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Li ZX, Huang J, Hu L, Jiang ZY, Ran L, Liang XY, She RL, Ma CY, Feng JH, Song JY, Qu XQ, Peng BQ, Wu KN, Kong LQ. Cross-sectional study of hepatitis B virus infection in female breast cancer patients in China for the first time diagnosed. Clin Transl Oncol 2025; 27:257-264. [PMID: 38958900 DOI: 10.1007/s12094-024-03578-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 06/17/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND The correlation between breast cancer and hepatitis B virus (HBV) remains inconclusive. This study aims to explore the serological status of HBV infection and past infection in different age groups of female breast cancer patients, patients with benign breast diseases, and individuals undergoing routine physical examinations. METHODS Serum data on HBV serological markers were collected and analyzed from 6072 female breast cancer patients first diagnosed from September 2012 to July 2020 at the First Affiliated Hospital of Chongqing Medical University, along with 4019 women with benign breast diseases and 54,740 healthy females undergoing routine physical examinations in the same period. The data were stratified by age for comparison between groups. RESULTS The prevalence of HBV infection and past infection in the breast cancer group (7.9%, 55.1%) was higher than that in the benign breast disease group (6.5%, 39.1%) and the healthy females group(5.0%, 17.6%);the rate of only HBV surface antibody positivity (HBsAb ( +)) in the breast cancer group (10.3%) was lower than that in the benign breast disease group (26.9%) and the healthy females group (49.2%), with significant differences between the three groups (p < 0.05). Stratified by age, the prevalence of HBV infection in the breast cancer group (8%, 8.9%) and benign breast disease group (7.75%, 8.1%)was higher than that in the healthy females group (4.5%, 6.3%) in the 30-39 and 40-49 age group, respectively. The past infection rate of HBV in the breast cancer group (24.8%, 45.0%) was higher than that in the benign breast disease group (16.1%, 35.4%) in the ≤ 29 and 30-39 age group, respectively.. The past infection rate of HBV in the breast cancer group was higher than that in the healthy females group in all age groups, while the rate of only HBsAb ( +) in the breast cancer group was lower than that in the benign breast disease group and the routine physical examination group in all age groups. CONCLUSIONS Breast cancer women and women with benign breast diseases have higher rates of hepatitis B virus infection and previous infections, with more significant differences among middle-aged women. Breast cancer women and women with benign breast diseases have lower rates of only HBsAb ( +) for HBV.
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Affiliation(s)
- Zhao-Xing Li
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jie Huang
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Lei Hu
- Information Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Zhi-Yu Jiang
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Liang Ran
- Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xin-Yu Liang
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Rui-Ling She
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Chen-Yu Ma
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jun-Han Feng
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jing-Yu Song
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xiu-Quan Qu
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Bai-Qing Peng
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Kai-Nan Wu
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Ling-Quan Kong
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Yano Y, Sato I, Imanishi T, Yoshida R, Matsuura T, Ueda Y, Kodama Y. Clinical Significance and Remaining Issues of Anti-HBc Antibody and HBV Core-Related Antigen. Diagnostics (Basel) 2024; 14:728. [PMID: 38611641 PMCID: PMC11011781 DOI: 10.3390/diagnostics14070728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/17/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Currently, hepatitis B virus (HBV) core antibody (anti-HBc antibody) and HBV core-related antigen (HBcrAg) are widely used as serum markers for diagnosis based on the HBV core region. This review focused on anti-HBc antibodies and HBcrAg and aimed to summarize the clinical significance of currently used assay systems and the issues involved. While anti-HBc is very significant for clinical diagnosis, the clinical significance of quantitative assay of anti-HBc antibody has been reevaluated with improvements in diagnostic performance, including its association with clinical stage and prediction of carcinogenesis and reactivation. In addition, concerning the new HBcrAg, a high-sensitivity assay method has recently been established, and its diagnostic significance, including the prediction of reactivation, is being reevaluated. On the other hand, the quantitative level of anti-HBc antibody expressed in different units among assay systems complicates the interpretation of the results. However, it is difficult to standardize assay systems as they vary in advantages, and caution is needed in interpreting the assay results. In conclusion, with the development of highly sensitive HBcrAg and anti-HBc antibody, a rapid and sensitive detection assay system has been developed and used in clinical practice. In the future, it is hoped that a global standard will be created based on the many clinical findings.
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Affiliation(s)
- Yoshihiko Yano
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (R.Y.); (T.M.); (Y.U.); (Y.K.)
- Department of Clinical Laboratory, Kobe University Hospital, Kobe 650-0017, Japan; (I.S.); (T.I.)
| | - Itsuko Sato
- Department of Clinical Laboratory, Kobe University Hospital, Kobe 650-0017, Japan; (I.S.); (T.I.)
| | - Takamitsu Imanishi
- Department of Clinical Laboratory, Kobe University Hospital, Kobe 650-0017, Japan; (I.S.); (T.I.)
| | - Ryutaro Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (R.Y.); (T.M.); (Y.U.); (Y.K.)
| | - Takanori Matsuura
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (R.Y.); (T.M.); (Y.U.); (Y.K.)
| | - Yoshihide Ueda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (R.Y.); (T.M.); (Y.U.); (Y.K.)
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (R.Y.); (T.M.); (Y.U.); (Y.K.)
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Liu H, He Z, Gui R, Guo J, Chen L, Zhong M, Li J, Cao L, Fan L. Stratified management based on surface antibody for the prevention of hepatitis B virus reactivation in lymphoma patients. Br J Haematol 2023; 203:571-580. [PMID: 37803485 DOI: 10.1111/bjh.19140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/25/2023] [Accepted: 09/25/2023] [Indexed: 10/08/2023]
Abstract
This study aimed to investigate a stratified approach based on hepatitis B virus (HBV) surface antibody (anti-HBs) for managing HBV reactivation (HBVr) in lymphoma patients with serological protection against HBV. A retrospective analysis was conducted on 209 lymphoma patients with a baseline anti-HBs titre of ≥10 iu/L, who were either positive or negative for HBV core antibody (anti-HBc). The results revealed that 15.7% of patients lost serological protection following 6-month anti-lymphoma therapy. With a median follow-up of 28.1 months, the cumulative rates of HBVr at 6 months, 2 years and 4 years were 2.9%, 4.7% and 6.3% respectively. Without intervention, the overall rate of reactivation was 2.0% for patients with isolated anti-HBs and 10.5% for those with positive anti-HBs and anti-HBc. To identify patients at high risk of losing seroprotection and susceptible to HBVr, a predictive model was developed. The high-risk group had significantly higher rates of serological protection loss (27.8% vs. 2.2%) and cumulative incidence of HBVr (22.0% vs. 0%) compared to the low-risk group. Overall, this study highlights the risk of HBVr in lymphoma patients with positive anti-HBs, with or without positive anti-HBc, and recommends periodic monitoring for low-risk patients and early intervention for high-risk patients.
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Affiliation(s)
- Hailing Liu
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhen He
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Renfu Gui
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingjing Guo
- Department of Geriatric, Nanjing Second Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lvwen Chen
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Miao Zhong
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianyong Li
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Cao
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Fan
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Watanabe M, Toyoda H, Kawabata T. Rapid quantification assay of hepatitis B virus DNA in human serum and plasma by Fully Automated Genetic Analyzer μTASWako g1. PLoS One 2023; 18:e0278143. [PMID: 36758029 PMCID: PMC9910706 DOI: 10.1371/journal.pone.0278143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Real-time monitoring of serum hepatitis B virus (HBV) levels is essential for the management of patients with chronic HBV infection in clinical practice, including monitoring the resistance of anti-HBV nucleotide analog or the detection of HBV reactivation. In this context, serum HBV deoxyribonucleic acid (DNA) quantification should be rapidly measured. A rapid HBV DNA quantification assay was established on the Fully Automated Genetic Analyzer, μTASWako g1. The assay performs automated sample preparation and DNA extraction, followed by the amplification and detection of quantitative polymerase chain reaction (PCR) combined with capillary electrophoresis (qPCR-CE) on integrated microfluidic chip. This study aimed to evaluate the analytical and clinical performance of HBV DNA assay on the μTASWako g1 platform in human serum and EDTA-plasma. The HBV DNA assay has a linear quantitative range from 20 to 108 IU/mL of HBV DNA with standard deviation (SD) of ≤0.14 log10 IU/mL. The limits of detection of the assay were 4.18 for the serum and 4.35 for EDTA-plasma. The HBV assay demonstrated the equivalent performance in both human serum and EDTA-plasma matrices. The HBV genotypes A to H were detected with an accuracy of ±0.34 log10 IU/mL. In quantification range, the HBV DNA assay was correlated with Roche cobas AmpliPrep/cobas TaqMan Ver2.0 (CAP/CTM v2) (r = 0.964). The mean difference (μTASWako g1-CAP/CTM v2) of the reported HBV DNA was -0.01 log10 IU/mL. Overall, the sensitivity, accuracy, and precision of the μTASWako g1 HBV assay were comparable to the existing commercial HBV DNA assay, and the assay can be completed within 110 min. This evaluation suggests that the HBV DNA assay on the μTASWako g1 is potentially applied for alternative method of the HBV viral load test, in particular with the advantage of the HBV DNA result availability within 2 h, improving the HBV infection management.
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Affiliation(s)
- Moto Watanabe
- Diagnostics Research Laboratories, FUJIFILM Wako Pure Chemical Corporation, Amagasaki, Hyogo, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Tomohisa Kawabata
- Department of Diagnostics Development, FUJIFILM Wako Pure Chemical Corporation, Chuo-Ku, Tokyo, Japan
- * E-mail:
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Dezan MGF, Cavalcante LN, Cotrim HP, Lyra AC. Hepatobiliary disease after bone marrow transplant. Expert Rev Gastroenterol Hepatol 2023; 17:129-143. [PMID: 36655915 DOI: 10.1080/17474124.2023.2169671] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/13/2023] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Bone marrow transplantation (BMT) is the standard treatment for several hematologic pathologies. Post-BMT patients may develop hepatobiliary complications that impact morbidity and mortality. The differential diagnosis may include drug-induced liver injury (DILI), sepsis-associated liver injury (SALI), sinusoidal obstruction syndrome (SOS), graft-versus-host disease (GVHD), viral hepatitis, ischemic and fulminant hepatitis, among others. AREA COVERED Defining the etiology of hepatobiliary injury is challenging due to the overlapping symptoms. Thus, it is necessary to be aware of and understand the clinical characteristics of these hepatobiliary complications and provide adequate management with possible better outcomes. We reviewed the scientific literature focused on early hepatobiliary complications associated with BMT. We searched the PubMed database using the following descriptors: hepatic complications, drug-induced liver disease, graft-versus-host disease, cholestasis, sepsis, sinusoidal obstruction syndrome, cytomegalovirus, viral hepatitis, bone marrow transplantation, and hematopoietic stem cell transplantation. EXPERT OPINION Post-BMT hepatobiliary complications comprise several differential diagnoses and are challenges for the hepatologist's clinical practice. When evaluating these patients, it is necessary to consider the temporality between the use of certain medications, the increase in liver enzymes, and the presence of infection, in addition to applying diagnostic criteria and complementary tests for a specific diagnosis.
