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Luo H, Tan G, Hu X, Li Y, Lei D, Zeng Y, Qin B. Triple motif proteins 19 and 38 correlated with treatment responses and HBsAg clearance in HBeAg-negative chronic hepatitis B patients during peg-IFN-α therapy. Virol J 2023; 20:161. [PMID: 37475028 PMCID: PMC10360334 DOI: 10.1186/s12985-023-02119-7] [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: 03/11/2023] [Accepted: 07/07/2023] [Indexed: 07/22/2023] Open
Abstract
OBJECTIVE To investigate whether the expression of triple motif protein 19/38 (TRIM19/38) mRNA in peripheral blood mononuclear cells (PBMCs) of HBeAg-negative chronic hepatitis B virus (HBV) carriers is associated with the response to pegylated interferon alpha (peg-IFN-α) treatment and HBsAg clearance. METHODS In this prospective study, HBeAg-negative chronic HBV carriers treated with peg-IFN-α completed 48 weeks of follow-up. After treatment with peg-IFN-α, the patients were divided into responders (R group) and nonresponders (NR group) according to the changes in HBV DNA and HBsAg levels at week 48 of treatment. According to whether serum HBsAg loss or seroconversion occurred, the patients were divided into a serological response group (SR group) and a nonserological response group (NSR group). The level of TRIM19/38 mRNA in PBMCs was detected by real-time fluorescence quantitative PCR. The diagnostic performance of TRIM19/38 was analysed by calculating the receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). RESULTS 43 HBeAg-negative chronic HBV carriers, 35 untreated CHB patients and 19 healthy controls were enrolled in this study. We found that TRIM19/38 mRNA levels were significantly lower in untreated CHB patients than in healthy controls. In HBeAg-negative chronic HBV carriers who underwent prospective follow-up, TRIM19/38 mRNA levels were negatively correlated with HBV DNA and ALT at baseline. Among the patients treated with peg-IFN-α, 16 patients achieved a treatment response (R group) and 27 patients did not achieve a treatment response (NR group). Compared with baseline, HBsAg levels in the R group decreased significantly at 12 and 24 weeks of treatment; at the early stage of peg-IFN-α treatment, the dynamic changes in TRIM19/38 mRNA levels in the R and NR groups were different, and the TRIM19/38 mRNA levels in the R group were significantly higher than those in the NR group, especially at 24 weeks of treatment. ROC curve analysis showed that the changes in mRNA levels of TRIM19 and TRIM38 predicted the treatment response, with AUCs of 0.694 and 0.757, respectively. Among the patients treated with peg-IFN-α, 11 patients achieved a serological response (SR group) and 32 patients did not achieve a serological response (NSR group). Compared with baseline, HBsAg levels in the SR group decreased significantly at 12 and 24 weeks of treatment; TRIM19/38 mRNA levels were significantly higher in the SR group than in the NSR group at week 24. CONCLUSION The higher level of TRIM19/38 mRNA in PBMCs of HBeAg-negative chronic HBV carriers may be related to the early treatment effect of peg-IFN-α and HBsAg clearance. TRIM19 and TRIM38 have clinical significance in predicting virological response and guiding treatment regimens.
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Affiliation(s)
- Haiying Luo
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016 China
- Central Laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guili Tan
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016 China
| | - Xiaoxia Hu
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016 China
- Central Laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yadi Li
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016 China
| | - Dingjia Lei
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016 China
| | - Yueying Zeng
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016 China
| | - Bo Qin
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016 China
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Tai J, Harrison AP, Chen HM, Hsu CY, Hsu TH, Chen CJ, Jeng WJ, Chang ML, Lu L, Tai DI. Acoustic radiation force impulse predicts long-term outcomes in a large-scale cohort: High liver cancer, low comorbidity in hepatitis B virus. World J Gastroenterol 2023; 29:2188-2201. [PMID: 37122600 PMCID: PMC10130974 DOI: 10.3748/wjg.v29.i14.2188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/15/2023] [Accepted: 03/23/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Acoustic radiation force impulse (ARFI) is used to measure liver fibrosis and predict outcomes. The performance of elastography in assessment of fibrosis is poorer in hepatitis B virus (HBV) than in other etiologies of chronic liver disease.
AIM To evaluate the performance of ARFI in long-term outcome prediction among different etiologies of chronic liver disease.
METHODS Consecutive patients who received an ARFI study between 2011 and 2018 were enrolled. After excluding dual infection, alcoholism, autoimmune hepatitis, and others with incomplete data, this retrospective cohort were divided into hepatitis B (HBV, n = 1064), hepatitis C (HCV, n = 507), and non-HBV, non-HCV (NBNC, n = 391) groups. The indexed cases were linked to cancer registration (1987-2020) and national mortality databases. The differences in morbidity and mortality among the groups were analyzed.
RESULTS At the enrollment, the HBV group showed more males (77.5%), a higher prevalence of pre-diagnosed hepatocellular carcinoma (HCC), and a lower prevalence of comorbidities than the other groups (P < 0.001). The HCV group was older and had a lower platelet count and higher ARFI score than the other groups (P < 0.001). The NBNC group showed a higher body mass index and platelet count, a higher prevalence of pre-diagnosed non-HCC cancers (P < 0.001), especially breast cancer, and a lower prevalence of cirrhosis. Male gender, ARFI score, and HBV were independent predictors of HCC. The 5-year risk of HCC was 5.9% and 9.8% for those ARFI-graded with severe fibrosis and cirrhosis. ARFI alone had an area under the receiver operating characteristic curve (AUROC) of 0.742 for prediction of HCC in 5 years. AUROC increased to 0.828 after adding etiology, gender, age, and platelet score. No difference was found in mortality rate among the groups.
CONCLUSION The HBV group showed a higher prevalence of HCC but lower comorbidity that made mortality similar among the groups. Those patients with ARFI-graded severe fibrosis or cirrhosis should receive regular surveillance.
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Affiliation(s)
- Jennifer Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | | | - Hui-Ming Chen
- Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Chiu-Yi Hsu
- Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Tse-Hwa Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Cheng-Jen Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Le Lu
- DAMO Academy, Alibaba Group, New York, NY 94085, United States
| | - Dar-In Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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Hung CH, Kee KM, Chen CH, Tseng PL, Tsai MC, Chen CH, Wang JH, Chang KC, Kuo YH, Yen YH, Hu TH, Lu SN. A Randomized Controlled Trial of Glycyrrhizin Plus Tenofovir vs. Tenofovir in Chronic Hepatitis B with Severe Acute Exacerbation. Clin Transl Gastroenterol 2017; 8:e104. [PMID: 28662023 PMCID: PMC5518952 DOI: 10.1038/ctg.2017.29] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 05/10/2017] [Indexed: 12/19/2022] Open
Abstract
Objectives: Severe acute exacerbation (SAE) of chronic hepatitis B (CHB) may progress to liver failure with high potential mortality despite the prompt treatment with nucleos(t)ide analogs. This study aimed to evaluate the efficacy and safety of glycyrrhizin in the treatment of CHB with SAE. Methods: Sixty patients with SAE of CHB were randomly treated with tenofovir plus intravenous glycyrrhizin (group A, n=30) or with tenofovir alone (group B, n=30). Primary end points were the improvement of serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and model for end-stage liver disease (MELD) score. Secondary end point was overall mortality or receipt of liver transplantation by week 24. Results: Patients in group A had significant reductions of serum AST and ALT levels from baseline at days 3, 5, 8, and 15 than those in group B (all P<0.05). The MELD score significantly decreased since week 1 in the group A patients, whereas there were no changes relative to baseline in group B patients at weeks 1 and 2. By week 24, one (3.3%) of group A patients and four (13.3%) of group B patients died (n=3) or received liver transplantation (n=1) (P=0.177). Multivariate analysis identified baseline MELD score (P=0.021) as an independent factor for mortality or receipt of liver transplantation. There were no differences in the rates of grade 3 hypertension, hypokalemia and ascites between two groups. Conclusions: Early introduction of glycyrrhizin can be safe and helpful for patients with SAE of CHB.
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Affiliation(s)
- Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Kwong-Ming Kee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Hung Chen
- Division of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
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Liaw YF, Chu CM. Immune Tolerance Phase of Chronic Hepatitis B. Gastroenterology 2017; 152:1245-1246. [PMID: 28273436 DOI: 10.1053/j.gastro.2016.11.057] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 11/18/2016] [Indexed: 01/05/2023]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Chia-Ming Chu
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Kennedy PTF, Bertoletti A, Mason WS. Reply. Gastroenterology 2017; 152:1246-1247. [PMID: 28273438 DOI: 10.1053/j.gastro.2017.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Affiliation(s)
- Patrick T F Kennedy
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
| | - Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-National University of Singapore Graduate Medical School, Singapore
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Zeng DW, Zhang JM, Liu YR, Dong J, Jiang JJ, Zhu YY. A Retrospective Study on the Significance of Liver Biopsy and Hepatitis B Surface Antigen in Chronic Hepatitis B Infection. Medicine (Baltimore) 2016; 95:e2503. [PMID: 26937895 PMCID: PMC4778991 DOI: 10.1097/md.0000000000002503] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
To investigate changes in the HBV replication level along with the natural course of chronic HBV infection and to examine the accuracy of the immune tolerant phase defined by the serological profile.A total of 390 chronic HBV-infected patients were retrospectively recruited for this study. They were classified into immune-tolerance (IT), immune-clearance (IC), low-replicative (LR), and HBeAg-negative hepatitis (ENH) phases according to serological profiles (single-standard, SS) or dual-standard (DS) with the inclusion of liver histology. Serum HBV DNA and HBsAg were quantitatively measured, and liver histology was quantitatively analyzed.The accuracy of the SS-defined IT phase was low, and active pathological changes were detected in 56 of 112 SS-defined IT patients. DS-defined IT patients had higher HBsAg levels (P = 0.0002) than the SS-defined patients. The quantitative HBsAg level can help identify SS-defined IT patients with potential liver injury. The area under the received operating characteristic curve for predicting the DS-defined IT phase was 0.831 (HBsAg 4.398 log IU/mL; sensitivity 87.5%; specificity 73.2%). HBV DNA was reduced by 4 logs, whereas HBsAg was only decreased by 2 logs with HBeAg positive to negative phase conversion.Approximately half of IT patients defined by SS may have medium or severe liver injury. Quantitative measurement of the HBsAg level can help identify SS-defined IT patients with potential liver injury.
