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Kosaka M, Fujino H, Tsuge M, Yamaoka K, Fujii Y, Uchikawa S, Ono A, Murakami E, Kawaoka T, Miki D, Hayes CN, Kashiyama S, Mokuda S, Yamazaki S, Oka S. Usefulness of serum HBV RNA levels for predicting antiviral response to entecavir treatment in patients with chronic hepatitis B. J Gastroenterol 2025; 60:469-478. [PMID: 39841247 PMCID: PMC11922970 DOI: 10.1007/s00535-025-02211-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 01/01/2025] [Indexed: 01/23/2025]
Abstract
BACKGROUND Hepatitis B virus (HBV) RNA is an important serum biomarker of hepatic covalently closed circular DNA (cccDNA) transcriptional activity; however, its clinical characteristics remain unclear. This study evaluated the clinical utility of HBV RNA levels in patients with chronic hepatitis B (CHB). METHODS We studied 87 CHB patients with serum HBV DNA levels ≥ 5.0 log IU/mL who initiated entecavir (ETV) treatment between 2000 and 2018. Serum HBV RNA levels were measured at three-time points: before ETV treatment, at 12 weeks, and at 48 weeks after starting ETV treatment. Clinical markers associated with the antiviral effects of ETV treatment were analyzed. RESULTS Serum HBV RNA levels decreased in both HBeAg-positive and -negative patients during the observation period. In HBeAg-positive patients, multivariable analysis showed that lower HBV RNA levels at 48 weeks of ETV treatment were independently associated with HBeAg seroconversion. Additionally, lower baseline HBV RNA levels significantly predicted virologic response in those patients. In contrast, among HBeAg-negative patients, lower HBV core-related antigen (HBcrAg) levels and the FIB-4 index were independently associated with virologic response. In HBeAg-positive patients, those with higher baseline HBV RNA levels showed a more significant reduction in hepatitis B surface antigen levels. CONCLUSION Serum HBV RNA levels predicted HBeAg seroconversion and early HBV DNA reduction in HBeAg-positive patients, while HBcrAg was significantly associated with virologic response in HBeAg-negative patients. These findings highlight the different predictive roles of HBV RNA and HBcrAg based on HBeAg status, which may provide individualized treatment strategies.
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Affiliation(s)
- Masanari Kosaka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Masataka Tsuge
- Liver Center, Hiroshima University Hospital, Hiroshima, Japan.
| | - Kenji Yamaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Seiya Kashiyama
- Section of Clinical Laboratory, Department of Clinical Practice and Support, Hiroshima University Hospital, Hiroshima, Japan
| | - Sho Mokuda
- Division of Laboratory Medicine, Hiroshima University Hospital, Hiroshima, Japan
| | - Shinichi Yamazaki
- Department of Clinical Practice and Support, Hiroshima University Hospital, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Zhang J, Yu S, Zhu K, Li S, Huang Y. Probability analysis of hepatocellular carcinoma in hepatitis patients in the gray zone. Front Med (Lausanne) 2024; 11:1464981. [PMID: 39776842 PMCID: PMC11703914 DOI: 10.3389/fmed.2024.1464981] [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: 07/15/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Objective To investigate the probability of hepatocellular carcinoma (HCC) in a large number of gray-zone (GZ) patients with chronic hepatitis B (CHB) in clinical practice. Methods The patients with CHB who were diagnosed and treated in our hospital from January 2013 to January 2023 were analyzed retrospectively. Results According to the different levels of HBeAg, ALT and HBV DNA, GZ patients were divided into four categories: (1) Gray zone A (GZ-A): HBeAg positive, normal ALT level, HBV DNA ≤ 106 IU/ml; (2) Gray zone B (GZ-B): HBeAg positive, ALT>ULN, HBV DNA ≤ 2 × 104 IU/ml; (3) Gray zone C (GZ-C): HBeAg negative, normal ALT level, HBV DNA ≥ 2 × 103 IU/ml; and (4) Gray zone D (GZ-D): HBeAg negative, ALT > ULN, serum HBV DNA ≤ 2 × 103 IU/ml. This observational study showed that after adjustment using inverse probability of treatment weighting (IPTW), the probability of developing HCC in the GZ group was similar to that in the immune-tolerant, HBeAg-positive immune active, and inactive groups. The IPTW-adjusted analysis revealed that the probability of developing HCC in the GZ-B subgroup was similar to that in the immune-active and HBeAg-negative immune-active groups. Conclusion The GZ group and GZ-B subgroup have a higher risk of HCC. Anti-hepatitis B virus therapy should be considered as early as possible for patients in the GZ group, especially in the GZ-B subgroup.
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Affiliation(s)
- Jianna Zhang
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sijie Yu
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Kailu Zhu
- Department of Infectious Diseases, Taizhou First People's Hospital, Taizhou, China
| | - Shibo Li
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Yu Huang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Bao H, Murakami S, Tsuge M, Uchida T, Uchikawa S, Fujino H, Ono A, Murakami E, Kawaoka T, Miki D, Hayes CN, Oka S. Alteration of Gene Expression After Entecavir and Pegylated Interferon Therapy in HBV-Infected Chimeric Mouse Liver. Viruses 2024; 16:1743. [PMID: 39599858 PMCID: PMC11598975 DOI: 10.3390/v16111743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Cross-sectional analyses using liver tissue from chronic hepatitis B patients make it difficult to exclude the influence of host immune responses. In this study, we performed next-generation sequencing using the livers of hepatitis B virus (HBV)-infected uPA/SCID mice with humanized livers before and after antiviral therapy (AVT) with entecavir and pegylated interferon, and then performed a comparative transcriptome analysis of gene expression alteration. After HBV infection, the expression of genes involved in multiple pathways was significantly altered in the HBV-infected livers. After AVT, the levels of 37 out of 89 genes downregulated by HBV infection were restored, and 54 of 157 genes upregulated by HBV infection were suppressed. Interestingly, genes associated with hypoxia and KRAS signaling were included among the 54 genes upregulated by HBV infection and downregulated by AVT. Several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were significantly downregulated by AVT, with a potential application for the suppression of hepato-carcinogenesis.
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Affiliation(s)
- Huarui Bao
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Serami Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Masataka Tsuge
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
- Liver Center, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Takuro Uchida
- Division of Travel Medicine and Health, Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University, Oita 879-5593, Japan;
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita 879-5593, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Hatsue Fujino
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Atsushi Ono
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Daiki Miki
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Clair Nelson Hayes
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (H.B.); (S.M.); (S.U.); (H.F.); (A.O.); (E.M.); (T.K.); (D.M.); (C.N.H.); (S.O.)
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Wang J, Yan X, Zhu L, Liu J, Qiu Y, Li Y, Liu Y, Xue R, Zhan J, Jiang S, Geng Y, Wan Y, Li M, Mao M, Gao D, Yin S, Tong X, Xia J, Ding W, Chen Y, Li J, Zhu C, Huang R, Wu C. Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone. Aliment Pharmacol Ther 2023; 57:464-474. [PMID: 36324235 DOI: 10.1111/apt.17272] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/08/2022] [Accepted: 10/15/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). AIMS To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. METHODS This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg-positive, normal ALT and HBV DNA ≤106 IU/ml (GZ-A); HBeAg-positive, elevated ALT and HBV DNA ≤2 × 104 IU/ml (GZ-B); HBeAg-negative, normal ALT and HBV DNA ≥2 × 103 IU/ml (GZ-C) and HBeAg-negative, elevated ALT and HBV DNA ≤2 × 103 IU/ml (GZ-D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. RESULTS Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg-positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg-negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ-D (42.6%) was the dominant category, followed by GZ-C (38.8%), GZ-A (10.3%) and GZ-B (8.3%). The highest proportion of significant histological disease was observed patients in GZ-B (100.0%), followed by GZ-A (84.0%), GZ-D (69.9%) and GZ-C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg-negative GZ. CONCLUSIONS Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg-positive and HBeAg-negative GZ CHB patients with high PT.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yuanwang Qiu
- Department of Infectious Diseases, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Yiguang Li
- Department of Infectious Diseases, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ruifei Xue
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Zhan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Suling Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Geng
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yawen Wan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, Jiangsu, China
| | - Ming Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Minxin Mao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dongmei Gao
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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Suehiro Y, Tsuge M, Kurihara M, Uchida T, Fujino H, Ono A, Yamauchi M, Naswa Makokha G, Nakahara T, Murakami E, Abe-Chayama H, Kawaoka T, Miki D, Imamura M, Aikata H, Nelson Hayes C, Fujita T, Chayama K. Hepatitis B Virus (HBV) Upregulates TRAIL-R3 Expression in Hepatocytes Resulting in Escape From Both Cell Apoptosis and Suppression of HBV Replication by TRAIL. J Infect Dis 2023; 227:686-695. [PMID: 35226068 DOI: 10.1093/infdis/jiac044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 02/06/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) evades host immunity by regulating intracellular signals. To clarify this immune tolerance mechanism, we performed gene expression analysis using HBV-infected humanized mouse livers. METHODS Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 3 (TRAIL-R3) was significantly upregulated in livers of HBV-infected human hepatocyte transplanted mice by cDNA microarray and next-generation sequencing. We analyzed the significance of TRAIL-R3 upregulation in HBV infection using human hepatocyte transplanted mice and HepG2 cell lines. RESULTS TRAIL-R3 induction by HBV infection was verified by in vitro and in vivo HBV replication models, and induction was inhibited by antiviral nucleot(s)ide analogue treatment. TRAIL-R3 transcription was regulated by the TRAIL-R3 promoter at -969 to -479 nucleotides upstream from the transcription start site, and by hepatitis B x (HBx) via activation of nuclear factor-κB (NF-κB) signal. TRAIL not only induced cell apoptosis but also inhibited HBV replication. TRAIL-R3 upregulation could inhibit both TRAIL-dependent apoptosis in HBV-infected hepatocytes and TRAIL-mediated suppression of HBV replication. CONCLUSIONS These results suggest a mechanism by which HBV persists by escaping host immunity through upregulation of TRAIL-R3. Development of novel drugs to inhibit this escape system might lead to complete HBV elimination from human hepatocytes.
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Affiliation(s)
- Yosuke Suehiro
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Mio Kurihara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, 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 Sciences, 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 Sciences, 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 Sciences, 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 Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, 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 Sciences, 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 Sciences, 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
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, 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 Sciences, 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 Sciences, 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 Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Fujita
- Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuaki Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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6
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Tsuge M. Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection? Viruses 2021; 13:v13101920. [PMID: 34696350 PMCID: PMC8541657 DOI: 10.3390/v13101920] [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: 08/20/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem that can lead to liver dysfunction, including liver cirrhosis and hepatocellular carcinoma (HCC). Current antiviral therapies can control viral replication in patients with chronic HBV infection; however, there is a risk of HCC development. HBV-related proteins may be produced in hepatocytes regardless of antiviral therapies and influence intracellular metabolism and signaling pathways, resulting in liver carcinogenesis. To understand the mechanisms of liver carcinogenesis, the effect of HBV infection in human hepatocytes should be analyzed. HBV infects human hepatocytes through transfer to the sodium taurocholate co-transporting polypeptide (NTCP). Although the NTCP is expressed on the hepatocyte surface in several animals, including mice, HBV infection is limited to human primates. Due to this species-specific liver tropism, suitable animal models for analyzing HBV replication and developing antivirals have been lacking since the discovery of the virus. Recently, a humanized mouse model carrying human hepatocytes in the liver was developed based on several immunodeficient mice; this is useful for analyzing the HBV life cycle, antiviral effects of existing/novel antivirals, and intracellular signaling pathways under HBV infection. Herein, the usefulness of human hepatocyte chimeric mouse models in the analysis of HBV-associated hepatocarcinogenesis is discussed.