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Affiliation(s)
- Maria Gabriela Fernandes Dezan
- Instituto D'Or de Pesquisa e Ensino (IDOR) and Hospital São Rafael Gastro-Hepatology Service, Hospital São Rafael, Salvador, Bahia, Brazil
- Gastro-Hepatology Service - University Hospital Professor Edgard Santos (HUPES), PPGMS - Federal University of Bahia, Salvador, Bahia, Brazil
| | - Lourianne Nascimento Cavalcante
- Instituto D'Or de Pesquisa e Ensino (IDOR) and Hospital São Rafael Gastro-Hepatology Service, Hospital São Rafael, Salvador, Bahia, Brazil
- Gastro-Hepatology Service - University Hospital Professor Edgard Santos (HUPES), PPGMS - Federal University of Bahia, Salvador, Bahia, Brazil
| | - Helma Pinchemel Cotrim
- Gastro-Hepatology Service - University Hospital Professor Edgard Santos (HUPES), PPGMS - Federal University of Bahia, Salvador, Bahia, Brazil
| | - Andre Castro Lyra
- Instituto D'Or de Pesquisa e Ensino (IDOR) and Hospital São Rafael Gastro-Hepatology Service, Hospital São Rafael, Salvador, Bahia, Brazil
- Gastro-Hepatology Service - University Hospital Professor Edgard Santos (HUPES), PPGMS - Federal University of Bahia, Salvador, Bahia, Brazil
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Suda G, Baba M, Yamamoto Y, Sho T, Ogawa K, Kimura M, Hosoda S, Yoshida S, Kubo A, Fu Q, Yang Z, Tokuchi Y, Kitagataya T, Maehara O, Ohnishi S, Yamada R, Ohara M, Kawagishi N, Natsuizaka M, Nakai M, Morikawa K, Furuya K, Suzuki K, Izumi T, Meguro T, Terashita K, Ito J, Kobayashi T, Tsunematsu I, Sakamoto N. Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation-related hepatitis. J Med Virol 2023; 95:e28452. [PMID: 36597900 DOI: 10.1002/jmv.28452] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 12/26/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023]
Abstract
No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing hepatitis B virus (HBV) reactivation has yet been reported. This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF. Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months. TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis.
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Affiliation(s)
- Goki Suda
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masaru Baba
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Hokkaido Hospital, Hokkaido, Japan
| | - Yoshiya Yamamoto
- Department of Gastroenterology and Hepatology, Hakodate City Hospital, Hokkaido, Japan
| | - Takuya Sho
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Koji Ogawa
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Megumi Kimura
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shunichi Hosoda
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Sonoe Yoshida
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akinori Kubo
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Qingjie Fu
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Zijian Yang
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoshimasa Tokuchi
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takashi Kitagataya
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Osamu Maehara
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Ren Yamada
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masatsugu Ohara
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoki Kawagishi
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masato Nakai
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kenichi Morikawa
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Ken Furuya
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Hokkaido Hospital, Hokkaido, Japan
| | - Kazuharu Suzuki
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Hakodate City Hospital, Hokkaido, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Sapporo City General Hospital, Hokkaido, Japan
| | - Takashi Meguro
- Department of Gastroenterology and Hepatology, Hokkaido Gastroenterology Hospital, Hokkaido, Japan
| | - Katsumi Terashita
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Sapporo Hokushin Hospital, Hokkaido, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, The Hokkaido Medical Center, Hokkaido, Japan
| | - Tomoe Kobayashi
- Department of Gastroenterology and Hepatology, Tomakomai City Hospital, Hokkaido, Japan
| | | | - Naoya Sakamoto
- Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Giordano C, Picardi M, Pugliese N, Vincenzi A, Abagnale DP, De Fazio L, Giannattasio ML, Fatigati C, Ciriello M, Salemme A, Muccioli Casadei G, Vigliar E, Mascolo M, Troncone G, Pane F. Lamivudine 24-month-long prophylaxis is a safe and efficient choice for the prevention of hepatitis B virus reactivation in HBsAg-negative/HBcAb-positive patients with advanced DLBCL undergoing upfront R-CHOP-21. Front Oncol 2023; 13:1130899. [PMID: 36890828 PMCID: PMC9986962 DOI: 10.3389/fonc.2023.1130899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 01/30/2023] [Indexed: 02/17/2023] Open
Abstract
Introduction Occult hepatitis B infection (OBI) is a condition where replication-competent hepatitis B virus-DNA (HBV-DNA) is present in the liver, with or without HBV-DNA in the blood [<200 international units (IU)/ml or absent] in HB surface antigen (HBsAg)-negative/HB core antibody (HBcAb)-positive individuals. In patients with advanced stage diffuse large B-cell lymphoma (DLBCL) undergoing 6 cycles of R-CHOP-21+2 additional R, OBI reactivation is a frequent and severe complication. There is no consensus among recent guidelines on whether a pre-emptive approach or primary antiviral prophylaxis is the best solution in this setting of patients. In addition, questions still unresolved are the type of prophylactic drug against HBV and adequate prophylaxis duration. Methods In this case-cohort study, we compared a prospective series of 31 HBsAg-/HBcAb+ patients with newly diagnosed high-risk DLBCL receiving lamivudine (LAM) prophylaxis 1 week before R-CHOP-21+2R until 18 months after (24-month LAM series) versus 96 HBsAg-/HBcAb+ patients (from January 2005 to December 2011) undergoing a pre-emptive approach (pre-emptive cohort) and versus 60 HBsAg-/HBcAb+ patients, from January 2012 to December 2017, receiving LAM prophylaxis [1 week before immunochemotherapy (ICHT) start until 6 months after] (12-month LAM cohort). Efficacy analysis focused primarily on ICHT disruption and secondarily on OBI reactivation and/or acute hepatitis. Results In the 24-month LAM series and in the 12-month LAM cohort, there were no episodes of ICHT disruption versus 7% in the pre-emptive cohort (P = 0.05). OBI reactivation did not occur in any of the 31 patients in the 24-month LAM series versus 7 out of 60 patients (10%) in the 12-month LAM cohort or 12 out of 96 (12%) patients in the pre-emptive cohort (P = 0.04, by χ 2 test). No patients in the 24-month LAM series developed acute hepatitis compared with three in the 12-month LAM cohort and six in the pre-emptive cohort. Discussion This is the first study collecting data regarding a consistent and homogeneous large sample of 187 HBsAg-/HBcAb+ patients undergoing standard R-CHOP-21 for aggressive lymphoma. In our study, 24-month-long prophylaxis with LAM appears to be the most effective approach with a null risk of OBI reactivation, hepatitis flare-up, and ICHT disruption.
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Affiliation(s)
- Claudia Giordano
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Marco Picardi
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Novella Pugliese
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Annamaria Vincenzi
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Davide Pio Abagnale
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Laura De Fazio
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Maria Luisa Giannattasio
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Carmina Fatigati
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Mauro Ciriello
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Alessia Salemme
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Giada Muccioli Casadei
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
| | - Elena Vigliar
- Department of Public Health, Federico II University Medical School Naples, Naples, Italy
| | - Massimo Mascolo
- Department of Advanced Biomedical Sciences, Federico II University Medical School, Naples, Italy
| | - Giancarlo Troncone
- Department of Public Health, Federico II University Medical School Naples, Naples, Italy
| | - Fabrizio Pane
- Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
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The Impact of b/tsDMARD Dose Reduction on Chronic Hepatitis B in Rheumatoid Arthritis Patients: A Two-Center Long-Term Safety Analysis. J Clin Med 2022; 12:jcm12010086. [PMID: 36614890 PMCID: PMC9821696 DOI: 10.3390/jcm12010086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/11/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND We aimed to investigate the change of hepatitis B virus (HBV) viral loads and HBV reactivation (HBVr) in rheumatoid arthritis (RA) patients after tapering the dose of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). METHODS This two-center analysis retrospectively investigated the virological and biochemical evidence of HBVr in RA patients who underwent b/tsDMARD dose reduction. Serum levels of viral loads were determined using real-time PCR. Serum levels of alanine transaminase (ALT) were determined using spectrophotometry. RESULTS Among a total of 40 HBsAg+ RA patients who tapered b/tsDMARDs, 14 (35%) used tocilizumab; 12 (30%) used tumor necrosis factor (TNF)-α inhibitors; and the rest used either abatacept or tofacitinib. We found that patients who had detectable HBV DNA before tapering achieved a one-log reduction in HBV DNA levels, in contrast to the findings in the other 12 patients who did not taper b/tsDMARDs (no change in HBV DNA levels with time). The incidence of HBVr (increased viral loads with hepatitis) was 4.62 (95%CI: 2.08, 10.28) and 2.26 (95%CI: 0.56, 9.02) events per 100 person-years before and after b/tsDMARD tapering, respectively. CONCLUSIONS The HBV viral load decreased after the tapering of b/tsDMARDs in RA patients with detectable HBV DNA. Dose reduction in b/tsDMARDs might be beneficial.
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Guo X, Ji T, Xin S, Xu J, Yu Y. A case report of hepatitis B virus reactivation 19 months after cessation of chemotherapy with rituximab. Front Immunol 2022; 13:1083862. [PMID: 36532005 PMCID: PMC9755885 DOI: 10.3389/fimmu.2022.1083862] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 11/21/2022] [Indexed: 12/05/2022] Open
Abstract
A 72-year-old woman presented to our hospital with elevation of serum transaminases. Her blood tests showed the hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) negative. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were given for the diffuse large B-cell lymphoma. She didn't receive anti- hepatitis B virus (HBV) drug for the isolated HBcAb positive. HBV reactivation confirmed based on the serum HBV DNA detectable until 19 months after stopping R-CHOP regimen. HBV DNA became undetectable after 4 weeks therapy with Tenofovir alafenamide fumarate (TAF). Serum transaminases went down to normal 3 months later after receiving TAF. HBV reactivation is a substantial risk for patients with isolated HBcAb positive receiving rituximab-containing chemotherapy without anti- HBV drug. Regular monitoring with a frequency of 1-3 months is the basis for timely diagnosis and treatment of HBV reactivation. Serum transaminases abnormalities may be the initial manifestation of HBV reactivation.
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Affiliation(s)
- Xiangjuan Guo
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China,Department of Infectious Diseases, Handan Central Hospital, Handan, China
| | - Tongtong Ji
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Shengliang Xin
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China,*Correspondence: Yanyan Yu, ; Jinghang Xu,
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China,*Correspondence: Yanyan Yu, ; Jinghang Xu,
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10
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Yamada R, Morikawa K, Hotta K, Iwami D, Tanabe T, Murai S, Shinohara N, Yoshida S, Hosoda S, Kubo A, Tokuchi Y, Kitagataya T, Kimura M, Yamamoto K, Nakai M, Sho T, Suda G, Natsuizaka M, Ogawa K, Sakamoto N. Incidence of post-transplant hepatitis B virus reactivation with the use of kidneys from donors with resolved hepatitis B virus infection. J Viral Hepat 2022; 29:976-985. [PMID: 36031873 DOI: 10.1111/jvh.13740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/11/2022] [Accepted: 07/19/2022] [Indexed: 12/09/2022]
Abstract
Donors with resolved hepatitis B virus (HBV) infection may be a solution for the organ shortage for kidney transplantation (KT). The purpose of this study was to clarify the current state of HBV markers after KT from donors with resolved HBV infection to HBV naïve recipients and the rate of HBV reactivation in recipients with resolved HBV infection. Furthermore, we investigated HBV covalently closed circular DNA (cccDNA) in transplanted organs from donors with resolved HBV infection and the capability of HBV replication in kidney cell lines. We retrospectively analysed the HBV status of 340 consecutive donors and recipients who underwent KT in a single centre. We prospectively measured cccDNA by real-time polymerase chain reaction in kidney biopsy specimens of 32 donors with resolved HBV infection. HBV reactivation was found in three recipients with resolved HBV infection (4.8%, 3/63) after KT. We analysed 45 cases of transplantation from donors with resolved HBV infection to HBV-naive recipients. One case (2.2%, 1/45) became seropositive for hepatitis B core antibody (anti-HBc) and in another case (2.2%, 1/45), HBV-DNA was detected qualitatively in an HBV naive recipient with a donor with resolved HBV infection. In the latter case, cccDNA was measured in the donor kidney during KT. HBV replication was observed in kidney cell lines with HBV plasmid transfection. In conclusion, the risk of reactivation in anti-HBc-positive donors is relatively low. However, post-transplant HBV monitoring should be conducted in all at-risk cases.
