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Hsieh CL, Chang LY, Chen PJ, Yeh SH. HBV polymerase recruits the phosphatase PP1 to dephosphorylate HBc-Ser170 to complete encapsidation. PLoS Pathog 2025; 21:e1012905. [PMID: 39932960 PMCID: PMC11813143 DOI: 10.1371/journal.ppat.1012905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
The HBV core (HBc) protein contains an N-terminal domain (NTD) for capsid assembly and an arginine-rich C-terminal domain (CTD) for pregenomic RNA (pgRNA) encapsidation. Phosphorylation of the HBc CTD, especially at Ser162 and Ser170, is essential for nucleation with the polymerase (Pol) to initiate pgRNA encapsidation. As capsids mature, the HBc CTD undergoes dephosphorylation, suggesting the involvement of a phosphatase in the late stage of encapsidation, which remains to be determined. Using a C-S170 antibody specific for non-phosphorylated HBc-Ser170, we observed a transition from a phosphorylated to a dephosphorylated state during pgRNA packaging. The Pol-dependent dephosphorylation of HBc-Ser170 was confirmed by the substitution of one single amino acid at Val782 in the RNase H domain, which abolished the dephosphorylation of HBc-Ser170. Immunoprecipitation, mass spectrometry analyses, and the protein structural analyses showed that the recruitment of the host phosphatase PP1 is dependent on the Pol-Val782 domain. This recruitment does not require HBc but does require Pol via epsilon RNA signal, suggesting that the Pol-pgRNA complex plays a key role in PP1 recruitment. Pol-pgRNA-PP1-mediated dephosphorylation of HBc-Ser170 is essential for the completion of pgRNA encapsidation and appears to be associated with late endosomes/multivesicular bodies (MVBs). Therefore, HBV Pol may play a dual role by initially bringing pgRNA to phosphorylated HBc and recruiting PP1 for later completion of RNA packaging into the capsids. These findings not only decipher the mechanism by which Pol-mediated dephosphorylation of HBc regulates pgRNA encapsulation, but also reveal the possibility of PP1 as a potential target for antiviral development.
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Affiliation(s)
- Chi-Ling Hsieh
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Li-Yang Chang
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Center of Precision Medicine, National Taiwan University, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
- Center of Precision Medicine, National Taiwan University, Taipei, Taiwan
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan
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Chang KC, Chang MH, Chen HL, Cheng FW, Wu JF, Su WJ, Hsu HY, Ni YH. Survey of hepatitis B virus infection status after 35 years of universal vaccination implementation in Taiwan. Liver Int 2024; 44:2054-2062. [PMID: 38700381 DOI: 10.1111/liv.15959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 02/06/2024] [Accepted: 04/18/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination. METHODS A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated. RESULTS After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed. CONCLUSION The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV.
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Affiliation(s)
- Kai-Chi Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
- Department and Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Fang-Wen Cheng
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Wei-Ju Su
- Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
- Department and Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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Qin A, Wu CR, Ho MC, Tsai CY, Chen PJ. Sequential Therapy with Ropeginterferon Alfa-2b and Anti-Programmed Cell Death 1 Antibody for Inhibiting the Recurrence of Hepatitis B-Related Hepatocellular Carcinoma: From Animal Modeling to Phase I Clinical Results. Int J Mol Sci 2023; 25:433. [PMID: 38203603 PMCID: PMC10778875 DOI: 10.3390/ijms25010433] [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: 12/06/2023] [Revised: 12/23/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC.
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Affiliation(s)
- Albert Qin
- Medical Research & Clinical Operations, PharmaEssentia Corporation, Taipei 115, Taiwan
| | - Chang-Ru Wu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chan-Yen Tsai
- Medical Research & Clinical Operations, PharmaEssentia Corporation, Taipei 115, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
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Lin HC, Liu J, Pan MH, Lee MH, Batrla-Utermann R, Lu SN, Jeng WJ, Yang HI, Chen CJ. Rapid Decline Rather Than Absolute Level of HBsAg Predicts Its Seroclearance in Untreated Chronic Hepatitis B Patients From Taiwanese Communities. Clin Transl Gastroenterol 2023; 14:e00586. [PMID: 36988242 PMCID: PMC10461935 DOI: 10.14309/ctg.0000000000000586] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
INTRODUCTION Hepatitis B surface antigen (HBsAg) clearance leads to favorable outcomes in patients with chronic hepatitis B. HBsAg levels <200 IU/mL with HBsAg decline >0.5 log 10 IU/mL in 1 year have been reportedly predictive of HBsAg loss. This study aimed to use the REVEAL-hepatitis B virus cohort to validate and simplify this prediction rule and verify whether the simplified algorithm can be used among various clinical subgroups. METHOD We analyzed 707 patients with untreated chronic hepatitis B who had 3 or more HBsAg measurements within 5 years before HBsAg seroclearance or last visit, greater than 1 year apart from one another. Rapid HBsAg decline was defined as HBsAg decline >0.5 log 10 IU/mL in 1 year or >1 log 10 IU/mL in 2 years. Sensitivity, specificity, positive predictive values, and negative predictive values were compared to assess the predictability of HBsAg seroclearance. RESULTS During a median follow-up of 10.7 years, 41 of the 707 patients cleared serum HBsAg. HBsAg levels at all measurements were lower ( P < 0.0001) and HBsAg decline was greater ( P < 0.0001) in patients with seroclearance compared with non-seroclearance patients. The predictive accuracy of predicting 1-year HBsAg loss using only the rapid decline algorithm (sensitivity = 0.4412, specificity = 0.9792, positive predictive value = 0.5172, negative predictive value = 0.972) was the same as the model combining rapid HBsAg decline and HBsAg levels <200 IU/mL. The simplified algorithm including only the rapid decline performed similarly among various levels of HBsAg, hepatitis B virus DNA, and alanine aminotransferase and was independent of inactive carrier state. DISCUSSION HBsAg decline >0.5 log 10 IU/mL/yr was a practical predictor of HBsAg seroclearance within 1 year in our community-based untreated cohort.
