A M Evens1, B D Jovanovic2, Y-C Su3, D W Raisch4, D Ganger5, S M Belknap6, M-S Dai7, B-C C Chiu8, B Fintel6, Y Cheng4, S-S Chuang9, M-Y Lee10, T-Y Chen11, S-F Lin12, C-Y Kuo13. 1. 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. 2. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Department of Preventive Medicine. 3. Division of Oncology, Dalin Tzu-Chi General Hospital, Chiayi, Taiwan. 4. Veterans Administration Cooperative Studies Program College of Pharmacy, University of New Mexico, Albuquerque, USA. 5. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Division of Hepatology. 6. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA; Department of Internal Medicine. 7. Division of Hematology/Oncology, Tri-Service General Hospital, Taipei, Taiwan. 8. Department of Health Studies, Division of Epidemiology, The University of Chicago, Chicago, USA. 9. Department of Pathology, Chi-Mei Medical Center, Tainan and Taipei Medical University, Taipei. 10. Division of Oncology, Chia-Yi Christian Hospital, Chiayi. 11. Division of Oncology, National Cheng Kung University Hospital, Tainan. 12. Faculty of Medicine and Division of Hematology & Oncology, Kaohsiung Medical University and Hospital, Kaohsiung. 13. Division of Hematology/Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Abstract
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.
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.