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Affiliation(s)
- Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Kiyohiko Hotta
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Daiki Iwami
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan.,Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Tatsu Tanabe
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Sachiyo Murai
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Koji Yamamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
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11
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Kawagishi N, Suda G, Sakamori R, Matsui T, Onozawa M, Yang Z, Yoshida S, Ohara M, Kimura M, Kubo A, Maehara O, Fu Q, Hosoda S, Tokuchi Y, Suzuki K, Nakai M, Sho T, Morikawa K, Natsuizaka M, Ogawa K, Sakai H, Ohnishi S, Baba M, Takehara T, Sakamoto N. Serum IL-1β predicts de novo hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C, not during anti-cancer/immunosuppressive therapy. Sci Rep 2022; 12:16800. [PMID: 36207368 PMCID: PMC9546937 DOI: 10.1038/s41598-022-21315-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 09/26/2022] [Indexed: 02/08/2023] Open
Abstract
De novo hepatitis B virus (HBV) reactivation occurs during direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-infected patients with resolved HBV infection. We evaluated the predictive factors, mechanical insight, and differences of cytokine levels during anti-cancer/immunosuppressive and DAA. Eleven, 35, and 19 HCV-infected patients with previous HBV infection with HBV reactivation during DAA treatment, previous HBV infection without HBV reactivation during DAA treatment, and without HBV infection resolution receiving DAA treatment, respectively, were enrolled. Clinical data and baseline cytokine levels were analyzed. Low baseline serum interleukin (IL)-1β levels predicted de novo HBV reactivation during DAA treatment (odds ratio: 47.6, 95% confidence interval: 6.94-333.3). HCV-infected patients with the IL-1β gene single nucleotide polymorphism rs16944 AA allele had significantly higher IL-1β levels; no HCV-infected patient with the IL-1β AA allele experienced HBV reactivation during DAA treatment. Compared to HCV-infected patients with HBV infection resolution, non-HCV infected patients with or without HBV reactivation during anti-cancer/immunosuppressive therapy or bone marrow transplantation had remarkably lower baseline IL-1β levels. Low IL-1β levels were not associated with HBV reactivation. IL-1β levels before DAA for HCV-infected patients with resolved HBV infection could predict HBV reactivation during DAA treatment.
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Affiliation(s)
- Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Masahiro Onozawa
- Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Zijian Yang
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Osamu Maehara
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Qingjie Fu
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Hajime Sakai
- Department of Hematology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Masaru Baba
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization Hokkaido Hospital, Hokkaido, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
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12
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Xu XB, Hu C, Yang HJ, Zheng SS. Isolated anti-HBc is an independent risk factor for tumor recurrence in intrahepatic cholangiocarcinoma after curative resection. Hepatobiliary Pancreat Dis Int 2022; 21:472-478. [PMID: 35948505 DOI: 10.1016/j.hbpd.2022.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a poorly understood and aggressive malignancy with increasing incidence and mortality. Hepatitis B virus (HBV) infection is recognized as one of the important risk factors of ICC. There are few reports focusing on whether isolated antibody to hepatitis B core antigen (isolated anti-HBc, IAHBc) have prognostic role in ICC, while positive hepatitis B surface antigen (HBsAg) has been reported to be associated with the prognosis of ICC. The aim of this study was to investigate the prognostic value of IAHBc in ICC patients after curative resection, in order to identify those who have the high risk of ICC recurrence in the early stage. METHODS We divided 209 ICC patients who underwent curative resection into 4 groups: group I (n = 40), HBsAg (-)/antibody to hepatitis B surface antigen (anti-HBs) (-)/anti-HBc (+); group II (n = 70), HBsAg (+)/anti-HBc (-); group III (n = 55), HBsAg (-)/anti-HBs (+)/anti-HBc (+); and group IV (n = 44), HBsAg (-)/anti-HBc (-). We compared the recurrence-free survival (RFS) and overall survival (OS) among these four groups. RESULTS The median follow-up time was 16.93 months (range 1-34.6 months). The 1- and 2-year RFS and OS rates were 60% and 42%, and 78% and 63% respectively in all patients. Compared to the whole non-IAHBc patients (group II + group III + group IV), IAHBc patients (group I) showed significantly lower RFS at 1 year (39.8% vs. 64.4%, P = 0.001) and 2 years (20.7% vs. 46.7%, P = 0.001). When compared to other three individual groups, IAHBc patients (group I) also had the lowest RFS. We did not find significant difference in OS among the four groups. Further multivariate analysis revealed that IAHBc was an independent risk factor of RFS. CONCLUSIONS IAHBc is an independent poor prognostic factor for tumor recurrence in ICC patients after curative resection.
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Affiliation(s)
- Xiao-Bo Xu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Pulsed Power Translational Medicine of Zhejiang Province, Hangzhou 310012, China
| | - Chen Hu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Han-Jin Yang
- Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
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13
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Hagiwara S, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Aoki T, Morita M, Chishina H, Komeda Y, Yoshida A, Hayashi H, Nakagawa K, Kudo M. Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection. Hepatol Res 2022; 52:754-761. [PMID: 35635496 DOI: 10.1111/hepr.13798] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/17/2022] [Accepted: 05/23/2022] [Indexed: 02/08/2023]
Abstract
AIM The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. METHODS This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. RESULTS Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. CONCLUSION In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masahiro Morita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hirokazu Chishina
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yoriaki Komeda
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Akihiro Yoshida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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Surrogate Markers for Hepatitis B Virus Covalently Closed Circular DNA. Semin Liver Dis 2022; 42:327-340. [PMID: 35445388 DOI: 10.1055/a-1830-2741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Chronic infection with the hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of the persistence of the viral template for the viral transcripts, covalently closed circular deoxyribonucleic acid (cccDNA). Detecting changes in cccDNA transcriptional activity is key to understanding fundamental virology, determining the efficacy of new therapies, and deciding the optimal clinical management of HBV patients. In this review, we summarize surrogate circulating biomarkers that have been used to infer cccDNA levels and activity in people with chronic hepatitis B. Moreover, we outline the current shortcomings of the current biomarkers and highlight the clinical importance in improving them and expanding their use.
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15
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Prevention of HBV Reactivation in Hemato-Oncologic Setting during COVID-19. Pathogens 2022; 11:pathogens11050567. [PMID: 35631088 PMCID: PMC9144674 DOI: 10.3390/pathogens11050567] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 02/04/2023] Open
Abstract
Onco-hematologic patients are highly susceptible to SARS-CoV-2 infection and, once infected, frequently develop COVID-19 due to the immunosuppression caused by tumor growth, chemotherapy and immunosuppressive therapy. In addition, COVID-19 has also been recognized as a further cause of HBV reactivation, since its treatment includes the administration of corticosteroids and some immunosuppressive drugs. Consequently, onco-hematologic patients should undergo SARS-CoV-2 vaccination and comply with the rules imposed by lockdowns or other forms of social distancing. Furthermore, onco-hematologic facilities should be adapted to new needs and provided with numerically adequate health personnel vaccinated against SARS-CoV-2 infection. Onco-hematologic patients, both HBsAg-positive and HBsAg-negative/HBcAb-positive, may develop HBV reactivation, made possible by the support of the covalently closed circular DNA (cccDNA) persisting in the hepatocytic nuclei of patients with an ongoing or past HBV infection. This occurrence must be prevented by administering high genetic barrier HBV nucleo(t)side analogues before and throughout the antineoplastic treatment, and then during a long-term post-treatment follow up. The prevention of HBV reactivation during the SARS-CoV-2 pandemic is the topic of this narrative review.
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Pley C, Lourenço J, McNaughton AL, Matthews PC. Spacer Domain in Hepatitis B Virus Polymerase: Plugging a Hole or Performing a Role? J Virol 2022; 96:e0005122. [PMID: 35412348 PMCID: PMC9093120 DOI: 10.1128/jvi.00051-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatitis B virus (HBV) polymerase is divided into terminal protein, spacer, reverse transcriptase, and RNase domains. Spacer has previously been considered dispensable, merely acting as a tether between other domains or providing plasticity to accommodate deletions and mutations. We explore evidence for the role of spacer sequence, structure, and function in HBV evolution and lineage, consider its associations with escape from drugs, vaccines, and immune responses, and review its potential impacts on disease outcomes.
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Affiliation(s)
- Caitlin Pley
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
| | - José Lourenço
- Department of Zoology, University of Oxford, Oxford, United Kingdom
- Biosystems and Integrative Sciences Institute, University of Lisbon, Lisbon, Portugal
| | - Anna L. McNaughton
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Nuffield Department of Medicine, University of Oxford Medawar Building, Oxford, United Kingdom
| | - Philippa C. Matthews
- Nuffield Department of Medicine, University of Oxford Medawar Building, Oxford, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Division of Infection and Immunity, University College London, London, United Kingdom
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17
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Daia MT, Median D, Buinoiu NF, Ciocarlan M, Iancu G, Panaitescu AM, Peltecu G, Streinu-Cercel A. COVID-19 Pandemic Impact on Cord Blood Collection for Stem Cell Use and Actual Perspectives. MÆDICA 2021; 16:189-193. [PMID: 34621337 DOI: 10.26574/maedica.2021.16.2.189] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Objective: The aim of the current study is to assess the prevalence of hepatitis B and the risk of hepatitis reactivation in carriers of hepatitis B virus (HBV) cancer patients who underwent chemotherapy for gynecologic and/or breast cancers in a single institution, during a period of five years, and to identify a relationship to some particular chemotherapy regimen, more prone to lead to reactivation. Material and methods: We conducted a retrospective chart review on all consecutive oncological patients treated for a gynecologic and/or breast cancers who presented for the first time to the Gynecologic Oncology Department of Filantropia Hospital, Bucharest, Romania, between January 2016 and December 2020. Results: A total of 1 895 patients diagnosed with ovarian, cervical, endometrial or breast cancers were admitted to hospital for systemic therapy during the mentioned period. Among these, only four patients (two patients with breast cancers, one cervical cancer and one endometrial carcinoma) were chronic carriers of HBV surface antigen (HBsAg positive). Patients received a variety of chemotherapeutic regimens including corticosteroids, gemcitabine, cisplatin, carboplatin, taxanes and anthracyclines. We report one reactivation that occurred in one occult carrier of hepatitis B virus diagnosed with breast cancer (HBsAg negative, hepatitis B core antibody positive - HBcAb), initially excluded from this study, as being screened negative for HBV, treated with taxanes-based chemotherapy and corticosteroids. Conclusion: HBV reactivation had a low incidence in our population of patients diagnosed with gynecologic or breast cancer who received systemic chemotherapy. The HBV reactivation risk was positively correlated with breast cancer and to taxanes-based regimens and glucocorticoids. Further studies to identify additional risk factors of HBV infection reactivation in gynecologic oncology patients and possible risk reducing measures are warranted.
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Affiliation(s)
| | | | | | | | - George Iancu
- Filantropia Clinical Hospital, Bucharest, Romania
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Watanabe T, Inoue T, Tanaka Y. Hepatitis B Core-Related Antigen and New Therapies for Hepatitis B. Microorganisms 2021; 9:microorganisms9102083. [PMID: 34683404 PMCID: PMC8537336 DOI: 10.3390/microorganisms9102083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The hepatitis B core-related antigen (HBcrAg) is an unprecedented novel HBV biomarker that plays an essential role in reflecting covalently closed circular DNA (cccDNA) in chronic hepatitis B (CHB) because its levels correlate with intrahepatic cccDNA and serum HBV DNA. In this review, we describe the clinical application of serum HBcrAg in CHB patients, with a particular focus on new therapies targeting intrahepatic HBV replication. (1) HBcrAg can be detected in clinical cases where serum HBV DNA is undetectable during anti-HBV therapy. (2) A highly sensitive HBcrAg assay (iTACT-HBcrAg) may be useful for monitoring HBV reactivation, as an alternative to HBV DNA. (3) Decreased HBcrAg levels have been significantly associated with promising outcomes in CHB patients, reducing the risk of progression or recurrence of hepatocellular carcinoma. Additionally, we focus on and discuss several drugs in development that target HBV replication, and monitoring HBcrAg may be useful for determining the therapeutic efficacies of such novel drugs. In conclusion, HBcrAg, especially when measured by the recently developed iTACT-HBcrAg assay, may be the most appropriate surrogate marker, over other HBV biomarkers, to predict disease progression and treatment response in CHB patients.