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Affiliation(s)
- Hsin-Che Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
| | - Jessica Liu
- Perinatal Epidemiology and Health Outcomes Research Unit, Division of Neonatology, Department of Pediatrics, School of Medicine, Stanford University and Lucile Packard Children's Hospital, Palo Alto, California, USA
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | | | - Sheng-Nan Lu
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Kaohsiung Branch, Kaohsiung, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
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5
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Bello KE, Mat Jusoh TNA, Irekeola AA, Abu N, Mohd Amin NAZ, Mustaffa N, Shueb RH. A Recent Prevalence of Hepatitis B Virus (HBV) Genotypes and Subtypes in Asia: A Systematic Review and Meta-Analysis. Healthcare (Basel) 2023; 11:healthcare11071011. [PMID: 37046937 PMCID: PMC10094200 DOI: 10.3390/healthcare11071011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/05/2023] Open
Abstract
Background and Aim: Despite introducing the hepatitis B virus (HBV) vaccine, the incidence of the Hepatitis B virus globally is still a major health concern. This systematic review and meta-analysis were conducted to provide detailed information on the prevalence of HBV genotypes and subtypes in circulation in Asia. Methods: A systematic search for articles describing the prevalence of HBV genotypes and subtypes in Asia was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Results: Our search returned 207 eligible articles involving 49,279 genotypes and 7457 subtypes representing 28 Asian countries. A meta-analysis was performed on our eligible studies using the Random effect Model. The pooled prevalence of HBV genotypes showed that genotype C (30.9%) (95% CI, 27.5–34.5%; I2 = 97.57%; p < 0.001) was the most common HBV genotype in Asia, followed by genotype B (17.8%) (95% CI, 15.5–20.4%; I2 = 97.26%; p < 0.001) and genotype D (15.4%) (95% CI, 11.8–19.8%). Vietnam had the highest prevalence of genotype B, Lebanon had the highest prevalence of genotypes C, and Jordan had the highest prevalence of genotype D. There was variation in genotypic prevalence with respect to the target genes for HBV genotyping. Reverse dot blot hybridization had the highest estimate of genotypes B and C. HBV subtype C2 (40.0%) (95% CI, 33.3–47.0) is the most prevalent HBV subtype. Conclusion: Evidence from this study reveals that HBV genotypes C and B are the most dominant HBV genotypes in Asia, and HBV subtype C2 is more endemic in Asia.
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Affiliation(s)
- Kizito Eneye Bello
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Department of Microbiology, Faculty of Natural Science, Kogi State University (Prince Abubakar Audu University), Anyigba 1008, Kogi State, Nigeria
| | - Tuan Nur Akmalina Mat Jusoh
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
| | - Ahmad Adebayo Irekeola
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Microbiology Unit, Department of Biological Sciences, College of Natural and Applied Sciences, Summit University Offa, Offa 4412, Kwara State, Nigeria
| | - Norhidayah Abu
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Advanced Materials Research Centre (A.M.R.E.C.), Lot 34 Jalan Hi-Tech 2/3, Kulim Hi-Tech Park, Kulim 09000, Kedah, Malaysia
| | - Nur Amalin Zahirah Mohd Amin
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
| | - Nazri Mustaffa
- Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Rafidah Hanim Shueb
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Institute for Research in Molecular Medicine (I.N.F.O.R.M.M.), Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
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6
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Chu YJ, Jeng WJ, Pan MH, Hu HH, Luo WS, Su CY, Chiang CT, Jen CL, Chen CJ, Yang HI. Serum soluble programmed death-1 levels predict the spontaneous HBeAg seroclearance in chronic hepatitis B. J Gastroenterol 2022; 57:423-432. [PMID: 35459967 DOI: 10.1007/s00535-022-01874-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/29/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS In chronic hepatitis B virus (HBV) infection, earlier seroclearance of hepatitis B e antigen (HBeAg) is associated with more favorable outcomes. Soluble programmed cell death 1 (sPD-1) has been implicated in higher viral load and hepatocellular carcinoma. We investigated the association between sPD-1 levels and spontaneous HBeAg seroclearance. METHODS Baseline serum samples from 488 HBeAg-seropositive patients in the REVEAL-HBV cohort were tested for sPD-1 levels. Among them, 329 with available follow-up serum samples were further assayed. Multivariate Cox regression analysis was used to estimate the adjusted rate ratio (aRR) and 95% confidence interval (CI) with adjustment of host and viral factors. The 66th percentile and an annual reduction of ≥ 10% were used as the cut-off point for baseline sPD-1 levels (high/low) and sPD-1 trajectory (decline/no decline), respectively. RESULTS Lower baseline sPD-1 levels [aRR (95% CI): 2.19 (1.47-3.27)] and long-term decline in sPD-1 levels [aRR (95% CI): 4.08 (2.79-5.97)] were both independent predictors for HBeAg seroclearance. However, further stratification analysis by HBV genotype showed that lower baseline sPD-1 levels were significantly associated with HBeAg seroclearance only in genotype C infection [aRR (95% CI): 4.47 (2.38-8.37)] but not in genotype B infection. On the other hand, long-term decline in sPD-1 levels was predictive for HBeAg seroclearance regardless of HBV genotype with aRR (95% CI) of 4.62 (2.71-7.88) and 2.95 (1.68-5.17), respectively, for genotypes B and C. CONCLUSION Serum sPD-1 levels may serve as a novel immunological predictor for spontaneous HBeAg seroclearance in patients with chronic hepatitis B.
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Affiliation(s)
- Yu-Ju Chu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hui-Han Hu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan.,School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Wen-Sheng Luo
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chien-Yu Su
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | | | - Chin-Lan Jen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan. .,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan.