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Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Department of Biomedical Science, Research and Development Division, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; ; Tel.: +81-82-257-1510
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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7
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Lin M, Guo R, Ma C, Zeng D, Su Z. Manganese Breaks the Immune Tolerance of HBs-Ag. Open Forum Infect Dis 2021; 8:ofab028. [PMID: 33614817 PMCID: PMC7885859 DOI: 10.1093/ofid/ofab028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 01/21/2021] [Indexed: 12/31/2022] Open
Abstract
Background Manganese (Mn2+) has been shown to promote type I interferon (IFN) production and activate the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) signaling pathway, suggesting that Mn2+ could be used as an adjuvant for vaccination. Methods In present study, the effects of Mn2+ on vaccination against hepatitis B virus (HBV) were evaluated. We treated mouse hepatocytes and kuppfer cells with Mn2+ with or without adeno-associated virus (AAV)–HBV infection. Expression of IFN-α and IFN-β and activation of TBK1 and IRF3 were monitored. Wild-type and STING-/- mice were treated with Mn2+ and then infected with AAV-HBV. Serum levels of HBV surface antigen (HBsAg), alanine aminotransferase (ALT) activity, IFN-α, and IFN-β were detected. Lymphocyte infiltration in the liver was evaluated. HBsAg-Tg mice were vaccinated with Mn2+ and HBsAg. The serum levels of HBsAg antibody, alanine transaminase activity, and IFN-β were monitored after vaccination. Results Mn2+ promoted IFN-α and IFN-β production in mouse hepatocytes and kuppfer cells. Mn2+ failed to promote IFN-α and IFN-β production in kuppfer cells deficient in STING. Mn2+ promoted activation/phosphorylation of TBK1 and IRF3 during AAV-HBV infection. Mn2+ decreased serum levels of HBsAG, increased serum levels of alanine aminotransferase (ALT), IFN-α and IFN-β, and enhanced lymphocyte infiltration and the percentage of IFN-γ-producing CD8+ T cells in the liver of AAV-HBV-infected mice. In contrast, Mn2+ treatment did not affect serum levels of HBsAG, ALT, IFN-α, or IFN-β in STING-deficient mice. Conclusions Mn2+ promoted HBsAG antibody, ALT, and IFN-β production after HBsAG immunization. Mn2+ promoted type I IFN production in AAV-HBV infection and HBsAG immunization and could be used as an adjuvant for vaccination.
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Affiliation(s)
- Mengxin Lin
- Department of Infectious Disease, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Ruyi Guo
- Department of Infectious Disease, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Cuiping Ma
- Department of Infectious Disease, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Dawu Zeng
- Liver Research Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Zhijun Su
- Department of Infectious Disease, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
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8
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Liu TW, Huang CF, Yeh ML, Tsai PC, Jang TY, Huang JF, Dai CY, Chuang WL, Yu ML. Less liver fibrosis marker increment in overweight chronic hepatitis B patients observed by age-adjusted Fibrosis-4 Index. BMJ Open Gastroenterol 2020; 7:bmjgast-2020-000543. [PMID: 33323472 PMCID: PMC7745320 DOI: 10.1136/bmjgast-2020-000543] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/22/2022] Open
Abstract
Background and aims Chronic hepatitis B patients in Taiwan with no or limited liver injury are not reimbursed for antiviral treatment by the Taiwan National Health Insurance (NHI). Innovative fibrosis marker, age-adjusted Fibrosis-4 Index (FIB4-AA), was implemented to evaluate the tendency of liver fibrosis in these patients. Methods The FIB-4 indices of 256 antiviral treatment-naïve chronic hepatitis B patients at Kaohsiung Medical University Hospital from 2003 to 2019 were reviewed. The difference in initial FIB-4 and last FIB4-AA was treated as a categorical variable, representing the tendency of liver fibrosis in each individual aside from ageing. Logistic regression was implemented to evaluate the three parameters most dependent on increment of FIB4-AA: e seroconversion, body mass index (BMI) and initial FIB-4 index. Results The yearly FIB-4 growth rate of an individual without chronic hepatitis was lower than that of the study group (0.0237 vs 0.0273 for males, 0.02 vs 0.0288 for females). Patients undergoing or completing e seroconversion were less prone to increment of FIB4-AA (p=0.036, OR 0.524). Logistic regression revealed that BMI ≥25 kg/m2 significantly less increment of FIB4-AA (p=0.001, OR 0.383, 95% CI 0.212 to 0.690), while patients with initial FIB-4 <1.29 were prone to increasing liver FIB4-AA (p=0.000, OR 3.687, 95% CI 1.999 to 6.797). Conclusion Chronic hepatitis B patients not meeting the reimbursement criteria of the Taiwan NHI are prone to increment of liver fibrosis marker. Overweight is associated with less increment of fibrosis marker, while initial FIB-4 <1.29 is associated with increasing fibrosis marker.
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Affiliation(s)
- Ta-Wei Liu
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.,Internal Medicine, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan.,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Tyng-Yuan Jang
- Internal Medicine, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan .,Hepatitis Center, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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9
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Wang J, Xia J, Yan X, Yang Y, Wei J, Xiong Y, Wu W, Liu Y, Chen Y, Jia B, Chen Z, Zhang Z, Ding W, Huang R, Wu C. The gamma-glutamyl transpeptidase to platelet ratio predicts liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase. Clin Res Hepatol Gastroenterol 2020; 44:913-922. [PMID: 32147439 DOI: 10.1016/j.clinre.2020.01.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/18/2020] [Accepted: 01/21/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND The gamma-glutamyl transpeptidase (GGT) to platelet ratio (GPR) was proposed as a novel index for predicting liver inflammation in chronic hepatitis B (CHB) patients. We aimed to investigate GPR for predicting significant liver inflammation in CHB patients with normal (≤1×upper limit of normal, ULN) or mildly elevated (≤2×ULN) alanine transaminase (ALT). METHODS AND METHODS 431 treatment-naïve CHB patients with normal or mildly elevated ALT who underwent liver biopsy were enrolled. Comparision of GPR and other parameters for significant liver inflammation (G≥3). RESULTS For patients with ALT≤2×ULN, the receiver-operating characteristic curves (AUROCs) of GPR in predicting significant liver inflammation were 0.837 (95%CI 0.796 to 0.878), 0.860 (95%CI 0.809 to 0.910) and 0.809 (95%CI 0.739 to 0.878) in the entire patients, HBeAg positive and HBeAg negative CHB patients, respectively. The diagnostic performance of GPR was higher than ALT (P<0.001, P<0.001, respectively), aspartate transaminase (AST) (P=0.001, P=0.003, respectively) and GGT (P=0.002, P=0.002, respectively) in the entire and HBeAg positive patients, but was comparable with AST (P=0.096) and GGT (P=0.273) in the HBeAg negative CHB patients. For patients with ALT≤1×ULN, the diagnostic accuracy of GPR was significantly higher than ALT, AST and GGT in the entire (P<0.001, P=0.008 and P=0.043, respectively) and HBeAg positive CHB patients (P<0.001, P=0.009 and P=0.024, respectively), while was comparable to AST (P=0.209) and GGT(P=0.555) in the HBeAg negative CHB patients. CONCLUSION GPR has a better diagnostic value than conventional parameters to predict significant liver inflammation in CHB patients with normal or mildly elevated ALT levels, especially for HBeAg positive CHB.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yue Yang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jie Wei
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yali Xiong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weihua Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yong Liu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Bei Jia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Zhong Chen
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Zhaoping Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
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10
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Jin J, Xu H, Wu R, Gao N, Wu N, Li S, Niu J. Identification of key genes and pathways associated with different immune statuses of hepatitis B virus infection. J Cell Mol Med 2019; 23:7474-7489. [PMID: 31565863 PMCID: PMC6815815 DOI: 10.1111/jcmm.14616] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/18/2019] [Accepted: 08/06/2019] [Indexed: 02/06/2023] Open
Abstract
We aimed to identify key genes and pathways associated with different immune statuses of hepatitis B virus (HBV) infection. The gene expression and DNA methylation profiles were analysed in different immune statuses of HBV infection. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified, followed by their functional and integrative analyses. The differential expression of IgG Fc receptors (FcγRs) in chronic HBV-infected patients and immune cells during different stages of HBV infection was investigated. Toll-like receptor (TLR) signalling pathway (including TLR6) and leucocyte transendothelial migration pathway (including integrin subunit beta 1) were enriched during acute infection. Key DEGs, such as FcγR Ib and FcγR Ia, and interferon-alpha inducible protein 27 showed correlation with alanine aminotransferase levels, and they were differentially expressed between acute and immune-tolerant phases and between immune-tolerant and immune-clearance phases. The integrative analysis of DNA methylation profile showed that lowly methylated and highly expressed genes, including cytotoxic T lymphocyte-associated protein 4 and mitogen-activated protein kinase 3 were enriched in T cell receptor signalling pathway during acute infection. Highly methylated and lowly expressed genes, such as Ras association domain family member 1 and cyclin-dependent kinase inhibitor 2A were identified in chronic infection. Furthermore, differentially expressed FcγR Ia, FcγR IIa and FcγR IIb, CD3- CD56+ CD16+ natural killer cells and CD14high CD16+ monocytes were identified between immune-tolerant and immune-clearance phases by experimental validation. The above genes and pathways may be used to distinguish different immune statuses of HBV infection.
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MESH Headings
- DNA Methylation/genetics
- DNA Methylation/immunology
- Female
- Gene Expression/genetics
- Hepatitis B/genetics
- Hepatitis B/immunology
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/virology
- Humans
- Killer Cells, Natural/immunology
- Male
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, IgG/genetics
- Receptors, IgG/immunology
- Signal Transduction/genetics
- T-Lymphocytes, Cytotoxic/immunology
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Affiliation(s)
- Jinglan Jin
- Department of Hepatology, The First Hospital of Jilin UniversityJilin UniversityChangchunChina
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin UniversityJilin UniversityChangchunChina
- Jilin Province Key Laboratory of Infectious DiseasesLaboratory of Molecular VirologyChangchunChina
| | - Ruihong Wu
- Department of Hepatology, The First Hospital of Jilin UniversityJilin UniversityChangchunChina
- Jilin Province Key Laboratory of Infectious DiseasesLaboratory of Molecular VirologyChangchunChina
| | - Na Gao
- Department of Infectious DiseaseThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
| | - Na Wu
- Lanshan People’s HospitalLinyiChina
| | - Shibo Li
- Department of Pediatrics, Genetics LaboratoryUniversity of Oklahoma Health Sciences Center (OUHSC)Oklahoma CityOKUSA
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin UniversityJilin UniversityChangchunChina
- Jilin Province Key Laboratory of Infectious DiseasesLaboratory of Molecular VirologyChangchunChina
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11
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Kurihara M, Tsuge M, Murakami E, Mori N, Ohishi W, Uchida T, Fujino H, Nakahara T, Abe-Chayama H, Kawaoka T, Miki D, Hiramatsu A, Imamura M, Kawakami Y, Aikata H, Ochi H, Zhang Y, Makokha GN, Hayes CN, Chayama K. The association between serum cytokine and chemokine levels and antiviral response by entecavir treatment in chronic hepatitis B patients. Antivir Ther 2019; 23:239-248. [PMID: 28933704 DOI: 10.3851/imp3196] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Although nucleoside/nucleotide analogue therapy is thought to suppress chronic hepatitis B (CHB) via regulation of inflammatory cytokines/chemokines, the mechanism is still unclear. In this study, serum cytokine/chemokine levels were measured in CHB patients treated with entecavir, and the association with antiviral response was analysed. METHODS A total of 78 Japanese patients with CHB were enrolled, and serum cytokine/chemokine levels were measured at baseline and at 12, 24 and 48 weeks of entecavir treatment using the MULTIPLEX kit. RESULTS Antiviral response to entecavir treatment was significantly associated with hepatitis B surface antigen (HBsAg) titre and serum interferon-gamma-inducible protein 10 (IP-10) level (12w; P=0.0002; OR=0.020 [95% CI 0.002, 0.156], P=0.003; OR=0.042 [95% CI 0.005, 0.336], respectively). HBe-positive patients whose serum macrophage-derived chemokine (MDC) level was lower (<582.83 pg/ml) and IP-10 level was higher (≥1,323.13 pg/ml) achieved hepatitis B e antigen (HBeAg) loss earlier than those who remained HBeAg-positive (P=0.044). HBsAg reduction by entecavir treatment was significantly associated with higher initial tumour necrosis factor-alpha (TNF-α) level (≥15.20 pg/ml) and higher alanine aminotransferase level (≥73 IU/l; P=0.009; OR=18.460 [95% CI 2.044, 166.709], P=0.022; OR=7.709 [95% CI 1.341, 44.327], respectively). CONCLUSIONS Results of the present study indicate that changes in cytokine/chemokine levels following entecavir therapy are associated with response to antiviral therapy in CHB patients. Monitoring of serum cytokine/chemokine levels could be useful for predicting reduction of HBV DNA and HBsAg and HBe seroconversion.