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Affiliation(s)
- Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
- Correspondence:
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19
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Lau G, Yu ML, Wong G, Thompson A, Ghazinian H, Hou JL, Piratvisuth T, Jia JD, Mizokami M, Cheng G, Chen GF, Liu ZW, Baatarkhuu O, Cheng AL, Ng WL, Lau P, Mok T, Chang JM, Hamid S, Dokmeci AK, Gani RA, Payawal DA, Chow P, Park JW, Strasser SI, Mohamed R, Win KM, Tawesak T, Sarin SK, Omata M. APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int 2021; 15:1031-1048. [PMID: 34427860 PMCID: PMC8382940 DOI: 10.1007/s12072-021-10239-x] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIM Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation. METHODS All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation. RECOMMENDATIONS We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.
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Affiliation(s)
- George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China.
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China.
| | - Ming-Lung Yu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tz-You 1st Rd, Chinese Taipei, Kaohsiung, Taiwan.
| | - Grace Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | | | - Hasmik Ghazinian
- Department of Hepatology, Nork Clinical Hospital of Infectious Diseases, Yerevan, Armenia
| | - Jin-Lin Hou
- Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Teerha Piratvisuth
- Department of Medicine, NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Beijing, China
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Gregory Cheng
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
- Faculty of Health Science, Macau University, Macau SAR, China
| | - Guo-Feng Chen
- Department of Liver Diseases, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Zhen-Wen Liu
- Research Center for Liver Transplantation, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Oidov Baatarkhuu
- Department of Infectious Diseases, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Ann Lii Cheng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Woon Leung Ng
- Department of Medicine, United Christian Hospital, Hong Kong SAR, China
| | - Patrick Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Tony Mok
- Department of Clinical Oncology, State Key Laboratory of South China, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jer-Ming Chang
- Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Saeed Hamid
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Rino A Gani
- Liver Transplantation Team, Ciptomangunkusumo Hospital, Jakarta, Indonesia
| | - Diana A Payawal
- Department of Medicine, Cardinal Santos Medical Center, Mandaluyong, Metro, Manila, Philippines
| | - Pierce Chow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Joong-Won Park
- Center for Liver Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Rosmawaiti Mohamed
- Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Khin Maung Win
- Yangon Gastroenterology and Liver Centre, Yangon, Myanmar
| | - Tanwandee Tawesak
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Masao Omata
- Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan
- The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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20
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Lin N, Verma D, Saini N, Arbi R, Munir M, Jovic M, Turak A. Antiviral nanoparticles for sanitizing surfaces: A roadmap to self-sterilizing against COVID-19. NANO TODAY 2021; 40:101267. [PMID: 34404999 PMCID: PMC8361009 DOI: 10.1016/j.nantod.2021.101267] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/05/2021] [Accepted: 08/08/2021] [Indexed: 05/13/2023]
Abstract
Nanoparticles provide new opportunities in merging therapeutics and new materials, with current research efforts just beginning to scratch the surface of their diverse benefits and potential applications. One such application, the use of inorganic nanoparticles in antiseptic coatings to prevent pathogen transmission and infection, has seen promising developments. Notably, the high reactive surface area to volume ratio and unique chemical properties of metal-based nanoparticles enables their potent inactivation of viruses. Nanoparticles exert their virucidal action through mechanisms including inhibition of virus-cell receptor binding, reactive oxygen species oxidation and destructive displacement bonding with key viral structures. The prevention of viral outbreaks is one of the foremost challenges to medical science today, emphasizing the importance of research efforts to develop nanoparticles for preventative antiviral applications. In this review, the use of nanoparticles to inactivate other viruses, such as influenza, HIV-1, or norovirus, among others, will be discussed to extrapolate broad-spectrum antiviral mechanisms that could also inhibit SARS-CoV-2 pathogenesis. This review analyzes the published literature to highlight the current state of knowledge regarding the efficacy of metal-based nanoparticles and other antiviral materials for biomedical, sterile polymer, and surface coating applications.
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Affiliation(s)
- Neil Lin
- Department of Engineering Physics, McMaster University, Hamilton, Canada
- Faculty of Health Science, McMaster University, Hamilton, Canada
| | - Daksh Verma
- Department of Engineering Physics, McMaster University, Hamilton, Canada
| | - Nikhil Saini
- Department of Engineering Physics, McMaster University, Hamilton, Canada
- W Booth School of Engineering Practice and Technology, McMaster University, Hamilton, Canada
| | - Ramis Arbi
- Department of Engineering Physics, McMaster University, Hamilton, Canada
| | - Muhammad Munir
- Department of Engineering Physics, McMaster University, Hamilton, Canada
| | | | - Ayse Turak
- Department of Engineering Physics, McMaster University, Hamilton, Canada
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21
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Inoue T, Matsui T, Tanaka Y. Novel strategies for the early diagnosis of hepatitis B virus reactivation. Hepatol Res 2021; 51:1033-1043. [PMID: 34272919 DOI: 10.1111/hepr.13699] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/04/2021] [Accepted: 07/09/2021] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) reactivation under systemic chemotherapy or immunosuppressive therapy is a serious complication among HBV-resolved patients. Some medications, such as more than 2 weeks of corticosteroid therapy, can influence HBV reactivation; therefore, screening tests that measure hepatitis B surface antigen (HBsAg), hepatitis B core antibody, and hepatitis B surface antibody before therapy are required. Additionally, because HBV reactivation has been reported in patients positive for HBsAg treated with immune checkpoint inhibitors (ICIs), the prophylactic administration of nucleos(t)ide analogues prior to administering ICIs is recommended for HBsAg-positive patients. Under these circumstances, highly sensitive novel biomarkers are expected to be used for the early diagnosis of HBV reactivation. A fully automated high-sensitivity HBsAg assay (detection limit: 5 mIU/ml) by Lumipulse HBsAg-HQ, with 10-fold higher sensitivity than that of conventional assays, is currently used. Furthermore, ultra-sensitive HBsAg assays using a semi-automated immune complex transfer chemiluminescence enzyme immunoassay (ICT-CLEIA; detection limit: 0.5 mIU/ml) have been developed. Recently, a fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg; cut-off value: 2.1 Log U/mL) has been developed and reported. The utility of ICT-CLEIA and iTACT-HBcrAg for the diagnosis of HBV reactivation appears comparable to the use of HBV DNA. In this review, we provide the latest information related to medications that influence HBV reactivation and recently developed novel biomarkers that predict and monitor HBV reactivation.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Yasuhito Tanaka
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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22
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Han L, Zhou J, Zhou K, Zhu X, Zhao L, Fang B, Yin Q, Wei X, Zhou H, Li L, Xu B, Zhang J, Song Y, Gao Q. Safety and efficacy of CAR-T cell targeting BCMA in patients with multiple myeloma coinfected with chronic hepatitis B virus. J Immunother Cancer 2021; 8:jitc-2020-000927. [PMID: 32792360 PMCID: PMC7430488 DOI: 10.1136/jitc-2020-000927] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2020] [Indexed: 12/18/2022] Open
Abstract
Background Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication in patients with chronic or resolved HBV infection undergoing anticancer therapy. There is a risk of HBV reactivation after infusion of chimeric antigen receptor (CAR) T cells for patients with refractory/relapsed (R/R) multiple myeloma (MM). Methods We administered B cell maturation antigen (BCMA) CAR-T cell by infusion to nine patients with R/R MM with chronic or resolved HBV infection. Patient serum was analyzed to determine the expression of five components of HBV and the copy number of HBV DNA. HBV reactivation was defined if a patient re-exhibited hepatitis B surface antigen (HBsAg) or HBV DNA regrowth after CAR-T therapy. Results In one patient who was HBsAg-positive, no HBV reactivation was observed during the follow-up period of 9.8 months after administration of anti-HBV drugs before and after CAR-T therapy. Among eight patients with MM who had resolved HBV infection, two patients administered prophylactic anti-HBV drugs did not exhibit HBV reactivation. Of the six patients who did not use prophylactic antiviral drugs, five did not exhibit HBV reactivation, while one showed recurrence of HBsAg without detection of HBV DNA or damage to liver function. The best objective response rate was 100%, and the progression-free survival (PFS) at 12 months was of 88.89% (median PFS was not observed). Conclusions These findings showed that BCMA CAR-T cell therapy could be used in patients with R/R MM with chronic or resolved HBV infection and that antiviral drugs should be administered in these patients during CAR-T cell therapy.
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Affiliation(s)
- Lu Han
- Department of Immunology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jian Zhou
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Keshu Zhou
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Xinghu Zhu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Lingdi Zhao
- Department of Immunology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Baijun Fang
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Qingsong Yin
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Xudong Wei
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Hu Zhou
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Linlin Li
- Department of Immunology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Bengling Xu
- Department of Immunology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jishuai Zhang
- The Shenzhen Pregene Biopharma Company, Ltd, Shenzhen, China
| | - Yongping Song
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Quanli Gao
- Department of Immunology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
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23
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Long-Term Safety in HBsAg-Negative, HBcAb-Positive Patients with Rheumatic Diseases Receiving Maintained Steroid Therapy after Pulse Therapy. J Clin Med 2021; 10:jcm10153296. [PMID: 34362079 PMCID: PMC8347429 DOI: 10.3390/jcm10153296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/18/2021] [Accepted: 07/22/2021] [Indexed: 12/20/2022] Open
Abstract
The risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative, antibody to hepatitis B core antigen (anti-HBc)-positive patients after glucocorticoid (GC) pulse therapy remains unclear. AIMS Our study aimed to examine the safety of GC pulse therapy in HBsAg-negative, anti-HBc-positive rheumatic patients. METHODS Medical records of HBsAg-negative, anti-HBc-positive patients receiving GC pulse therapy to treat rheumatic diseases were reviewed. The primary outcome was HBV-associated hepatitis occurring within the first year after GC pulse therapy; the secondary outcome was HBsAg seroreversion occurring during the follow-up period. RESULTS We identified 5222 HBsAg-negative, anti-HBc-positive patients with rheumatic diseases who had attended Taichung Veterans General Hospital from October 2006 to December 2018. A total of 689 patients had received GC pulse therapy, with 424 patients being analyzed. Hepatitis was noted in 28 patients (6.6%) within the first year after GC pulse therapy, but none had been diagnosed as HBV-associated hepatitis. Three patients (0.7%) later developed HBsAg seroreversion, with a median interval of 97 months from the first episode of GC pulse therapy. These cases concurrently had maintained high dose oral prednisolone (≥20 mg prednisolone daily for over 4 weeks). CONCLUSIONS Amongst the HBsAg-negative, anti-HBc-positive rheumatic patients treated with GC pulse therapy, the risk of HBV-associated hepatitis within the first year was low. HBsAg seroreversion may have developed in the later stage, but only in those patients who had maintained high-dose oral steroid.
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24
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Chang WY, Chiu YC, Chiu FW, Hsu YC, Tseng TC, Cheng PN, Yang SS, Liu CJ, Su TH, Yang HC, Liu CH, Chen PJ, Chen DS, Kao JH. High Risk of Clinical Relapse in Patients With Chronic Hepatitis B Virus Infection After Cessation of Prophylactic Antiviral Therapy for Rituximab-Containing Chemotherapy. J Infect Dis 2021; 222:1345-1352. [PMID: 32396638 DOI: 10.1093/infdis/jiaa256] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Prophylaxis with nucleos(t)ide analogue (NA) is recommended to prevent hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-positive patients receiving rituximab-based B-cell depletion therapy. However, little is known about the risk of clinical relapse after withdrawal of NA. METHODS We retrospectively analyzed 77 noncirrhotic HBsAg carriers with hematological cancer who received rituximab-containing chemotherapy. All of them received either prophylactic entecavir or tenofovir therapy. The risk of clinical relapse and hepatic decompensation after cessation of NA was explored. RESULTS Clinical relapse and hepatic decompensation developed in 25 (32.5 %) and 11 (14.3 %) of the patients, respectively, and 2 patients died of hepatic decompensation. Most of the hepatic events occurred within 1 year (20 of 25; 80.0%) after stopping NA. A higher pretreatment viral load (≥2000 vs <2000 IU/mL) was associated with increased risks of clinical relapse (hazard ratio, 3.47; 95% confidence interval, 1.56-7.73) and hepatic decompensation (9.91; 2.14-45.92). Of 51 patients with pretreatment viral load <2000 IU/mL, clinical relapse occurred in 10 (19.6 %) and hepatic decompensation in 2 (3.9%). CONCLUSIONS Pretreatment HBV DNA ≥2000 IU/mL is associated with increased risk of liver-related disease after cessation of prophylactic NA therapy in patients who received rituximab-containing chemotherapy.