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7
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Cheng HR, Yang HC, Lin SR, Yang TY, Lin YY, Su TH, Tseng TC, Liu CJ, Kao JH. Combined viral quasispecies diversity and hepatitis B core-related antigen predict off-nucleos(t)ide analog durability in HBeAg-negative patients. Hepatol Int 2021; 15:582-592. [PMID: 33886088 DOI: 10.1007/s12072-021-10186-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/31/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Viral quasispecies dynamics between pre- and post-nucleos(t)ide analog (NA) therapy remains unclear. AIM This study aimed to investigate the HBV quasispecies evolution and its relationship with durability of off-therapy responses in HBeAg-negative chronic hepatitis B (CHB) patients who stopped NA therapy. METHODS Fifty-four HBeAg-negative CHB patients who stopped NAs, including 19 virological controllers (VC) who maintained serum HBV DNA < 2000 IU/mL beyond 1-year off-therapy, and 35 virological relapsers (VR) experiencing virological relapse within 1-year off-therapy were recruited. Viral quasispecies was analyzed by deep sequencing. Hepatitis B core-related antigen (HBcrAg) and HBsAg were also measured. RESULTS VC had significantly higher baseline viral quasispecies diversity of the precore/core gene, measured by nucleotide diversity, than VR. Low baseline viral nucleotide diversity (< 0.01) and high HBcrAg (≧ 2.0 KU/mL), but not HBsAg, at end of treatment (EOT) were significantly associated with higher risk of 1-year virological relapse (hazard ratio [HR] 6.09 and 3.31, respectively). Combination of low baseline viral nucleotide diversity and high HBcrAg at EOT could identify patients at high risk (HR 15.82). Further analysis of the evolution of HBV whole genome showed that HBV nucleotide diversity negatively correlated with serum HBV DNA levels. Notably, the viral quasispecies diversity between pre- and post-NA treatment remained relatively unchanged. CONCLUSION Higher baseline HBV quasispecies diversity associates with more durable off-therapy viral suppression in HBeAg-negative CHB patients. Combination of baseline viral nucleotide diversity and HBcrAg at EOT can identify patients at high risk for virological relapse after stopping NAs.
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Affiliation(s)
- Huei-Ru Cheng
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
| | - Hung-Chih Yang
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Su-Ru Lin
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
| | - Ta-Yu Yang
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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8
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Tseng TC, Liu CJ, Yang WT, Hsu CY, Hong CM, Su TH, Tsai CH, Chen CL, Yang HC, Liu CH, Chen HH, Chen PJ, Kao JH. Serum hepatitis B core-related antigen level stratifies risk of disease progression in chronic hepatitis B patients with intermediate viral load. Aliment Pharmacol Ther 2021; 53:908-918. [PMID: 33465271 DOI: 10.1111/apt.16266] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/27/2020] [Accepted: 01/04/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND Patients with chronic hepatitis B virus (HBV) infection are at risk of developing liver disease. Serum hepatitis B core-related antigen (HBcrAg) is a new biomarker for intrahepatic templates for HBV replication. AIM To explore whether a high HBcrAg level is associated with increased risk of cirrhosis, especially in patients with intermediate viral load (HBV DNA 2000-19 999 IU/mL) due to their moderate risk of disease progression. METHODS A total of 1673 treatment-naïve, non-cirrhotic patients with negative hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) level <40 U/L at baseline were enrolled. We explored the relationship between baseline levels of HBcrAg and cirrhosis development in all patients, and whether a higher HBcrAg level (<10 vs ≥10 KU/mL) was associated with an increased risk of disease progression in those with intermediate viral load. RESULTS Of the 1673 patients, 104 developed cirrhosis after a mean follow-up of 15.9 years. Higher HBcrAg levels were associated with increased incidence of cirrhosis, cirrhosis-related complications, and liver-related death. In 445 patients with intermediate viral load, the cirrhosis risk stratified by HBcrAg level of 10 KU/mL yielded a hazard ratio of 3.22 (95% CI: 1.61-6.47). The risk stratification remained significant when exploring other pre-cirrhosis endpoints, including HBeAg-negative hepatitis, hepatitis flare, and HBV DNA >20 000 IU/mL after 3 years of follow-up. CONCLUSIONS In HBeAg-negative patients with normal ALT levels, higher HBcrAg levels are associated with increased risk of cirrhosis. Among those with intermediate viral load, HBcrAg <10 KU/mL defines a low-risk group for disease progression.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Yang Hsu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chun-Ming Hong
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Hospital Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Hsueh Tsai
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsiu-Hsi Chen
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
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9
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Hsu CS, Liu WL, Li Q, Lowey B, Hertz L, Chao YC, Liang TJ, Chen DS, Kao JH. Hepatitis C virus genotypes 1-3 infections regulate lipogenic signaling and suppress cholesterol biosynthesis in hepatocytes. J Formos Med Assoc 2020; 119:1382-1395. [PMID: 32284164 PMCID: PMC11492201 DOI: 10.1016/j.jfma.2020.03.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/18/2020] [Accepted: 03/23/2020] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Patients with different hepatitis C virus (HCV) genotype infections are associated with varying metabolic disorders. Although alteration of lipid metabolism has been confirmed as a virus-induced metabolic derangement in chronic hepatitis C patients, the impact of various HCV genotypes on hepatic cholesterol metabolism remains elusive. In this study, we thus investigated the HCV genotype-specific lipogenic and cholesterol metabolism profiles in an in vitro cell culture system. METHODS We first conducted HCV cell culture system (HCVcc) assays by infecting Huh7.5.1 cells with multiple infection-competent HCV strains, including the genotype 2a JFH1 and JFH1-based intergenotypic recombinants 1b and 3a. We then examined the expression levels of various lipid and cholesterol-related genes. RESULTS The data showed that infection with individual HCV genotypes exerted unique gene expression regulatory effects on lipoproteins and cholesterol metabolism genes. Of note, all HCV strains suppressed cholesterol biosynthesis in hepatocytes through downregulating the expression of HMG-CoA reductase (HMGCR) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) - two essential enzymes for cholesterol biosynthesis. These HCV-mediated inhibitory effects could be reversed by treatment with sofosbuvir, a pangenotypic NS5B inhibitor. In addition, overexpression of HCV genotype 1b, 2a or 3a core protein significantly suppressed HMGCR mRNA transcription and translation, thus diminished cellular cholesterol biosynthesis. Nonetheless, the core protein had no effect on FDFT1 expression. CONCLUSION Although HCV infection regulates host lipid metabolism in a genotype-specific manner, its inhibition on hepatocellular cholesterogenic gene expression and total cholesterol biosynthesis is a common effect among HCV genotype 1b, 2a and 3a.
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Affiliation(s)
- Ching-Sheng Hsu
- Liver Diseases Research Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan; School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Wei-Liang Liu
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Qisheng Li
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Brianna Lowey
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Laura Hertz
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - You-Chen Chao
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Nankang, 11549, Taiwan
| | - Jia-Horng Kao
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
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10
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Jangam D, Butzmann A, Sridhar K, Deresinski S, Banaei N, Shigeo Ohgami R. Significance of bacterial and viral genotypes as a risk factor in driving cancer (Review). Mol Clin Oncol 2020; 13:3-12. [PMID: 32499911 PMCID: PMC7265216 DOI: 10.3892/mco.2020.2043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022] Open
Abstract
Microbes have been known to drive human cancers for over half a century. However, despite the association of bacterial and viral infections with a high risk of cancer, most infections do not result in the development of cancer. Additionally, certain bacteria and viruses, considered to drive oncogenesis, are commonly prevalent in the global population. The current study performed a comprehensive meta-analysis of primary literature data to identify particular aspects of microbial genotypes as crucial factors that dictate the cancer risks associated with infection. The results indicated the importance of incorporating microbial genotype information with human genotypes into clinical assays for the more efficient diagnosis and prognosis of patients with cancer. The current review focuses on the importance of microbial genotypes and specific genes and genetic differences that are important to human oncogenesis.