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Affiliation(s)
- Mio Kurihara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Nami Mori
- Department of Hepatology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Waka Ohishi
- Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Yizhou Zhang
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
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12
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Wang J, Xia J, Zhang R, Yan X, Yang Y, Zhao X, Chang H, Wang G, Chen G, Liu Y, Chen Y, Jia B, Zhang Z, Ding W, Huang R, Wu C. A novel index using routine clinical parameters for predicting significant liver inflammation in chronic hepatitis B. J Viral Hepat 2018; 25:1151-1160. [PMID: 29741221 DOI: 10.1111/jvh.12925] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 04/20/2018] [Indexed: 12/14/2022]
Abstract
Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n = 346) and validation cohorts (n = 173). Based on routine clinical parameters, gamma-glutamyl transpeptidase (GGT; P = 0.031) and platelets (PLT; P < 0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742-0.839), 0.783 (95% CI: 0.717-0.849) and 0.791 (95% CI: 0.716-0.867) in the entire patients with CHB, HBeAg-positive CHB patients and HBeAg-negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg-positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg-negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg-positive CHB patients, but was comparable with GGT in HBeAg-negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg-positive CHB.
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Affiliation(s)
- J Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - J Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - R Zhang
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - X Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Y Yang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - X Zhao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - H Chang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - G Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - G Chen
- Department of Infectious Diseases, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Y Liu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Y Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - B Jia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Z Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - W Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - R Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - C Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
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13
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Sun Y, Wang S, Yi Y, Zhang J, Duan Z, Yuan K, Liu W, Li J, Zhu Y. The Hepatitis B Surface Antigen Binding Protein: An Immunoglobulin G Constant Region-Like Protein That Interacts With HBV Envelop Proteins and Mediates HBV Entry. Front Cell Infect Microbiol 2018; 8:338. [PMID: 30319994 PMCID: PMC6167546 DOI: 10.3389/fcimb.2018.00338] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 09/06/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a leading cause of liver cirrhosis, liver cancer, and liver failure, affecting 350 million people worldwide. Currently available anti-HBV drugs include (PEGylated-) interferon-α and nucleos(t)ide analogs, which can cause significant side effects and drug-resistance in many cases of long-term treatment. The lack of a reliable and robust in vitro infection system is a major barrier for understanding the HBV life cycle and discovering novel therapeutic targets. In the present study, we demonstrate that overexpression of the hepatitis B surface antigen binding protein (SBP) in HepG2 cells (HepG2-SBP) resulted in their susceptibility to HBV infection. HepG2-SBP cells supported the uptake of the viral surface protein (HBsAg-preS), HBV-pseudotyped virus, and live HBV in patient sera. Moreover, SBP-mediated HBsAg-preS uptake, and HBV pseudotyped virus infections were efficiently blocked by preS1- and SBP-specific antibodies. These observations suggest that SBP is involved in HBV entry and that HepG2-SBP cells can serve as a cellular model to study the post-binding steps of HBV infection.
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Affiliation(s)
- Yeping Sun
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Shanshan Wang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Yong Yi
- The 306th Hospital of People's Liberation Army, Beijing, China
| | - Jing Zhang
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Kehu Yuan
- Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, Shenzhen, China
| | - Wenjun Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Jing Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Yiping Zhu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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14
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Tsuge M, Hiraga N, Zhang Y, Yamashita M, Sato O, Oka N, Shiraishi K, Izaki Y, Makokha GN, Uchida T, Kurihara M, Nomura M, Tsushima K, Nakahara T, Murakami E, Abe-Chayama H, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Fujita T, Chayama K. Endoplasmic reticulum-mediated induction of interleukin-8 occurs by hepatitis B virus infection and contributes to suppression of interferon responsiveness in human hepatocytes. Virology 2018; 525:48-61. [PMID: 30240958 DOI: 10.1016/j.virol.2018.08.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 08/06/2018] [Accepted: 08/28/2018] [Indexed: 01/14/2023]
Abstract
The events in the immune response to hepatitis B virus (HBV) remain unclear. We analyzed the direct influence of HBV on gene expression in human hepatocytes under immunodeficient conditions using a human hepatocyte chimeric mouse model. HBV-infected or non-infected chimeric mouse livers were collected, and gene expression profiles were compared. Since IL-8 was the most significantly up-regulated gene at 8 weeks after HBV infection, we focused on IL-8 and found that HBx and the large HBs (L-HBs) protein induce transcription of IL-8 via endoplasmic reticulum stress. This stress induces IL-8 transcription via NFAT activation and contributes to suppression of interferon responsiveness in HBV-infected human hepatocytes. In the present study, we identified a novel regulatory mechanism in which the L-HBs protein activates IL-8 via endoplasmic reticulum stress, suggesting a key role for IL-8 in the immune response to HBV and a potential new target for antiviral treatments of HBV infection.
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Affiliation(s)
- Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Yizhou Zhang
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | | | | | - Naoya Oka
- Hiroshima University, Hiroshima, Japan.
| | | | - Yu Izaki
- Department of Surgery, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan.
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Mio Kurihara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Motonobu Nomura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Ken Tsushima
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Hiromi Abe-Chayama
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan.
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
| | - Takashi Fujita
- Laboratory of Molecular Genetics, Department of Genetics and Molecular Biology, Institute for Virus Research Kyoto University, Kyoto, Japan.
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan.
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15
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Tatsukawa Y, Tsuge M, Kawakami Y, Murakami E, Kurihara M, Nomura M, Tsushima K, Uchida T, Nakahara T, Miki D, Kawaoka T, Abe-Chayama H, Imamura M, Aikata H, Ochi H, Hayes CN, Kawakami H, Chayama K. Reduction of hepatitis B surface antigen in sequential versus add-on pegylated interferon to nucleoside/nucleotide analogue therapy in HBe-antigen-negative chronic hepatitis B patients: a pilot study. Antivir Ther 2018; 23:639-646. [DOI: 10.3851/imp3240] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2018] [Indexed: 10/14/2022]
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16
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Kim DY, Lee HW, Song JE, Kim BK, Kim SU, Kim DY, Ahn SH, Han KH, Park JY. Switching from tenofovir and nucleoside analogue therapy to tenofovir monotherapy in virologically suppressed chronic hepatitis B patients with antiviral resistance. J Med Virol 2017; 90:497-502. [PMID: 29077211 DOI: 10.1002/jmv.24986] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/27/2017] [Indexed: 12/30/2022]
Abstract
It is unclear whether chronic hepatitis B (CHB) patients with antiviral resistance, who achieve a complete virologic response (CVR) with tenofovir disoproxil fumarate (TDF) and nucleoside analogue (NUC) combination therapy, maintain CVR if switched to TDF monotherapy. We investigated the persistence of CVR after cessation of NUC in virologically suppressed antiviral resistant CHB patients using TDF+NUC combination therapy. This study recruited 76 antiviral-resistant CHB patients showing CVR on TDF+entecavir (ETV) (n = 52), TDF+lamivudine (LAM; n = 14), and TDF+telbivudine (LdT; n = 10) combination therapy, who were switched to TDF monotherapy as step-down therapy. At baseline, 47 patients were male and the median age was 53.0 years (range: 30-78 years); 72.3% cases were hepatitis B e antigen-positive (HBeAg+) and 23.7% were of liver cirrhosis. The median duration of TDF+NUC combination therapy was 20.8 months (range: 3-46 months). At a median follow-up of 24.7 months (range: 12-48 months) after switching to TDF monotherapy, all 76 patients maintained CVR, regardless of the duration of combination therapy and the type of prior NUC and antiviral resistance. Renal dysfunction was not observed during the treatment period. The step-down strategy of switching from TDF+NUC combination therapy to TDF monotherapy in virologically suppressed CHB patients with antiviral resistance should be considered.
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Affiliation(s)
- Dong Yun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Jeong Eun Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Liver Center, Severance Hospital, Seoul, South Korea
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17
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Development of a Novel Site-Specific Pegylated Interferon Beta for Antiviral Therapy of Chronic Hepatitis B Virus. Antimicrob Agents Chemother 2017; 61:AAC.00183-17. [PMID: 28373196 DOI: 10.1128/aac.00183-17] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/08/2017] [Indexed: 12/22/2022] Open
Abstract
Although nucleot(s)ide analogues and pegylated interferon alpha 2a (PEG-IFN-α2a) can suppress hepatitis B virus (HBV) replication, it is difficult to achieve complete HBV elimination from hepatocytes. A novel site-specific pegylated recombinant human IFN-β (TRK-560) was recently developed. In the present study, we evaluated the antiviral effects of TRK-560 on HBV replication in vitro and in vivo. In vitro and in vivo HBV replication models were treated with antivirals including TRK-560, and changes in HBV markers were evaluated. To analyze antiviral mechanisms, cDNA microarray analysis and an enzyme-linked immunoassay (ELISA) were performed. TRK-560 significantly suppressed the production of intracellular HBV replication intermediates and extracellular HBV surface antigen (HBsAg) (P < 0.001 and P < 0.001, respectively), and the antiviral effects of TRK-560 were enhanced in combination with nucleot(s)ide analogues, such as entecavir and tenofovir disoproxil fumarate. The reduction in HBV DNA levels by TRK-560 treatment was significantly higher than that by PEG-IFN-α2a treatment both in vitro and in vivo (P = 0.004 and P = 0.046, respectively), and intracellular HBV covalently closed circular DNA (cccDNA) reduction by TRK-560 treatment was also significantly higher than that by PEG-IFN-α2a treatment in vivo (P = 0.0495). cDNA microarrays and ELISA for CXCL10 production revealed significant differences between TRK-560 and PEG-IFN-α2a in the induction potency of interferon-stimulated genes. TRK-560 shows a stronger antiviral potency via higher induction of interferon-stimulated genes and stronger stimulation of immune cell chemotaxis than PEG-IFN-α2a. As HBsAg loss and HBV cccDNA eradication are important clinical goals, these results suggest a potential role for TRK-560 in the development of more effective treatment for chronic hepatitis B infection.