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Affiliation(s)
- Wei-Yuan Chang
- Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Yen-Cheng Chiu
- Department of Gastroenterology and Hepatology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Fang-Wei Chiu
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pin-Nan Cheng
- Department of Gastroenterology and Hepatology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.,PhD Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Microbiology, National Taiwan University College of Medicine Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Genomics Research Center, Academia Sinica, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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25
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Hara T, Oka K, Iwai N, Inada Y, Tsuji T, Okuda T, Nagata A, Komaki T, Kagawa K. Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. Intern Med 2021; 60:417-421. [PMID: 32963163 PMCID: PMC7925277 DOI: 10.2169/internalmedicine.5678-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation.
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Affiliation(s)
- Tasuku Hara
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
| | - Kohei Oka
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
| | - Naoto Iwai
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
| | - Yutaka Inada
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
| | - Toshifumi Tsuji
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
| | - Takashi Okuda
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
| | - Akihiro Nagata
- Department of Pathology, Fukuchiyama City Hospital, Japan
| | - Toshiyuki Komaki
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
| | - Keizo Kagawa
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Japan
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26
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Teraoka Y, Imamura M, Uchida T, Ohya K, Morio K, Fujino H, Ono A, Nakahara T, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Abe-Chayama H, Nelson Hayes C, Aikata H, Chayama K. Abatacept treatment for patients with severe acute hepatitis caused by hepatitis B virus infection-Pilot study. J Viral Hepat 2021; 28:400-409. [PMID: 33197288 DOI: 10.1111/jvh.13441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/01/2020] [Accepted: 10/19/2020] [Indexed: 12/09/2022]
Abstract
Although glucocorticoids have been used for immunosuppression of patients with primary hepatitis B virus (HBV) infection-induced severe hepatitis, the treatment is associated with a high frequency of adverse events. We conducted a pilot study for evaluating the efficacy and safety of abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin (CTLA4), for acute hepatitis B. Five patients with severe acute hepatitis B (prothrombin activity ≤ 60%) were treated for immunosuppression by abatacept. Four patients received abatacept concurrently with methylprednisolone, and another patient was treated with abatacept alone. Rapid decrease in serum alanine aminotransferase levels, increase in prothrombin activity and improvement of general condition were obtained in four out of five patients. The patient with the most severe hepatitis underwent liver transplantation due to exacerbation of hepatitis in spite of treatment with both abatacept and methylprednisolone. None of the patients developed significant adverse events associated with the use of abatacept. Hepatitis B surface antigen (HBsAg) became negative in all five patients. The effect of abatacept and methylprednisolone for severe hepatitis B was compared using a mouse model. Rapid reduction in mouse serum HBV DNA and human albumin levels and elevation of serum interferon-gamma and granzyme A levels were observed in HBV-infected human hepatocyte-transplanted immunodeficient mice that were administered human peripheral blood mononuclear cells. These hepatocyte injuries were inhibited to a greater extent by abatacept compared to methylprednisolone. Abatacept might be an effective therapy alternative to methylprednisolone to reduce acute massive liver damage for patients with severe acute hepatitis caused by HBV infection.
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Affiliation(s)
- Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kazuki Ohya
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
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Belov BS, Muravyeva NV, Tarasova GM. Regarding the problem of viral hepatitis reactivation in rheumatic diseases: risks and curation issues. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2020:98-106. [DOI: 10.21518/2079-701x-2020-19-98-106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Ito S. Updates on management strategies of hepatitis B virus reactivation in patients with resolved hepatitis virus B infection undergoing immunosuppressive therapy in rheumatology and the current situation in Niigata Rheumatic Center. Mod Rheumatol 2020; 31:775-782. [PMID: 33021133 DOI: 10.1080/14397595.2020.1832731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
With the introduction of methotrexate, biological disease-modifying antirheumatic drugs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), the disease activity of patients with rheumatoid arthritis has been dramatically ameliorated. However, these drugs have strong immunosuppressive effects and can cause reactivation of hepatitis B virus (HBV) in patients with resolved HBV infection. Corticosteroids or immunosuppressants used for other connective tissue diseases or vasculitis also carry a risk of inducing reactivation of HBV. Therefore, every rheumatologist should know how to detect the resolved infection of HBV in patients with rheumatic diseases receiving immunosuppressive therapy and how to monitor it when resolved infection is revealed. Of note, the cut-off index was changed from 2.1 log copies/ml to 20 IU/ml (1.3 Log IU/ml) in 2017. Rheumatologists should start nucleic acid analog administration at reactivation of HBV while performing ongoing immunosuppressive therapy in order to prevent severe or fulminant hepatitis. A low titer of HBs antibody (Ab) or lack of HBs Ab is a risk factor of reactivation of HBV. However, the reactivation of HBV cannot be prevented by HBs Ab titers at baseline or changes overtime. Rheumatologists should recognize that every immunosuppressive therapy, regardless of the mode of action, has a potential risk of reactivation. To facilitate proper management of patients with HBV infection, collaboration between rheumatologists and hepatologists is strongly encouraged. Patients' education, systems for checking electronic medical charts, and multidisciplinary efforts are considered important for detecting HBV reactivation.
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Affiliation(s)
- Satoshi Ito
- Department of Rheumatology, Niigata Rheumatic Center, Shibata City, Niigata, Japan
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Hepatitis B virus reactivation during temozolomide administration for malignant glioma. Int J Clin Oncol 2020; 26:305-315. [PMID: 33118116 DOI: 10.1007/s10147-020-01814-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/13/2020] [Indexed: 10/23/2022]
Abstract
INTRODUCTION The purpose of this study is to clarify the clinical features of temozolomide (TMZ)-related hepatitis B virus (HBV) reactivation and to identify HBV reactivation predictive factors. METHOD We retrospectively reviewed the clinical course of 145 patients newly diagnosed or with recurrent malignant glioma treated with TMZ. Before treatment, we screened patients for HB surface antigen (HBsAg) positivity (HBV carrier) and HBsAg negativity. Patients were also screened for antibody for HB core antigen (anti-HBc) positivity and/or for HB surface antigen positivity (resolved HBV infection). The patients were monitored by HBV DNA, alanine, and aspartate aminotransaminase during and after the completion of TMZ. HBV carriers and those with resolved HBV infections with HBV reactivation received preemptive entecavir treatment. In those with resolved HBV infections, we analyzed clinical characters for the predictive factors for HBV reactivation. RESULTS In one of two HBV carriers, HBV DNA turned positive 8 months after the completion of TMZ and entecavir. In four (16.7%) of 24 resolved HBV infections, HBV DNA turned detectable at completion of concomitant radiation and TMZ or during monthly TMZ. HBV DNA turned negative with entecavir in all patients without liver dysfunction. In resolved HBV infections, those with a high anti-HBc titer had significantly higher incidence of HBV reactivation than those with low anti-HBc titers (60% vs. 5.3%: p = 0.018). CONCLUSION Screenings, monitoring, and preemptive entecavir were important for preventing TMZ-related HBV reactivations. Anti-HBc titers could be the predictive markers for HBV reactivation in the those with resolved HBV infections.
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Chen MH, Chen MH, Chou CT, Hou MC, Tsai CY, Huang YH. Low but Long-lasting Risk of Reversal of Seroconversion in Patients With Rheumatoid Arthritis Receiving Immunosuppressive Therapy. Clin Gastroenterol Hepatol 2020; 18:2573-2581.e1. [PMID: 32205219 DOI: 10.1016/j.cgh.2020.03.039] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/04/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS In patients who have resolved hepatitis B virus (HBV) infection, treatment of rheumatoid arthritis (RA) can result in reappearance of hepatitis B surface antigen (HBsAg), called reverse seroconversion. We investigated clinical features and outcomes of reverse seroconversion in patients who received immunosuppressant or biologic therapy for RA. METHODS We identified 1494 patients with RA (925 who resolved HBV infection) and available data on levels of antibody to HB core antigen and HBsAg who had attended Taipei Veterans General Hospital from January 2007 through December 2017. We identified 17 cases (median age, 66 years) who were negative for HBsAg before treatment of RA and reverse seroconversion (HBsAg reappearance) after glucocorticoid treatment (n = 13) and/or biologic therapy (adalimumab, n = 2; etanercept, n = 1; rituximab, n = 9; or abatacept, n = 4). Four patients were positive for antibodies against HBsAg (seroconverted) before the immunosuppressive treatment. RESULTS The median time from immunosuppressive treatment to reverse seroconversion was 120 months (range, 20-264 months), whereas the time from biologic therapy treatment to reverse seroconversion was 66 months (range, 10-105 months). After reverse seroconversion, 8 individuals (47.1%) were positive for HB e antigen; 9 cases (52.9%) did not have a flare of alanine transaminase. However, 3 patients (17.6%) developed liver decompensation. CONCLUSIONS In patients who resolved HBV infection and received immunosuppressant treatment of RA, risk of reversal of seroconversion is low but persists for up to 10 years. Patients with RA who previously resolved HBV infections should be monitored for levels of HBsAg and HBV DNA once immunosuppressive treatment of RA begins.
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Affiliation(s)
- Ming-Han Chen
- Division of Allergy, Immunology, Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei; Faculty of Medicine
| | | | - Chung-Tei Chou
- Division of Allergy, Immunology, Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei; Faculty of Medicine
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chang-Youh Tsai
- Division of Allergy, Immunology, Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei; Faculty of Medicine.
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei.
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31
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Rodríguez M, Buti M, Esteban R, Lens S, Prieto M, Suárez E, García-Samaniego J. Consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B virus infection (2020). GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:559-587. [PMID: 32778356 DOI: 10.1016/j.gastrohep.2020.03.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection remains a global public health problem. HBV vaccination is the most effective tool to reduce the incidence of HBV disease. Despite there has not been new clinical developments for the treatment of chronic hepatitis B in the last few years, changing epidemiology and current insights on natural history, diagnostic tools and therapy indications make necessary an update of the former version of the consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B infection published in 2012. The current document updates the management of chronic hepatitis B. The treatment of choice is the long-term administration of a nucleos(t)ide analogue with high barrier to resistance (entecavir, tenofovir or tenofovir alafenamide). Pegylated interferon may be an option in patients with non-advanced liver disease, but its applicability is limited due to the low efficacy and poor tolerability. All patients must be monitored for the risk of progression to advanced liver disease and development of hepatocellular carcinoma.
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Affiliation(s)
- Manuel Rodríguez
- Sección de Hepatología, Servicio de Digestivo, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España.
| | - María Buti
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Rafael Esteban
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Sabela Lens
- Servicio de Hepatología, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Universidad de Barcelona, Barcelona, España
| | - Martín Prieto
- Sección de Hepatología, Servicio de Medicina Digestiva, Hospital Universitari ì Politècnic La Fe, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Valencia, España
| | - Emilio Suárez
- Unidad de Enfermedades Digestivas, Hospital Universitario Virgen de Valme, Sevilla, España
| | - Javier García-Samaniego
- Unidad de Hepatología, Hospital Universitario La Paz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, España.
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Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020; 50:892-923. [PMID: 32343469 DOI: 10.1111/hepr.13504] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology published the first version of the Guidelines for the Management of Hepatitis B in 2013 (first English version in 2014), and has since been publishing updates to the Guidelines as new drugs become available, with the latest original Japanese version being Version 3.1. Herein, the Drafting Committee publishes the second English version that contains all the changes made since the first English version of the guidelines was published in 2014. This 2019 version covers: (i) the nucleos(t)ide analogs, tenofovir disoproxil fumarate and tenofovir alafenamide; (ii) updates to treatment recommendations and management of drug-resistant hepatitis B virus that reflect the new availability of these drugs; and (iii) new information about hepatitis B virus reactivation with each update. This latest update also contains information about treatment goals, indications for treatment and cessation of nucleos(t)ide analog therapy, most of which were covered by the first version.