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Affiliation(s)
- Da-Wu Zeng
- From Liver Center (D-WZ, Y-RL, JD, J-JJ, Y-YZ); and Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Taijiang District, Fuzhou, Fujian, China (J-MZ)
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Ricardo-Lax I, Ramanan V, Michailidis E, Shamia T, Reuven N, Rice CM, Shlomai A, Shaul Y. Hepatitis B virus induces RNR-R2 expression via DNA damage response activation. J Hepatol 2015; 63:789-96. [PMID: 26026873 DOI: 10.1016/j.jhep.2015.05.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 04/21/2015] [Accepted: 05/19/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Hepatitis B virus (HBV) infects and replicates in quiescent hepatocytes, which are deficient in dNTPs, the critical precursors of HBV replication. Most tumor viruses promote dNTP production in host cells by inducing cell proliferation. Although HBV is known as a major cause of hepatocellular carcinoma, it does not lead to cellular proliferation. Instead, HBV acquires dNTPs by activating the expression of the R2 subunit of the Ribonucleotide Reductase (RNR) holoenzyme, the cell cycle gene that is rate-limiting for generation of dNTPs, without inducing the cell cycle. We wished to elucidate the molecular basis of HBV-dependent R2 expression in quiescent cells. METHODS Quiescent HepG2 cells were transduced with an HBV-containing lentiviral vector, and primary human hepatocytes were infected with HBV. DNA damage response and RNR-R2 gene expression were monitored under this condition. RESULTS We report here that HBV-induced R2 expression is mediated by the E2F1 transcription factor, and that HBV induces E2F1 accumulation, modification and binding to the R2 promoter. We found that Chk1, a known E2F1 kinase that functions in response to DNA damage, was activated by HBV. In cells where Chk1 was pharmacologically inhibited, or depleted by shRNA-mediated knockdown, HBV-mediated R2 expression was severely attenuated. Furthermore, we found that HBV attenuates DNA repair, thus reducing cellular dNTP consumption. CONCLUSIONS Our findings demonstrate that HBV exploits the Chk1-E2F1 axis of the DNA damage response pathway to induce R2 expression in a cell cycle-independent manner. This suggests that inhibition of this pathway may have a therapeutic value for HBV carriers.
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Affiliation(s)
- Inna Ricardo-Lax
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Vyas Ramanan
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
| | - Eleftherios Michailidis
- Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, United States
| | - Tal Shamia
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Nina Reuven
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, United States
| | - Amir Shlomai
- Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, United States.
| | - Yosef Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
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Peng YC, Lin CL, Hsu WY, Chang CS, Yeh HZ, Kao CH. Risk of liver cirrhosis in patients with tuberculosis: a nationwide cohort study. Eur J Clin Invest 2015; 45:663-9. [PMID: 25903030 DOI: 10.1111/eci.12453] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 04/19/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND Most of the previous reports found cirrhosis patients with a high risk of subsequent tuberculosis (TB). However, data about the risk of developing liver cirrhosis in TB patients are limited. As a hepatitis endemic area, the risk of liver cirrhosis in patients with TB should be elucidated in Taiwan. METHODS We conducted the study using Taiwan's National Health Insurance Research Database. Patients with TB (n = 9339) were identified as the TB cohort and matched with a control (n = 37 356). Each study participant was followed until diagnosis of liver cirrhosis, loss of follow-up, death, withdrawal from the insurance or until 31 December 2011. RESULTS A cumulative incidence of liver cirrhosis in the TB cohort had a significantly higher risk for liver cirrhosis compared with the control (log-rank test, P < 0·001). The overall incidence of liver cirrhosis was significantly higher in the TB group than in controls [3·83 vs. 2·02 per 1000 person-year; crude hazard ratio (HR) = 1·88; 95% confidence interval (CI) = 1·59-2·23]. After controlling for age, gender and comorbidities, the risk was 1·79-fold (95% CI = 1·50-2·14) higher in the TB group than in the controls. Analysis by Cox proportional hazard regression revealed that TB increased the risk of cirrhosis in patients with either hepatitis B (adjusted HR = 1·91; 95% CI = 1·05-3·47) or hepatitis C (adjusted HR = 2·56; 95% CI = 1·37-4·78). CONCLUSION An increased incidence of liver cirrhosis was observed among TB patients in Taiwan.
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Affiliation(s)
- Yen-Chun Peng
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Wan-Yun Hsu
- Department of Nursing, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chi-Sen Chang
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hong-Zen Yeh
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,National Yang-Ming University, Taipei, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.,Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
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Deroubaix A, Osseman Q, Cassany A, Bégu D, Ragues J, Kassab S, Lainé S, Kann M. Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus. J Gen Virol 2014; 96:183-195. [PMID: 25274856 DOI: 10.1099/vir.0.064816-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Biopsies from patients show that hepadnaviral core proteins and capsids - collectively called core - are found in the nucleus and cytoplasm of infected hepatocytes. In the majority of studies, cytoplasmic core localization is related to low viraemia while nuclear core localization is associated with high viral loads. In order to better understand the molecular interactions leading to core localization, we analysed transfected hepatoma cells using immune fluorescence microscopy. We observed that expression of core protein in the absence of other viral proteins led to nuclear localization of core protein and capsids, while expression of core in the context of the other viral proteins resulted in a predominantly cytoplasmic localization. Analysis of which viral partner was responsible for cytoplasmic retention indicated that the HBx, surface proteins and HBeAg had no impact but that the viral polymerase was the major determinant. Further analysis revealed that ϵ, an RNA structure to which the viral polymerase binds, was essential for cytoplasmic retention. Furthermore, we showed that core protein phosphorylation at Ser 164 was essential for the cytoplasmic core localization phenotype, which is likely to explain differences observed between individual cells.
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Affiliation(s)
- Aurélie Deroubaix
- Hepatitis Virus Diversity Research Programme, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.,CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Quentin Osseman
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Aurélia Cassany
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Dominique Bégu
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Jessica Ragues
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Somar Kassab
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Sébastien Lainé
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Université Montpellier 1, CPBS, UMR 5236 CNRS, Montpellier, France
| | - Michael Kann
- Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,CHU de Bordeaux, Bordeaux, France.,CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
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10
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Li Q, Lu F, Deng G, Wang K. Modeling the effects of covalently closed circular DNA and dendritic cells in chronic HBV infection. J Theor Biol 2014; 357:1-9. [DOI: 10.1016/j.jtbi.2014.04.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 04/13/2014] [Accepted: 04/29/2014] [Indexed: 12/12/2022]
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11
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Cao W, Qiu Z, Zhu T, Li Y, Han Y, Li T. CD8+ T cell responses specific for hepatitis B virus core protein in patients with chronic hepatitis B virus infection. J Clin Virol 2014; 61:40-6. [PMID: 25049205 DOI: 10.1016/j.jcv.2014.06.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 06/03/2014] [Accepted: 06/22/2014] [Indexed: 12/23/2022]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection includes a set of heterogeneous clinical patterns, and core-protein-specific T cell response is important for virus control and disease progression, yet is not well elucidated. OBJECTIVES To analyze the phenotypic and functional profiles of HBV-core-protein-specific CD8+ T cells in different clinical patterns of chronic HBV infection. STUDY DESIGN A total of 46 HBV patients were recruited and classified according to their clinical status. CD8+ T cell responses in different patterns of chronic HBV infections were tested with flow cytometry using overlapping 15-mer peptides covering HBV core protein. Meanwhile, the CCR7/CD27 phenotypes of these CD8+ T cells were also determined. RESULTS Frequencies of gamma interferon (IFN-γ) positive CD8+ T cells in inactive HBV surface antigen (HBsAg) carriers in response to the core protein peptide pools were generally stronger than those of chronic HBV carriers and resolved individuals, especially with regards to peptide pool C13-C24. Moreover, phenotypic studies further highlighted the group of CD8+ CCR7-CD27+ T memory cells, which showed significantly higher levels of IFN-γ secretion in inactive HBsAg carriers than those in chronic hepatitis B patients, chronic HBV carriers and resolved individuals. CONCLUSIONS Core-protein-specific T cell response plays an important role in chronic HBV infection. Inactive HBsAg carriers showed a much stronger core-protein-specific cytotoxic T cell response than other types of chronically infected patients. CD8+ CCR7-CD27+ T memory lymphocytes may be crucial in the immune pathogenesis of chronic HBV infection.
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Affiliation(s)
- Wei Cao
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuaifu Yuan, Dongcheng District, Beijing 100730, China
| | - Zhifeng Qiu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuaifu Yuan, Dongcheng District, Beijing 100730, China
| | - Ting Zhu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuaifu Yuan, Dongcheng District, Beijing 100730, China
| | - Yanling Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuaifu Yuan, Dongcheng District, Beijing 100730, China
| | - Yang Han
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuaifu Yuan, Dongcheng District, Beijing 100730, China
| | - Taisheng Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuaifu Yuan, Dongcheng District, Beijing 100730, China.
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12
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Spaziante M, Biliotti E, Grieco S, Palazzo D, Esvan R, Taliani G. Anti-HBs seroconversion during treatment with entecavir in a patient with chronic hepatitis B virus infection on hemodialysis. J Med Virol 2013; 86:139-43. [PMID: 24136393 DOI: 10.1002/jmv.23795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2013] [Indexed: 11/07/2022]
Abstract
Hepatitis B (HBV) virus infection is one of the most important causes of liver disease in patients with end-stage renal failure on hemodialysis. The natural history of chronic HBV infection acquired in childhood starts with an immune tolerant phase, followed by an immune clearance phase that may lead to the inactive carrier state or the development of chronic liver disease. Information on antiviral therapy administered very early during the immune clearance phase are lacking and no data exist on the treatment of early immune activation in the hemodialysis setting. This report describes the case of a patient affected by end-stage renal failure and HBeAg-positive chronic HBV virus infection treated very early during the immune clearance phase of HBV infection with an adjusted-dose of nucleoside analogue entecavir. The patient achieved a very rapid HBV-DNA undetectability, anti-HBe, and anti-HBs seroconversion. This is the first report of antiviral therapy with entecavir started during the immune reactive phase of HBV infection in a patient on hemodialysis and it suggests that antiviral treatment can enhance the effects of host immune activation resulting in biochemical, serological, and viral response, even in end-stage renal failure patients with partial immunodeficiency. Antiviral therapy with entecavir in the setting of hemodialysis was safe and well tolerated.
