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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1930
CORRESPONDENCE
To the editor:
Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy
The chimeric monoclonal anti-CD20 antibody rituximab targets and destroys B
lymphocytes and is used increasingly in the treatment of B-cell non-Hodgkin
lymphoma.1,2
In spite of rituximab-induced B-cell depletion, the incidence of infectious
complications does not appear to be generally increased, but there have been
isolated reports of viral
infections3-5
and hepatitis B virus (HBV) reactivations in hepatitis B surface antigen
(HBsAg) carriers.6
We present the case of a previously HbsAg-negative patient with high titers of
antibodies against HBsAg (anti-HBs) who developed fulminant hepatitis B
following the administration of rituximab.
A 73-year-old male had been treated with 5 courses of
cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy from
March 2002 to June 2002 and subsequent rituximab from July 2002 to September
2002 for diffuse large-cell lymphoma. The patient had suffered from acute
hepatitis B 15 years ago. He had developed complete resolution with high
titers of anti-HBs antibodies (> 1000 IU/L) and no serological
evidence of HBsAg in the routine test
(Table 1). In September 2002,
the patient was admitted to the hospital with acute hepatitis. HBsAg and a
high load of HBV DNA (8.6 x 108 copies/mL) were detected,
whereas anti-HBs antibodies remained positive (868 IU/L). Under antiviral
treatment with lamivudine, the viremia decreased to 2.4 x 105
copies/mL within 2 weeks. Nevertheless, hepatic function did not recover, and
the patient died 19 days after admission.
Sequence analysis of polymerase chain reaction (PCR) products amplified
from the S region revealed 5 remarkable mutations in the major antigenic
region (L110R, R122K, Y/F134S, P142L, and D144A), the latter 3 of which have
already been noted in HBV escape mutants after vaccination
failure.7 These
mutations are compatible with an escape of an endogenous HBV strain from the
patient's own anti-HBs that was nonpathogenic until the administration of
rituximab. A highly sensitive quantitative
PCR8 for the HBV DNA
S region revealed a small amount of homogeneous HBV DNA (50 ± 20
copies/mL, Table 1), with an
identical HBsAg sequence in a 2-year-old blood sample from the patient that
had tested negative for HBsAg.
HBV replication has been shown to persist at very low levels after
resolution of acute hepatitis B, regardless of coexisting anti-HBs, and is
kept at low levels by antiviral cellular immune
responses.9 Despite
the potential persistence of HBV in hepatocytes and mononuclear cells,
symptomatic HBV infection is uncommon in patients with pre-existing anti-HBs
antibodies after conventional chemotherapy. However, since the anti-CD20
antibody was introduced, this case is already the second instance of fulminant
hepatitis B reactivation in an anti-HBs–positive patient after the
combined administration of CHOP and subsequent
rituximab.10 Our
findings suggest that HBV escape mutants can be essential for this
reactivation. Testing for hepatitis B core and surface antibody is necessary
before administration of rituximab, and close monitoring for active HBV
infection by quantitative HBV DNA assays needs to be performed during
anti–CD20 antibody treatment in positive cases, since HBsAg routine
tests may be unreliable in heavily mutated variants. Controlled trials will
have to show if prophylactic antiviral therapy is justified for patients with
a history of hepatitis B receiving rituximab.
Timm H. Westhoff,
Friederike Jochimsen,
Alexander Schmittel,
Marina Stöffler-Meilicke,
Jürgen H. Schäfer,
Walter Zidek,
Wolfram H. Gerlich, and
Eckhard Thiel
Correspondence: Timm Henning Westhoff, Universitätsklinikum Benjamin
Franklin, Medizinische Klinik IV, Hindenburgdamm 30, 12200 Berlin, Germany;
e-mail:
t.westhoff{at}web.de.
References
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