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Chen Z, Engle RE, Shen CH, Zhao H, Schuck PW, Danoff EJ, Nguyen H, Nishimura N, Bock KW, Moore IN, Kwong PD, Purcell RH, Govindarajan S, Farci P. Distinct disease features in chimpanzees infected with a precore HBV mutant associated with acute liver failure in humans. PLoS Pathog 2020; 16:e1008793. [PMID: 32866189 PMCID: PMC7485984 DOI: 10.1371/journal.ppat.1008793] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 09/11/2020] [Accepted: 07/08/2020] [Indexed: 01/04/2023] Open
Abstract
Transmission to chimpanzees of a precore hepatitis B virus (HBV) mutant implicated in acute liver failure (ALF) in humans did not cause ALF nor the classic form of acute hepatitis B (AHB) seen upon infection with the wild-type HBV strain, but rather a severe AHB with distinct disease features. Here, we investigated the viral and host immunity factors responsible for the unusual severity of AHB associated with the precore HBV mutant in chimpanzees. Archived serial serum and liver specimens from two chimpanzees inoculated with a precore HBV mutant implicated in ALF and two chimpanzees inoculated with wild-type HBV were studied. We used phage-display library and next-generation sequencing (NGS) technologies to characterize the liver antibody response. The results obtained in severe AHB were compared with those in classic AHB and HBV-associated ALF in humans. Severe AHB was characterized by: (i) the highest alanine aminotransferase (ALT) peaks ever seen in HBV transmission studies with a significantly shorter incubation period, compared to classic AHB; (ii) earlier HBsAg clearance and anti-HBs seroconversion with transient or undetectable hepatitis B e antigen (HBeAg); (iii) limited inflammatory reaction relative to hepatocellular damage at the ALT peak with B-cell infiltration, albeit less extensive than in ALF; (iv) detection of intrahepatic germline antibodies against hepatitis B core antigen (HBcAg) by phage-display libraries in the earliest disease phase, as seen in ALF; (v) lack of intrahepatic IgM anti-HBcAg Fab, as seen in classic AHB, but at variance with ALF; and (vi) higher proportion of antibodies in germline configuration detected by NGS in the intrahepatic antibody repertoire compared to classic AHB, but lower than in ALF. This study identifies distinct outcome-specific features associated with severe AHB caused by a precore HBV mutant in chimpanzees, which bear closer resemblance to HBV ALF than to classic AHB. Our data suggest that precore HBV mutants carry an inherently higher pathogenicity that, in addition to specific host factors, may play a critical role in determining the severity of acute HBV disease.
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Affiliation(s)
- Zhaochun Chen
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Ronald E. Engle
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Chen-Hsiang Shen
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Huaying Zhao
- Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Peter W. Schuck
- Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Emily J. Danoff
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Hanh Nguyen
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Norihisa Nishimura
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Kevin W. Bock
- Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Ian N. Moore
- Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Peter D. Kwong
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Robert H. Purcell
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Sugantha Govindarajan
- Department of Pathology, University of Southern California, Los Angeles, California, United States of America
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
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Kusumoto S, Tanaka Y, Suzuki R, Watanabe T, Nakata M, Sakai R, Fukushima N, Fukushima T, Moriuchi Y, Itoh K, Nosaka K, Choi I, Sawa M, Okamoto R, Tsujimura H, Uchida T, Suzuki S, Okamoto M, Takahashi T, Sugiura I, Onishi Y, Kohri M, Yoshida S, Kojima M, Takahashi H, Tomita A, Atsuta Y, Maruyama D, Tanaka E, Suzuki T, Kinoshita T, Ogura M, Ueda R, Mizokami M. Ultra-high sensitivity HBsAg assay can diagnose HBV reactivation following rituximab-based therapy in patients with lymphoma. J Hepatol 2020; 73:285-293. [PMID: 32194183 DOI: 10.1016/j.jhep.2020.03.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 12/15/2022]
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.
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Affiliation(s)
- Shigeru Kusumoto
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ritsuro Suzuki
- Department of Oncology/Hematology, Shimane University Hospital, Izumo, Japan
| | - Takashi Watanabe
- Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan
| | - Masanobu Nakata
- Department of Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Rika Sakai
- Department of Hematology and Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Noriyasu Fukushima
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Takuya Fukushima
- Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | | | - Kuniaki Itoh
- Divisions of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kisato Nosaka
- Department of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan
| | - Ilseung Choi
- Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Rumiko Okamoto
- Department of Oncology, Chibanishi general Hospital, Chiba, Japan
| | - Hideki Tsujimura
- Division of Hematology-Oncology, Chiba Cancer Center, Chiba, Japan
| | - Toshiki Uchida
- Department of Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
| | - Sachiko Suzuki
- Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Masataka Okamoto
- Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tsutomu Takahashi
- Department of Oncology/Hematology, Shimane University Hospital, Izumo, Japan
| | - Isamu Sugiura
- Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Yasushi Onishi
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan
| | - Mika Kohri
- Department of Hematology, International Medical Center, Saitama Medical University, Hidaka, Japan
| | - Shinichiro Yoshida
- Department of Hematology, National Hospital Organization Nagasaki Medical Center, Ohmura, Japan
| | - Minoru Kojima
- Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan
| | - Hiroyuki Takahashi
- Department of Hematology and Clinical Immunology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Akihiro Tomita
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiko Atsuta
- Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Maruyama
- Department of Hematology, National Cancer Center Hospital, Tokyo, Japan
| | - Eiji Tanaka
- Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takayo Suzuki
- Department of Hematology, Kusatsu General Hospital, Kusatsu, Japan
| | | | - Michinori Ogura
- Department of Hematology and Oncology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Ryuzo Ueda
- Department of Tumor Immunology, Aichi Medical University School of Medicine, Aichi, Japan
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.
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Screening and Evaluation of Novel Compounds against Hepatitis B Virus Polymerase Using Highly Purified Reverse Transcriptase Domain. Viruses 2020; 12:v12080840. [PMID: 32752057 PMCID: PMC7472185 DOI: 10.3390/v12080840] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) polymerase seems to be very hard to express and purify sufficiently, which has long hampered the generation of anti-HBV drugs based on the nature of the polymerase. To date, there has been no useful system developed for drug screening against HBV polymerase. In this study, we successfully obtained a highly purified reverse transcriptase (RT) domain of the polymerase, which has a template/primer and substrate binding activity, and established a novel high-throughput screening (HTS) system using purified RT protein for finding novel polymerase inhibitors. To examine whether the assay system provides reliable results, we tested the small scale screening using pharmacologically active compounds. As a result, the pilot screening identified already-known anti-viral polymerase agents. Then, we screened 20,000 chemical compounds and newly identified four hits. Several of these compounds inhibited not only the HBV RT substrate and/ template/primer binding activity, but also Moloney murine leukemia virus RT activity, which has an elongation activity. Finally, these candidates did show to be effective even in the cell-based assay. Our screening system provides a useful tool for searching candidate inhibitors against HBV.
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Davis JS, Ferreira D, Paige E, Gedye C, Boyle M. Infectious Complications of Biological and Small Molecule Targeted Immunomodulatory Therapies. Clin Microbiol Rev 2020; 33:e00035-19. [PMID: 32522746 PMCID: PMC7289788 DOI: 10.1128/cmr.00035-19] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks. Contrary to the hope that these more specific agents would have minimal and predictable infectious sequelae, infectious complications have emerged as a major stumbling block for many of these agents. Furthermore, the growing number and complexity of available biologic agents makes it difficult for clinicians to maintain current knowledge, and most review articles focus on a particular target disease or class of agent. In this article, we review the current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents, aiming to create a single resource relevant to a broad range of clinicians and researchers. For each of 19 classes of agent, we discuss the mechanism of action, the risk and types of infectious complications, and recommendations for prevention of infection.
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Affiliation(s)
- Joshua S Davis
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
| | - David Ferreira
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Emma Paige
- Department of Infectious Diseases, Alfred Hospital, Melbourne, VIC, Australia
| | - Craig Gedye
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
- Department of Oncology, Calvary Mater Hospital, Newcastle, NSW, Australia
| | - Michael Boyle
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
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Liu XQ, Ohsaki E, Ueda K. Establishment of a system for finding inhibitors of ε RNA binding with the HBV polymerase. Genes Cells 2020; 25:523-537. [PMID: 32415897 PMCID: PMC7496097 DOI: 10.1111/gtc.12778] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/14/2020] [Accepted: 05/08/2020] [Indexed: 12/18/2022]
Abstract
Although several nucleo(s)tide analogs are available for treatment of HBV infection, long‐term treatment with these drugs can lead to the emergence of drug‐resistant viruses. Recent HIV‐1 studies suggest that combination therapies using nucleo(s)tide reverse transcriptase inhibitors (NRTIs) and non‐nucleo(s)tide reverse transcriptase inhibitors (NNRTIs) could drastically inhibit the viral genome replication of NRTI‐resistant viruses. In order to carry out such combinational therapy against HBV, several new NRTIs and NNRTIs should be developed. Here, we aimed to identify novel NNRTIs targeting the HBV polymerase terminal protein (TP)‐reverse transcriptase (RT) (TP‐RT) domain, which is a critical domain for HBV replication. We expressed and purified the HBV TP‐RT with high purity using an Escherichia coli expression system and established an in vitro ε RNA‐binding assay system. Then, we used TP‐RT in cell‐free assays to screen candidate inhibitors from a chemical compound library, and identified two compounds, 6‐hydroxy‐DL‐DOPA and N‐oleoyldopamine, which inhibited the binding of ε RNA with the HBV polymerase. Furthermore, these drugs reduced HBV DNA levels in cell‐based assays as well by inhibiting packaging of pregenome RNA into capsids. The novel screening system developed herein should open a new pathway the discovery of drugs targeting the HBV TP‐RT domain to treat HBV infection.
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Affiliation(s)
- Xiao-Quan Liu
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Eriko Ohsaki
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Keiji Ueda
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Japan
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Kikuchi T, Kusumoto S, Tanaka Y, Oshima Y, Fujinami H, Suzuki T, Totani H, Kinoshita S, Asao Y, Narita T, Ito A, Ri M, Komatsu H, Iida S. Hepatitis B virus reactivation in a myeloma patient with resolved infection who received daratumumab-containing salvage chemotherapy. J Clin Exp Hematop 2020; 60:51-54. [PMID: 32404569 PMCID: PMC7337267 DOI: 10.3960/jslrt.19034] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
A 72-year-old female complaining of back pain was diagnosed with IgG-κ multiple myeloma. After osteosynthesis for fracture of the left femoral shaft due to myeloma, she received bortezomib, melphalan, and prednisolone as an initial regimen for multiple myeloma, but discontinued it after three courses due to progressive disease. The patient subsequently received lenalidomide and dexamethasone as a second-line regimen for 2.5 years, and pomalidomide and dexamethasone as a third-line regimen for only 2 months. An anti-CD38 monoclonal antibody, daratumumab (DARA), and bortezomib and dexamethasone (DVd) as a fourth-line regimen were administered for refractory myeloma. However, hepatitis B virus (HBV) reactivation occurred on day 15 of the third course of DVd. The HBV DNA level in peripheral blood suddenly increased to 2.2 log IU/mL. An anti-HBV nucleotide analog, entecavir, was subsequently administered when the HBV DNA level increased to 2.6 log IU/mL. No HBV-related hepatitis was observed during follow-up. DARA can improve the prognosis of patients with multiple myeloma, but also potentially increase the risk of HBV reactivation. Host and viral risk factors need to be identified in such patients in order to implement a more cost-effective strategy against HBV reactivation.