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Affiliation(s)
- Martina Spaziante
- Clinica Malattie Infettive e Tropicali, Sapienza University of Rome, Rome, Italy
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13
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Healy SA, Gupta S, Melvin AJ. HIV/HBV coinfection in children and antiviral therapy. Expert Rev Anti Infect Ther 2013; 11:251-63. [PMID: 23458766 DOI: 10.1586/eri.13.2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Small cohort studies from countries where both HIV and HBV are endemic demonstrate prevalence rates of chronic hepatitis B in HIV-infected children of between 1 and 49%. While data on coinfected children are limited, results from studies in adults with HIV/HBV coinfection raise the concern that coinfected children may be at a higher risk of liver disease, hepatic fibrosis and cirrhosis. With the scale-up of combination antiretroviral therapy worldwide, of which lamivudine is included in most first-line regimens, coinfected children treated with lamivudine risk development of HBV resistance mutations. This article summarizes the current literature relevant to HIV/HBV coinfection in children, the options for treatment and highlights priorities for future research.
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Affiliation(s)
- Sara A Healy
- Seattle Biomedical Research Institute, Seattle, WA, USA
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14
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Chen CT, Chen JY, Wang JH, Chang KC, Tseng PL, Kee KM, Chen PF, Tsai LS, Chen SC, Lin SC, Lu SN. Diabetes mellitus, metabolic syndrome and obesity are not significant risk factors for hepatocellular carcinoma in an HBV- and HCV-endemic area of Southern Taiwan. Kaohsiung J Med Sci 2013; 29:451-9. [PMID: 23906236 DOI: 10.1016/j.kjms.2012.12.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 07/04/2012] [Indexed: 02/07/2023] Open
Abstract
A prominent factor in hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). Diabetes mellitus (DM), metabolic syndrome (MetS), and obesity have also been implicated in HCC development, but these associations are not observed in all HBV- and HCV-endemic areas. We attempted to clarify the role of these factors in HCC development in an HBV- and HCV-endemic area in southern Taiwan. A community-based health examination was conducted in 2004 in Tainan County. After individuals with incomplete data and those with known HCC were excluded, there were 56,231 participants who were over 40 years of age. A further 262 HCC cases were identified from the National Cancer Registration Database records from 2005 to 2007. The hepatitis B surface antigen (HBsAg) seropositivity, anti-HCV seropositivity, platelet count, serum biochemical data, blood pressure, sociodemographic information, and anthropometric measurements were analyzed. Survival analyses were used to identify the associations between these factors and HCC. For the 262 HCC cases, male gender and age greater than 65 years were risk factors. Furthermore, a high alanine aminotransferase level, chronic HBV and/or HCV infection, and liver cirrhosis were also risk factors for HCC. However, DM, MetS and obesity were not associated with HCC development in the non-HBV-/non-HCV-infected, HBV, HCV, or dual B/C groups. In this HBV- and HCV- endemic area, DM, MetS and obesity were not risk factors for developing HCC.
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Affiliation(s)
- Chao-Tung Chen
- Department of Family Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan
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Roushan MRH, Bijani A, Ramzaninejad S, Roushan MH, Amiri MJS, Baiani M. HBeAg seroconversion in children infected during early childhood with hepatitis B virus. J Clin Virol 2012; 55:30-3. [PMID: 22727680 DOI: 10.1016/j.jcv.2012.05.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 05/09/2012] [Accepted: 05/15/2012] [Indexed: 12/26/2022]
Abstract
BACKGROUND Seroconversion of hepatitis B e-antigen (HBeAg) to anti-HBe is associated with lower viral load and liver diseases. OBJECTIVES The purpose of this study was to assess the seroconversion rate of HBeAg to anti-HBe in children who acquired hepatitis B virus (HBV) infection during early childhood. STUDY DESIGN From September 1990 to December 2010, 139 HBeAg-positive children were followed up. Eighty-one subjects were of failure of hepatitis B immune globulin (HBIG) and hepatitis B vaccine at birth and 58 children <10 years of age who were born before 1990 did not receive HBIG and hepatitis B vaccine. HBsAg, HBeAg, anti-HBs and anti-HBe were assessed every 6 months. RESULTS Sixty-two (44.6%) cases were males and 77 (55.4%) were females. The mean duration of follow-up was 18 ± 6.6 years. Twenty-four (17.3%) mothers were HBeAg positive and 115 (82.7%) were anti-HBe positive. Eighty-two (59%) children became anti-HBe positive. The seroconversion rates in the first, second and third decades were 25%, 63.4% and 70.5%, respectively (p<0.001). The children of anti-HBe-positive mothers had a higher seroconversion rate than the HBeAg-positive mothers (75% vs. 33.9%, p<0.0001). Time to seroconversion in children born to HBeAg-positive mothers was similar to those born to anti-HBe positive mothers (hazard ratio (HR)=1.03, p=0.973). Time to seroconversion in children who received hepatitis B vaccine and HBIG was shorter than those who did not (HR=6.35, p<0001). CONCLUSIONS HBeAg seroconversion in the second and the third decades was higher than that in the first decade. Children born to anti-HBeAg-positive mothers and those who received HBIG and hepatitis B vaccine had higher seroconversion rates.
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Sallam TA, Raja'a YA, Bahaj S, Al-Shami AM, Lu M, Roggendorf M, Tong CYW. Hepatitis B virus carrier rate, prevalence and susceptibility and impact of immunization program among households in the city of Taiz, Yemen. Vaccine 2012; 30:5564-8. [PMID: 22717331 DOI: 10.1016/j.vaccine.2012.06.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 05/20/2012] [Accepted: 06/05/2012] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To examine the carrier rate, prevalence and susceptibility to hepatitis B virus infection in the city of Taiz, Yemen. METHODS In a community-based household survey 521 subjects from 98 randomly selected households were enrolled. Carrier rate, prevalence and susceptibility of hepatitis B virus infection in the city of Taiz, Yemen were examined. RESULTS The median age of the subjects was 19 years (range <1-85 years), 219 (42.0%) of whom were males and 305 (58.0%) were females. The HBsAg carrier rate was 4.2% (22/521), the prevalence was 16.9% (88/521) and the susceptibility rate was 57.5% (287/499). Male vs female carrier rate, prevalence and susceptibility rate were comparable. Children (age ≤ 18 years) vs adults had carrier rates of 2.7% vs 5.7% (odds ratio=2.2) and a prevalence of 5.1% vs 28.4% (OR: 5.6). The carrier rate, prevalence and immunity to HBV among subjects who reported vaccination vs those unvaccinated was; 2.1% vs 5.5%, 11.3 vs 20.8% and 53.1% vs 18.8%. A proportion of 47.2% of subjects who aged ≤ 10 years had isolated anti-HBs. Of 142 of the cohort born after full implementation of vaccination program (age:≤ 9 years) 72 (50.7%) were immune and 70 (49.3%) were susceptible whereas of 357 subjects borne before program implementation (Age:≥ 10 years) 140 (39.2%) were immune and 217 (60.8%) were susceptible (p<0.02 (Pearson) OR: 1.6 CI=0.42-0.93). CONCLUSIONS An intermediate endimicity was identified in Taiz city. Vaccination reduced carrier rate prevalence and susceptibility among vaccinated subjects. The high rate of subjects with isolated anti- HBs together with the reduced susceptibility rate among the cohort born after inclusion of HBV vaccine to EPI reflects impact of the program. Improving vaccination coverage will further reduce susceptibility rate.
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Affiliation(s)
- T A Sallam
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Sana'a University, Sana'a, Yemen.