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Affiliation(s)
- Diwash Jangam
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Alexandra Butzmann
- Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Kaushik Sridhar
- Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
| | | | - Niaz Banaei
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Robert Shigeo Ohgami
- Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
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11
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Chen CM, Ouyang S, Lin LY, Wu LJ, Xie TA, Chen JJ, Li ZX, Zhu GD, Ji TX, Pan ZY, Xia Y, Guo XG. Diagnostic accuracy of LAMP assay for HBV infection. J Clin Lab Anal 2020; 34:e23281. [PMID: 32157743 PMCID: PMC7370716 DOI: 10.1002/jcla.23281] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 02/13/2020] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
Background Detection of hepatitis B virus (HBV) is vital for the diagnosis of hepatitis B infection. A novel test loop‐mediated isothermal amplification (LAMP) has been successfully applied to detect various pathogens. However, the accuracy of LAMP in diagnosing HBV remains unclear. Therefore, in the present study, the accuracy of LAMP for HBV detection was evaluated systematically. Methods Embase, Cochrane Library, and PubMed databases were searched for studies using LAMP to detect HBV. Then, two researchers extracted data and assessed the quality of literature using the QUADAS‐2 tool independently. I2 statistic and chi‐square test were analyzed to investigate the heterogeneity, and Deek's funnel plot assessed the publication bias. The pooled sensitivity (SEN), specificity (SPE), positive LR (PLR), negative LR (NLR), diagnostic odds ratio (DOR), and 95% confidence intervals were displayed in forest plots. We calculated the area under the curve (AUC) to assess the overall efficiency of LAMP for HBV detection. Results A total of nine studies with 1298 samples were finally included in this evaluation. The pooled sensitivity and specificity of HBV detection were 0.91 (95% CI: 0.89 ~ 0.92) and 0.97 (95% CI: 0.94 ~ 0.99), respectively. The PLR, NLR, and DOR were 16.93 (95% CI: 6.15 ~ 46.55), 0.08 (95% CI: 0.05 ~ 0.14), and 397.57 (95% CI: 145.41 ~ 1087.07). Besides, the AUC was 0.9872, and Deek's plot suggested that there existed publication bias in the studies. Conclusion Compared with PCR, LAMP is a simple, rapid, and effective assay to diagnose HBV. However, additional evidence is essential to confirm that LAMP can replace other methods in diagnosing HBV infection.
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Affiliation(s)
- Chu-Mao Chen
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shi Ouyang
- Department of Infectious Disease, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Li-Ying Lin
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Li-Juan Wu
- Baoan Maternal and Child Health Hospital, Jinan University, Shenzhen, China
| | - Tian-Ao Xie
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Juan-Jiang Chen
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhen-Xing Li
- Department of Respiratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Guo-Dong Zhu
- Department of Geriatrics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Tian-Xing Ji
- Department of Clinical Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhi-Yong Pan
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Yong Xia
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Xu-Guang Guo
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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12
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Tseng TC, Liu CJ, Hsu CY, Hong CM, Su TH, Yang WT, Chen CL, Yang HC, Huang YT, Fang-Tzu Kuo S, Liu CH, Chen PJ, Chen DS, Kao JH. High Level of Hepatitis B Core-Related Antigen Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection of Intermediate Viral Load. Gastroenterology 2019; 157:1518-1529.e3. [PMID: 31470004 DOI: 10.1053/j.gastro.2019.08.028] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC). Serum levels of HB core-related antigen (HBcrAg) have been associated with active replication of HBV. We investigated whether HBcrAg levels are associated with development of HCC, especially in patients who do not require antiviral treatment. METHODS We collected data from 2666 adults positive for hepatitis B surface antigen (HBsAg), infected with HBV genotypes B or C, and without liver cirrhosis, who had long-term follow-up at the National Taiwan University Hospital from 1985 through 2000. None of the patients received antiviral treatment during the follow-up. Baseline levels of HBV DNA, HBsAg, and HBcrAg were determined retrospectively and participants were followed for a mean of 15.95 years. The primary end point was an association between serum level of HBcrAg and HCC development. RESULTS HCC developed in 209 patients in the cohort (incidence rate, 4.91 cases/1000 person-years). We found a positive association between baseline level of HBcrAg and HCC development; HBcrAg level was an independent risk factor in multivariable analysis. In the subgroup of hepatitis B e antigen-negative patients with HBV DNA levels from 2000 to 19,999 IU/mL (intermediate viral load [IVL]) and normal levels of alanine aminotransferase, HBcrAg levels of 10 KU/mL or more identified patients at increased risk of HCC (hazard ratio, 6.29; confidence interval, 2.27-17.48). Patients with an IVL and a high level of HBcrAg had a risk for HCC that did not differ significantly from that of patients with a high viral load (≥20,000 IU/mL). Patients with an IVL but a low level of HBcrAg had a low risk of HCC, with an annual incidence rate of 0.10% (95% confidence interval, 0.04%-0.24%). CONCLUSIONS In a long-term follow-up study of 2666 patients with chronic HBV infection (genotypes B or C), level of HBcrAg is an independent risk factor of HCC. Moreover, HBcrAg level of 10 KU/mL identifies patients with an IVL who are at high risk for HCC.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chen-Yang Hsu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chun-Ming Hong
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Division of Hospital Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | | | - Chen-Hua Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Jia-Horng Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
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13
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Chen HS, Wu JF, Su TH, Chen HL, Hsu HY, Xia NS, Chen PJ, Chang MH. Baseline Level of Hepatitis B Core Antibody Predicts Spontaneous Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Children With a Normal Alanine Aminotransferase Level. Hepatology 2019; 70:1903-1912. [PMID: 31121067 DOI: 10.1002/hep.30788] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/19/2019] [Indexed: 12/11/2022]
Abstract
It is not clear whether baseline hepatitis B core antibody (anti-HBc) level in hepatitis B e antigen (HBeAg)-positive children with a normal alanine aminotransferase (ALT) level is predictive of spontaneous HBeAg seroconversion. We investigated the correlation between anti-HBc level and the natural course of chronic hepatitis B (CHB) virus (HBV) infection in children, particularly the ability of baseline anti-HBc level to predict spontaneous HBeAg seroconversion during long-term follow-up. HBeAg-positive children with untreated CHB and a normal ALT level were followed longitudinally. Anti-HBc level was determined by double-sandwich immunoassay. Effects of anti-HBc levels and other parameters on spontaneous HBeAg seroconversion and the natural course of CHB were assessed. A total of 182 children (106 males) with a median age at enrollment of 10.6 years (interquartile range [IQR], 10.3-15.3) were followed for a median of 19.8 years (IQR, 11.9-21.9). Spontaneous HBeAg seroconversion occurred in 85 children (46.7%) during the follow-up. A baseline anti-HBc titer of >500 IU/mL (hazard ratio [HR] = 2.81), HBV genotype B and B + C (HR = 3.46), and a baseline hepatitis B surface antigen titer of ≤4.8 log10 IU/mL (HR = 3.09) were predictive of spontaneous HBeAg seroconversion, based on multivariable survival analysis (P < 0.001). In cases remaining HBeAg positive, their anti-HBc levels increased gradually during follow-up because of ongoing inflammation. Conclusion: Baseline anti-HBc level is predictive of spontaneous HBeAg seroconversion in HBeAg-positive children with a normal ALT level. Anti-HBc level reflects anti-HBV immune response in the HBeAg-positive normal ALT phase of CHB.