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Affiliation(s)
- Takaki Kikuchi
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shigeru Kusumoto
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshiko Oshima
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Haruna Fujinami
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tomotaka Suzuki
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Haruhito Totani
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shiori Kinoshita
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yu Asao
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tomoko Narita
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Asahi Ito
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masaki Ri
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirokazu Komatsu
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shinsuke Iida
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Yamauchi R, Takeyama Y, Takata K, Fukunaga A, Sakurai K, Tanaka T, Fukuda H, Fukuda S, Kunimoto H, Umeda K, Morihara D, Yokoyama K, Irie M, Shakado S, Sakisaka S, Hirai F. Hepatitis B Virus Reactivation after Receiving Cancer Chemotherapy under Administration of Leuprorelin Acetate. Intern Med 2020; 59:1163-1166. [PMID: 31956202 PMCID: PMC7270765 DOI: 10.2169/internalmedicine.3805-19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
An 88-year-old man was admitted for elevated liver enzyme levels. Nine years earlier, the patient had been diagnosed with diffuse large B-cell lymphoma (DLBCL) and undergone rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin, prednisone (R-CHOP) therapy. This patient previously had had a hepatitis B virus (HBV) infection before chemotherapy. After the chemotherapy, he was administered an luteinizing hormone-releasing hormone (LHRH) agonist for prostate cancer. We diagnosed him with HBV reactivation because of positive serum HBV-DNA. HBV reactivation can occur a long time after chemotherapy, particularly if another treatment with immunity-altering drugs is added. In such cases, additional surveillance may be required to detect HBV reactivation.
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Affiliation(s)
- Ryo Yamauchi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Yasuaki Takeyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | | | | | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Hiromi Fukuda
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Sho Fukuda
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Hideo Kunimoto
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Kaoru Umeda
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Daisuke Morihara
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Makoto Irie
- Department of Gastroenterology, Fukuoka University Nishijn Hospital, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
- General Medical Research Center, Fukuoka University Faculty of Medicine, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
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Niizuma K, Ogawa Y, Kogure T, Tominaga T. Case reports of latent HBV hepatitis in patients after neurosurgical treatment for hypothalamic and pituitary tumors. BMC Infect Dis 2020; 20:230. [PMID: 32188424 PMCID: PMC7081602 DOI: 10.1186/s12879-020-04971-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 03/13/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a major public health problem worldwide. More than 2 billion people have been exposed to HBV, and about 257 million individuals are chronic carriers of HBV. HBV reactivation has been increasingly reported in HBV carriers who have undergone immunosuppression or chemotherapy, resulting in mortality. Treatment of hypothalamic/pituitary tumors in HBV carriers requires extensive care to avoid HBV reactivation as steroid therapy is required after surgery for hypothalamic/pituitary tumors. CASE PRESENTATION This retrospective review identified 5 patients, who were HBV carriers positive for hepatitis B surface antigen among 1352 patients with surgically treated hypothalamic/pituitary tumor in Kohnan Hospital between February 2007 and April 2017. Transsphenoidal surgery was performed with particular attention to prevent damage to the pituitary gland, with delicate manipulation to minimize postoperative steroid coverage. All patients received nucleot(s)ide analogue to control HBV-DNA levels before the surgery. As a result, all patients had a good clinical course. Blood examinations found a transient increase of liver enzymes and HBV-DNA levels in all patients, which started to decrease within 2 weeks after surgery. No specific treatment other than nucleot(s)ide analogues was needed to maintain liver function, and all patients returned to their previous activities including reinstatement. CONCLUSION Initiation of nucleot(s)ide analogues administration prior to the surgery for hypothalamic/pituitary tumors can be an effective strategy for preventing reactivation in HBV carriers. Appropriate screening of the patient's HBV phase, optimal timing of nucleot(s)ide analogues -administration, and administration period of nucleot(s)ide analogues need to be established.
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Affiliation(s)
- Kuniyasu Niizuma
- Department of Neurosurgical Engineering and Translational Neuroscience, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi Japan
- Department of Neurosurgical Engineering and Translational Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Miyagi Japan
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi Japan
| | - Yoshikazu Ogawa
- Department of Neurosurgery, Kohnan Hospital, 4-20-1 Nagamachiminami, Taihaku-ku, Sendai, Miyagi 982-8523 Japan
| | - Takayuki Kogure
- Department of Gastroenterology and Hepatology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi Japan
| | - Teiji Tominaga
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi Japan
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Koutsianas C, Thomas K, Vassilopoulos D. Reactivation of hepatitis B virus infection in rheumatic diseases: risk and management considerations. Ther Adv Musculoskelet Dis 2020; 12:1759720X20912646. [PMID: 32206094 PMCID: PMC7076579 DOI: 10.1177/1759720x20912646] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/11/2020] [Indexed: 12/14/2022] Open
Abstract
In patients with rheumatic diseases undergoing immunosuppressive treatment, hepatitis B virus reactivation (HBVr) has been long recognized as a major treatment-related adverse event with substantial morbidity and mortality. Because HBVr is easily preventable with appropriate screening and monitoring strategies, and, when indicated, prophylactic antiviral treatment, awareness of this complication is of the utmost importance, especially in the era of biologic treatments. As a condition, it continues to be topical, in view of the emergence of novel classes of immunosuppressive drugs (i.e. Janus kinase inhibitors) acquiring licenses for a variety of rheumatic diseases. The class-specific risk of these agents for HBVr has not yet been determined. Moreover, ambiguity still exists for the management of patients planned to be treated with traditional agents, such as cyclophosphamide and glucocorticoids, particularly in the setting of resolved HBV infection. Clinicians in the field of rheumatic diseases should be tailoring their practice according to the host's profile and treatment-specific risk for HBVr. In this review, the authors attempt to critically review the existing literature and provide practical advice on these issues.
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Affiliation(s)
- Christos Koutsianas
- Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, Athens, Greece
| | - Konstantinos Thomas
- Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, Athens, Greece
| | - Dimitrios Vassilopoulos
- Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, 114 Vass. Sophias Ave., Athens, 115 27, Greece
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Cheung CKM, Law MF, Chao DC, Wong SH, Ho R, Chao ACW, Lai JWY, Chan TYT, Tam MTK, Lau SLF, Tam THC. Prevention of hepatitis B virus reactivation in patients with hematological malignancies and resolved hepatitis B virus infection: a systematic review and meta-analysis. J Dig Dis 2020; 21:160-169. [PMID: 32040243 DOI: 10.1111/1751-2980.12848] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/25/2020] [Accepted: 02/06/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Patients with resolved hepatitis B virus (HBV) infection are at risk of HBV reactivation during treatment for hematological malignancies. We conducted a systematic review and meta-analysis of the data on the efficacy of antiviral prophylaxis for the prevention of HBV reactivation in this group of patients. METHODS We conducted a systemic literature search of PubMed including MEDLINE and EMBASE databases to 31 January 2019 to identify studies published in English comparing antiviral prophylaxis with no prophylaxis for HBV reactivation in patients treated for hematological malignancies. The search terms used were ("occult hepatitis B" OR "resolved hepatitis B") AND ("reactivation") AND ("haematological malignancy" OR "hematological malignancy" OR "chemotherapy" OR "immunotherapy" OR "chemoimmunotherapy" OR "lymphoma" OR "leukemia" OR "transplant"). The primary outcome was the reactivation of HBV infection. Pooled estimates of relative risk (RR) were calculated. RESULTS We identified 13 relevant studies including two randomized controlled trials (RCT), one post hoc analysis from RCT and 10 cohort studies. There was a trend towards a lower rate of HBV reactivation using antiviral prophylaxis, but the difference was not significant (RR 0.57, 95% confidence interval [CI] 0.23-1.40, P = 0.22). When limiting the analysis to the three prospective studies of patients receiving anti-CD20 monoclonal antibodies, we found antiviral prophylaxis was associated with a significantly lower risk of HBV reactivation (RR 0.17, 95% CI 0.06-0.49, P = 0.001). CONCLUSION Antiviral prophylaxis reduced the risk of HBV reactivation in patients receiving anti-CD20 monoclonal antibodies for hematological malignancies but not in a broader group of patients receiving anticancer therapy.
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Affiliation(s)
- Carmen Ka Man Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Man Fai Law
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - David Chun Chao
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Sunny Hei Wong
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Rita Ho
- Department of Medicine, North District Hospital, Hong Kong SAR, China
| | - Amelia Chien Wei Chao
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Jennifer Wing Yan Lai
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Ted Yun Tat Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Mark Tsz Kin Tam
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Sam Lik Fung Lau
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Tommy Ho Chi Tam
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China
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Mei T, Noguchi H, Hisadome Y, Kaku K, Nishiki T, Okabe Y, Nakamura M. Hepatitis B virus reactivation in kidney transplant patients with resolved hepatitis B virus infection: Risk factors and the safety and efficacy of preemptive therapy. Transpl Infect Dis 2020; 22:e13234. [PMID: 31856328 DOI: 10.1111/tid.13234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 11/29/2019] [Accepted: 12/09/2019] [Indexed: 11/30/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) reactivation is associated with complications and adverse outcomes in patients with clinically resolved HBV infection who are seronegative for hepatitis B surface antigen (HBs Ag), and seropositive for hepatitis B core antibody (HBc Ab) and/or hepatitis B surface antibody (HBs Ab) before kidney transplantation (KT). METHODS We retrospectively analyzed 52 patients with resolved HBV infection who were HBV-DNA negative. HBV-DNA after KT was evaluated, and the occurrence of HBV reactivation and outcomes were monitored. We defined HBV reactivation as seropositivity for HBV-DNA at or above the minimal detection level of 1.0 log IU/mL and treated preemptively (using entecavir) when the HBV-DNA level was at or above 1.3 log IU/mL, in accordance with the Japanese Guidelines for HBV treatment. RESULTS Among the 52 patients, the mean age was 57.2 ± 10.8 years. The median HBc Ab titer was 12.8 (interquartile range, 4.6-42.6) cutoff index, and five (9.6%) cases of HBV reactivation occurred. No patients developed graft loss and died due to HBV reactivation. Statistical analysis showed that age and HBc Ab titer were significant risk factors for HBV reactivation (P = .037 and P = .042, respectively). No significant differences were found between graft survival and the presence or absence of HBV reactivation. CONCLUSION These results suggest that HBc Ab titer and age could be significant risk factors for HBV reactivation. Resolution of HBV infection did not appear to be associated with patient or graft survival, regardless of whether HBV reactivation occurred, when following our preemptive strategy.
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Affiliation(s)
- Takanori Mei
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Noguchi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yu Hisadome
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keizo Kaku
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Yasuhiro Okabe
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Entecavir is Safe and Effective in Long Term for the Treatment of Hepatitis B in Immunocompromised Children. J Clin Exp Hepatol 2020; 10:150-154. [PMID: 32189930 PMCID: PMC7067991 DOI: 10.1016/j.jceh.2019.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 04/03/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Hepatitis B infection is common in patients with cancer, and prompt treatment is necessary; otherwise, it can result in life-threatening complications. The objective of this study was to assess the long-term safety and efficacy of entecavir in immunocompromised children with hepatitis B. METHODS This single-center prospective study was conducted on children with different malignancies referred to our department with evidence of hepatitis B infection. Only those children were included in the study who had HBsAg positive and alanine aminotransferase (ALT) more than 2 times the upper limit of normal and whose hepatitis B virus (HBV) DNA was more than 20,000IU/ml. These children were put on entecavir and prospectively observed upto 192 weeks. Primary efficacy end point was the proportion of patients who achieved undetectable HBV DNA at 48 weeks of treatment. Other efficacy end points were the proportion of patients with HBeAg seroconversion, undetectable HBV DNA, and ALT normalization at weeks 48 and 96 weeks. RESULTS A total of 41 children met the inclusion criteria, of which 5 children died because of malignancy and 5 were lost to follow-up. Mean log DNA was 7.67 at the start which after starting entecavir reduced to 4.1, 2.8, 1.19, 1.09, and 0.84 at 12, 24, 48, 72, and 96 weeks, respectively (P value < 0.0001). Mean ALT decreased from 332.5 which reduced to 190, 115, 63, and 46 at 4, 12, 24, and 48 weeks, respectively (P < 0.0001). 67.7% achieved the primary outcome and had undetectable DNA at 48 weeks which increased to 26 (83.9%) at 96 weeks. At 48 weeks, 80.6% patients achieved ALT normalization. Thirty percent developed HBeAg seroconversion. Two patients developed virological breakthrough, one at 96 weeks and another at 192 weeks. No significant adverse effects were observed. CONCLUSION Entecavir is safe and effective in long term for the treatment of hepatitis B in immunocompromised children.