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Specific expression of human interferon-gamma controls hepatitis B virus replication in vitro in secreting hepatitis B surface antigen hepatocytes. J Virol Methods 2012; 180:84-90. [DOI: 10.1016/j.jviromet.2011.12.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 11/04/2011] [Accepted: 12/30/2011] [Indexed: 12/31/2022]
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Chen CH, Wang JH, Lu SN, Hu TH, Hung CH, Chang MH, Changchien CS, Lee CM. Treatment response and evolution of HBV resistance during lamivudine plus adefovir or entecavir therapy in patients with adefovir-resistant mutants. Antivir Ther 2012; 17:701-9. [PMID: 22358132 DOI: 10.3851/imp2074] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2011] [Indexed: 12/25/2022]
Abstract
BACKGROUND Here, we investigated the treatment response and evolution of HBV resistance during lamivudine (LAM) plus adefovir (ADV) and entecavir (ETV) monotherapy in patients with ADV-resistant mutants. METHODS Of the 53 patients with ADV-resistant mutants, 25 received combined LAM plus ADV therapy (LAM+ADV group) and 28 received ETV monotherapy (ETV group) for at least 12 months (median 24 months and range 12-67 months). RESULTS During 24 months therapy, no significant difference was noted in HBV DNA reduction from baseline, HBV DNA<200 copies/ml, hepatitis B e antigen loss and ALT normalization between the two groups. In the LAM+ADV group, patients with single rtN236T resistant mutation had higher rates of undetectable HBV DNA than those with the double mutant rtA181T/V+rtN236T at months 3-18 of therapy. No virological breakthrough occurred except for one patient with rtN236T resistant mutation who experienced virological and biochemical breakthrough after the emergence of an additional rtA181T mutant under LAM+ADV therapy. Of the 28 patients receiving ETV monotherapy, ETV-resistant mutants developed in 8. The cumulative rates of ETV-resistant mutations and virological breakthrough at months 12, 24 and 36 were 3.6%, 25.7% and 46.8%, respectively. ADV-resistant mutations were rapidly replaced by LAM-resistant mutations (median 12 months) followed by ETV-resistant mutations. CONCLUSIONS There was no significant difference in virological response between the LAM+ADV and ETV groups in patients with ADV-resistant mutants. LAM+ADV were less effective in patients with the double mutant rtA181T/V+rtN236T than the single rtN236T mutation. The incidence of ETV-resistant mutation was high in patients with LAM/ADV-resistant mutants treated with ETV monotherapy.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Chen CH, Lee CM, Hung CH, Wang JH, Hu TH, Changchien CS, Lu SN. Hepatitis B virus genotype B results in better immediate, late and sustained responses to peginterferon-alfa in hepatitis-B-e-antigen-positive patients. J Gastroenterol Hepatol 2011; 26:461-8. [PMID: 21332543 DOI: 10.1111/j.1440-1746.2010.06429.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIMS This study investigated outcome predictors in hepatitis-B-e-antigen (HBeAg)-positive chronic hepatitis B patients treated with peginterferon alfa-2a. METHODS A total of 88 HBeAg-positive patients receiving peginterferon alfa-2a for 6 months and followed up for at least 24 weeks were prospectively analyzed. Precore and core promoter genes of hepatitis B virus (HBV) were sequenced from the serial serum samples of 88 patients. RESULTS After 24 weeks of follow up, 38.6% and 28.4% of patients achieved HBeAg clearance and combined response, respectively. Multivariate analysis disclosed that pretreatment HBeAg sample to cut-off (S/Co) ratio ≤ 200, alanine aminotransferase > 200 IU/mL, HBV genotype B and T1846 were independent factors for HBeAg clearance, and HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for combined response. HBeAg S/Co ratio ≤ 10 at week 12 of therapy was the useful factor for treatment response and had a greater power (P = 0.012) to predict HBeAg clearance than HBV DNA. Patients with HBeAg clearance had a higher frequency of A1896 mutation at baseline and during therapy than those without HBeAg clearance, and the frequency of A1896 decreased during treatment. During follow up, delayed HBeAg seroconversion and reactivation of HBV after HBeAg clearance were observed in eight non-responders and 20 patients with HBeAg clearance, respectively. HBV genotype B was a significant factor to predict both responses. CONCLUSIONS Pretreatment HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for treatment response to peginterferon. Genotype-B-infected patients had higher probability of delayed HBeAg clearance and sustained response. Rapid decrease of HBeAg titer was useful on treatment predictor.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Utama A, Siburian MD, Purwantomo S, Intan MDB, Kurniasih TS, Gani RA, Achwan WA, Arnelis, Lelosutan SAR, Lukito B, Harmono T, Zubir N, Julius, Soemohardjo S, Lesmana LA, Sulaiman A, Tai S. Association of core promoter mutations of hepatitis B virus and viral load is different in HBeAg(+) and HBeAg(-) patients. World J Gastroenterol 2011; 17:708-16. [PMID: 21390140 PMCID: PMC3042648 DOI: 10.3748/wjg.v17.i6.708] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 11/25/2010] [Accepted: 12/02/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify the prevalence of hepatitis B e antigen (HBeAg) and to assess the association of hepatitis B virus (HBV) core promoter mutations and viral load in Indonesian patients.
METHODS: Sixty-four patients with chronic hepatitis, 65 with liver cirrhosis and 50 with hepatocellular carcinoma were included in this study. HBeAg and hepatitis B e antibody (HBeAb) tests were performed using enzyme-linked immunosorbent assay and the mutations were analyzed by sequencing. Viral load was measured by real-time polymerase chain reaction.
RESULTS: Of 179 patients, 108 (60.3%) were HBeAg(-) and 86 (79.6%) of these HBeAg(-) patients had been seroconverted. The A1896 mutation was not found in HBeAg(+) patients, however, this mutation was detected in 70.7% of HBeAg(-) patients. This mutation was frequently found when HBeAg was not expressed (87.7%), compared to that found in HBeAg seroconverted patients (65.1%). The A1899 mutation was also more prevalent in HBeAg(-) than in HBeAg(+) patients (P = 0.004). The T1762/A1764 mutation was frequently found in both HBeAg(+) and HBeAg(-) patients, however, the prevalence of this mutation did not significantly differ among the two groups (P = 0.054). In HBeAg(+) patients, the T1762/A1764 mutation was correlated with lower HBV DNA (P < 0.001). The A1899 mutation did not correlate with HBV DNA (P = 0.609). In HBeAg(-) patients, the T1762/A1764 mutation alone was not correlated with HBV DNA (P = 0.095), however, the presence of either the T1762/A1764 or A1896 mutations was associated with increased HBV DNA (P < 0.001).
CONCLUSION: The percentage of HBeAg(-) patients is high in Indonesia, and most of the HBeAg(-) patients had been seroconverted. The A1896 mutation was most likely the major cause of HBeAg loss. The T1762/A1764 mutation alone was associated with lower viral loads in HBeAg(+) patients, but not in HBeAg(-) patients.
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Increased intrahepatic apoptosis but reduced immune activation in HIV-HBV co-infected patients with advanced immunosuppression. AIDS 2011; 25:197-205. [PMID: 21076271 DOI: 10.1097/qad.0b013e3283410ccb] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE to determine if intrahepatic immune activation is increased in HIV-hepatitis B virus (HBV) co-infected patients compared to HBV mono-infected patients and whether this reduced following HBV-active antiretroviral therapy (ART) in HIV-HBV co-infected patients. DESIGN : Case-control observational study. METHODS we examined liver biopsies for markers of T-cell and monocyte infiltration and activation, natural killer cells, hepatic stellate cell (HSC) activation (staining for alpha smooth muscle actin) and apoptosis [using terminal dUTP nick-end labelling (TUNEL)] in treatment-naive Asian HIV-HBV co-infected (n = 16) and HBV mono-infected patients matched for age and HBV e-antigen status (n = 16). Liver biopsies from a subset of co-infected patients (n = 15) were also compared prior to and following 48 weeks of HBV-active ART. RESULTS HIV-HBV co-infected patients had a median CD4 T-cell count of 25 cells/microl and lower alanine aminotransferase levels than HBV mono-infected patients (P = 0.03). In HIV-HBV co-infected patients, hepatocyte apoptosis was increased (P = 0.04) but there were fewer intrahepatic CD4 and CD8 T cells (P < 0.001), lower activation of intrahepatic T cells, Kupffer cells and HSC (P = 0.002, 0.008 and < 0.001, respectively). Following ART, there was a significant decrease in intrahepatic HBsAg staining (P = 0.04) and Kupffer cell activation (P = 0.003). CONCLUSIONS we found no evidence of increased intrahepatic mononuclear and HSC activation in this cohort of HIV-HBV co-infected individuals with advanced immune suppression. An increase in intra-hepatic apoptosis in HIV-HBV co-infected individuals may potentially contribute to accelerated fibrosis in this setting.
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Thompson AJV, Nguyen T, Iser D, Ayres A, Jackson K, Littlejohn M, Slavin J, Bowden S, Gane EJ, Abbott W, Lau GKK, Lewin SR, Visvanathan K, Desmond PV, Locarnini SA. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010; 51:1933-44. [PMID: 20512987 DOI: 10.1002/hep.23571] [Citation(s) in RCA: 323] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. CONCLUSION The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker.
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Affiliation(s)
- Alexander J V Thompson
- Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
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Cohen D, Adamovich Y, Reuven N, Shaul Y. Hepatitis B virus activates deoxynucleotide synthesis in nondividing hepatocytes by targeting the R2 gene. Hepatology 2010; 51:1538-46. [PMID: 20155784 DOI: 10.1002/hep.23519] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
UNLABELLED Hepatitis B virus (HBV) causes liver diseases from acute hepatitis to cirrhosis and liver cancer. Currently, more than 350 million people are chronic HBV carriers, with devastating prognosis. HBV is a small enveloped noncytopathic virus, containing a circular partially double-stranded DNA genome, and exhibits strong tropism for human liver cells. Infected individuals (acute and chronic) secrete about 10(7) to 10(11) virions per day to the bloodstream, with each infected cell releasing 50-300 viruses per day. HBV infects nondividing hepatocytes and replicates by reverse-transcribing the pregenomic RNA to DNA in the host cells. The level of deoxyribonucleotide triphosphates (dNTPs) in nondividing cells is too low to support viral replication and enable the high yield of secreted virions. Here, we report production of dNTPs by viral-dependent transcription activation of R2, the key component of ribonucleotide reductase (RNR), and show that this process is critical for the HBV life-cycle. This was found in an established HBV-positive cell line and was reproduced by HBV DNA-transduced cells, in both culture and mice. Furthermore, the viral hepatitis B X protein is essential in activating R2 expression by blocking access of Regulatory factor x1, a repressor of the R2 gene. CONCLUSION Our findings demonstrate that the hepatitis B X protein is critical in infecting nonproliferating hepatocytes, which contain a low dNTP level. In addition, we provide molecular evidence for a new mechanism of HBV-host cell interaction where RNR-R2, a critical cell-cycle gene, is selectively activated in nonproliferating cells. This mechanism may set the stage for formulating a new category of anti-HBV drugs.
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Affiliation(s)
- Dorit Cohen
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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Abstract
Hepatitis B and its complications are one of the major global health problems. Around 2 billion individuals are infected by hepatitis B virus (HBV) worldwide, more than 350 million are chronically infected, and approximately 15 to 40 percents of them will develop serious complications such as liver cirrhosis, hepatic failure, or hepatocellular carcinoma (HCC). The worldwide prevalence of chronic HBV infection ranges from 0.1 to 20 percent and varies widely in different geographic areas. According to the prevalence rate, WHO has classified countries into 3 levels: high areas (>8%) such as Africa, Asia, Western Pacific and Middle East; intermediate areas (2–8%) such as South America and Eastern Europe, and low areas (<2%) such as Western Europe, North America, and Australia.