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18
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Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. J Gastroenterol 2016; 51:1073-1080. [PMID: 26943168 DOI: 10.1007/s00535-016-1189-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 02/16/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Interferon and nucleotide/nucleoside analogues are the main treatments for chronic hepatitis B. These drugs effectively reduce serum hepatitis B virus (HBV) DNA titers but fail to sufficiently reduce hepatitis B surface antigen (HBsAg) levels. Following the recent identification of sodium taurocholate cotransporting polypeptide as a receptor for HBV entry, inhibition of HBV entry has become an attractive therapeutic target for chronic hepatitis B treatment. We therefore evaluated the antiviral effects of antibody to HBsAg (anti-HBs) immunoglobulin (HBIG), which can inhibit HBV entry, by in an vivo study and a clinical trial. METHODS In the in vivo study, HBV-infected mice were generated from human hepatocyte chimeric mice and treated with HBIG. A clinical trial evaluating HBIG therapy in patients was also performed. RESULTS In the mouse study, HBV DNA titers were reduced and serum HBsAg titers decreased to undetectable levels following high-dose HBIG injection. On the basis of this result, eight chronic hepatitis B patients, who had received long-term nucleotide analogue treatment, were treated with monthly HBIG injections as an additional treatment. After 1 year of treatment, an HBsAg level reduction of more than 1 log IU/mL was observed in four patients, and three patients became anti-HBs positive. No adverse events occurred during HBIG therapy. CONCLUSION These results suggest that monthly HBIG injection might benefit patients with chronic hepatitis B whose HBsAg titer becomes lower following long-term nucleotide/nucleoside analogue treatment.
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19
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Narciso-Schiavon JL, Schiavon LDL, Carvalho-Filho RJD, Emori CT, Maryia FA, Bordin JO, Silva AEB, Ferraz MLG. Clinical and epidemiological profile of female blood donors with positive serology for viral hepatitis B. Rev Soc Bras Med Trop 2016; 48:524-31. [PMID: 26516960 DOI: 10.1590/0037-8682-0157-2015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 08/14/2015] [Indexed: 11/21/2022] Open
Abstract
INTRODUCTION Since women are frequently the minority among blood donors worldwide, studies evaluating this population usually reflect male features. We assessed the features of female blood donors with positive serology for HBV and compared them with those of men.METHODS The study comprised consecutive blood donors referred to a specialized liver disease center to be evaluated due to HBsAg- and/or anti-HBc-positive tests. RESULTS The study encompassed 1,273 individuals, 219 (17.2%) of whom were referred due to positive HBsAg test and 1,054 (82.8%) due to reactive anti-HBc test. Subjects' mean age was 36.8±10.9 years, and 28.7% were women. Female blood donors referred for positive HBsAg screening tests demonstrated higher prevalence of healthcare workers (9.3% vs 2.5%) and lower prevalence of sexual risk behaviors (15.1% vs 41.1%) and alcohol abuse (1.9% vs 19.8%) compared to men. Women had lower ALT (0.6 vs 0.8×ULN), AST (0.6 vs 0.8×ULN), direct bilirubin (0.2 vs 0.3mg/dL), and alkaline phosphatase (0.5 vs 0.6×ULN) levels and higher platelet count (223,380±50,293 vs 195,020±53,060/mm3). Women also had a higher prevalence of false-positive results (29.6% vs 17.0%). No differences were observed with respect to liver biopsies. Female blood donors referenced for reactive anti-HBc screening tests presented similar clinical, epidemiological, and biochemical characteristics to those reported for positive HBsAg screening tests and similarly had a higher prevalence of false-reactive results. CONCLUSIONS Compared to men, female blood donors with positive HBsAg and/or anti-HBc screening tests demonstrated higher prevalence of professional risk and false-positive results and reduced alteration of liver chemistry.
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Affiliation(s)
- Janaína Luz Narciso-Schiavon
- Núcleo de Estudos em Gastroenterologia e Hepatologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Leonardo de Lucca Schiavon
- Núcleo de Estudos em Gastroenterologia e Hepatologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | | | - Christine Takemi Emori
- Divisão de Gastroenterologia, Setor de Hepatites, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Fernando Akio Maryia
- Divisão de Gastroenterologia, Setor de Hepatites, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - José Orlando Bordin
- Divisão de Hematologia, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | | | - Maria Lucia Gomes Ferraz
- Divisão de Gastroenterologia, Setor de Hepatites, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
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20
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Murakami E, Tsuge M, Hiraga N, Kan H, Uchida T, Masaki K, Nakahara T, Ono A, Miki D, Kawaoka T, Abe H, Imamura M, Aikata H, Ochi H, Hayes CN, Akita T, Tanaka J, Chayama K. Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones. J Infect 2015; 72:91-102. [PMID: 26515673 DOI: 10.1016/j.jinf.2015.09.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 08/23/2015] [Accepted: 09/14/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) has been approved for chronic hepatitis B treatment, and favorable susceptibility of hepatitis B virus (HBV) has been indicated. However, differences in TDF susceptibility among HBV genotypes and drug-resistant strains are unclear. In this study, TDF susceptibilities between genotypes A and C were evaluated in vitro and in vivo using several drug-resistant HBV clones. METHODS HBV expression plasmids were constructed from sera of HBV carriers, and drug-resistant substitutions were introduced by site-directed mutagenesis. TDF susceptibility was evaluated by changes of core-associated HBV replication intermediates in vitro or by change of serum HBV DNA in human hepatocyte chimeric mice carrying each HBV clone in vivo. RESULTS TDF susceptibilities of lamivudine-resistant clones (rtL180M/M204V) and lamivudine plus entecavir-resistant clones (rtL180M/S202G/M204V) were similar to wild type clones in vitro. However, lamivudine plus adefovir-resistant clones (rtA181T/N236T) acquired tolerance to TDF, and the rtN236T mutation was considered to be a causal substitution for TDF resistance. Furthermore, genotypic differences in TDF susceptibility were also observed between genotypes A and C in vitro, and the differences could be confirmed in vivo (p = 0.023). CONCLUSIONS The present study indicates that TDF susceptibility varies among HBV genotypes and drug-resistant HBV clones.
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Affiliation(s)
- Eisuke Murakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Junko Tanaka
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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21
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Viganò M, Bhoori S, Lampertico P, Donato MF, Iavarone M, Grossi G, Facciorusso A, Caccamo L, Rossi G, Colombo M, Mazzaferro V. Extended survival of patients with persistently suppressed hepatitis B transplanted for hepatocellular carcinoma. Liver Int 2015; 35:2187-93. [PMID: 25809541 DOI: 10.1111/liv.12835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 03/17/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) has become a major cause of liver-related death and indication to liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection following the widespread adoption of antiviral therapy with nucleos(t)ide analogs (NUCs). Yet, the long-term outcome of patients undergoing liver transplantation for an HCC developed during effective NUC treatment is unknown. METHODS We evaluated 101 patients with persistently compensated cirrhosis who were consecutively transplanted for HCC in two centers in Milan. At LT, 91 (90%) patients had undetectable serum HBV DNA (<12 IU/ml) and 90 (89%) were within Milan criteria (MC). All patients received post-transplant HBV prophylaxis with specific immunoglobulins (HBIgs) and NUCs. End-points were long-term patient survival and recurrence of HCC and HBV. RESULTS During 106 (range 3-165) months following LT, HCC recurred in 11 (11%) patients (nine beyond MC at explant, two with HBV recurrence). Age (HR 1.1, 95%CI 1.0-1.2, P = 0.04) and exceeding MC (HR 9.6, 95%CI 2.9-32, P < 0.0001) were the only independent pretransplant predictors of tumour recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared with 45% among those beyond MC at LT (P = 0.004). Overall, 18 patients (18%, nine HCC, nine non liver-related events) died with a 10-year cumulative probability of overall and liver-related survival of 79% and 89% respectively. CONCLUSIONS Extended survival of HBV cirrhotics transplanted for HCC can be achieved by coupling MC at listing with persistent pharmacological suppression of HBV.
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Affiliation(s)
- Mauro Viganò
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - Sherrie Bhoori
- Gastroenterology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Pietro Lampertico
- Gastroenterology Unit, "A. M. and A. Migliavacca" Center for Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Maria Francesca Donato
- Gastroenterology Unit, "A. M. and A. Migliavacca" Center for Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Massimo Iavarone
- Gastroenterology Unit, "A. M. and A. Migliavacca" Center for Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Glenda Grossi
- Gastroenterology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Antonio Facciorusso
- Gastroenterology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Lucio Caccamo
- Liver Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giorgio Rossi
- Liver Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Massimo Colombo
- Gastroenterology Unit, "A. M. and A. Migliavacca" Center for Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Vincenzo Mazzaferro
- Gastroenterology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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Peng J, Cao J, Yu T, Cai S, Li Z, Zhang X, Sun J. Predictors of sustained virologic response after discontinuation of nucleos(t)ide analog treatment for chronic hepatitis B. Saudi J Gastroenterol 2015; 21:245-53. [PMID: 26228369 PMCID: PMC4542424 DOI: 10.4103/1319-3767.161645] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS The aim of this study was to identify the predictors for relapse after discontinuation of oral nucleos(t)ide analog treatment for chronic hepatitis B (CHB). PATIENTS AND METHODS We evaluated patients who were receiving long-term, regular antiviral therapy with nucleos(t)ide analogs, and subsequently achieved the discontinuation criteria from the Asia-Pacific guideline. After they voluntarily discontinued the drug therapy, data were prospectively collected to observe the potential virologic relapse, and the parameters that predicted recurrence were analyzed. RESULTS Sixty-five patients met the inclusion criteria, and were included in this study. Twenty-eight patients relapsed, and the accumulative recurrence rates at the 3-month, 6-month, and 1-year follow-ups were 13.85%, 32.31%, and 49.23%, respectively. There was no difference in the accumulative recurrence rate 12 months after discontinuation among patients who were positive or negative for the hepatitis B e antigen (HBeAg) before they received the medication. Logistic regression analysis revealed that the time to complete response, age at discontinuation, and HBsAg levels at discontinuation affected the rate of relapse. CONCLUSIONS Among patients who received orally administrated nucleos(t)ide analogs, serum levels of HBsAg, age at discontinuation, and the time to complete response might be used as a guide to discontinue treatment. Among younger patients, those with low serum HBsAg levels, and those with an earlier complete response, the risk of relapse is lower and discontinuation is much safer.