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Affiliation(s)
- Ho-Sheng Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Ning-Shao Xia
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
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14
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Nasseri B, Soleimani N, Rabiee N, Kalbasi A, Karimi M, Hamblin MR. Point-of-care microfluidic devices for pathogen detection. Biosens Bioelectron 2018; 117:112-128. [PMID: 29890393 PMCID: PMC6082696 DOI: 10.1016/j.bios.2018.05.050] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/22/2018] [Accepted: 05/28/2018] [Indexed: 12/22/2022]
Abstract
The rapid diagnosis of pathogens is crucial in the early stages of treatment of diseases where the choice of the correct drug can be critical. Although conventional cell culture-based techniques have been widely utilized in clinical applications, newly introduced optical-based, microfluidic chips are becoming attractive. The advantages of the novel methods compared to the conventional techniques comprise more rapid diagnosis, lower consumption of patient sample and valuable reagents, easy application, and high reproducibility in the detection of pathogens. The miniaturized channels used in microfluidic systems simulate interactions between cells and reagents in microchannel structures, and evaluate the interactions between biological moieties to enable diagnosis of microorganisms. The overarching goal of this review is to provide a summary of the development of microfluidic biochips and to comprehensively discuss different applications of microfluidic biochips in the detection of pathogens. New types of microfluidic systems and novel techniques for viral pathogen detection (e.g. HIV, HVB, ZIKV) are covered. Next generation techniques relying on high sensitivity, specificity, lower consumption of precious reagents, suggest that rapid generation of results can be achieved via optical based detection of bacterial cells. The introduction of smartphones to replace microscope based observation has substantially improved cell detection, and allows facile data processing and transfer for presentation purposes.
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Affiliation(s)
- Behzad Nasseri
- Departments of Microbiology and Microbial Biotechnology and Nanobiotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran; Chemical Engineering Deptartment and Bioengineeing Division, Hacettepe University, 06800 Beytepe, Ankara, Turkey.
| | - Neda Soleimani
- Departments of Microbiology and Microbial Biotechnology and Nanobiotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
| | - Navid Rabiee
- Department of Chemistry, Shahid Beheshti University, Tehran, Iran.
| | - Alireza Kalbasi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Mahdi Karimi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
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15
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Prabhu GRD, Witek HA, Urban PL. Chemical clocks, oscillations, and other temporal effects in analytical chemistry: oddity or viable approach? Analyst 2018; 143:3514-3525. [PMID: 29850665 DOI: 10.1039/c7an01926b] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Most analytical methods are based on "analogue" inputs from sensors of light, electric potentials, or currents. The signals obtained by such sensors are processed using certain calibration functions to determine concentrations of the target analytes. The signal readouts are normally done after an optimised and fixed time period, during which an assay mixture is incubated. This minireview covers another-and somewhat unusual-analytical strategy, which relies on the measurement of time interval between the occurrences of two distinguishable states in the assay reaction. These states manifest themselves via abrupt changes in the properties of the assay mixture (e.g. change of colour, appearance or disappearance of luminescence, change in pH, variations in optical activity or mechanical properties). In some cases, a correlation between the time of appearance/disappearance of a given property and the analyte concentration can be also observed. An example of an assay based on time measurement is an oscillating reaction, in which the period of oscillations is linked to the concentration of the target analyte. A number of chemo-chronometric assays, relying on the existing (bio)transformations or artificially designed reactions, were disclosed in the past few years. They are very attractive from the fundamental point of view but-so far-only few of them have be validated and used to address real-world problems. Then, can chemo-chronometric assays become a practical tool for chemical analysis? Is there a need for further development of such assays? We are aiming to answer these questions.
