title: Clinical characteristics and molecular analysis of hepatitis B virus reactivation in hepatitis B surface antigen-negative patients during or after immunosuppressive or cytotoxic chemotherapy.
abstract: OBJECTIVE
  Reactivation of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-positive patients treated with immunosuppressive or cytotoxic chemotherapy is well known and has emerged as an important clinical issue. The risk is low, but reactivation of HBV in HBsAg-negative patients after resolution of HBV infection also occurs; however, the clinical and virological characteristics remain somewhat unclear. We investigated HBsAg-negative patients who developed HBV reactivation during or after immunosuppressive or cytotoxic chemotherapy to clarify the clinical and virological features.
  
  
  METHODS
  Reactivation of HBV in 30 previously infected that is HBsAg-negative patients during or after immunosuppressive or cytotoxic chemotherapy was examined. Direct sequencing at the time of reactivation was used to evaluate 11 patients.
  
  
  RESULTS
  The majority of patients had diffuse large B cell lymphoma treated by rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Fulminant hepatic failure developed in three patients, who did not survive. HBV subgenotypes A2/Ae (n = 1), B1/Bj (n = 2), and C2/Ce (n = 8) were detected. There were no significant differences in the prevalence of BCP/PC variants between HBV reactivation and acute self-limited hepatitis patient groups. BCP and PC variants were not associated with development of fulminant hepatic failure from HBV reactivation. The prevalence of HBV S region variants, including immune-escape mutants, among reactivation patients was significantly higher than that in acute self-limited hepatitis patients.
  
  
  CONCLUSIONS
  Reactivation risk factors included male sex, advanced age, and hematological malignancy. HBV S gene immune-escape mutants were frequently found in the HBsAg-negative reactivation patients during or after immunosuppressive or cytotoxic chemotherapy.
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Kazuhiko
authors.identifier: http://orcid.org/0000-0002-7919-6071
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. masaishi@med.nagoya-u.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishigami
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ishizu
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Kuzuya
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology, Komaki City Hospital, 1-20 Joubushi, Komaki, 485-8520, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tachi
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Internal Medicine, Banbuntane Hotokukai Hospital, Fujita Health University School of Medicine, 3-6-10 Otobashi, Nakagawa-ku, Nagoya, 454-8509, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Katano
authors.affiliation: Division of Liver and Biliary Diseases, Department of Internal Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshioka
authors.affiliation: Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, 503-8502, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Toyoda
authors.affiliation: Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, 503-8502, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumada
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hirooka
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006509:Hepatitis B / Q000276:immunology / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000097:blood*; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D012307:Risk Factors; D016415:Sequence Alignment; D012737:Sex Factors; D014775:Virus Activation / Q000187:drug effects* / Q000276:immunology
chemical_list: D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents
keywords: Genotype; Hepatitis B virus; Phylogenetic analysis; Reactivation