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Affiliation(s)
- Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China,Address for correspondence: Dr. Jie Peng, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious diseases, Nanfang Hospital, Southern Medical University No. 1838 Guangzhou Road, Guangzhou 510515, China. E-mail:
| | - Jiawei Cao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Tao Yu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shaohang Cai
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhandong Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Liu TW, Yeh ML, Huang CF, Lin IL, Huang JF, Dai CY, Chen YL, Chuang WL, Yu ML. Clinical performance of a new hepatitis B surface antigen quantitative assay with automatic dilution. Kaohsiung J Med Sci 2014; 31:26-33. [PMID: 25600917 DOI: 10.1016/j.kjms.2014.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 07/13/2014] [Accepted: 08/16/2014] [Indexed: 12/22/2022] Open
Abstract
Hepatitis B virus surface antigen (HBsAg) levels reflect disease status and can predict the clinical response to antiviral treatment; however, the emergence of HBsAg mutant strains has become a challenge. The Abbott HBsAg quantification assay provides enhanced detection of HBsAg and HBsAg mutants. We aimed to evaluate the performance of the Abbott HBsAg quantification assay with automatic sample dilutions (shortened as automatic Architect assay), compared with the Abbott HBsAg quantification assay with manual sample dilutions (shortened as manual Architect assay) and the Roche HBsAg quantification assay with automatic sample dilutions (shortened as Elecsys). A total of 130 sera samples obtained from 87 hepatitis B virus (HBV)-infected patients were collected to assess the correlation between the automatic and manual Architect assays. Among the 87 patients, 41 provided 42 sera samples to confirm the linearity and reproducibility of the automatic Architect assay, and find out the correlation among the Elecsys and two Architect assays. The coefficients of variation (0.44-9.53%) and R(2) = 0.996-1, which were both determined using values obtained from the automatic Architect assay, showed good reproducibility and linearity. Results of the two Architect assays demonstrated a feasible correlation (n = 130 samples; R = 0.898, p < 0.01). With regard to subgroups, correlations between the two Architect assays were better in the hepatitis B e antigen (HBeAg)-negative group (HBeAg-negative group vs. HBeAg-positive group: R = 0.885 vs. R = 0.865, both p < 0.01) and low HBV DNA group (low DNA group vs. high DNA group: R = 0.886 vs. R = 0.844, both p < 0.01). Significant correlations were also found between the results of the Elecsys and Architect assays (R > 0.93 in all cases). In conclusion, the correlation between the automatic and manual dilution Architect assays was feasible, particularly in the HBeAg-negative and low DNA groups. With lower labor costs and less human error than the manual version, the Abbott automatic dilution Architect assay provided a good clinical performance with regard to the HBsAg levels.
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Affiliation(s)
- Ta-Wei Liu
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - I-Ling Lin
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yao-Li Chen
- College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of General Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
| | - Wan-Long Chuang
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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24
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Kountouras DA. Viral Hepatitis B and C. Cure or Treatment? THALASSEMIA REPORTS 2014. [DOI: 10.4081/thal.2014.4870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
HBV and HCV infections are among the most important global health problems; both represent also the leading cause of cirrhosis and HCC worldwide. HBV treatment cannot be considered cure but effective viral suppression can be achieved and remains the current principal goal of therapy. Talking about HCV treatment today equals to talking about total cure of the patient, with treatments of very high SVR rates, shorter if not shortest duration, minimal risk for resistance, pangenotypic and practically with no serious adverse events, no fibrosis or previous treatment status limitations, but also with a very high cost.
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El Sherbini A, Omar A. Treatment of children with HBeAg-positive chronic hepatitis B: a systematic review and meta-analysis. Dig Liver Dis 2014; 46:1103-10. [PMID: 25195086 DOI: 10.1016/j.dld.2014.08.032] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 07/27/2014] [Accepted: 08/03/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Effective management of children with chronic hepatitis B is still an unresolved issue. AIM To assess the outcome of different therapeutic regimens among children with HBeAg-positive chronic hepatitis B. METHODS Electronic database searches identified clinical trials that completed specific periods of treatment and follow-up. Sustained response rates were defined by the loss of HBV DNA and HBeAg, and by the normalization of liver enzymes. The loss of HBsAg and seroconversion to anti-HBs were also listed. RESULTS Our searches found 20 eligible articles (1112 enrolled patients, 2-18 years old). Interferon-alpha therapy showed significantly higher sustained response rate and loss of HBsAg than no therapy (Odd's ratio 3.0, 95% confidence interval 1.6-5.4; and 2.3, 1.1-11.3, respectively). The sustained response rate was not significantly different between interferon and interferon plus lamivudine, or plus prednisone, or plus hepatitis B vaccine; this rate was significantly higher for interferon compared with combined interferon plus levamisole or vitamin E. CONCLUSION Interferon-alpha is still the most effective treatment option for children with HBeAg-positive chronic hepatitis B. Randomized trials are warranted for further comparing interferon to newer antiviral agents in terms of efficacy, safety, emergence of mutant variants, and cost/benefit ratio.
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Affiliation(s)
| | - Asmaa Omar
- Public Health, Preventive and Social Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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26
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Kim MN, Lee CK, Ahn SH, Lee S, Kim SU, Kim DY, Kim HS, Han KH, Chon CY, Park JY. Maintaining remission in lamivudine-resistant patients with a virological response to adefovir add-on lamivudine after stopping lamivudine therapy. Liver Int 2014; 34:1543-9. [PMID: 24330475 DOI: 10.1111/liv.12437] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 12/07/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS We examined the durability of the virological response after discontinuing lamivudine (LVD) in chronic hepatitis B (CHB) patients with LVD-resistant hepatitis B virus (HBV), who responded to LVD plus adefovir (ADV) combination therapy, and the outcome of switching to ADV monotherapy compared to maintaining combination therapy. METHODS This study enrolled 72 patients with undetectable viral loads (≤12 IU/ml) and normal alanine aminotransferase levels after ADV add-on therapy for at least 6 months in LVD-resistant CHB patients. The enrolled patients were randomly assigned to continue with LVD-ADV combination therapy or switch to ADV monotherapy (n = 36 per group). Virological rebound was defined as HBV DNA detection at more than 12 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. RESULTS During 96 weeks of follow-up, 100% (36/36) of the patients in the LVD-ADV combination maintained group had persistently undetectable HBV DNA, compared with 94.4% (34/36) patients in the ADV monotherapy switched group. These two patients had undetectable HBV DNA after switching back to LVD-ADV combination therapy. There were no significant differences in the HBsAg levels between the two treatment groups during the 96-week follow-up period. CONCLUSIONS In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 94.4% of the patients for 96 weeks. Prior complete viral suppression with LVD-ADV combination therapy conferred a significant advantage in patients who switched to ADV monotherapy. LVD may be discontinued in patients who show a complete virological response to LVD-ADV combination therapy for at least 6 months.
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Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; Liver Cirrhosis Clinical Research Center, Seoul, Korea
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27
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Watanabe T, Tokumoto Y, Hirooka M, Koizumi Y, Tada F, Ochi H, Abe M, Kumagi T, Ikeda Y, Matsuura B, Takada K, Hiasa Y. An HBV-HIV co-infected patient treated with tenofovir-based therapy who achieved HBs antigen/antibody seroconversion. Intern Med 2014; 53:1343-6. [PMID: 24930654 DOI: 10.2169/internalmedicine.53.2131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The present report describes a case of a patient with hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infection who was treated with tenofovir disoproxil (TDF)-based highly active antiretroviral therapy (HAART) and who achieved HBs antigen (Ag)/antibody (Ab) seroconversion. An 18-year-old Japanese man with HIV and HBV co-infection presented to our hospital. His CD4 count was decreased, and TDF-based HARRT was started. At 30 months after initiation of therapy, HBsAg was not detected. At 36 months after initiation of therapy, HBsAb was detected. We conclude that TDF-based therapy is useful for the management of patients with HBV and HIV co-infection.
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Affiliation(s)
- Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Japan
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28
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Yue PYK, Wong YY, Wong KYK, Tsoi YK, Leung KSY. Current evidence for the hepatoprotective activities of the medicinal mushroom Antrodia cinnamomea. Chin Med 2013; 8:21. [PMID: 24180549 PMCID: PMC3819176 DOI: 10.1186/1749-8546-8-21] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 10/23/2013] [Indexed: 02/07/2023] Open
Abstract
Antrodia cinnamomea (AC) is an endemic mushroom species of Taiwan, and has been demonstrated to possess diverse biological and pharmacological activities, such as anti-hypertension, anti-hyperlipidemia, anti-inflammation, anti-oxidation, anti-tumor, and immunomodulation. This review focuses on the inhibitory effects of AC on hepatitis, hepatocarcinoma, and alcohol-induced liver diseases (e.g., fatty liver, fibrosis). The relevant biochemical and molecular mechanisms are addressed. Overall, this review summarizes the hepatoprotective activities in vitro and in vivo. However, there is no doubt that human and clinical trials are still limited, and further studies are required for the development of AC-related products.
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Affiliation(s)
- Patrick Ying-Kit Yue
- Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Yi-Yi Wong
- Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Kay Yuen-Ki Wong
- Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Yeuk-Ki Tsoi
- Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Kelvin Sze-Yin Leung
- Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
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Jun CH, Hong HJ, Chung MW, Park SY, Cho SB, Park CH, Joo YE, Kim HS, Choi SK, Rew JS. Risk factors for hepatocellular carcinoma in patients with drug-resistant chronic hepatitis B. World J Gastroenterol 2013; 19:6834-6841. [PMID: 24187458 PMCID: PMC3812482 DOI: 10.3748/wjg.v19.i40.6834] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 08/10/2013] [Accepted: 09/04/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the risk factors and characteristics of hepatocellular carcinoma (HCC) in the patients with drug-resistant chronic hepatitis B (CHB).
METHODS: A total of 432 patients with drug-resistant CHB were analyzed retrospectively from January 2004 to December 2012. The patients were divided into two groups: the HCC group (n = 57) and the non-HCC group (n = 375). Two groups compared using logistic regression for various patients and viral characteristics in order to identify associated risk factors for HCC. Secondarily, patient and tumor characteristics of HCC patients with naïve CHB (N group, n = 117) were compared to the HCC group (R group, n = 57) to identify any difference in HCC characteristics between them.
RESULTS: A significant difference was found for age, platelet count, alpha-fetoprotein (AFP), positivity of HBeAg, seroconversion rate of HBeAg, virologic response, the Child-Pugh score, presence of rtM204I, and the duration of antiviral treatment in non-HCC and HCC group. Cirrhosis, age (> 50 years), HBeAg (+), virologic non-responder status, and rtM204I mutants were independent risk factors for the development of HCC. The R group had lower serum C-reactive protein (CRP) and AFP levels, earlier stage tumors, and a shorter mean tumor surveillance period than the N group. However, the total follow-up duration was not significantly different between the two groups.
CONCLUSION: 13.2% of patients with drug-resistant CHB developed HCC. Age, cirrhosis, YIDD status, HBeAg status, and virologic response are associated with risk of HCC. Patients with drug-resistant CHB and these clinical factors may benefit from closer HCC surveillance.
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Tsuge M, Murakami E, Imamura M, Abe H, Miki D, Hiraga N, Takahashi S, Ochi H, Nelson Hayes C, Ginba H, Matsuyama K, Kawakami H, Chayama K. Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients. J Gastroenterol 2013; 48:1188-204. [PMID: 23397114 DOI: 10.1007/s00535-012-0737-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Accepted: 12/12/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Treatment for chronic hepatitis B has improved drastically with the use of nucleot(s)ide analogues (NAs). However, NA therapy typically fails to eliminate Hepatitis B virus (HBV) completely, and it is difficult to discontinue these therapies. We previously demonstrated that NA therapy induced immature viral particles, including HBV RNA in sera of chronic hepatitis B patients. In the study reported here, we analyzed the association between HBV RNA titer and the recurrence rate of hepatitis after discontinuation of NA therapy. METHODS The study cohort comprised 36 patients who had discontinued NA therapy. Serum HBV DNA or DNA plus RNA levels were measured by real time PCR and statistical analyses were performed using clinical data and HBV markers. RESULTS At 24 weeks after discontinuation of NA therapy, HBV DNA rebound was observed in 19 of the 36 patients (52.8 %), and alanine aminotransferase (ALT) rebound was observed in 12 of 36 patients (33.3 %). Multivariate statistical analysis was used to identify factors predictive of HBV DNA rebound. The HBV DNA + RNA titer following 3 months of treatment was significantly associated with HBV DNA rebound [P = 0.043, odds ratio (OR) 9.474, 95 % confidence interval (CI) 1.069-83.957)]. Absence of hepatitis B e antigen (HBeAg) at the end of treatment was significantly associated with ALT rebound (P = 0.003, OR 13.500, 95 % CI 2.473-73.705). In HBeAg-positive patients, the HBV DNA + RNA titer after 3 months of treatment was marginally associated with ALT rebound (P = 0.050, OR 8.032, 95 % CI 0.997-64.683). CONCLUSIONS Monitoring of serum HBV DNA + RNA levels may be a useful method for predicting re-activation of chronic hepatitis B after discontinuation of NA therapy.