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Affiliation(s)
- Gurpur Rakesh D Prabhu
- Department of Applied Chemistry, National Chiao Tung University, 1001 University Rd., Hsinchu, 30010, Taiwan
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16
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Tseng TC, Liu CJ, Su TH, Yang WT, Chen CL, Yang HC, Kuo SFT, Liu CH, Chen PJ, Chen DS, Kao JH. Fibrosis-4 index predicts cirrhosis risk and liver-related mortality in 2075 patients with chronic HBV infection. Aliment Pharmacol Ther 2018; 47:1480-1489. [PMID: 29601647 DOI: 10.1111/apt.14619] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 01/26/2018] [Accepted: 02/28/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Fibrosis-4 index (FIB-4) is a surrogate marker for hepatic fibrosis in hepatitis B virus (HBV) carriers. AIM To investigate whether FIB-4 index stratifies the risks of adverse liver events. METHODS A total of 2075 treatment-naïve, noncirrhotic the patients with chronic HBV infection were included. Most of them (82.1%) were HBeAg-negative patients and their baseline FIB-4 levels were explored to stratify the risks of cirrhosis, cirrhosis-related complications and liver-related mortality. RESULTS During a mean follow-up period of 15.47 years, we found a higher baseline FIB-4 index was associated with increased incidence rates of cirrhosis in addition to the common host and viral factors. Patients with FIB-4 >1.29, compared to those with FIB-4 <1.29, were associated with increased risks of cirrhosis, cirrhosis-related complications and liver-related mortality with the hazard ratio (95% confidence interval) of 6.19 (4.76-8.05), 6.88, (3.68-12.86) and 7.79, (4.54-13.37) respectively. Within the first 3 years of follow-up, FIB-4 remained stable and its kinetics were consistently associated with the develoopment of adverse liver events. Furthermore, FIB-4 index of 1.29 was able to stratify all the risks of adverse liver events even in HBeAg-negative patients with a low risk of disease progression (HBV DNA <2000 IU/mL, HBsAg <1000 IU/mL and ALT <40 U/L). Only 1 patient with FIB-4 index <1.29 developed cirrhosis but not other events within 15 years of follow-up. CONCLUSIONS In noncirrhotic patients with chronic HBV infection, a higher FIB-4 index was associated with increased risks of adverse liver events. FIB-4 index <1.29 is useful for the prediction of the lowest risks of disease progression.
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Affiliation(s)
- T-C Tseng
- Department of Internal Medicine, National Taiwan University Hospital, New Taipei City, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - C-J Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - T-H Su
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - W-T Yang
- Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - C-L Chen
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - H-C Yang
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Microbiology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - S F-T Kuo
- Royal Hobart Hospital, Hobart, Australia
| | - C-H Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - P-J Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - D-S Chen
- Genomics Research Center Academia Sinica, Taipei, Taiwan
| | - J-H Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
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17
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Quoc NB, Phuong NDN, Chau NNB, Linh DTP. Closed tube loop-mediated isothermal amplification assay for rapid detection of hepatitis B virus in human blood. Heliyon 2018; 4:e00561. [PMID: 29560471 PMCID: PMC5857714 DOI: 10.1016/j.heliyon.2018.e00561] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 01/23/2018] [Accepted: 02/26/2018] [Indexed: 12/16/2022] Open
Abstract
Recently, many studies have demonstrated the significant advantages of loop-mediated isothermal amplification (LAMP) based methods over serological tests and PCR for rapid detection of microbial pathogens. Here, a rapid LAMP assay was developed to detect the hepatitis B virus (HBV) from DNA, and particularly, blood samples from infected patients using a commercially available master mix and portable real-time fluorometer. The final optimized fluorescence-based LAMP assay provided significant amplification time of less than 15 minutes compared with over 1 hour for PCR and an opened tube LAMP system described previously. Results indicated that fluorescence-based LAMP assay was more sensitive than PCR as a rapid, sensitive, efficient, and highly reliable approach for rapid detection of HBV.
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Affiliation(s)
- Nguyen Bao Quoc
- Research Institute for Biotechnology and Environment, Nong Lam University, Ho Chi Minh City, Vietnam
- Corresponding author.
| | - Nguyen Doan Nguyen Phuong
- Research Institute for Biotechnology and Environment, Nong Lam University, Ho Chi Minh City, Vietnam
| | | | - Do Thi Phuong Linh
- Specialized Medical Center, National Institute of Malariology, Parasitology and Entomology, Ho Chi Minh City, Vietnam
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18
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Tseng TC, Liu CJ, Su TH, Yang WT, Chen CL, Yang HC, Wang CC, Kuo SFT, Liu CH, Chen PJ, Chen DS, Kao JH. Fibrosis-4 Index Helps Identify HBV Carriers With the Lowest Risk of Hepatocellular Carcinoma. Am J Gastroenterol 2017; 112:1564-1574. [PMID: 28853728 DOI: 10.1038/ajg.2017.254] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 07/14/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Several viral and host risk factors have been used to predict risks of hepatocellular carcinoma (HCC) in patients with chronic infection of hepatitis B virus (HBV). However, little is known whether fibrosis-4 (FIB-4) index, a liver fibrosis biomarker, helps identify non-cirrhotic patients with the lowest HCC risk. METHODS A total of 2075 treatment-naive Taiwanese patients with chronic HBV infection were followed for an average period of 16.02 years. None of them had liver cirrhosis at baseline. We explored whether a low FIB-4 index complements the favourable predictors to defines patients with the lowest HCC risk. The finding was validated in 532 non-cirrhotic patients receiving long-term nucleos(t)ide analogue (NUC) treatment with suppressed viral replication. RESULTS A total of 137 treatment-naive and 10 NUC-treated patients developed HCC, respectively. We found that HCC risk started to increase when baseline FIB-4 index >1.29 in the treatment-naive cohort. Patients with FIB-4 >1.29, compared to those with FIB-4 <1.29, were associated with a higher risk of HCC with hazards ratio of 5.56 (95% confidence interval: 3.93-7.86). More importantly, among patients with low viral load (HBV DNA level <2,000 IU/ml), baseline FIB-4 index helped stratify different HCC risks such that none of 326 HBeAg-negative patients with FIB-4 index <1.29, ALT level <40 U/l, and HBsAg level <1,000 IU/ml developed HCC. In addition, the patients with the FIB-4 index <1.29 consistently had the lowest HCC risks in the validation cohort receiving long-term NUC treatment. CONCLUSIONS In non-cirrhotic patients with chronic HBV infection, FIB-4 index <1.29 complements the existing clinical profile to define patients with the lowest HCC risk.
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Affiliation(s)
- Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, New Taipei City, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | | | - Chen-Hua Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Jia-Horng Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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19
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Chavan YG, Pawar SR, Wani M, Raut AD, Misra RN. Hepatitis B virus DNA polymerase gene polymorphism based prediction of genotypes in chronic HBV patients from Western India. Afr Health Sci 2017; 17:762-772. [PMID: 29085404 PMCID: PMC5656201 DOI: 10.4314/ahs.v17i3.19] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Background Hepatitis B Virus (HBV) infection is one of the major causes of liver cirrhosis, hepatocellular carcinoma and deaths due to the acute or chronic consequences worldwide. HBV is distributed into various genotypes based on nucleic acid sequence variation. Objectives To develop a method of HBV genotyping and drug resistance interpretation using partial sequencing of polymerase gene. Methods This study was performed on 98 HBV infected patients' serum samples from Western India. A nested PCR protocol was designed for amplification of pol gene from HBV genome and Sanger's sequencing of the gene fragment. Sequences were aligned with HBV reference sequences for phylogenetic analysis and for characterization of genetic diversity. Drug resistance mutations were screened using HBVSeq program from Stanford University. Results Distribution of HBV genotypes showed predominance of genotype D, circulating in 76 (77.55%) patients (p < 0.05). Genotypes A and C were less prevalent and were identified in 4 (4.08%) and 18 (18.37%) patients, respectively. Anti-retroviral drug resistance mutations were not detected in any patient. Conclusion A method for determination of HBV genotypes using pol gene sequencing which simultaneously detects major drug resistance mutations has been established. HBV genetic diversity may play an important role in treatment decision.
