in HBV DNA level by PCR to 10 4 copies/ml). The antiviral agent used most extensively as prophylactic therapy in clinical studies is lamivudine mg daily. Although there are limited data on other antiviral medications, adefovir or entecavir may be considered as alternative treatments in lamivudine-resistant patients or as first-line drugs in primary prophylaxis of HBV reactivation. References 1. Keeffe EB, Dietrich DT, Han SB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 2004;2: Keeffe EB. Hepatitis B virus reactivation with chemotherapy: diagnosis and prevention with antiviral prophylaxis. Rev Gastroenterol Disord 2004;4: Lok AS, McMahon BJ. AASLD Practice Guidelines. Chronic hepatitis B. Available: Accessed: November 20, Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 1982;96: Lok ASF, Liang RS, Chiu EKW, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991;100: Galbraith RM, Eddleston AL, Williams R, et al. Fulminant hepatic failure in leukaemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet 1975;2: Thung SN, Gerber MA, Klion F, et al. Massive hepatic necrosis after chemotherapy withdrawal in a hepatitis B virus carrier. Arch Intern Med 1985;145: Wands JR, Chura CM, Roll FJ, et al. Serial studies of hepatitisassociated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology 1975;68: Alexopoulos CG, Vaslamatzis M, Hatzidimitriou G. Prevalence of hepatitis B virus marker positivity and evolution of hepatitis B virus profile, during chemotherapy, in patients with solid tumors. Br J Cancer 1999;81: Lau JYN, Lai CL, Lin HJ, et al. Fatal reactivation of chronic hepatitis B virus infection following withdrawal of chemotherapy in lymphoma patients. QJM 1989;73: Lau GKK, Leung YH, Fong DYT, et al. High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation. Blood 2002;99: Shibolet O, Ilan Y, Gillis S, et al. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 2002;100: Yeo W, Chan PKS, Chan HLY, et al. Hepatitis B virus reactivation during cytotoxic chemotherapy-enhanced viral replication precedes overt hepatitis. J Med Virol 2001;65: Liang RHS, Lok ASF, Lai CL, et al. Hepatitis B infection in patients with lymphomas. Hematol Oncol 1990;8: Yeo W, Chan PK, Hui P, et al. Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study. J Med Virol 2003;70: Zhong S, Yeo W, Schroder C, et al. High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy. J Viral Hepat 2004;11: Yeo W, Chan PKS, Zhong S, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol 2000;62: Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120: Markovic S, Drozina G, Vovk M, et al. Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepatogastroenterology 1999;46: Liang R, Lau GKK, Kwong YL. Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem. J Clin Oncol 1999;17: Hoofnagle JH, Seeff LB, Bales ZB, et al. Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen. N Engl J Med 1978;298: Marusawa H, Imoto S, Yoshihide U, et al. Reactivation of latently infected hepatitis B virus in a leukemia patient with antibodies to hepatitis B core antigen. J Gastroenterol 2001; 36: Kawatani T, Suou T, Tajima F, et al. Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies. Eur J Haematol 2001; 67: Dai MS, Lu JJ, Chen YC, et al. Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients. Cancer 2001; 92: Kosaka Y, Takase K, Kojima M, et al. Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen. Gastroenterology 1991;100: Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 2004;90: Rossi G. Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neo-

6 September 2006 HBV REACTIVATION AFTER CYTOTOXIC CHEMOTHERAPY 1081 plasias treated with chemotherapy. Leuk Lymphoma 2003;44: Cheng AL, Hsiung CA, Su IJ, et al. Lymphoma Committee of Taiwan Cooperative Oncology Group. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBVcarriers with lymphoma. Hepatology 2003;37: Shimizu D, Nomura K, Matsumoto Y, et al. Hepatitis B virus reactivation in a patient undergoing steroid-free chemotherapy. World J Gastroenterol 2004;10: Jang JW, Choi JY, Bae SH, et al. Transarterial chemo-lipiodolization can reactivate hepatitis B virus replication in patients with hepatocellular carcinoma. J Hepatol 2004;41: Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003;125: Wands JR, Chura CM, Roll FJ, et al. Serial studies of hepatitisassociated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology 1975;68: Lau GKK, He ML, Fong DYT, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogenic hematopoietic cell transplantation. Hepatology 2002;36: Idilman R, Arat M, Soydan E, et al. Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies. J Viral Hepat 2004;11: Liang R, Lok ASF, Lai CL, et al. Hepatitis B infection in patients with lymphomas. Hematol Oncol 1990;8: Lok ASF. The maze of treatments for hepatitis B. N Engl J Med 2005;352: Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39: Yeo W, Chan PKS, Ho WM, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol 2004;22: Li YH, He YF, Jiang WQ, et al. Lamivudine prophylaxis reduces the incidence and severity of hepatitis in hepatitis B virus carriers who receive chemotherapy for lymphoma. Cancer 2006;106: Hui CK, Cheung WW, Au WY, et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut 2005;54: Mancuso A, Luigi P. Lamivudine for chemotherapy-induced reactivation of HBV: prophylaxis or treatment? Am J Gastroenterol 2002;97: Dai MS, Chao TY, Kao WY. Delayed hepatitis B reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP. Ann Hematol 2004;83: Ohmoto K, Tsuduki M, Yamamoto S. Combined lamivudine and interferon- therapy for chemotherapy-induced reactivation of hepatitis B virus. Am J Gastroenterol 2003;98: Enomoto M, Nishiguchi S, Seki S, et al. Adefovir dipivoxil to prevent exacerbation of lamivudine-resistant hepatitis B infection during chemotherapy for non-hodgkin s lymphoma. Am J Gastroenterol 2004;99: Leaw SJ, Yen CJ, Huang WT, et al. Preemptive use of interferon or lamivudine for hepatitis B reactivation in patients with aggressive lymphoma receiving chemotherapy. Ann Hematol 2004;83: Nagamatsu H, Itano S, Nagaoka S, et al. Prophylactic lamivudine administration prevents exacerbation of liver damage in HBe antigen positive patients with hepatocellular carcinoma undergoing transhepatic arterial infusion chemotherapy. Am J Gastroenterol 2004;99: Address requests for reprints to: Arie Regev, MD, University of Miami Leonard M. Miller School of Medicine, Center for Liver Diseases, 1500 NW 12th Avenue, Suite 1101, Miami, Florida ARegev@ med.miami.edu; fax: (305) Supported by the 2004 American Association for the Study of Liver Diseases Advanced Hepatology Fellowship Award (A.L.M.).