Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports.
BACKGROUND
Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined.


METHODS
We completed a comprehensive literature search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed.


RESULTS
One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0-12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R [proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9-34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4-31.1]. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01-16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ(2) = 2.12, P = 0.5473).


CONCLUSIONS
The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University. Electronic address: a-evens@northwestern.edu.
A M
AM
Evens
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Department of Preventive Medicine.
B D
BD
Jovanovic
Division of Oncology, Dalin Tzu-Chi General Hospital, Chiayi, Taiwan.
Y-C
YC
Su
Veterans Administration Cooperative Studies Program College of Pharmacy, University of New Mexico, Albuquerque, USA.
D W
DW
Raisch
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Division of Hepatology.
D
D
Ganger
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Department of Internal Medicine.
S M
SM
Belknap
Division of Hematology/Oncology, Tri-Service General Hospital, Taipei, Taiwan.
M-S
MS
Dai
Department of Health Studies, Division of Epidemiology, The University of Chicago, Chicago, USA.
B-C C
BC
Chiu
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Department of Internal Medicine.
B
B
Fintel
Veterans Administration Cooperative Studies Program College of Pharmacy, University of New Mexico, Albuquerque, USA.
Y
Y
Cheng
Department of Pathology, Chi-Mei Medical Center, Tainan and Taipei Medical University, Taipei.
S-S
SS
Chuang
Division of Oncology, Chia-Yi Christian Hospital, Chiayi.
M-Y
MY
Lee
Division of Oncology, National Cheng Kung University Hospital, Tainan.
T-Y
TY
Chen
Faculty of Medicine and Division of Hematology & Oncology, Kaohsiung Medical University and Hospital, Kaohsiung.
S-F
SF
Lin
Division of Hematology/Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
C-Y
CY
Kuo
D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D006509:Hepatitis B / Q000139:chemically induced* / Q000150:complications; D006515:Hepatitis B virus; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D000069283:Rituximab; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab