Molecular characterization of a variant virus that caused de novo hepatitis B without elevation of hepatitis B surface antigen after chemotherapy with rituximab

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J Med Virol. 2008 Dec;80(12):2069-78.

Molecular characterization of a variant virus that caused de novo hepatitis B

without elevation of hepatitis B surface antigen after chemotherapy with

rituximab.

Miyagawa M, Minami M, Fujii K, Sendo R, Mori K, Shimizu D, Nakajima T, Yasui K,

Itoh Y, Taniwaki M, Okanoue T, Yoshikawa T.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science,

Kyoto Prefectural University of Medicine, Kyoto, Japan.

Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen

(HBsAg)-negative patients following treatment with rituximab has been reported

increasingly. The aim of this study was to investigate the molecular mechanisms

underlying HBV reactivation in an HBsAg-negative patient. HBV was reactivated in

a 75-year-old man following chemotherapy with rituximab, without elevation of

HBsAg. The patient's full-length HBV genome was cloned and the entire sequence

was determined. Transfection studies were performed in vitro using recombinant

wild-type HBV (wild-type), the patient's HBV (patient), and two chimeric HBV

constructs, in which the preS/S region of the patient and wild-type virus had

been exchanged with one another. Secreted HBsAg and intra- and extra-cellular

HBV DNA were measured. The number of amino acid substitutions in HBV from this

patient was much higher than in previous reports of HBV mutants, such as occult

HBV and vaccine escape HBV mutants. Levels of HBsAg and HBV DNA production in

vitro were significantly lower in the patient compared to wild-type

transfections. From analyses of the chimeric constructs, the altered preS/S

region was responsible mainly for this impairment. These results show that

highly mutated HBV can reactivate after chemotherapy with rituximab, despite an

unusually large number of mutations, resulting in impaired viral replication in

vitro. Severe immune suppression, probably caused by rituximab, may permit

reactivation of highly mutated HBV. These findings have important clinical

implications for the prevention and management of HBV reactivation and may

explain partially the mechanism of recent, unusual cases of HBV reactivation. J.

Med. Virol. 80:2069-2078, 2008. © 2008 Wiley-Liss, Inc.

PMID: 19040281 [PubMed - in process]