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Key Words
- AASLD, American Association of Study of Liver Diseases
- ADR, adverse drug reaction
- ALT, alanine aminotransferase
- CHB, chronic hepatitis B
- CT, chemotherapy
- EASL, European Association of Study of Liver
- HBV, hepatitis B virus
- HBVR, hepatitis B virus reactivation
- HCC, hepatocellular carcinoma
- INASL, Indian National Association of Study of Liver
- PCR, polymerase chain reaction
- TAF, tenofovir alafenamide
- USG, ultrasonography
- chemotherapy
- reactivation
- transfusion
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Reactivation of Hepatitis B Virus in Patients with Multiple Myeloma. Cancers (Basel) 2019; 11:cancers11111819. [PMID: 31752356 PMCID: PMC6895787 DOI: 10.3390/cancers11111819] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/16/2019] [Accepted: 11/17/2019] [Indexed: 12/11/2022] Open
Abstract
Reactivation of hepatitis B virus (HBV) is a well-known complication in patients with hematological malignancies during or after cytotoxic chemotherapy. If the initiation of antiviral therapy is delayed in patients with HBV reactivation, these patients can develop severe hepatitis and may die of fulminant hepatitis. The preventive strategy for HBV reactivation in patients with malignant lymphoma has already been established based on some prospective studies. As there was an increased number of novel agents being approved for the treatment of multiple myeloma (MM), the number of reported cases of HBV reactivation among MM patients has gradually increased. We conducted a Japanese nationwide retrospective study and revealed that HBV reactivation in MM patients is not rare and that autologous stem cell transplantation is a significant risk factor. In this study, around 20% of all patients with HBV reactivation developed HBV reactivation after 2 years from the initiation of therapy, unlike malignant lymphoma. This might be due to the fact that almost all of the patients received chemotherapy for a long duration. Therefore, a new strategy for the prevention of HBV reactivation in MM patients is required.
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Abstract
PURPOSE OF REVIEW To provide an update on recent studies of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in cancer patients with an emphasis on viral reactivation after cancer treatment, new antiviral therapies, and safety concerns. RECENT FINDINGS The diagnostic criteria for HBV reactivation in patients receiving cancer therapy were revised in 2018. HBV reactivation in these patients is preventable, even with the use of new cancer therapies. HCV reactivation also has been reported in cancer patients, particularly those with hematologic malignancies, and is not a virologic condition usually associated with poor outcome. Prophylaxis to prevent HCV reactivation is not recommended because therapy with direct-acting antivirals eradicates the infection in the majority of cancer patients. SUMMARY Cancer patients with HBV or HCV infection are at risk for viral reactivation, with many similarities between these two infections. Patients at high risk for reactivation will benefit significantly from taking oral antivirals, which will reduce the risk of HBV reactivation or prevent development of HCV reactivation following its virologic cure.
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Lee HL, Jang JW, Han JW, Lee SW, Bae SH, Choi JY, Han NI, Yoon SK, Kim HJ, Lee S, Cho SG, Min CK, Kim DW, Lee JW. Early Hepatitis B Surface Antigen Seroclearance Following Antiviral Treatment in Patients with Reactivation of Resolved Hepatitis B. Dig Dis Sci 2019; 64:2992-3000. [PMID: 30982209 DOI: 10.1007/s10620-019-05614-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 04/04/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Long-term results on hepatitis B virus (HBV) reactivation in patients with resolved infection during anti-cancer therapy are unknown. This study investigated long-term risk and therapeutic endpoints including hepatitis B surface antigen (HBsAg) seroclearance following antiviral therapy in patients developing reactivation of resolved HBV. METHODS The study included 528 consecutive HBsAg-negative/hepatitis B core antibody-positive patients who underwent rituximab treatment or hematopoietic stem cell transplantation (HSCT) between 2006 and 2016. Long-term outcomes of patients with reactivation after antiviral therapy were examined in comparison with 37 HBsAg-positive chronic carriers under the same medical settings. RESULTS The 7-year cumulative rate of HBV reactivation was 10.8% and 57.9% in patients receiving rituximab treatment and HSCT, respectively. After antiviral initiation, patients with reactivation of resolved HBV showed significantly higher 1-year cumulative rates of hepatitis B e antigen seroconversion (69.2% vs. 22.6%, P = 0.008) and HBsAg seroclearance (61.8% vs. 3.3%, P < 0.001) than chronic HBsAg carriers. Reactivation of resolved HBV was independently predictive of HBsAg seroclearance in a combined group of reactivated patients and chronic HBsAg carriers. Low viral load at reactivation was predictive of HBsAg seroclearance in reactivated patients. The majority of patients with HBsAg seroclearance developed anti-HBs. None of the reactivated patients who achieved HBsAg seroclearance relapsed after cessation of antiviral therapy. CONCLUSIONS HBsAg seroclearance rapidly occurs following antiviral therapy for reactivation of resolved HBV infection, suggesting distinct clinical phenotypes as well as shorter duration of HBV infection associated with this particular disease setting-HBV reactivation.
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Affiliation(s)
- Hae Lim Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Ji Won Han
- Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Nam Ik Han
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hee-Je Kim
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seok Lee
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seok-Goo Cho
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chang-Ki Min
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Dong-Wook Kim
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Wook Lee
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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48
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Ehrenstein B. [Interpretation of tuberculosis and hepatitis screening before immunosuppressive treatment]. Z Rheumatol 2019; 77:493-507. [PMID: 29947949 DOI: 10.1007/s00393-018-0488-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
An unrecognized latent tuberculosis infection (LTBI) may be reactivated under immunosuppressive therapy and become life threatening. Diagnosing LTBI requires the combination of targeted patient history and physical examination with the results of an interferon-gamma release assay (IGRA) and in addition, a chest X‑ray is needed to rule out active tuberculosis. Established therapies for LTBI reduce the reactivation risk by approximately 80%. For the initial screening of an HBV infection HBsAg and anti-HBc are determined. Hereby, HBsAg carriers (high HBV reactivation risk, indications for antiviral prophylaxis) and serologically resolved HBV infections (low HBV reactivation risk, use of prophylaxis only in high-risk immunosuppression) can be reliably detected. A previously unrecognized HCV infection, with an increased risk of developing liver cirrhosis during immunosuppression, can be detected in screening by anti-HCV antibodies and be successfully treated with antivirals without interferon.
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Affiliation(s)
- B Ehrenstein
- Klinik und Poliklinik für Rheumatologie/Klinische Immunologie, Asklepios Klinikum Bad Abbach, 93077, Bad Abbach, Deutschland.
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49
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Akinbami A, Badiru M, Uche E, Onyekwere C, Ismail K, Olowoselu O, Oluwole E, Suleiman A, Augustine B, Olaosebikan H. The Prevalence of Occult Hepatitis B Infection among Blood Donors in Lagos, Nigeria. Niger Med J 2019; 60:22-26. [PMID: 31413431 PMCID: PMC6677000 DOI: 10.4103/nmj.nmj_29_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background: In occult hepatitis B virus (HBV) infection, the HBV DNA is present in the blood or liver tissue in patients negative for hepatitis B surface antigen (HBsAg) with or without anti-HBV antibodies. Thus, the absence of HBsAg in the blood only reduces the risk of transmission and is not sufficient enough to ensure the absence of HBV infection. Aim: This study was aimed at determining the prevalence of occult HBV infection among blood donors in Lagos. Study Designs: A cross-sectional study was done among 101 consenting blood donors at Lagos State University Teaching Hospital, Ikeja, between November 2016 and January 2017. Materials and Methods: HBV DNA analysis and viral load were done at the Molecular Laboratory of National Sickle Cell Centre, Idi Araba, Lagos, for all the HBsAg negative blood donors screened by rapid kit at Ikeja. Results: The prevalence of occult HBV DNA among the participants was 3% consisting of 3% prevalence of HBV DNA surface antigen and 0% prevalence for precore and core of the HBV DNA. Conclusion: The low prevalence (3%) of occult HBV seen in our study does not make it cost-effective to routinely screen blood donors or the general population for HBV infection using DNA polymerase chain reaction.
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Affiliation(s)
- Akinsegun Akinbami
- Department of Haematology and Blood Transfusion, Lagos State University College of Medicine, Lagos, Nigeria
| | - Mulikat Badiru
- Department of Haematology and Blood Transfusion, Lagos State University College of Medicine, Lagos, Nigeria
| | - Ebele Uche
- Department of Haematology and Blood Transfusion, Lagos State University College of Medicine, Lagos, Nigeria
| | - Charles Onyekwere
- Department of Internal Medicine, Lagos State University College of Medicine, Lagos, Nigeria
| | - Kamal Ismail
- Department of Haematology and Blood Transfusion, Lagos State University College of Medicine, Lagos, Nigeria
| | - Olusola Olowoselu
- Department of Haematology and Blood Transfusion, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Esther Oluwole
- Department of Community Health and Primary Care, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Aisha Suleiman
- Department of Haematology and Blood Transfusion, Faculty of Basic Clinical Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - Benjamin Augustine
- Department of Haematology and Blood Transfusion, Faculty of Basic Clinical Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - Hakeem Olaosebikan
- Department of Internal Medicine, Lagos State University College of Medicine, Lagos, Nigeria
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50
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Ataca Atilla P, Yalçıner M, Atilla E, İdilman R, Beksaç M. Hepatitis B Reactivation Rate and Fate Among Multiple Myeloma Patients Receiving Regimens Containing Lenalidomide and/or Bortezomib. Turk J Haematol 2019; 36:266-273. [PMID: 31368290 PMCID: PMC6863023 DOI: 10.4274/tjh.galenos.2019.2019.0103] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective: Reactivation of the hepatitis B virus (HBV) refers to an increase in HBV replication in a patient with inactive or resolved HBV. In this retrospective study, our aim is to present and compare HBV reactivation in multiple myeloma (MM) patients who received lenalidomide and/or bortezomib at any time during treatment, evaluate the factors associated with reactivation, and demonstrate the outcome of patients. Materials and Methods: We evaluated 178 MM patients who received lenalidomide (n=102) and/or bortezomib (n=174) during their treatment schedules. The HBsAg, anti-HBc, anti-HBs, HBeAg, and anti-HBe were detected by chemiluminescence by ARCHITECT lab analyzers using commercially available kits (Abbott, USA). HBV-DNA titers were determined by quantitative PCR. The results were evaluated by IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA). Results: HBV reactivation was diagnosed in 6 patients (3%) after bortezomib and in 8 patients (8%) after bortezomib and lenalidomide. Three of the patients in each group had HBsAg+, HBeAg+, AntiHBeAg-, AntiHBc-, and AntiHBS+ status, whereas 5 patients in the bortezomib- and lenalidomide-treated group and 3 patients in the bortezomib-treated group had HBsAg-, HBeAg-, AntiHBeAg-, AntiHBc-, and AntiHBS+ status prior to treatment. There were no statistical differences observed between HBV reactivation in the bortezomib-treated or bortezomib- and lenalidomide-treated groups in terms of age at diagnosis, sex, International Staging System subtype, frequency of extramedullary disease, dialysis requirement, or receiving of autologous stem cell transplantation. In patients who received antiviral prophylaxis, a higher incidence of HBV reactivation was detected in HBsAg-positive patients compared to HBsAg-negative patients (4/4, 100% vs. 2/7, 29%; p=0.045). The 3-year and 5-year overall survival rates were similar in patients with or without HBV reactivation (83% vs. 84%, 73% vs. 74%, p=0.84). Conclusion: Close follow-up is recommended for not only HBsAg-positive but also HBsAg-negative patients.
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Affiliation(s)
- Pınar Ataca Atilla
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Merih Yalçıner
- Ankara University Faculty of Medicine, Department of Internal Medicine, Ankara, Turkey
| | - Erden Atilla
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Ramazan İdilman
- Ankara University Faculty of Medicine, Department of Gastroenterology, Ankara, Turkey
| | - Meral Beksaç
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
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