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Cao B, Liu X, Hou F, Li W, Han Z, Zhang Q, Dai Y, Xu C, Qi H. The haplotype of the MxA gene promoter is associated with hepatitis B virus infection in a Chinese population. Liver Int 2009; 29:1383-8. [PMID: 19744071 DOI: 10.1111/j.1478-3231.2009.02053.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIM The Myxovirus resistance protein A gene (MxA) is a key component of the innate antiviral response and has previously been shown to inhibit several viruses. This study was designed to assess whether the haplotype in the MxA promoter region was associated with hepatitis B virus (HBV) infection in a Chinese population. METHODS Three hundred and twelve HBV-infected patients and 317 healthy volunteers were enrolled in this study. Two polymorphisms of -88 and -123 located in the MxA gene promoter were identified by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS The individual possessing haplotype GA, which was constructed by the two polymorphisms of -88G and -123A in the MxA gene promoter, was significantly associated with HBV infection [possessing one copy odds ratio (OR)=1.69, 95% confidence interval (CI) 1.21-2.35; two copy OR=2.84, 95% CI 1.12-7.21 respectively]. CONCLUSIONS This case-control study suggested that the haplotype GA in the MxA gene promoter region would increase the susceptibility to HBV infection in a Chinese population.
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Affiliation(s)
- Bangwei Cao
- Department of Anti-Infection and Institute of Clinical Pharmacology, Peking University First Hospital, #1 Xi An Men Da Jie Street, Western District, Beijing, China.
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Chen CH, Changchien CS, Lee CM, Tung WC, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN. A study on sequence variations in pre-S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non-B, non-C hepatocellular carcinoma patients in Taiwan. Int J Cancer 2009; 125:621-9. [DOI: 10.1002/ijc.24416] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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27
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Choi JW, Ahn SH, Park JY, Chang HY, Kim JK, Baatarkhuu O, Kim DY, Han KH, Chon CY. Hepatitis B e antigen-negative mutations in the precore and core promoter regions in Korean patients. J Med Virol 2009; 81:594-601. [PMID: 19235871 DOI: 10.1002/jmv.21452] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Most patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B have variants of the hepatitis B virus (HBV) that include mutations in the precore or core promoter regions of the HBV genome. The aim of this study was to investigate the patterns of precore and core promoter mutations and their relationship to HBeAg expression in Korean patients. Four hundred seventy-five Korean patients with chronic HBV infection between February 1995 and December 2003 were enrolled in this study. There were 236 HBeAg-positive and 239 HBeAg-negative patients. Blood samples were tested for HBsAg, anti-HBs, HBeAg, hepatitis B e antibody (anti-HBe), liver function tests, and serum HBV DNA. Mutations in the precore and core promoter regions were determined by direct sequencing. In the core promoter region, the C1740, C1753, T1762/A1764, and T1766 mutations were associated with HBeAg escape (all; P < 0.05). In the precore region, a higher frequency of the C1802, A1828, T1846, A1850, C1858, T1862, and A1896 mutations was found in HBeAg-negative patients (all; P < 0.05). In particular, the A1896 mutation was associated with high serum levels of ALT and HBV DNA in HBeAg-negative patients (P = 0.014 and 0.026, respectively). Mutations around the Kozak sequence (nucleotides 1809-1812) were found in 6.7% of patients and were not associated with undetectable HBeAg (P = 0.13). In Korean patients, various mutations in the precore and core promoter regions were associated with HBeAg escape and amelioration of hepatic inflammation in HBeAg- negative patients. Only the A1896 mutation contributed to HBeAg-negative chronic hepatitis B.
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Affiliation(s)
- Jong Won Choi
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
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Chen CH, Changchien CS, Lee CM, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN. Combined mutations in pre-s/surface and core promoter/precore regions of hepatitis B virus increase the risk of hepatocellular carcinoma: a case-control study. J Infect Dis 2008; 198:1634-42. [PMID: 18939932 DOI: 10.1086/592990] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND We sought to investigate the role of sequence variations in pre-S/surface and basal core promoter (BCP)/precore regions of the hepatitis B virus (HBV) in hepatocellular carcinoma (HCC). METHODS The direct sequencing in pre-S/surface and BCP/precore regions of HBV was determined for 80 patients with HCC and 160 control patients with HBV infection. RESULTS Compared with control patients, patients with HCC had higher frequencies of pre-S deletions and amino acid substitutions at codon 4, 7, and 81 in pre-S1 genes; at the start codon in pre-S2 genes; and at codon 68 in surface genes. Patients also had a lower frequency of amino acid substitution at codon 2 in pre-S2 genes, compared with control patients. In BCP/precore regions, patients with HCC had higher frequencies of C or G1753, A1762/T1764, T1846, and A1899. Multivariate analysis showed that pre-S deletions, I68T surface gene, T1762/A1764, and A1899 were independent factors associated with the development of HCC. The HBV strain with a complex mutation pattern rather than a single mutation was associated with HCC, and the HCC risks increased for patients having these factors in combination. CONCLUSIONS Pre-S deletions, I68T in surface gene, T1762/A1764, and A1899 were independent risk factors for HCC. Combination of these viral mutations appeared to increase the risk of HCC.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
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Abstract
Three nucleotide/nucleoside analogs are used for chronic hepatitis B (HBV): lamivudine, adefovir dipivoxil, and entecavir. Lamivudine and adefovir are advantageous for oral administration and safety but induce a sustained response after withdrawal of therapy in only a minority of patients. Thus, the treatment should be given in trials in a majority of patients for a long period of time. In addition, the long-term efficacy of lamivudine is limited by the frequent emergence of drug-resistant HBV mutants. Adefovir is associated with a low frequency of resistance, but its antiviral effect is not optimal. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of HBV-DNA polymerase and it inhibits both priming and elongation steps of viral DNA replication. In phase II and III clinical trials, entecavir was found to be superior to lamivudine for all primary end points evaluated in both nucleoside-naive and lamivudine-resistant patients, and it was effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has shown cases of viral resistance to this drug. The approved dosage in treatment-naive patients is 0.5 mg per day orally, whereas in patients who have failed lamivudine therapy or who are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg per day. Recent preliminary results show that clevudine, telbivudine, and emtricitabine may be potent analogs available for the treatment of HBV. Further studies are being conducted to assess the long-term efficacy and safety of these drugs.
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Chen Y, Mahato RI. siRNA pool targeting different sites of human hepatitis B surface antigen efficiently inhibits HBV infection. J Drug Target 2008; 16:140-8. [PMID: 18274934 DOI: 10.1080/10611860701878750] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The main objective was to determine whether a pool of small interfering RNAs (siRNAs) targeting different regions of hepatitis B virus surface antigen (HBsAg) efficiently inhibits hepatitis B virus (HBV) infection. siRNAs targeting different regions of HBsAg were transfected into HBV-producing HepG2.2.15 cells and at 72 h post-transfection, the culture medium was collected for ELISA to determine HBsAg, while total RNA was isolated from the cells for real-time PCR. Three siRNA sequences that efficiently inhibited HBV infection were converted into small hairpin RNAs (shRNAs) and then cloned into a single plasmid psiSTRIKE driven by a single U6 promoter. These shRNA expressing plasmids were tested for HBsAg gene silencing in HepG2.2.15 cells. A pool of siRNAs targeting HBsAg efficiently inhibited HBV replication and antigen expression when transfected into HepG2.2.15 cells, compared with the use of single siRNA. Similarly, the plasmid encoding three different shRNAs driven by a single U6 promoter was more effective in silencing HBsAg at DNA, mRNA and protein levels compared with the plasmid encoding single shRNA. No apoptotic change was observed in the cells when the plasmid was transfected at a dose of 0.5-2 microg/1 x 10(6) cells after complex formation with Lipofectamine LTX. Furthermore, transfection with siRNA or shRNA did not increase interferon-gamma (IFNs-gamma) release, suggesting no induction of IFN response. In conclusion, a pool of chemically synthesised siRNAs as well as the shRNA expression plasmid encoding multiple shRNAs targeting different regions of HBsAg showed high gene silencing in HepG2.2.15 cells.
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Affiliation(s)
- Yong Chen
- Huaian 4th People's Hospital, Jiangsu, PR China
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31
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Abstract
Three nucleotide/nucleoside analogs are currently used for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, and entecavir. Lamivudine and adefovir are beneficial for oral administration and safety, but only a few of the patients treated experience a sustained response after therapy withdrawal. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of chronic hepatitis B virus DNA polymerase, inhibiting both the priming and elongation steps of viral DNA replication. In phase II and phase III clinical trials, entecavir was found to be superior to lamivudine for all primary end points evaluated in both nucleoside-naive and lamivudine-resistant patients as well as being effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has shown evidence of cases of viral resistance to this drug. The approved dosage in treatment-naive patients is 0.5 mg per day orally, whereas in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg per day.
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Palumbo E, Scotto G, Faleo G, Cibelli DC, Saracino A, Angarano G. Prevalence of HBV-genotypes in immigrants affected by HBV-related chronic active hepatitis. ARQUIVOS DE GASTROENTEROLOGIA 2008; 44:54-7. [PMID: 17639184 DOI: 10.1590/s0004-28032007000100012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/13/2006] [Accepted: 07/25/2006] [Indexed: 01/01/2023]
Abstract
BACKGROUND The genetic heterogeneity of the HBV genome has been established and eight genotypes can be classified according to the criterion of >8% differences in the complete nucleotide sequence of the viral genome. AIMS To evaluate the prevalence of HBV-infection in a population of immigrants and to determine in patients with detectable serum HBV-DNA the HBV-genotypes. METHODS Between January 2005 and December 2005 a total of 556 immigrants were tested for HBsAg. In HBsAg positive patients the biochemical and virological activity of infection and the possible presence of co-infections (HCV, HDV, HIV) were evaluated. In patients with detectable serum HBV DNA, the HBV-genotype was determined by INNOLiPA. RESULTS Among the 556 subjects tested, 60 (10.7%) resulted HBsAg positive. All were men, and 42 (70%) come from Africa, 10 (16.6%) from Asia and 9 (14.4%) from East-Europe. 28/60 (46.6%) patients presented normal ALT levels (<40 IU/L) and undetectable serum HBV DNA (<100 copies/mL in real-time PCR), while 32 (53.4%) patients had ALT levels above laboratory normal values and detectable serum HBV DNA. Genotype distribution was as follow: genotype E, 16 (50%), genotype D, 9 (28.1%), genotype A, 7 (21.9%). CONCLUSION Our study evidences a moderate prevalence of HBV-infection in immigrants, particularly in sub-Saharan African people, and the potentiality of migratory flow in the introduction of genotype non-D hepatitis B virus, potentially characterized by a different natural history and, possibly, a different response to antiviral treatment.