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Affiliation(s)
- Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Toyama T, Ishida H, Ishibashi H, Yatsuhashi H, Nakamuta M, Shimada M, Ohta H, Satoh T, Kato M, Hijioka T, Takano H, Komeda T, Yagura M, Mano H, Watanabe Y, Kobayashi M, Mita E. Long-term outcomes of add-on adefovir dipivoxil therapy to ongoing lamivudine in patients with lamivudine-resistant chronic hepatitis B. Hepatol Res 2012; 42:1168-74. [PMID: 22594879 DOI: 10.1111/j.1872-034x.2012.01038.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Add-on adefovir dipivoxil (ADV) therapy has been a standard rescue treatment for patients with lamivudine (LAM)-resistant chronic hepatitis B, but the overall benefits of long-term add-on ADV therapy are still limited. The aim of this study was to evaluate the long-term efficiency of add-on ADV treatment and to explore predictive factors associated with it. METHODS A total of 158 patients with LAM-resistant chronic hepatitis B were included in this retrospective, multicenter, nationwide study in Japan. After confirming LAM resistance, ADV was added to LAM treatment. Three types of events were considered as outcomes: virological response, hepatitis B e antigen (HBeAg) clearance and alanine aminotransferase (ALT) normalization. Virological response was defined as serum hepatitis B virus (HBV) DNA levels of less than 3 log copies/mL. Baseline factors contributing to these outcomes were examined by univariate and multivariate analyses. RESULTS The median total duration of ADV treatment was 41 months (range, 6-84). The rate of virological response was 90.8% at 4 years of treatment; HBeAg clearance and ALT normalization were achieved by 34.0% and 82.7%, respectively, at the end of follow up. Each outcome had different predictive factors: baseline HBV DNA and albumin level were predictive factors for virological response, history of interferon therapy and ALT level for HBeAg clearance, and sex and baseline albumin level for ALT normalization. CONCLUSION Long-term add-on ADV treatment was highly effective in LAM-resistant chronic hepatitis B patients in terms of virological and biochemical responses. Lower HBV replication and lower albumin level at baseline led to better outcomes.
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Affiliation(s)
- Takashi Toyama
- Department of Gastroenterology and Hepatology, NHO, Osaka National Hospital, Osaka, Japan
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Souza LO, Perez RM, Carvalho-Filho RJ, Matos CA, Moutinho RS, Silva IS, Medina-Pestana JO, Silva AE, Ferraz ML. Unexpected distribution of Hepatitis B genotypes in patients with kidney disease: Comparison with immunocompetent subjects. J Med Virol 2012; 84:1548-52. [PMID: 22930501 DOI: 10.1002/jmv.23357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Cho HJ, Kim SS, Ahn SJ, Bae CB, Kim HG, Kim YJ, Lee SK, Song GW, Kim DJ, Hwang SG, Yang JM, Kim YB, Park YN, Cho SW, Cheong JY. Serum markers for predicting significant necroinflammatory activity in patients with chronic hepatitis B. Clin Biochem 2012; 45:1564-7. [PMID: 22885475 DOI: 10.1016/j.clinbiochem.2012.07.107] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 07/18/2012] [Accepted: 07/24/2012] [Indexed: 12/19/2022]
Abstract
OBJECTIVES The aim of this study was to determine the serum markers that predict significant inflammation in patients with chronic hepatitis B (CHB). DESIGN AND METHODS Between October 2005 and June 2009, 384 subjects with CHB were enrolled. RESULTS Multiple logistic regression analysis identified the ALT, hyaluronic acid (HA) and procollagen III N-terminal peptide (PIIINP) as independent predictors of significant inflammation (grade≥3). We constructed a formula for predicting significant inflammation. A significant inflammation (SI) score=1.773×ALT score+1.599×PIIINP score+0.677×HA score-1.962. The area under receiver operating characteristic curve of the SI score was 0.831. The sensitivity, specificity, positive predictive value and negative predictive value of the SI score were 79.5%, 70.8%, 76.8% and 74.3%, respectively. CONCLUSIONS A simple scoring system including ALT, PIIINP and HA is an accurate non-invasive predictor of significant inflammatory activities in patients with CHB.
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Affiliation(s)
- Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
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Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, Jeon WK, Kim BI. The influence of YMDD mutation patterns on clinical outcomes in patients with adefovir add-on lamivudine combination treatment. Liver Int 2012; 32:303-10. [PMID: 22098177 DOI: 10.1111/j.1478-3231.2011.02647.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2011] [Accepted: 08/22/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIM The aim of this study was to assess the patterns of lamivudine (LAM)-resistant mutations and the influence on biochemical and virological responses to adefovir (ADV) add-on LAM combination therapy in patients with LAM-resistant chronic hepatitis B (CHB). METHODS Seventy-eight CHB patients with confirmed genotypic resistance to LAM, who initiated ADV add-on LAM combination treatment, were enrolled at our institution between April 2007 and April 2009. RESULTS The baseline tyrosine-methionine-aspartate-aspartate (YMDD) mutation patterns were as follows: rtM204I 45 (57.7%); and rtM204V + rtM204I/V 33 (42.3%). The decrease in the mean ± standard deviation (SD) serum log(10) HBV-DNA level did not differ between the patients carrying the rtM204I vs. rtM204IV +rtM204I/V mutations at 3, 6 and 12 months after the initiation of ADV add-on LAM combination treatment. The proportion of patients who achieved ALT normalization (<40 IU/L) 12 months after the initiation of ADV add-on LAM combination treatment were significantly higher in patients with a rtM204I mutation than rtM204V+ rtM204I/V mutations (39 [86.7%] vs. 22 [66.7%], P = 0.05). The proportion of patients in whom the log(10) HBV-DNA decreased <2 log(10) copies/ml, 6 months after the initiation of ADV add-on LAM combination treatment (non-responders), was significantly higher in patients with a rtM204V + rtM204I/V mutations than rtM204I mutation (7 [21.2%] vs. 2 [4.4%], P = 0.032). CONCLUSION Biochemical response at 12 months from baseline was better in patients with a rtM204I mutation than rtM204V+ rtM204I/V mutations. In addition, early treatment failure was more common in patients with rtM204V+ rtM204I/V mutations than a rtM204I mutation.
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Affiliation(s)
- Hong J Kim
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea.
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Cheong JY, Kim DJ, Hwang SG, Yang JM, Kim YB, Park YN, Cho SW. Serum markers for necroinflammatory activity in patients with chronic viral hepatitis and normal or mildly elevated aminotransferase levels. Liver Int 2011; 31:1352-8. [PMID: 21745311 DOI: 10.1111/j.1478-3231.2011.02570.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Reports on the usefulness of serum markers for predicting liver necroinflammation are limited. The aim of this study was to determine the serum markers that predict significant inflammation in patients with chronic hepatitis B (CHB) and C (CHC) and normal or mildly elevated serum aminotransferase levels. METHODS Two hundred twenty-seven patients with CHB or CHC with normal or mildly elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (≤60 IU/L) were enrolled in this study. Significant inflammation was defined as inflammatory grade ≥3 activities using the Batt-Ludwig scoring system. The correlation between liver histology and serum markers of liver inflammation was analysed. RESULTS Forty-eight (21.1%) and eight patients (3.5%) had grade 3 and 4 inflammation respectively. Univariate analysis revealed that age, platelet coun, and AST, ALT, γ-glutamyl transpeptidase, alkaline phosphatase, hyaluronic acid, haptoglobin, apolipoprotein A1 and procollagen III N-terminal peptide levels were significantly different between the patients with and without significant inflammation. There were no significant differences in the cytokeratin-18 fragment levels between the two groups. On the basis of multivariate analysis, the AST and apolipoprotein A1 levels and stage of fibrosis were highly predictive of significant inflammation. Using AST and apolipoprotein cut-off values ≥44 IU/L and ≤100 ng/ml, respectively, the presence of significant inflammation was predicted with high specificity (96.5%) and with a negative predictive value of 76.3%. CONCLUSION The AST and apolipoprotein A1 levels were shown to be independent predictors of significant inflammatory activities in patients with CHB and CHC and normal or mildly elevated aminotransferase levels.
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Affiliation(s)
- Jae Y Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
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Cai Z, Lou G, Cai T, Yang J, Wu N. Development of a novel genotype-specific loop-mediated isothermal amplification technique for Hepatitis B virus genotypes B and C genotyping and quantification. J Clin Virol 2011; 52:288-94. [PMID: 21908234 DOI: 10.1016/j.jcv.2011.08.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 08/02/2011] [Accepted: 08/15/2011] [Indexed: 01/05/2023]
Abstract
BACKGROUND There is the need for a rapid, economical method for genotyping Hepatitis B virus (HBV) to support clinical practice. OBJECTIVES To develop a novel HBV genotyping process using genotype specific loop mediated isothermal amplification (LAMP). STUDY DESIGN HBV genotypes B and C specific LAMP methods were evaluated using standard panel. A comparative analysis of the LAMP test against Taqman assay using 105 clinical samples, was undertaken to evaluate the quantitation capacity of the method. 111 clinical samples were used to test the clinical applicability of the genotype specific LAMP method. The results were compared with those obtained by real-time PCR based genotyping and sequencing. RESULTS Using genotype-specific primers, the LAMP assay correctly identified all predefined genotypes B and C, and no cross-reaction was observed. Real-time format of this assay provides simultaneous identification and quantification of genotypes B and C. The detection sensitivity of the method was found to be 323 and 515 copies/ml for genotypes B and C specific LAMP assay respectively. High correlation (R(2)=0.91) and good agreement between the LAMP method and the real-time PCR test were achieved for HBV quantitation. Samples from 111 HBV-infected patients were genotyped with LAMP, revealing 53% HBV as genotype B, 36% as genotype C, and 12% as mixed genotypes B and C. LAMP method showed coincidence rates of 96.7% with the real-time PCR genotyping results. CONCLUSION This approach is a promising tool for HBV genotyping and quantitation. It appears to be useful for routine clinical practice even in field investigation.
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Affiliation(s)
- Zhejun Cai
- The Second Clinical Medicine College, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
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Kumar A, Dwivedi M, Misra SP, Narang S, Tiwari BK, Pandey R. Clinical profile, genotype and management updates of hepatitis B virus. INDIAN JOURNAL OF VIROLOGY : AN OFFICIAL ORGAN OF INDIAN VIROLOGICAL SOCIETY 2011; 22:1-10. [PMID: 23637496 PMCID: PMC3550728 DOI: 10.1007/s13337-011-0037-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Accepted: 05/07/2011] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) is a well known agent of acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Around 400 million people worldwide carrier of HBV of which more than 250 million reside in Asia, and 1-2 million people have died from it. It has a partially double-stranded DNA, having 3.2-kb genome size and replicate via reverse transcription of RNA intermediate. In the natural history or during the antiviral therapy of chronic HBV infection, seroconversion from HBeAg to anti-HBeAg is usually accompanied by a decrease in viral replication and remission of liver disease. Based on genomic sequence data HBV is classified into eight genotypes A-H and four major serotypes ayw, ayr, adw and adr on the basis of complete genome and S gene sequence analysis. Genotypes and serotypes are useful tools in understanding the epidemiology of HBV infection. HBV genotypes have distinct geographical distributions. The HBV variants appear during HBeAg seroconversion and they bring mutations in the precore region (PC) that prevent HBeAg synthesis. Another common HBeAg variant is the basal core promoter mutant (BCP) characterized by point mutation in the promoter of both HBeAg mRNA and core protein mRNA. The most frequent core promoter mutation is the double A1762T and G1764A nucleotide exchange, which results in a substantial decrease in HBeAg expression but enhanced viral genome replication. The approved antiviral drugs such as Interferon, lamivudine, adefovir dipivoxil, entecavir and telbivudine for purpose of treating chronic HBV infection is to prevent or stop the progression of liver injury by suppressing viral replication or eliminating infection. Sustained losses of viral markers of active viral replication (HBeAg and HBV DNA) are the standard end point of the therapies.