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20
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Hsu HY, Chang MH, Ni YH, Chiang CL, Wu JF, Chen HL, Chen PJ, Chen DS. Chronologic changes in serum hepatitis B virus DNA, genotypes, surface antigen mutants and reverse transcriptase mutants during 25-year nationwide immunization in Taiwan. J Viral Hepat 2017; 24:645-653. [PMID: 28182307 DOI: 10.1111/jvh.12687] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 01/25/2017] [Indexed: 12/12/2022]
Abstract
We investigated breakthrough infection and hepatitis B virus (HBV) genetic changes in immunized subjects after 25 years of a universal infant immunization. Specifically, serum HBV DNA, genotypes, surface antigen mutants and nucleoside analog-resistant (NAr) mutants were assessed in 2853 subjects (<25 years old) surveyed in 2009, and these data were compared with the data from previous serosurveys. A comparison across different age-stratified groups using the 2009 data revealed a significant increase in the seropositive rate of anti-HBc (5.51% vs 12.38%, P=.001) and HBV DNA (1.13% vs 3.96%, P=.007) between those 17-22 and 23-24 years of age, possibly due to selective infant immunization in 1984-1986. Well-characterized NAr mutants, potential NAr mutants and surface "a" determinant mutants were detected in none, 15 (45.5%) and nine (27.3%) of 33 HBV DNA-positive subjects, respectively. Of 15 immunized, HBV DNA-positive young adults (18-24 years), three (20%) carried "a" determinant mutants. Amongst 1176 HBsAg-negative subjects evaluated for occult HBV infection, those seropositive for anti-HBc had a higher seropositive rate for HBV DNA (10/110, 9.1% vs 7/1066, 0.66%; P<.001) and "a" determinant mutants (4/110, 3.6% vs 0/1066; P<.001) than those seronegative for anti-HBc. Overall, the HBsAg-positive subjects in six serosurveys showed no significant increase in genotype C frequency in the comparison between the vaccinated and unvaccinated cohorts (25/98, 25.5% versus 14/79, 17.7%, P=.188). Over the 25-year programme, there was no increase in the prevalence of genotype C in HBsAg carriers and no increase in breakthrough HBV infection or surface mutant prevalence beyond adolescence. Nucleic acid amplification should still be considered the primary screening method for occult hepatitis B detection in high-risk recipients.
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Affiliation(s)
- H-Y Hsu
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - M-H Chang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Y-H Ni
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - C-L Chiang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - J-F Wu
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - H-L Chen
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - P-J Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - D-S Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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21
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Lin YM, Chen BF. A putative hepatitis B virus splice variant associated with chronic hepatitis and liver cirrhosis. Virology 2017; 510:224-233. [PMID: 28750326 DOI: 10.1016/j.virol.2017.07.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 07/19/2017] [Accepted: 07/20/2017] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) pre-S deletion was associated with chronic hepatitis (CH) and liver cirrhosis (LC); however, the type of pre-S deletion associated with these conditions and the mechanism of the generation of pre-S deletion remain unknown. Here, pre-S sequences from asymptomatic carriers (ASCs) and carriers with CH or LC were analyzed. The results indicated that deletion in the S promoter and the C-terminal half of the pre-S1 region was more frequent in CH and LC patients than in ASCs. RNA splicing analysis revealed that one type of pre-S1 deletion mutant, termed spPS1, was derived from splicing. This variant was associated with CH (12.7% vs. 1.8%, P = 0.06) and LC (14.5% vs. 1.8%, P = 0.032) when compared with ASC. In conclusion, spPS1, a putative splice variant; S promoter deletion mutant; and deletion in the C-terminal half of the pre-S1 region were closely associated with CH and LC development.
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Affiliation(s)
- Yu-Min Lin
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Bing-Fang Chen
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
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22
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Chen BF. Different pre-S deletion patterns and their association with hepatitis B virus genotypes. World J Gastroenterol 2017. [PMID: 27672298 DOI: 10.3748/wjg.v22.i35.8041.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/29/2022] Open
Abstract
AIM To investigate the associations of different types of pre-S deletions with hepatitis B virus (HBV) genotypes. METHODS The sequences of the pre-S region, basal core promoter (BCP) mutation, and precore (PC) mutation were examined through direct DNA sequencing or clonal analysis and sequencing in 273 HBV carriers, namely 55 asymptomatic carriers, 55 carriers with chronic hepatitis (CH), 55 with liver cirrhosis (LC), 53 with liver cirrhotic hepatocellular carcinoma (LC-HCC), and 55 with noncirrhotic HCC. A total of 126 HBV carriers (46.2%) harbored pre-S deletions. The DNA sequences of pre-S deletion mutants from 43 age-matched genotype B (HBV/B)-infected carriers and 43 age-matched genotype C (HBV/C)-infected carriers were further examined, aligned, and compared. RESULTS No significant difference was observed in the mean age distribution (P = 0.464), male sex (P = 0.805), viral load (P = 0.635), or BCP mutation (P = 0.117) between the HBV/B and HBV/C groups. However, the rate of PC mutation was significantly higher in the HBV/B-infected carriers than in the HBV/C-infected carriers (P = 0.003). Both genotypes exhibited a high rate of deletion in the C-terminal half of the pre-S1 region and N-terminus of the pre-S2 region (86.0% and 79.1% in the HBV/B group; 69.8% and 72.1% in the HBV/C group, respectively). Epitope mapping showed that deletion in several epitope sites was frequent in both genotypes, particularly pS1-BT and pS2-B2. Conversely, the rate of pS2-B1 deletion was significantly higher in the HBV/B group (72.1% vs 37.2%, P = 0.002), and the rate of pS2-T deletion was significantly higher in the HBV/C group (48.8% vs 25.6%, P = 0.044). Functional mapping showed that the rate of deletion in three functional sites (the nucleocapsid binding site, start codon of M, and site for viral secretion) located in the N-terminus of the pre-S2 region was significantly higher in the HBV/B group (P < 0.05). One type of N-terminus pre-S1 deletion mutant with deletion of the start codon of the L protein was frequently observed in the HBV/C group (20.9% vs 9.3%, P = 0.228), particularly in the LC patients (42.9% vs 12.5%). Different patterns of pre-S deletions were also found between the HBV/B and HBV/C groups according to different clinical outcomes. In CH patients, deletion in the site for polymerized human serum albumin was more frequent in the HBV/B group (88.9% vs 36.4%, P = 0.028). In the LC-HCC patients, the rate of deletion in the pre-S2 region was significantly higher in the HBV/B group than in the HBV/C group (P < 0.05). CONCLUSION HBV/B- and HBV/C-infected carriers exhibit different patterns of pre-S deletion, which may be associated with the progression of liver diseases.