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Affiliation(s)
- Emilio Palumbo
- Clinic of Infectious Diseases, University of Foggia, Italy.
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Yim HJ, Byun KS, Chang YJ, Suh YS, Yeon JE, Lee CH, Kwon JA, Yoo W, Kim SO, Hong SP. Levels of hepatitis B virus (HBV) replication during the nonreplicative phase: HBV quantification by real-time PCR in Korea. Dig Dis Sci 2007; 52:2403-9. [PMID: 17429737 DOI: 10.1007/s10620-006-9140-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2005] [Accepted: 11/10/2005] [Indexed: 12/18/2022]
Abstract
The levels of HBV replication in the nonreplicative phase are not clear. We conducted this study to evaluate the levels of viral replication during the nonreplicative phase in chronic HBV-infected Korean patients using real-time PCR. A total of 125 patients were classified into three groups: inactive HBsAg carriers, inactive liver cirrhosis patients, and resolved chronic HBV-infected patients with loss of HBsAg. The real-time PCR detected HBV DNA in 112 cases (89.6%). The mean levels of HBV DNA were 3.84, 4.10, and 3.31 log copies/ml in the three groups, respectively (P <0.01). Ninety-five percent of inactive HBsAg carriers showed levels of HBV DNA lower than 6 x 10(4) copies/ml. In conclusion, we showed different levels of HBV DNA exactly in three groups during nonreplicative phases. We suggest that the cutoff level of HBV DNA in inactive HBsAg carriers should be readjusted to a lower level in future studies.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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34
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Chen CH, Lee CM, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN, Changchien CS. Clinical significance and evolution of core promoter and precore mutations in HBeAg-positive patients with HBV genotype B and C: a longitudinal study. Liver Int 2007; 27:806-15. [PMID: 17617124 DOI: 10.1111/j.1478-3231.2007.01505.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS The aims of this longitudinal study were to investigate whether the clinical outcome and evolution of core promoter and precore mutations were different during hepatitis B e antigen (HBeAg) seroconversion between hepatitis B virus (HBV) genotypes B and C in HBeAg-positive patients with chronic hepatitis B. PATIENTS AND METHODS The core promoter and precore sequences were determined from serial sera of 156 HBeAg-positive patients with chronic HBV infection. RESULTS In HBV genotype C, the T1762/A1764 mutant was detected earlier than the A1896 mutant, and the frequency was significantly higher than in HBV genotype Ba over the entire follow-up period. In HBV genotype Ba, A1896 was found earlier than the T1762/A1764 mutant, and the frequency was significantly higher than in genotype C only before HBeAg seroconversion, and the A1896 mutant played an important role in HBeAg seroconversion in HBV genotype Ba. In addition, the T1846 variant was an independent factor associated with HBeAg seroconversion. Furthermore, HBV genotype C was associated with the development of G or C1753 and T1766/A1768 mutations, and the reactivation of hepatitis after HBeAg seroconversion. Based on Cox's regression analysis, the significant risk factors of liver cirrhosis were older age at entry [hazard ratio (HR)=1.085, 95% confidence interval (CI)=1.036-1.136, P=0.001], alanine transaminase (ALT) >80 U/l (HR=3.48, 95% CI=1.37-8.86, P=0.009), and the T1762/A1764 mutant (HR=5.54, 95% CI=2.18-14.08, P<0.001). CONCLUSIONS Our study showed that different HBV genotypes were associated with various mutations in the core promoter and precore regions during HBeAg seroconversion. T1762/A1764 mutation could be useful in predicting clinical outcomes in HBeAg-positive patients with HBV infection.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Abstract
The aim of this review is to examine the impact of hepatitis B virus (HBV) genotypes on biochemical and virologic response to antiviral drugs (alfa-interferon and pegylated-interferon alfa-2b, lamivudine, and adefovir dipivoxil) actually used for the treatment of chronic hepatitis, HBV related. International literature evidences that HBV genotypes D and C are associated with a lower rate of favorable response to alfa-interferon and pegylated-interferon alfa-2b therapy than genotypes A and B. The rate of resistance to lamivudine was higher in patients with genotype A infection than in patients infected by genotype D, whereas no difference in the risk of lamivudine resistance is found between patients with genotype B and patients with genotype C. In regard to the new nucleotide analogue, adefovir dipivoxil, a preliminary trial appears to provide no evidence of any difference in virologic response among the different HBV genotypes. The current study has determined that the different HBV genotypes have a very important impact on response to antiviral therapy, in particular interferon treatment. For this reason, determining the HBV genotype could be helpful for predicting the outcome of antiviral therapy in patients affected by chronic hepatitis B.
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Affiliation(s)
- Emilio Palumbo
- Department of Pediatrics, Hospital of Sondrio, Sondrio, Italy.
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36
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Chen CJ, Iloeje UH, Yang HI. Serum hepatitis B virus DNA as a predictor of the development of cirrhosis and hepatocellular carcinoma. ACTA ACUST UNITED AC 2007. [DOI: 10.1007/bf02942173] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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37
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Sheen IS, Tsou YK, Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC, Chang ML, Yeh CT. Nuclear HBcAg and histology activity index as independent predictors of the expression of singly spliced HBV-RNA. J Viral Hepat 2007; 14:70-4. [PMID: 17212647 DOI: 10.1111/j.1365-2893.2006.00781.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Although hepatitis B virus (HBV) RNA splicing has been reported by many researchers, the clinical significance of this event remains illusive. The present study was designed to investigate the clinical roles of singly spliced HBV-RNA. Liver biopsy tissues obtained from 32 consecutive patients were subjected to reverse transcriptase-polymerase chain reaction for the detection of singly spliced and unspliced HBV-RNA. Stepwise linear regression model was used to estimate the ratio of singly spliced to unspliced (S/US) HBV-RNA in the presence of the following variables: age, gender, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alpha-foetoprotein, status of HBV e antigen (HBeAg), status of antibody to HBeAg, HBV-DNA, histology activity index (HAI), fibrotic score, grade of cytoplasmic HBV core antigen (HBcAg), grade of nuclear HBcAg, genotype, status of precore-stop-mutation, basal core promoter mutation, previous lamivudine therapy and superinfection by other hepatitis viruses. The results showed that HAI (beta = -0.2616; P = 0.011) and grade of nuclear HBcAg expression (beta = 0.5599; P =0.0067) were two independent predictors for the expression of singly spliced HBV-RNA. Further categorical analysis showed that patients with HAI score <or=6 and grading of nuclear HBcAg >or=2 have significantly higher S/US ratios. In conclusion, nuclear HBcAg and HAI are two independent predictors for the expression of singly spliced HBV-RNA.
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Affiliation(s)
- I-S Sheen
- Liver Research Unit, Chang Gung Medical Center, Taipei, Taiwan
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Tsai MC, Kee KM, Chen YD, Lin LC, Tsai LS, Chen HH, Lu SN. Excess mortality of hepatocellular carcinoma and morbidity of liver cirrhosis and hepatitis in HCV-endemic areas in an HBV-endemic country: geographic variations among 502 villages in southern Taiwan. J Gastroenterol Hepatol 2007; 22:92-8. [PMID: 17201888 DOI: 10.1111/j.1440-1746.2006.04489.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIMS The aim of this study was to investigate excess mortality for hepatocellular carcinoma (HCC) and prevalence of hepatitis and liver cirrhosis (LC) in hepatitis C virus (HCV)-endemic areas in Taiwan, which is a hepatitis B virus (HBV)-endemic country. METHODS Tainan County, located in southern Taiwan, consists of 533 villages in 31 townships. A total of 56 702 subjects >or= 40 years old (mean age, 60.9 +/- 11.8 years) were enrolled from 502 of the 533 villages between April and November 2004 (n >or= 20/village). Serum blood HBV surface antigen (HBsAg), antibody to HCV (anti-HCV) and alanine transaminase (ALT) levels and platelet counts were measured. Township-specific mortality for liver cancer (ICD = 155) for both sexes between 1992 and 2001 were obtained from official publications. RESULTS The prevalence of anti-HCV in Tainan County was 10.2% (township range, 2.6-30.9%; village range, 0-90.5%). The prevalence of HBsAg was 10.9% (township range, 5.5-17.2%; village range, 0-30.8%). The prevalence of hypertransaminemia (serum ALT > 40 IU/L) was 12.8%. At township levels, prevalence of anti-HCV (r2 = 0.92, P < 0.001), HBsAg and anti-HCV (multiple r2 = 0.94) were correlated with hypertransaminemia prevalence by single and multiple linear analysis, respectively. At village levels, prevalence of anti-HCV (r2 = 0.52, P < 0.001), HBsAg and anti-HCV (multiple r2 = 0.53) were each correlated with prevalence of hypertransaminemia, respectively. The prevalence of thrombocytopenia (<150,000 platelets/microL) was 5.5%, and adopted as a surrogate prevalence for LC. At township levels, prevalence of anti-HCV (r2 = 0.58) was the only factor correlated by multivariate analysis with prevalence of thrombocytopenia. At village levels, prevalence of anti-HCV and female-to-male ratio (multiple r2 = 0.43) were each independently associated with prevalence of thrombocytopenia. At township levels, HBsAg prevalence (r2 = 0.42) was more correlated with HCC mortality than anti-HCV prevalence (r2 = 0.28) for male subjects, while anti-HCV prevalence (r2 = 0.45) was more correlated with HCC mortality than HBsAg prevalence (r2 = 0.14) for female subjects. Prevalence of HBV and HCV infection were associated by multivariate analysis with both male (multiple r2 = 0.62) and female (multiple r2 = 0.53) HCC mortality. CONCLUSIONS Prevalence of anti-HCV showed significant correlations with prevalence of hypertransaminemia, thrombocytopenia and liver cancer mortality. The findings indicate excessive mortality due to HCC, and LC and hepatitis prevalence in HCV-endemic areas in Taiwan, an HBV-endemic country.