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Affiliation(s)
- Ajay Kumar
- />Centre for Biotechnology, Allahabad Central University, Allahabad, India
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | - Manisha Dwivedi
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | - S. P. Misra
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | - Sushil Narang
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | | | - Renu Pandey
- />Centre for Biotechnology, Allahabad Central University, Allahabad, India
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Gisbert JP, Chaparro M, Esteve M. Review article: prevention and management of hepatitis B and C infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2011; 33:619-33. [PMID: 21416659 DOI: 10.1111/j.1365-2036.2010.04570.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Viral hepatitis is a very common infection. AIM To review the prevention and management of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in inflammatory bowel disease (IBD). METHODS Bibliographical searches were performed in MEDLINE up to September 2010. RESULTS The prevalence of both HBV and HCV infection in IBD patients is now similar to that of the general population. All IBD patients should be screened for HBV markers at diagnosis. Liver dysfunction in IBD patients treated with immunosuppressants is more frequent and severe in HBV than in HCV carriers and is associated with combined immunosuppression. Inpatients receiving anti-TNF drugs, HBV reactivation is common unless anti-viral prophylaxis is administered. HBsAg-positive patients should receive anti-viral prophylaxis before starting immunosuppressants. As interferon might worsen underlying IBD, nucleoside ⁄ nucleotide analogues are preferred for anti-viral prophylaxis in patients with HBV (tenofovir ⁄ entecavir are preferred to lamivudine). IBD patients should be vaccinated against HBV at diagnosis. The response rate to HBV vaccination is low, mainly in those receiving anti-TNF therapy. The serological response to HBV vaccine should be confirmed, and patients with an inadequate response should receive a second full series of vaccine. Peginterferon (ribavirin) for HCV infection is as effective and safe as in non-IBD patients. CONCLUSIONS The present manuscript poses a series of questions on the prevention and management of HBV/HCV infection in IBD, and attempts to answer them using scientific evidence in order to provide practical conclusions for the clinician.
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Affiliation(s)
- J P Gisbert
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria, Princesa (IP), Madrid, Spain.
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Yao Y, Zhang J, Tan DQ, Chen XY, Ye DF, Peng JP, Li JT, Zheng YQ, Fang L, Li YK, Fan MX. Interferon-γ Improves Renal Interstitial Fibrosis and Decreases Intrarenal Vascular Resistance of Hydronephrosis in an Animal Model. Urology 2011; 77:761.e8-13. [DOI: 10.1016/j.urology.2010.10.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Revised: 09/20/2010] [Accepted: 10/13/2010] [Indexed: 12/01/2022]
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Kosinska AD, Zhang E, Lu M, Roggendorf M. Therapeutic vaccination in chronic hepatitis B: preclinical studies in the woodchuck. HEPATITIS RESEARCH AND TREATMENT 2010; 2010:817580. [PMID: 21188201 PMCID: PMC3003998 DOI: 10.1155/2010/817580] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 07/29/2010] [Indexed: 02/07/2023]
Abstract
Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to a satisfactory result. Induction of HBV-specific T cells by therapeutic vaccination or immunotherapies may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients did not result in effective control of HBV infection, suggesting that new formulations of therapeutic vaccines are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing the new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments with nucleos(t)ide analogues, DNA vaccines, and protein vaccines were tested in the woodchuck model. In this paper we summarize the available data concerning therapeutic immunization and gene therapy using recombinant viral vectors approaches in woodchucks, which show encouraging results. In addition, we present potential innovations in immunomodulatory strategies to be evaluated in this animal model.
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Affiliation(s)
- Anna D. Kosinska
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
| | - Ejuan Zhang
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
| | - Michael Roggendorf
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstraβe 179, 45122, Essen, Germany
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Importance of serum concentration of adefovir for Lamivudine-adefovir combination therapy in patients with lamivudine-resistant chronic hepatitis B. Antimicrob Agents Chemother 2010; 54:3205-11. [PMID: 20498322 DOI: 10.1128/aac.01372-09] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Lamivudine (LMV)-adefovir pivoxil (ADV) combination therapy suppresses the replication of LMV-resistant hepatitis B virus (HBV), although its efficacy in suppressing HBV varies among patients. This study analyzed the clinical, virological, and pharmaceutical factors that influence the effect of the combination therapy. Patients negative for hepatitis B virus e antigen (HBeAg) and with low HBV DNA titers immediately prior to the combination therapy effectively cleared serum HBV DNA (P=0.0348 and P=0.0310, respectively). The maximum concentration of ADV in serum (ADV Cmax) was higher in patients who showed HBV DNA clearance (P=0.0392), and the cumulative clearance rates of HBV DNA were significantly higher in patients with ADV Cmax equal to or greater than 24 ng/ml (P=0.0284). HBeAg negativity and lower HBV DNA at the start of the combination therapy and higher ADV Cmax were found to be independent factors for serum HBV DNA clearance. Serum creatinine increased significantly during the combination therapy, and the ADV Cmax was higher in patients with low creatinine clearance rates. In conclusion, higher serum concentrations of ADV are associated with a good response to therapy based on clearance of HBV DNA in serum. However, care should be taken to prevent worsening of renal function due to high ADV serum concentrations.
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Chen EQ, Wang LC, Lei J, Xu L, Tang H. Meta-analysis: adefovir dipivoxil in combination with lamivudine in patients with lamivudine-resistant hepatitis B virus. Virol J 2009; 6:163. [PMID: 19818142 PMCID: PMC2764700 DOI: 10.1186/1743-422x-6-163] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 10/09/2009] [Indexed: 02/05/2023] Open
Abstract
Background Currently, there are no conclusive results on the efficacy of adefovir dipivoxil (ADV) plus lamivudine (LAM) in LAM-resistant patients with chronic hepatitis B (CHB). The aim of study was to evaluate the efficacy of rescue therapy with ADV plus LAM compared to ADV monotherapy in LAM-resistant CHB patients. Results We searched PUBMED, EMBASE, Web of Science, CNKI (National Knowledge Infrastructure), VIP database, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Six eligible trials (442 patients in total) were included and evaluated for methodologic quality and heterogeneity. Greater virological response and lower emergence rate of ADV-associated mutants was observed in ADV plus LAM compared to ADV monotherapy (both P < 0.05). On the contrary, the rate of ALT normalization, HBeAg clearance and seroconversion were all similar between ADV plus LAM and ADV (all P > 0.05). Additionally, adding-on or switch-to ADV was both well tolerated. Conclusion The combination of ADV with LAM was superior in inhibiting HBV replication and preventing drug resistance as compared to ADV alone for LAM-resistant CHB patients.
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Affiliation(s)
- En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
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Silva LCD, Nova MLD, Ono-Nita SK, Pinho JRR, Sitnik R, Santos VAD, Carrilho FJ. Simultaneous quantitation of serum HBV DNA and HBeAg can distinguish between slow and fast viral responses to antiviral therapy in patients with chronic hepatitis B. Rev Inst Med Trop Sao Paulo 2009; 51:261-8. [DOI: 10.1590/s0036-46652009000500005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2009] [Accepted: 09/28/2009] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND: The quantitation of serum HBeAg is not commonly used to monitor viral response to therapy in chronic hepatitis B. METHODS: In this study, 21 patients receiving varying therapies were followed and their viral response monitored by concomitant viral load and HBeAg quantitation in order to study the meaning and the kinetics of both parameters. RESULTS: It was possible to distinguish between three different patterns of viral response. The first was characterized by a simultaneous decrease in serum HBV DNA and HBeAg. The second pattern was characterized by a decrease in serum HBeAg but persistent detection of HBV DNA. The third pattern was characterized by undetectable HBV DNA with persistent HBeAg positivity, which points to a non-response (Pattern III-B) except when HBeAg levels showed a slow but steady drop, characterizing a "slow responder" patient (Pattern III-A). CONCLUSIONS: The first pattern is compatible with a viral response. A long-term HBeAg seropositivity with a slow and persistent decrease (Pattern III-A) is also compatible with a viral response and calls for a prolongation of anti-viral treatment.
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Lei RX, Shi H, Peng XM, Zhu YH, Cheng J, Chen GH. Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection. Hepatology 2009; 50:763-71. [PMID: 19492430 DOI: 10.1002/hep.23062] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
UNLABELLED Hepatitis B e antigen (HBeAg) is a viral strategy of immune response evasion associated with hepatitis B virus (HBV) persistence. Spontaneous HBeAg seroconversion is usually accompanied by liver disease remission. Unfortunately, this goal is difficult to achieve and requires expensive and time-consuming treatment. Furin, a proprotein convertase, is involved in HBeAg maturation and is therefore a potential therapeutic target or indicator for predicting disease progression and antiviral response. Here we demonstrate that healthy Han Chinese from southern China (an endemic area of HBV infection) harbor a common single nucleotide polymorphism (SNP; -229 C/T) in a 1268-bp region of the P1 promoter of the furin gene [FES upstream region (Fur)]. A luciferase reporter gene assay showed that transcription activity is about 3 times higher in allele T carriers than in allele C carriers of this SNP. Allele T includes a suboptimal transcription factor NF-E2 [i.e., nuclear factor (erythroid-derived 2)]-binding motif according to bioinformatics and studies using site-directed mutagenesis. We also observed that individuals carrying allele T were more likely to become persistently infected. When persistently infected patients were divided into subgroups according to recent guidelines and HBeAg-defective virus infection was taken into account, patients with allele T or genotype TT had a decreased likelihood of HBeAg seroconversion or an increased likelihood of progressing to HBeAg-negative chronic hepatitis B or liver cirrhosis if accompanied by HBeAg-defective virus infection. CONCLUSION The common SNP in the P1 promoter of the Fur gene affects furin transcription activity and HBV infection outcome, possibly by increasing furin messenger RNA expression, and this suggests that furin is a potential therapeutic target and that this SNP is a potential predictor of disease progression or therapeutic response.
