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Reactivation of the hepatitis B virus (HBV) and subsequent fulminant hepatitis have been reported following myeloablative chemotherapy and stem cell transplantation for leukemia patients with HBV infection.1 Interferon is effective in approximately 30% of such patients with chronic HBV infection.2 However, adverse effects including fever, malaise, anorexia and depression are major concerns with interferon treatment. Lamivudine is a nucleoside analogue which specifically inhibits viral reverse transcriptase while suppressing HBV replication.3 A trial of lamivudine for chronic HBV infection has demonstrated that it significantly reduces HBV DNA and alanine aminotransferase (ALT) levels.45 In the present study, lamivudine was administered to an HBsAg-positive leukemia patient to prevent progression to fulminant hepatitis following autologous PBSC transplantation.

Case report

A 33-year-old Japanese man was diagnosed with acute myelogenous leukemia (FAB classification, M2) and found to be an asymptomatic carrier of HBV. After achieving complete remission with induction chemotherapy, he received consolidation chemotherapy twice (Figure 1).6 His clinical course was uneventful until following his second consolidation chemotherapy when HBV DNA and ALT levels increased to 3800 meq/ml (measured by branched DNA probe method7) and 217 U/l, respectively. With bed rest only these levels decreased to normal by 3 months.

Figure 1
figure 1

Chart showing serum levels of alanine aminotransferase (upper panel) and HBV DNA (lower panel) before and after lamivudine therapy. It shows clear correlation between HBV load and hepatitis which means hepatitis was caused by HBV. Lamivudine therapy kept viral load at a low level and successfully prevented acute exacerbation of hepatitis. IDR, idarubicin; MIT, mitoxantrone; VP16, etoposide; Ara-C, cytosine arabinoside; BU, busulfan; PBSCH, peripheral blood stem cell harvest; PBSCT, peripheral blood stem cell transplantation.

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Since his leukemic cells had poor prognostic karyotypes (trisomy 8 and 21), the patient decided to receive an autologous peripheral blood stem cell transplantation as further treatment. The pretransplant conditioning regimen consisted of busulfan, cytosine arabinoside and etoposide (BEA regimen).6 Granulocyte colony-stimulating factor (G-CSF) was administered concurrently with the BEA regimen during conditioning. Lamivudine (Glaxo Wellcome Research and Development, Greenford, UK) 100 mg/day was administered orally starting on day −1. Peripheral blood stem cells (3.7 × 106 CD34+ cells/kg) which had been collected during recovery after consolidation chemotherapy were infused on day 0.

Post transplantation, granulocytes exceeded 500 × 106/l and platelets exceeded 20 × 109/l on days 14 and 18, respectively. HBV DNA or ALT levels were not elevated during the therapy (Figure 1), and lamivudine administration was discontinued 3 months after transplantation. The patient subsequently experienced HBV DNA elevation 4 months later, but this was successfully treated with readministration of lamivudine. There were no adverse effects during lamivudine therapy. Lamivudine therapy was stopped when the patient suffered a relapse of his leukemia. Despite re-induction chemotherapy, the patient did not achieve complete remission and died of pneumonia 3 months after relapse. HBV DNA did not become elevated and he did not develop hepatitis, even after the discontinuation of lamivudine.

Discussion

Patients with HBV infection are at risk of an exacerbation of viral hepatitis after cytotoxic treatment.1 There are no specific markers to anticipate viral reactivation, and every patient with HBV needs to be carefully monitored during chemotherapy.

Lamivudine, an oral nucleoside analogue, has shown promise in patients with chronic hepatitis B.3 It inhibits viral reverse transcriptase and suppresses viral replication. It has also recently been reported that this drug is also useful for the treatment of viral hepatitis after cytotoxic therapy.89 In the present patient lamivudine appeared to work to not only avoid HBV exacerbation during transplantation, but also to treat reactivation of HBV later.

Lamivudine can be administered without significant adverse effects, but one of the concerns with this treatment is the emergence of viral mutants. A trial of lamivudine for chronic HBV infection has demonstrated that long-term usage of this drug is associated with HBV tyrosine-methionine-aspartate-aspartate (YMDD) motif mutation, and the incidence of exacerbation is much higher in patients with this mutation.10 As a result it is not recommended that this drug be administered for long periods of time. We therefore stopped lamivudine 3 months after transplantation and then carefully followed the serum viral DNA levels. The patient experienced viral DNA elevation 4 months later, but was again successfully treated with readministration of lamivudine, indicating the virus was still sensitive to this drug. Thus, it would appear that lamivudine should be administered for as short a time as possible, and the HBV DNA level carefully monitored, so that the drug can be readministered without delay if necessary.

These results suggest that lamivudine may be useful in the prophylaxis of HBV fulminant hepatitis following myeloablative therapy and stem cell transplantation, and that a prospective study of lamivudine for stem cell transplantation in HBsAg-positive patients is warranted.