Lamivudine treatment for chronic replicative hepatitis B virus infection after allogeneic bone marrow transplantation

Summary:Hepatitis B virus (HBV) reactivation after allogeneic haematopoietic stem cell transplantation (allo-HSCT) is well known in HBsAg-positive carriers but has only occasionally been reported in patients with resolved HBV infection. We investigated six allo-HSCT recipients with pretransplant anti-HBs and anti-HBc antibodies for serologic markers of HBV infection and for the presence of HBV-DNA in serum. Reverse seroconversion, that is, reappearance of HBsAg after a gradual loss of anti-HBs, but no severe liver damage was observed in three patients at 14, 22 and 12 months after HSCT, respectively. There was an increase in HBV-DNA concentration prior to reverse seroconversion. One patient was repeatedly HBV-DNA positive (10 2 -10 3 copies/ml) without reverse seroconversion. Sequencing of the HBsAg and precore region derived from the four HBV-DNA-positive patients showed no relevant mutations. In conclusion, this study demonstrated a high risk (50%) of reverse seroconversion in allo-HSCT recipients with resolved HBV infection. A highly sensitive HBV-DNA assay (TaqMan-PCR) allowed early identification of the individual patients at risk. Reactivation of HBV is a well-known complication in patients with chronic hepatitis B virus (HBV) infection undergoing immunosuppressive or cytotoxic therapy. HBsAg-positive recipients of haematopoietic stem cell transplantation (HSCT) have a higher incidence of clinical hepatitis associated with HBV reactivation, most often during immunological recovery. 1 The proposed mechanism is an increase in viral replication in the liver during the period of immunosuppression, followed by an immune mediated destruction of infected hepatocytes after cessation of immunosuppressive therapy. The risk of fatal HBV liver disease among patients who are persistently HBsAg positive after HSCT is approximately 12%. 2 HBV reactivation has also been observed in HBsAgnegative HSCT recipients with antibodies against HBs and HBc antigens (anti-HBs and anti-HBc, respectively), that is, in patients with resolved HBV infection. Therefore, the presence of these antibodies does not necessarily reflect viral clearance. In individuals with resolved infection, HBV has been shown to persist in a 'latent' state in the liver and in peripheral blood mononuclear cells. 3,4 However, there are no data about the percentage of patients who keep a transcriptionally active HBV genome for years or decades after complete clinical and serological recovery from acute hepatitis. In these patients, immunosuppression and loss of recipient B and T cell repertoire during allo-HSCT may lead to viral reactivation with reappearance of HBsAg after a gradual loss of anti-HBs; this has been termed 'reverse seroconversion'. To further characterize the risk of HBV reactivation in allo-HSCT recipients with resolved HBV infection, we investigated consecutive serum samples from six anti-HBs and anti-HBc-positive patients after allo-HSCT for the presence of HBV-DNA and for serologic markers of HBV infection. Methods and patients PatientsFrom 1...

Section: Discussionmentioning

confidence: 99%

Reactivation of resolved hepatitis B virus infection after allogeneic haematopoietic stem cell transplantation

Knöll

Boehm

Hahn

et al. 2004

“…It has also recently been reported that this drug is also useful for the treatment of viral hepatitis after cytotoxic therapy. 8,9 In the present patient lamivudine appeared to work to not only avoid HBV exacerbation during transplantation, but also to treat reactivation of HBV later.…”

Section: Discussionmentioning

confidence: 99%

Lamivudine therapy for a hepatitis B surface antigen (HBsAg)-positive leukemia patient receiving myeloablative chemotherapy and autologous stem cell transplantation