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Affiliation(s)
- Rui Xiang Lei
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, People's Republic of China
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Elefsiniotis I, Buti M, Jardi R, Vezali E, Esteban R. Clinical outcome of lamivudine-resistant chronic hepatitis B patients with compensated cirrhosis under adefovir salvage treatment. Importance of HCC surveillance. Eur J Intern Med 2009; 20:478-81. [PMID: 19712848 DOI: 10.1016/j.ejim.2008.12.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2008] [Revised: 11/17/2008] [Accepted: 12/18/2008] [Indexed: 12/24/2022]
Abstract
BACKGROUND Data concerning the outcome of lamivudine-resistant (LAM-R) chronic hepatitis B (CHB) patients with compensated cirrhosis under adefovir (ADV) treatment are limited. The aim of our study was to evaluate the medium term outcome of these, high-risk for fatal events, patients. METHODS 31 LAM-R patients with compensated cirrhosis who had been treated with ADV monotherapy (n=8) or ADV plus LAM (n=23) for a mean of 27.6 months, were evaluated. Virological response (VR) was defined as HBV-DNA levels <10(4) copies/ml within the first year of treatment. RESULTS Twenty-three patients (74.19%) achieved VR. Six patients (19.35%) developed ADV-related mutations (annual incidence 11%). Liver-related death, liver decompensation and hepatocellular carcinoma (HCC) were observed in 12.9%, 16.12% and 16.12% of patients, respectively. HCC (annual incidence 9.1%) was the main cause of liver decompensation (4/5, 80%) and of liver-related deaths (3/4, 75%). HCC development was not related to patients' age (p=0.440), HBeAg status (p=0.245), HBV genotype (p=0.598), baseline ALT levels (p=0.981), baseline viral load (p= 0.464), VR (p=0.504) as well as emergence of ADV resistance (p=0.871). CONCLUSIONS ADV suppresses viral replication in more than 70% of LAM-R cirrhotic patients during the first year of treatment. Despite that, HCC is frequently observed in these high-risk patients, irrespective of virological response or emergence of ADV resistance.
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Affiliation(s)
- I Elefsiniotis
- University Department of Internal Medicine, Elena Venizelou Hospital, Athens, Greece.
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Yang J, Cai T, Lou GQ. Anti-hepatitis B virus treatment guided by long-term virus kinetics stepwise tracing. J Gastroenterol Hepatol 2009; 24:1008-16. [PMID: 19220675 DOI: 10.1111/j.1440-1746.2008.05759.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Biphasic modeling of viral kinetics provided valuable information to rapidly assess potential antiviral regimens during the beginning of therapy, but has not been performed over the long term. METHODS In 11 chronic hepatitis B patients with lamivudine treated per day, the model with delay time was applied to examine phase transition and analyze viral kinetics parameters. RESULTS Viral decay conformed to a biphasic mode during the first 4 weeks, with the complex profile appeared in the later period. Lamivudine treatment resulted in a mean log hepatitis B virus (HBV)-DNA decline of 1.77 +/- 0.55 after 4 weeks and 3.79 +/- 1.70 log after 24 weeks. The median effectiveness of blocking viral replication was 96% (range, 89-99%). The median rate of free virus clearance and infected cell loss was 1.1/day and 0.03/day, respectively. Through phase transition determination and stepwise modeling process, viral kinetics were evaluated for complex decay profile during long-term therapy. Moreover, with the abnormal kinetics tracked, an occasion of add-on combined therapy was developed to treat patients with emerging virus mutants. CONCLUSION The present study using mathematical modeling of viral decay may be a useful approach to evaluate optimal individualized therapy for HBV infection in a continuous long-term manner.
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Affiliation(s)
- Jin Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, China
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Wang F, Wang H, Shen H, Meng C, Weng X, Zhang W. Evolution of hepatitis B virus polymerase mutations in a patient with HBeAg-positive chronic hepatitis B virus treated with sequential monotherapy and add-on nucleoside/nucleotide analogues. Clin Ther 2009; 31:360-6. [PMID: 19302908 DOI: 10.1016/j.clinthera.2009.02.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2008] [Indexed: 12/26/2022]
Abstract
BACKGROUND Nucleoside/nucleotide analogues are a fundamental tool for the treatment of chronic hepatitis B virus (HBV). Sequential anti-HBV treatment might lead to the selection of mutations. OBJECTIVE This report aimed to analyze the genetic evolution of the reverse-transcriptase (RT) gene of viral quasispecies in a patient with hepatitis B e antigen (HBeAg)-positive chronic HBV who received, sequentially, lamivudine (LAM), adefovir dipivoxil (ADV), and ADV + telbivudine (LDT) combination treatment over a total of 108 weeks. METHODS A 20-year-old Chinese man presented to Huashan Hospital, Fudan University, Shanghai, People's Republic of China, with hepatitis B surface antigen-positive and HBeAg-positive chronic HBV and was sequentially treated with LAM 100 mg/d for 18weeks,ADV 10mg/d for 68weeks, and ADV 10mg/d + LDT 600 mg/d combination treatment for 22 weeks. Compliance was monitored every 4 weeks using a pill count. For genotypic analysis, the RT region of the polymerase gene from the serum of this patient was amplified, cloned, and sequenced. Fifty clones with HBV insert were selected for sequencing at weeks 0 (baseline), 18, 22, 60, 70, 86, and 108. RESULTS The rtM204V/L LAM-resistance mutation was detected in 4.4% (2/45) of clones prior to LAM treatment. At week 18 during LAM treatment, the rtM204I mutation became predominant, being present in 79.5% (35/44) of clones. The rtM204I mutation was associated with compensatory mutations (rtL180M and rtT184L). A total of 9.1% (4/44) of the clones harbored the rtL180M + rtT184L + rtM204I mutations. Two new mutations, rtL229V and rtV191I, were detected in 75.0% (33/44) and 11.4% (5/44) of clones, respectively. At week 22 during ADV treatment, LAM-resistance mutations (rtL180M, rtT184L, rtM204I, rtV191I, and rtL229V) were not detected. At week 86 during ADV therapy, the rtN236T ADV-resistance mutation was detected in 58.8% (20/34) of clones. A total of 20.6% (7/34) of the clones harbored the rtK212T + rtM250L mutation, and rtA181V was found in 2.9% (1/34) of the clones. At week 108, after the patient had been receiving ADV + LDT combination therapy for 22 weeks, rtS202G and rtI269T had emerged, representing 28.9% (13/45) and 8.9% (4/45), respectively, of the viral population during ADV + LDT combination treatment. We also detected several polymorphic sites,including rtF221Y, rtS223A, rtI224V, rtN238H, rtL267Q, and rtQ271M, during the sequential treatment. After 22 weeks of combination treatment, HBV DNA count was decreased to less than the lower limit of quantitation (<200 copies/mL). CONCLUSIONS This report identified HBV mutations that escaped the antiviral pressure of LAM, ADV, and ADV + LDT in this patient and provided insight into the process of mutation selection through genotypic analysis during antiviral treatment. Mutations selected under sequential treatments of LAM, ADV, and ADV + LDT can lead to a series of compensatory mutations, which partially restore the level of viral replication. ADV administered in combination with LDT appeared to be effective in this selected case with clinical or virologic resistance to sequential treatment with LAM and ADV.
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Affiliation(s)
- Feifei Wang
- Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
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Poynard T, Ngo Y, Marcellin P, Hadziyannis S, Ratziu V, Benhamou Y. Impact of adefovir dipivoxil on liver fibrosis and activity assessed with biochemical markers (FibroTest-ActiTest) in patients infected by hepatitis B virus. J Viral Hepat 2009; 16:203-13. [PMID: 19175871 DOI: 10.1111/j.1365-2893.2008.01065.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The aim was to assess the utility of FibroTest-ActiTest (FT-AT) as noninvasive markers of histological changes in patients with chronic hepatitis. Patients with chronic hepatitis B (HBeAg+ and HBeAg-) randomized in two trials of adefovir (ADV) vs placebo, with available paired liver biopsies and FT-AT at baseline and after 48 weeks of treatment were included. The predictive value of FT-AT was assessed using the area under the receiver operating characteristics curves (AUROCs) for the diagnosis of bridging fibrosis, cirrhosis and moderate-severe necroinflammatory activity. The impact of treatment with ADV vs placebo was assessed on liver injury according to baseline stage and virological response at 48 weeks. The analysis of 924 estimates for the diagnosis of bridging fibrosis, cirrhosis and moderate or severe necroinflammatory activity yielded FT-AT AUROCs: 0.76 +/- 0.02 (standardized 0.81 +/- 0.02), 0.81 +/- 0.02 and 0.80 +/- 0.01, respectively. Similar impacts of ADV on liver fibrosis and activity were observed both with paired biopsy (fibrosis stage from 1.6 to 1.4, activity grade from 2.5 to 1.3) and paired biomarkers (FT from 0.44 to 0.40, AT from 0.62 to 0.25) (P < 0.0001). FibroTest-ActiTest provides a quantitative estimate of liver fibrosis and necroinflammatory activity in patients with chronic hepatitis B and may be an alternative to reduce the need for liver biopsy.
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Affiliation(s)
- T Poynard
- Pitié-Salpêtrière, Université Paris, Paris, France.
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Cha CK, Kwon HC, Cheong JY, Cho SW, Hong SP, Kim SO, Yoo WD. Association of lamivudine-resistant mutational patterns with the antiviral effect of adefovir in patients with chronic hepatitis B. J Med Virol 2009; 81:417-24. [PMID: 19152409 DOI: 10.1002/jmv.21402] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Adefovir has a potent antiviral activity as a rescue treatment against lamivudine-resistant strains. The aim of this study was to assess the patterns of lamivudine-resistant mutations and their influence on the virologic response to adefovir rescue therapy in patients with lamivudine-resistant chronic hepatitis B. Sixty-seven patients with lamivudine-resistant chronic hepatitis B were treated with adefovir monotherapy. Baseline blood samples were analyzed for lamivudine-resistant mutations via restriction fragment mass polymorphism. Virologic responses, ALT normalization and loss of HBeAg were assessed. Serum HBV DNA levels were measured using real-time PCR at baseline and 24 weeks of adefovir therapy. Of the 67 patients with chronic hepatitis B, 65 patients (97%) had lamivudine-resistant mutations in the YMDD motif [27 (41%) rtM204I, 22 (34%) rtM204V, and 16 (25%) rtM204I/V]. In addition to the YMDD mutations, the rtL180M, rtL80I, and rtV173L mutations were also present in 78%, 43%, and 11% of patients, respectively. The rtM204V mutation always accompanied rtL180M, and rtL80I was always observed in conjunction with rtM204I. Decrease in mean serum HBV did not differ between patients carrying the rtM204I versus rtM204V mutant at week 24 (-3.3 vs. -3.3 log(10) copies/ml, respectively; P = 0.303). The presence of the rtL180M, rtL80I, and rtV173L did not significantly affect viral load reduction during adefovir administration. These results demonstrate that the rtL80I mutant is co-selected with rtM204I as a compensatory mutation in the same manner as rtL180M with rtM204V, and that adefovir shows similar antiviral efficacy against all of the evaluated patterns of lamivudine-resistant HBV mutations.
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Affiliation(s)
- Choong Keun Cha
- Internal Medicine, CHA Biomedical Center, Pochon CHA University College of Medicine, Seoul, South Korea
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Gurtsevitch VE. Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis. BIOCHEMISTRY (MOSCOW) 2008; 73:504-13. [PMID: 18605975 DOI: 10.1134/s0006297908050039] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Chronic infections caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) are the main risk factors for the development of hepatocellular carcinoma (HCC) in humans. Both viruses cause a wide spectrum of clinical manifestations ranging from healthy carrier state to acute and chronic hepatitis, liver cirrhosis, and HCC. HBV and HCV belong to different viral families (Hepadnoviridae and Flaviviridae, respectively); they are characterized by different genetic structures. Clinical manifestations of these viral infections result from the interaction between these viruses and host hepatocytes (i.e. between viral and cell genomes). Proteins encoded by both viruses play an important role in processes responsible for immortalization and transformation of these cells. Chronic inflammation determined by host immune response to the viral infection, hepatocyte death and their compensatory proliferation, as well as modulation of expression of some regulatory proteins of the cell (growth factors, cytokines, etc.) are the processes that play the major role in liver cancer induced by HBV and HCV.
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Affiliation(s)
- V E Gurtsevitch
- Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia.
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