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Affiliation(s)
- Meng-Chin Tsai
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Scotto G, Palumbo E, Fazio V, Cibelli DC, Saracino A, Tartaglia A, Angarano G. Prolonged lamivudine treatment in patients with chronic active anti-HBe-positive hepatitis. Am J Ther 2006; 13:218-22. [PMID: 16772763 DOI: 10.1097/01.mjt.0000158341.93235.5e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The efficacy of lamivudine (LAM) at 100 mg/d for 1 year in normalizing serum ALT levels and suppressing HBV DNA has been demonstrated in many studies. However, frequent relapses make long-term results modest. In the present study, we evaluated the efficacy of LAM administered for 3 years in patients with chronic active anti-HBe-positive hepatitis. Thirty-four patients with chronic active anti-HBe-positive hepatitis were treated with LAM (100 mg) once daily for 3 years. Before treatment, all patients demonstrated serum ALT levels >2 times normal levels for >6 months and HBV DNA positivity >5 pg/mL as determined by the sandwich hybridization test for nucleic acid. Both ALT and HBV DNA were monitored during therapy. After 12 months of therapy, 24 of 34 patients (70.6%) showed evidence of HBV DNA clearance and normal ALT levels; 22 of 34 (64.7%) and 19 of 34 (55.8%) patients maintained a complete response after 2 and 3 years of therapy, respectively. The long-term LAM therapy (>1 year) was not associated with an increase in the response of intially nonresponder patients. The YMDD variant emerged in 17.6% of patients in the first year, in 35.2% during the second year, and 52.9% during the third year of treatment. LAM was well tolerated during the 3-year therapy in all patients. Patients with chronic active anti-HBe-positive hepatitis demonstrated that the LAM response rate tends to decrease over time due to the emergence of YMDD variants.
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Affiliation(s)
- Gaetano Scotto
- Infectious Diseases Unit, University of Foggia, Foggia, Italy.
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Zhang JK, Guo J, Cheng J, Wang DQ, Lun YZ, Zhao LF, Lan XY, Hong Y, Mao Y. Cloning of spliced variant HBeBP4A of hepatitis B virus e antigen binding protein 4. Shijie Huaren Xiaohua Zazhi 2006; 14:1462-1465. [DOI: 10.11569/wcjd.v14.i15.1462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To clone a new gene, binding protein 4 spliced variant HBeBP4A of hepatitis B virus e antigen (HBeAg), and to explore its function and structure by bioinformatical analysis.
METHODS: HBeBP4A was amplified by reverse transcription-polymerase chain reaction (RT-PCR) using HepG2 cDNA as template and inserted into pGEM-T easy vector by TA cloning. Recombinant eukaryotic expression vector (pcDNATM3.1/myc-HisA-HBeBP4A) was constructed by subcloning followed by restriction enzyme digestion analysis and sequencing. Bioinformatical methods were used to analyze its possible physical and chemical characteristics, structure, and function.
RESULTS: Spliced form of HBeBP4, named HBeBP4A, was amplified successfully by RT-PCR from HepG2 cDNA. Bioinformatical analysis showed that its new open reading frame (ORF) is 1104 bp in length and translated a protein containing 367 amino acid residues.
CONCLUSION: A new gene, spliced variant HBeBP4A of HBeAg binding protein 4, is recognized, and its recombinant eukaryotic expression vector is constructed.
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Lu SN, Chen CH, Chen TM, Lee PL, Wang JH, Tung HD, Hung CH, Lee CM, Changchien CS. Hepatitis B virus infection in adolescents in a rural township—15 years subsequent to mass hepatitis B vaccination in Taiwan. Vaccine 2006; 24:759-65. [PMID: 16159687 DOI: 10.1016/j.vaccine.2005.08.062] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2005] [Accepted: 08/16/2005] [Indexed: 01/05/2023]
Abstract
In Taiwan, decrease of both infection and carrier rates of hepatitis B virus (HBV) have been documented especially in metropolitan areas after universal HBV vaccination. This study investigated HBV infection status in a rural township 15 years after the program began. Three cross-sectional studies were conducted in 1999, 2000 and 2003, to recruit all the students of the only junior middle school, born from July 1984 to June 1991, in a township in central Taiwan. Serum samples were tested for HBsAg, anti-HBs and anti-HBc. Subjects identified to be neither positive for HBsAg nor anti-HBs were given a booster dose of HBV vaccine. Subjects lacking an anamnestic anti-HBs response were given a complete 3-dose vaccination. A total of 1454 (98.5%) students responded. The prevalence rate of HBsAg decreased 57% [from 12.5% in 1984 to 5.4% in 1991, P < 0.005 (chi2-test for linear trends)], and anti-HBc positive rate dropped 68% (from 31.9 to 10.2%, P < 0.001). An anamnestic anti-HBs response developed after a vaccine booster among 433 (72%) anti-HBs negative and 12 (66.7%) anti-HBc alone subjects. And 93 (94.9%) anti-HBs negative and 1 (16.7%) anti-HBc alone subject developed a primary anti-HBs response after catch-up vaccination. Viremia was detected for two anti-HBc alone subjects without anamnestic or primary response. The vaccination program has decreased the number of those infected and carrier rates in either urban or rural areas in Taiwan. However, the prevalence of HBsAg and anti-HBc in rural area were much higher than urban area.
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Affiliation(s)
- Sheng-Nan Lu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung 833, Taiwan.
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Chen CH, Lee CM, Lu SN, Changchien CS, Eng HL, Huang CM, Wang JH, Hung CH, Hu TH. Clinical significance of hepatitis B virus (HBV) genotypes and precore and core promoter mutations affecting HBV e antigen expression in Taiwan. J Clin Microbiol 2006; 43:6000-6. [PMID: 16333089 PMCID: PMC1317177 DOI: 10.1128/jcm.43.12.6000-6006.2005] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
To assess the prevalence and clinical significance of hepatitis B virus (HBV) genotypes and precore and core promoter mutations in Taiwan, a cohort of 200 Taiwanese chronic hepatitis B patients was analyzed. The HBV genotypes and sequences of the precore and the core promoter regions were determined in 66 asymptomatic carriers and 134 patients who had liver biopsy-verified chronic hepatitis and liver cirrhosis. The HBV e-antigen (HBeAg)-negative patients had a higher frequency of mutations at core promoter nucleotides 1753 and 1773 and precore nucleotides 1846, 1896, and 1899 than HBeAg-positive patients. Among the 200 patients, the frequencies of genotype C, T1762 and A1764, C1753, T1766 and A1768, and A1896 mutations increased and the frequencies of T or G1752, T1773, G1799, and C1858 mutations decreased with advancing liver diseases. These factors were different between those with HBeAg-positive status and those with HBeAg-negative status. Based on multiple logistic regression analysis, the risk factors of liver cirrhosis for 200 patients were the presence of T1762 and A1764 mutations (odds ratio [OR] = 11.11; 95% confidence interval [CI] = 3.91 to 31.25; P < 0.001), age > or =35 years (OR = 3.42; 95% CI = 1.33 to 8.77; P = 0.011), and genotype C (OR = 2.87; 95% CI = 1.21 to 6.81; P = 0.017). Further categorical analysis found that 62.1% of patients with genotype C, T1762 and A1764 mutations and age > or =35 years had liver cirrhosis. None of the 55 patients infected with the genotype B, A1762 and G1764 wild type and age <35 years showed liver cirrhosis. In conclusion, our data suggest that pathogenic differences between HBeAg-positive and -negative patients may exist. In Taiwan, HBV genotype C and the T1762 and A1764 mutations may play a role in HBV-related liver cirrhosis, and these could serve as molecular markers for prediction of the clinical outcomes of chronic HBV patients.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaoshiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan
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Chen CH, Lee CM, Lu SN, Changchien CS, Wang JC, Wang JH, Hung CH, Hu TH. Comparison of sequence changes of precore and core promoter regions in HBeAg-positive chronic hepatitis B patients with and without HBeAg clearance in lamivudine therapy. J Hepatol 2006; 44:76-82. [PMID: 16298013 DOI: 10.1016/j.jhep.2005.08.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2005] [Revised: 07/27/2005] [Accepted: 08/31/2005] [Indexed: 01/24/2023]
Abstract
BACKGROUND/AIMS The aim of this study was to compare the serial sequence changes of precore and core promoter regions in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with and without HBeAg clearance in lamivudine treatment. METHODS Precore and core promoter genes of the hepatitis B virus (HBV) were sequenced from five serial serum samples of 74 HBeAg-positive CHB patients received lamivudine for 9-12 months (34 complete responders and 40 non-responders). RESULTS Before lamivudine therapy, stepwise logistic regression analysis disclosed that ALT level > or =300 U/L, A1896 mutant, and log HBV DNA levels were the major determinants for complete response. In addition, Cox regression showed that age < 35 years and G1752 mutant were independent factors for sustained response. Compared with complete responders, a higher frequency of mutation in nucleotides 1773, 1802, 1803, 1845, 1850, and 1858 was found in the non-responders during therapy. Lamivudine therapy resulted in a further increase in T1762/1764 mutants and a further decrease in A1896 mutant during treatment and after HBeAg clearance in complete responders. CONCLUSIONS T1762/A1764 mutation (not A1896) played an important role in lamivudine-induced HBeAg clearance. Moreover, T1773, C1802, G1803, T1846, A1850, and C1858 mutations might have significant correlation with HBeAg nonseroconversion.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan, ROC