Uchida

Gondo

Himeji

et al. 2000

Summary:Hepatitis B virus (HBV) can be a cause of fatal liver failure after chemotherapy for viral carrier patients and limits the indication of myeloablative therapy for them. We describe an HBsAg-positive leukemia patient who successfully underwent autologous PBSC transplant. After chemotherapeutic treatment his serum HBV DNA level rose in association with hepatitis. To prevent progression to fulminant hepatitis, we administered lamivudine, a viral reverse transcriptase inhibitor, during the transplantation procedure. The patient did not show any increase of HBV DNA or a worsening of his hepatitis. Thus, lamivudine may be a promising treatment for HBsAg-positive patients receiving myeloablative chemotherapy and autologous stem cell transplantation. Bone Marrow Transplantation (2000) 26, 1243-1245. Keywords: lamivudine; hepatitis type B; stem cell transplantation 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. 4,5 In the present study, lamivudine was administered to an HBsAg-positive leukemia patient to prevent progression to fulminant hepatitis following autologous PBSC transplantation. Case reportA 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 method 7 ) and 217 U/l, respectively. With bed rest only these levels decreased to normal by 3 months.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 × 10 6 CD34 + cells/kg) which had been collected during recovery after consolidation chemotherapy were infused on day 0.Post transplantation, granulocytes exceeded 500 × 10 6 /l and...

“…5,6 Several studies have shown the effectiveness of lamivudine for inhibition of HBV reactivation and for clinical and pathological improvement in hepatic dysfunction even in patients with hematological diseases after stem cell transplantation. 7,8 Here, we report a successful allogeneic BMT from an HBV-positive sibling donor (HBV carrier) into a patient with severe aplastic anemia complicated by chronic hepatitis B, using lamivudine. …”

mentioning

confidence: 99%

Successful allogeneic bone marrow transplantation from an HBV-positive donor into an HBV-positive recipient using lamivudine

Hashino

Takahata

Nozawa

et al. 2002

Summary:A 21-year-old woman with severe aplastic anemia underwent allogeneic bone marrow transplantation from an HLA-identical sibling donor. The patient also had chronic hepatitis B and the donor was an HBV carrier. To decrease HBV and improve hepatic dysfunction before BMT, the patient had received lamivudine for 6 months. After marrow transfusion, administration of lamivudine was continued to inhibit replication of donor-derived HBV. The patient showed hematological engraftment on day 13 without any serious liver dysfunction. Eight months after BMT, she is now alive and well without chronic liver GVHD or reactivation of hepatitis B. HBV-DNA was not detected in the patient's serum. Administration of lamivudine to a BMT recipient with chronic hepatitis B may be a safe and promising way to prevent fatal liver dysfunction in the setting of allogeneic BMT, even in the event of BMT from an HBV-positive donor. Bone Marrow Transplantation (2002) 29, 269-271. DOI: 10.1038/sj/bmt/1703350 Keywords: allogeneic bone marrow transplantation; hepatitis B virus; lamivudine Allogeneic BMT has become one of the most effective treatment modalities for patients with hematological diseases. However, myeloablative and immunosuppressive conditioning, acute and chronic GVHD, and administration of immunosuppressive drugs for prophylaxis and treatment of GVHD enhance viral replication with a consequent increase in viral carriers. Reactivation of hepatitis B virus (HBV) infection after allogeneic BMT is well known in carriers. 1 Although hepatitis B surface antigen (HBsAg) positivity in the recipient is not generally considered to be a strict contraindication for BMT, patients with chronic HBV infection have a high risk of severe hepatic failure, leading to fulminant hepatitis with a fatal outcome, after transplantation due to reactivation of HBV. 2,3 Moreover, the use of HBsAg-positive donors, particularly if hepatitis B e antibody (anti-HBe) positive, has been shown to increase the risk of severe liver disease in BMT recipients, and hepatitis B surface antibody (anti-HBs) positivity has been shown to prevent severe liver damage. 4 Recently, lamivudine, which is one of the reverse transcriptase inhibitors of human immunodeficiency virus (HIV) and has been used to treat patients with HIV infection, has been administered to patients with chronic hepatitis B. 5,6 Several studies have shown the effectiveness of lamivudine for inhibition of HBV reactivation and for clinical and pathological improvement in hepatic dysfunction even in patients with hematological diseases after stem cell transplantation. 7,8 Here, we report a successful allogeneic BMT from an HBV-positive sibling donor (HBV carrier) into a patient with severe aplastic anemia complicated by chronic hepatitis B, using lamivudine. Case reportIn October 1996, a 21-year-old woman was diagnosed with severe aplastic anemia. She was treated with a combination of cyclosporin A, anti-thymocyte globulin (ATG), and granulocyte colony-stimulating factors, but her pancytopenia did not impro...