Lamivudine Therapy for Chemotherapy-Induced Reactivationof Hepatitis B Virus Infection

Aijaz Ahmed, M.D., and Emmet B. Keeffe, M.D.Division of Gastroenterology, Department of Medicine, Stanford University School of Medicine, Stanford, California

A 54-yr-old man with lymphoma and serological evi-dence of prior hepatitis B virus (HBV) infection, withdetectable anti-HBc and anti-HBs, was treated with in-tensive chemotherapy. He had reactivation of HBV in-fection with acute hepatitis B manifest by detectableHBsAg and elevated aminotransferase levels>1000IU/L. He was treated with lamivudine 150 mg daily andhad prompt resolution of acute hepatitis B with return ofelevated aminotransferases to normal, and initial loss ofHBeAg with later loss of HBsAg. Lamivudine was con-tinued during the course of further chemotherapy asprophylaxis against repeat HBV reactivation. Lamivu-dine is a nucleoside analogue that is a potent inhibitor ofHBV reverse transcriptase and HBV replication. Lami-vudine therapy should be considered for the treatmentof HBV reactivation and might play a future role aspreemptive therapy of HBV reactivation in patients withprior hepatitis B or chronic hepatitis B with inactiveviral replication. (Am J Gastroenterol 1999;94:249–251.© 1999 by Am. Coll. of Gastroenterology)

INTRODUCTION

Lamivudine inhibits hepatitis B virus (HBV) reverse tran-scriptase and effectively reduces hepatitis B viremia in acuteand chronic hepatitis B (1, 2). Lamivudine and other inhib-itors of HBV reverse transcriptase have the potential tosubstantially alter the current approach to the treatment ofpatients with HBV infection. Lamivudine therapy has beensuggested for treating subjects who are unlikely to respondto interferon, including patients with immunosuppressionand high levels of serum HBV DNA (3, 4). Lamivudinerapidly reduces serum HBV DNA in patients reinfectedafter liver transplantation, regardless of the type of immu-nosuppressive agents used, in patients with advanced ac-quired immunodeficiency syndrome, and in patients receiv-ing chemotherapeutic agents (2, 3, 5, 6). These patients mayneed to continue lamivudine treatment indefinitely, becausebiochemical and virological relapse of HBV infection typ-ically occurs within weeks of discontinuation of antiviraltherapy.

Cancer chemotherapy-induced HBV reactivation has abroad spectrum of manifestations, ranging from slight ele-vation of aminotransferase levels to fatal fulminant hepati-tis. We present a patient with serological evidence of pastHBV infection who had acute HBV reactivation after re-ceiving chemotherapeutic agents. The acute HBV reactiva-tion was successfully treated with lamivudine, with decreaseof aminotransferase levels to normal, and loss of HBsAg.

CASE REPORT

A 54-yr-old man with follicular small cell (low grade)lymphoma was treated with two courses of CVP (chloram-bucil, vincristine, procarbazine) and six courses of CHOP(cyclophosphamide, hydroxydaunomycin, oncovin, pred-nisone) and, subsequently experienced the sudden onset offatigue. Complete evaluation revealed new elevation of livertests with an alanine aminotransferase (ALT) level of 832IU/L, aspartate aminotransferase (AST) 622 IU/L, total bil-irubin 0.9 mg/dL, albumin 4.3 g/dL, and normal prothrom-bin time. Serological studies showed positive HBsAg,HBeAg, and anti-HBc IgM, with negative anti-HBe andanti-HBs. Serum HBV DNA was detectable at a titer of22.6 3 106 Eq/mL (normal,,0.7 3 106 Eq/mL). Thesetests were consistent with acute/active hepatitis B. A posi-tive total anti-HAV with a negative IgM anti-HAV excludedacute hepatitis A, and anti-HCV was negative. Laboratorydata available from 1 yr ago showed a normal liver chem-istry panel (total bilirubin, ALT, AST, and alkaline phos-phatase), equivocal positive anti-HBc, low-level positiveanti-HBs, and negative HBsAg, IgM anti-HBc, HBeAg, andanti-HBe suggesting previous exposure to hepatitis B viruswith recovery.

The serological pattern suggested reactivation of latentHBV infection secondary to chemotherapy. At this point,lamivudine therapy at a dose of 150 mgp.o. once a day wasinitiated. The liver enzyme and bilirubin abnormalitiespeaked 12 days later, with ALT 1514 IU/L, AST 2128 IU/L,alkaline phosphatase 315 IU/L, and total bilirubin 1.9 mg/dL. After 1 month of lamivudine therapy, ALT was 66 IU/L,AST 102 IU/L, alkaline phosphatase 145 IU/L, HBV DNA,0.7 3 106 Eq/mL, and HBeAg became negative. How-ever, anti-HBe remained negative and HBsAg remainedpositive. After 4 months of lamivudine therapy, all liverReceived Jan. 27, 1998; accepted July 10, 1998.

