Activation of occult hepatitis B from a seronegative patient after hematopoietic cell transplant: a cautionary tale

We have previously reviewed the risks for developing acute hepatitis B following hematopoietic cell transplantation (HCT).1 When a transplant recipient is seronegative for all hepatitis B virus (HBV) screening tests and the donor is HBV DNA negative, the risk of HBV infection in the recipient is considered to be negligible. In this letter we present a patient who was HBV seronegative and HBV DNA negative before transplantation but developed serious acute hepatitis B at 7 months after transplantation. He was born in India and had emigrated to the United States 9 years before transplantation. This case illustrates the clinical relevance of “occult” HBV in patients from areas where HBV infection is endemic (reviewed in Bréchot et al2).

A 43-year-old man with chronic myelogenous leukemia underwent pretransplantation evaluation: serum aspartate (AST) and alanine aminotransferase (ALT) levels were normal, serum was negative for the HB surface antigen (HBsAg), the antibody to HB surface antigen (anti-HBs), the antibody to HB core antigen (anti-HBc), and HBV DNA by a sensitive real-time polymerase chain reaction (PCR).3The donor was seropositive for anti-HBc, but serum HBV DNA was negative by PCR. The patient underwent cytoreductive therapy with busulfan and cyclosphosphamide and received prophylaxis for graft-versus-host disease (GVHD) with methotrexate and cyclosporine but developed grade II acute GVHD of the intestine on day +25. Gastrointestinal symptoms responded to 2 mg/kg/d of prednisone. Serum bilirubin, AST, ALT, and alkaline phosphatase levels were initially within normal limits, but following cessation of prednisone on day +94 and cyclosporine on day +212, the patient developed fever, anorexia, arthralgias, loose stools, and mild elevations of ALT and alkaline phosphatase (Figure1). A diagnosis of chronic GVHD, based on histologic examination of colonic and gastroduodenal biopsy specimens, prompted treatment with cyclosporine on day +221. But serum ALT and alkaline phosphatase became more deranged, and prednisone was added and cyclosporine tapered on day +236. On day +330 anorexia and low-grade fevers persisted, and HBV testing revealed that HBsAg and anti-HBc were positive and the serum HBV DNA load was 1.63 × 10⁸copies/mL. Lamivudine was prescribed at 100 mg daily from day +354. At the day +357 evaluation, clinical manifestations of chronic GVHD were minimal. Liver biopsy confirmed hepatitis B infection and excluded a concomitant diagnosis of GVHD. Examination of the bone marrow revealed early cytogenetic relapse of CML. Accelerated taper of prednisone therapy was accompanied by a 2-log fall in plasma HBV DNA; however, jaundice and alanine aminotransferase levels above 1000 IU/mL developed. Because of concern that prednisone might stimulate viral replication,4 the dose was not substantially increased. Cyclosporine was reinitiated, and the lamivudine dose was doubled. Three months later, the patient is clinically much improved, with a viral load of 4.7 × 10³ copies/mL and normal liver tests.

We reasoned that there were only 3 possibilities to explain this patient's development of acute hepatitis B at 7 months after transplantation. First, HBV may have been acquired after his transplantation through blood products, intravenous drug use, or sexual transmission. The second possibility was that the donor had low-level viremia, or had intracellular HBV in the infused hematopoietic cells, below the detection limit of our PCR. To test this hypothesis, we re-examined archived pretransplantation samples of donor and recipient sera (stored at −20°C) and leukocytes (stored in a liquid nitrogen tank at −180°C) for the presence of HBV DNA using a PCR assay sensitive to 25 genome copies/mL. DNA was extracted from either 400 μL of serum or 10 × 10⁶ peripheral blood mononuclear cells (PBMCs) and then subjected to proteinase treatment before being used for PCR. The absence of HBV DNA was confirmed in all samples. The third, and our preferred, possible explanation was that the patient had come to transplantation with occult HBV infection, confined to the liver, with no serologic markers or viremia2 until reactivation occurred in the context of posttransplantation immunosuppression. Acute hepatitis subsequently developed during the period of immune reconstitution at a time when the viral load was extremely high.

If a patient was born in a hepatitis B endemic region, negative pretransplantation serum screening results for HBV do not negate the possibility of acute hepatitis B arising after transplantation. In such situations, early reduction of the hepatitis B viral load using antiviral therapy needs to occur before immunosuppressive therapies are tapered so that the risk of acute viral hepatitis is minimized. To accomplish such preemptive therapy, we recommend that clinicians should consider the possibility of occult HBV reactivation in patients from hepatitis B endemic areas at approximately 80 days after transplantation, irrespective of pretransplantation serology.