Shigeru Kusumoto1, Yasuhito Tanaka2, Ritsuro Suzuki3, Takashi Watanabe4, Masanobu Nakata5, Rika Sakai6, Noriyasu Fukushima7, Takuya Fukushima8, Yukiyoshi Moriuchi9, Kuniaki Itoh10, Kisato Nosaka11, Ilseung Choi12, Masashi Sawa13, Rumiko Okamoto14, Hideki Tsujimura15, Toshiki Uchida16, Sachiko Suzuki17, Masataka Okamoto18, Tsutomu Takahashi3, Isamu Sugiura19, Yasushi Onishi20, Mika Kohri21, Shinichiro Yoshida22, Minoru Kojima23, Hiroyuki Takahashi24, Akihiro Tomita25, Yoshiko Atsuta26, Dai Maruyama27, Eiji Tanaka28, Takayo Suzuki29, Tomohiro Kinoshita30, Michinori Ogura31, Ryuzo Ueda32, Masashi Mizokami33. 1. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 2. Department of Virology and Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 3. Department of Oncology/Hematology, Shimane University Hospital, Izumo, Japan. 4. Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan. 5. Department of Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, Japan. 6. Department of Hematology and Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan. 7. Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. 8. Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan. 9. Department of Hematology, Sasebo City General Hospital, Sasebo, Japan. 10. Divisions of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa, Japan. 11. Department of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan. 12. Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 13. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan. 14. Department of Oncology, Chibanishi general Hospital, Chiba, Japan. 15. Division of Hematology-Oncology, Chiba Cancer Center, Chiba, Japan. 16. Department of Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan. 17. Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan. 18. Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan. 19. Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan. 20. Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan. 21. Department of Hematology, International Medical Center, Saitama Medical University, Hidaka, Japan. 22. Department of Hematology, National Hospital Organization Nagasaki Medical Center, Ohmura, Japan. 23. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan. 24. Department of Hematology and Clinical Immunology, Yokohama City University School of Medicine, Yokohama, Japan. 25. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 26. Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan. 27. Department of Hematology, National Cancer Center Hospital, Tokyo, Japan. 28. Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, Matsumoto, Japan. 29. Department of Hematology, Kusatsu General Hospital, Kusatsu, Japan. 30. Japanese Red Cross Aichi Blood Center, Aichi, Japan. 31. Department of Hematology and Oncology, Kasugai Municipal Hospital, Kasugai, Japan. 32. Department of Tumor Immunology, Aichi Medical University School of Medicine, Aichi, Japan. 33. Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan. Electronic address: mmizokami@hospk.ncgm.go.jp.
Abstract
BACKGROUND & AIMS: HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study. METHODS: HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. RESULTS: Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p <0.05). CONCLUSIONS: A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. CLINICAL TRIAL NUMBER: UMIN000001299. LAY SUMMARY: Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.
BACKGROUND & AIMS: HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study. METHODS: HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. RESULTS: Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p <0.05). CONCLUSIONS: A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. CLINICAL TRIAL NUMBER: UMIN000001299. LAY SUMMARY: Hepatitis B virus can be reactivated in lymphomapatients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.
Authors: Anna Kramvis; Kyong-Mi Chang; Maura Dandri; Patrizia Farci; Dieter Glebe; Jianming Hu; Harry L A Janssen; Daryl T Y Lau; Capucine Penicaud; Teresa Pollicino; Barbara Testoni; Florian Van Bömmel; Ourania Andrisani; Maria Beumont-Mauviel; Timothy M Block; Henry L Y Chan; Gavin A Cloherty; William E Delaney; Anna Maria Geretti; Adam Gehring; Kathy Jackson; Oliver Lenz; Mala K Maini; Veronica Miller; Ulrike Protzer; Jenny C Yang; Man-Fung Yuen; Fabien Zoulim; Peter A Revill Journal: Nat Rev Gastroenterol Hepatol Date: 2022-07-20 Impact factor: 73.082