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 1, 1999Copyright © 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00Published by Elsevier Science Inc. PII S0002-9270(98)00689-3

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chemistry values were normal, HBsAg was undetectable,HBV DNA was 4.13 103 Eq/mL (normal,,1.0 3 103),and HBeAg and anti-HBe remained negative.

Despite successful therapy against active HBV infection,the low grade non-Hodgkin lymphoma did not respond totwo cycles of CVP, eight cycles of CHOP, and three cyclesof fludarabine. Lamivudine therapy was continued to pre-vent further HBV reactivation in view of ongoing combi-nation chemotherapy with VP-16, prednisone, cytoxan, andprocarbazine in an effort to treat the lymphoma. The mark-ers of active HBV disease did not recur and liver testsremained normal.

DISCUSSION

Reactivation of HBV replication is a well known com-plication in patients with chronic HBV infection who re-ceive cytotoxic or immunosuppressive therapy (7–22). Al-though hepatitis, secondary to reactivation of HBVreplication, can also occur spontaneously in patients whohave recovered from previous HBV infection, the incidenceis low (19). The mechanism of acute hepatic injury inpatients with hepatitis B, after the withdrawal or duringtherapy with immunosuppressive agents, has not beenclearly elucidated. It has been hypothesized that immuno-suppression enhances HBV replication, resulting in in-creased hepatocyte infection by virus (8, 10, 12). The with-drawal of cytotoxic or immunosuppressive agents leads torestoration of immune function, resulting in rapid destruc-tion of infected hepatocytes. This event may present over awide range of severity, from slight elevation of aminotrans-ferases to fatal fulminant hepatitis (23–27). In patients withchronic HBV infection, increased HBV replication (charac-terized by presence of serum HBV DNA and HBeAg) hasbeen shown during chemotherapy before the onset of acutehepatic injury (12, 24). It has been speculated that patientswho demonstrate an increase in serum HBV DNA whengiven immunosuppressive agents are those who are at riskfor the development of acute hepatic injury on withdrawal.It has been recommended that patients being considered ascandidates for cancer chemotherapy, especially those whoare at high risk from previous exposure to hepatitis B,undergo periodic testing for HBsAg (12, 24).

Several therapeutic options have been proposed to reducethe risk of reactivation of HBV in patients with inactivechronic hepatitis B or a history of HBV infection, followinguse of chemotherapeutic agents (20, 28). One strategy is totreat HBsAg positive patients with less aggressive chemo-therapeutic agents. Fatal reactivation, however, has beenreported even in patients treated with a single immunosup-pressive agent (8, 11, 15). Some studies suggested that theantiviral effects of interferon against HBV may be enhancedby a priming course of corticosteroids (29, 30). However,the response to interferon therapy with or without pred-nisone priming, is poor even in immunocompetent patients(31–34). These observations lead to the recommendation

that patients with chronic HBV infection with malignanciesreceiving cytotoxic therapy be closely monitored every 1–2wk (35).

Recently, a variety of nucleoside analogues have beenstudied as possible therapeutic agents for treating chronicHBV infection (1). Lamivudine, a (2) enantiomer of 39-thia-cytidine, is not only a potent inhibitor of HBV replica-tion, but is also less toxic to marrow progenitor cells andmitochondria than other nucleoside analogues (36). Lami-vudine and other inhibitors of HBV reverse transcriptasehave the potential to substantially alter the current approachto the treatment of patients with HBV infection. Reportsfrom the European lamivudine trial indicate that, after 6months of therapy, ALT levels become normal in the ma-jority of treated patients, and piecemeal necrosis improves(37, 38). Chronic lamivudine therapy has been suggested fortreating subjects who are unlikely to respond to interferon,particularly those with immunosuppression or with highlevels of serum HBV DNA. Lamivudine rapidly reducesserum HBV DNA, regardless of the type of immunosup-pression following liver transplantation, in patients withadvanced acquired immunodeficiency syndrome, and pa-tients receiving chemotherapeutic agents (2, 3).

We recommend that chemotherapy-induced HBV reacti-vation in patients with chronic hepatitis B or the presence ofactive HBV infection be treated with lamivudine, and thatantiviral therapy be extended throughout the course of che-motherapy. This therapy may result in a decreased incidenceof fulminant hepatic failure, which is potentially fatal inthese immunosuppressed subjects (20). Two recent experi-ences, using famciclovir therapy after bone marrow trans-plantation (39) and lamivudine therapy after renal transplan-tation (40), in a total of 14 patients support thisrecommendation. Both drugs reduced hepatitis due to HBVreactivation in the setting of transplantation with immuno-suppression. There may also be a future role for preemptivetherapy of HBV reactivation in patients with stable chronichepatitis B, and possibly patients with prior resolved HBV,with a nucleoside analogue such as lamivudine.

Reprint requests and correspondence: Emmet B. Keeffe, M.D., StanfordUniversity Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA94304-1509.

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