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Chen CH, Wang JH, Lee CM, Hung CH, Hu TH, Wang JC, Lu SN, Changchien CS. Virological response and incidence of adefovir resistance in lamivudine-resistant patients treated with adefovir dipivoxil. Antivir Ther 2006; 11:771-778. [PMID: 17310821 DOI: 10.1177/135965350601100604] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND AIMS The incidence of adefovir dipivoxil (ADV) resistance in patients with lamivudine (3TC)-resistant mutants who received ADV therapy remains unclear. The aims of this study were to determine the virological response to ADV, the incidence and the risk factors of ADV resistance, and the associated factors of initial virological response (IVR) in lamivudine-resistant patients. PATIENTS AND METHODS Forty-six consecutive lamivudine-resistant chronic hepatitis B patients treated with ADV for more than 12 months with or without 3TC overlapping were prospectively examined for virological response and adefovir resistance. RESULTS IVR was documented in 24 (52.2%) of patients. Of the 46 patients, 11 had ADV resistance (5 rtN236T, 5 rtA181T, 1 rtA181T and rtN236T). The cumulative incidence of ADV resistance at month 6, 12, 18 and 24 was 0%, 6.5%, 24.6% and 38.3% respectively. Compared with those without ADV resistance, patients with ADV resistance had a significantly higher rate of liver cirrhosis. Based on Cox regression analysis, the significant risk factor of ADV resistance was younger age (OR=0.92, 95% CI=0.86-0.99, P=0.023) and liver cirrhosis (OR=5.3, 95% CI=1.12-25.09, P=0.036). In addition, patients with ADV resistance were associated with higher HBV DNA levels and lower HBV DNA reduction in first 6 months of ADV treatment than those without ADV resistance. CONCLUSION Only half of our patients achieved IVR on ADV treatment. The incidence of ADV resistance was high in 3TC-resistant patients treated with ADV.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung Univeristy College of Medicine, Kaohsiung, Taiwan
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Li MW, Hou W, Wo JE, Liu KZ. Character of HBV (hepatitis B virus) polymerase gene rtM204V/I and rtL180M mutation in patients with lamivudine resistance. J Zhejiang Univ Sci B 2005; 6:664-7. [PMID: 15973769 PMCID: PMC1389801 DOI: 10.1631/jzus.2005.b0664] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To investigate the relationship between HBV (hepatitis B virus) polymerase gene 180 and 204 sites mutation and lamivudine resistance. METHODS One hundred forty-one patients with lamivudine resistance after lamivudine treatment and 60 chronic hepatitis B patients without lamivudine treatment were enrolled in this study. The serum HBV DNA mutation was analyzed by sequence detection via polymerase chain reaction (PCR). The sequences of the same patient were analyzed before and after lamivudine treatment. RESULTS One hundred and nine lamivudine resistance patients had HBV YMDD (tyrosine-methionine-aspartate-aspartate) mutation. Among them, 45 patients had rtL180M/M204V mutation (41.28%), 28 patients had rtL180M/M204I mutation (25.70%) and 36 patients had rtM204I mutation (33.02%). There were 6 patients with rtL180M mutation in 32 lamivudine resistance patients. Sixty chronic hepatitis patients without lamivudine treatment had no mutations. CONCLUSIONS HBV mutations, which play an important role in lamivudine resistance usually locate at polymerase gene 204 site; 180 site mutation was also observed in these patients. Evaluation of the anti-virus therapy by surveillance of the two sites mutations is of importance.
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Affiliation(s)
- Min-wei Li
- Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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Cheng TL, Chang WW, Su IJ, Lai MD, Huang W, Lei HY, Chang WT. Therapeutic inhibition of hepatitis B virus surface antigen expression by RNA interference. Biochem Biophys Res Commun 2005; 336:820-30. [PMID: 16153600 DOI: 10.1016/j.bbrc.2005.08.173] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2005] [Accepted: 08/22/2005] [Indexed: 12/11/2022]
Abstract
RNA interference (RNAi) mediated inhibition of virus-specific genes has emerged as a potential therapeutic strategy against virus induced diseases. Human hepatitis B virus (HBV) surface antigen (HBsAg) has proven to be a significant risk factor in HBV induced liver diseases, and an increasing number of mutations in HBsAg are known to enhance the difficulty in therapeutic interventions. The key challenge for achieving effective gene silencing in particular for the purpose of the therapeutics is primarily based on the effectiveness and specificity of the RNAi targeting sequence. To explore the therapeutic potential of RNAi on HBV induced diseases in particular resulted from aberrant or persistent expression of HBsAg, we have especially screened and identified the most potent and specific RNAi targeting sequence that directly mediated inhibition of the HBsAg expression. Using an effective DNA vector-based shRNA expression system, we have screened 10 RNAi targeting sequences (HBsAg-1 to 10) that were chosen from HBsAg coding region, in particular the major S region, and have identified four targeting sequences that could mediate sequence specific inhibition of the HBsAg expression. Among these four shRNAs, an extremely potent and highly sequence specific HBsAg-3 shRNA was found to inhibit HBsAg expression in mouse HBV model. The inhibition was not only preventive in cotransfection experiments, but also had therapeutic effect as assessed by post-treatment protocols. Moreover, this HBsAg-3 shRNA also exhibited a great potency of inhibition in transgenic mice that constitutively expressed HBsAg. These results indicate that HBsAg-3 shRNA can be considered as a powerful therapeutic agent on HBsAg induced diseases.
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Affiliation(s)
- Tsung-Lin Cheng
- Institute of Basic Medical Sciences, National Cheng Kung University Medical College, 1, University Road, Tainan 701, Taiwan, ROC
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Marrone A, Zampino R, Portella G, Grimaldi M, Durante-Mangoni E, Mangoni ED, Santarpia L, Ruggiero G, Utili R. Three-phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B. J Viral Hepat 2005; 12:186-91. [PMID: 15720534 DOI: 10.1111/j.1365-2893.2005.00619.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Alpha-interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)-DNA was evaluated during treatment and core-promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV-DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti-HBe seroconversion. One patient presented core-promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three-phase sequential combined lamivudine/IFN treatment reduced HBV-DNA serum level, but did not lead to HBeAg and HBV-DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.
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Affiliation(s)
- A Marrone
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy.
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Chen CH, Lee CM, Wang JH, Tung HD, Hung CH, Lu SN. Correlation of quantitative assay of hepatitis B surface antigen and HBV DNA levels in asymptomatic hepatitis B virus carriers. Eur J Gastroenterol Hepatol 2004; 16:1213-8. [PMID: 15489584 DOI: 10.1097/00042737-200411000-00021] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This study was to elucidate the correlation between quantity of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels in asymptomatic carriers. METHODS Based on the presence of the hepatitis B e antigen (HBeAg) and HBV DNA levels, 67 asymptomatic carriers were divided into four groups. HBV DNA was determined by hybridization (sensitivity 141 500 copies/ml) and polymerase chain reaction (PCR, sensitivity < 10 copies/ml). Cases of groups I (n = 18), II (n = 17) and III (n = 16) were negative for HBeAg and had HBV DNA levels of < 10 (PCR undetectable), 10 to 10 (PCR detectable) and > 10 copies/ml (hybridization detectable), respectively. Cases of group IV (n = 16) were positive for HBeAg and high HBV DNA levels (> 2 x 10 copies/ml). HBsAg was determined quantitatively by the ARCHITECT HBsAg assay. RESULTS Our data showed HBsAg levels were correlated with HBV DNA (r = 0.709; P < 0.001) on a log scale. The mean log HBsAg (IU/ml) of groups I, II, III and IV were 2.68 +/- 0.8, 2.93 +/- 1.03, 3.22 +/- 0.45, 4.83 +/- 0.19, respectively. That of group IV was significantly higher than the mean log HBsAg of any other group (P < 0.001). The best cut-off for HBsAg in differentiating group IV from other groups was 15 000 IU/ml with both sensitivity and specificity of 100%. That of group I was significantly lower than those of group III (P = 0.035) and IV (P < 0.001). The best cut-off in differentiating group I from the other groups was 1600 IU/ml with a sensitivity of 69.4% and a specificity of 66.7%. CONCLUSION Quantitative measurement of HBsAg titres may be an easy and economical reference for HBV replication in HBV carriers.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Sharara AI, Ramia S, Ramlawi F, Farhat B, Bahlawan M, Farhat U, Alameddine M, Nour E, Sayegh R, Yaghi C, Assi H, Ferzli A, Shatila R. Prevalence of restriction fragment length polymorphism patterns of hepatitis B virus compatible with genotype D in Lebanon. Eur J Clin Microbiol Infect Dis 2004; 23:861-3. [PMID: 15480884 DOI: 10.1007/s10096-004-1222-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- A I Sharara
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Chen CH, Lee CM, Lu SN, Wang JH, Tung HD, Hung CH, Chen WJ, Changchien CS. Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants. J Hepatol 2004; 41:454-61. [PMID: 15336449 DOI: 10.1016/j.jhep.2004.04.032] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2004] [Revised: 04/12/2004] [Accepted: 04/29/2004] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS The aim of this study was to compare the clinical outcome between patients continuing and discontinuing lamivudine therapy after the biochemical breakthrough of hepatitis B virus tyrosine-methionine-aspartate-aspartate (YMDD) mutant. METHODS YMDD mutants were detected in 51 chronic hepatitis B patients who experienced a flare-up of alanine aminotransferase (ALT) during lamivudine treatment. Twenty-seven of them discontinued lamivudine therapy (group A), and 24 continued therapy (group B) after biochemical breakthrough. The follow-up period was 12 months in both the groups. RESULTS There was no significant difference between groups A and B in the incidence and severity of ALT peaks and hepatic decompensation within the first 3 months after biochemical breakthrough. After the fourth month of biochemical breakthrough, however, group A experienced acute exacerbation more frequently [20/26 (77%) vs. 7/23 (30%); P=0.002] and higher ALT peaks than group B. The same result was found when the patients were divided into naïve and retreated or cirrhotic and non-cirrhotic groups. Hepatic decompensation at the onset of biochemical breakthrough was associated with higher mortality (OR=70, 95% CI=6.06-807.75). CONCLUSIONS Patients who discontinued lamivudine therapy increased the frequency of flare-ups and higher ALT peaks than those who continued therapy after 4 months post-breakthrough.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan
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