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Affiliation(s)
- Bing-Fang Chen
- Bing-Fang Chen, School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan
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23
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Jiang H, Wu D, Song L, Yuan Q, Ge S, Min X, Xia N, Qian S, Qiu X. A Smartphone-Based Genotyping Method for Hepatitis B Virus at Point-of-Care Settings. SLAS Technol 2016; 22:122-129. [PMID: 27899699 DOI: 10.1177/2211068216680163] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
We reported a rapid, convenient, and easy-to-use genotyping method for hepatitis B virus (HBV) based on the smartphone at point-of-care (POC) settings. To perform HBV genotyping especially for genotypes A, B, C, and D, a smartphone is used to image and analyze a one-step immunoassay lateral flow strip functionalized with genotype-specific monoclonal antibodies (mAbs) on multiple capture lines. A light-emitting diode (LED) positioned on the top of the lateral flow strip is used to shine the multiple capture lines for excitation. Fluorescence detection is obtained with a smartphone whose camera is used to take the fluorescent images. An intelligent algorithm is developed to first identify each capture line from the fluorescent image and then determine the HBV genotype based on a genotyping model. Based on the pattern of the detection signal from different samples, a custom HBV genotyping model is developed. Custom application software running on a smartphone is developed with Java to collect and analyze the fluorescent image, display the genotyping result, and transmit it if necessary. Compared with the existing methods with nucleic acid analysis, more convenient, instant, and efficient HBV genotyping with significantly lower cost and a simpler procedure can be obtained with the developed smartphone POC HBV genotyping method.
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Affiliation(s)
- Huiqin Jiang
- 1 Institute of Microfluidic Chip Development in Biomedical Engineering, College of Information Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Di Wu
- 1 Institute of Microfluidic Chip Development in Biomedical Engineering, College of Information Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Liuwei Song
- 2 National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Quan Yuan
- 2 National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Shengxiang Ge
- 2 National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Xiaoping Min
- 2 National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Ningshao Xia
- 2 National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Shizhi Qian
- 3 Institute of Micro/Nanotechnology, Old Dominion University, Norfolk, VA, USA
| | - Xianbo Qiu
- 1 Institute of Microfluidic Chip Development in Biomedical Engineering, College of Information Science and Technology, Beijing University of Chemical Technology, Beijing, China
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Wen WH, Huang CW, Chie WC, Yeung CY, Zhao LL, Lin WT, Wu JF, Ni YH, Hsu HY, Chang MH, Lin LH, Chen HL. Quantitative maternal hepatitis B surface antigen predicts maternally transmitted hepatitis B virus infection. Hepatology 2016; 64:1451-1461. [PMID: 27044007 DOI: 10.1002/hep.28589] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 03/23/2016] [Accepted: 03/27/2016] [Indexed: 12/20/2022]
Abstract
UNLABELLED Despite immunoprophylaxis, hepatitis B virus (HBV) transmission in highly viremic mothers remains a global health issue. Using quantitative maternal surface antigen (HBsAg) to predict HBV infection in infants has not been investigated. We enrolled 526 mother-infant pairs with positive maternal HBsAg under current immunoprophylaxis. Maternal viral load and quantitative HBsAg were measured in the peripartum period. Infant HBsAg seropositivity for more than 6 months was defined as chronic infection. Rates of chronic infection in infants at various maternal HBsAg levels were estimated using a multivariate logistic regression model. Results showed that maternal HBsAg was positively correlated with maternal viral load (r = 0.69; P < 0.001) and accurately predicted maternal viral load above 6, 7, and 8 log10 IU/mL with an area under the receiver operating characteristic curve (AUC) of 0.97, 0.98, and 0.95. Nineteen infants were chronically infected. After adjustment for the other risk factor, maternal HBsAg level was significantly associated with risk of infection (adjusted odds ratio for each log10 IU/mL increase, 15.02; 95% confidence interval [CI], 3.89-57.94; P < 0.001). The AUC for predicting infection by quantitative maternal HBsAg was comparable to that by maternal viral load (0.89 vs. 0.87; P = 0.459). Estimated rates of infection at maternal HBsAg levels of 4, 4.5, and 5 log10 IU/mL were 2.4% (95% CI, 0.1-4.6; P = 0.04), 8.6% (95% CI, 4.5-12.7; P < 0.001), and 26.4% (95% CI, 12.6-40.2; P < 0.001). CONCLUSION Quantitative maternal HBsAg predicts infection in infants as well as maternal viral load does. Antiviral therapy may be considered in pregnant women with an HBsAg level above 4-4.5 log10 IU/mL to interrupt mother-to-infant transmission. (Hepatology 2016;64:1451-1461).
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Affiliation(s)
- Wan-Hsin Wen
- Department of Pediatrics, Cardinal Tien Hospital, New Taipei City, Taiwan
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Chi-Wen Huang
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Wei-Chu Chie
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chun-Yan Yeung
- Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
| | - Lu-Lu Zhao
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Wen-Terng Lin
- Department of Pediatrics, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Lung-Huang Lin
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
- Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan.
| | - Huey-Ling Chen
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan.
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25
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Chen BF. Different pre-S deletion patterns and their association with hepatitis B virus genotypes. World J Gastroenterol 2016; 22:8041-8049. [PMID: 27672298 PMCID: PMC5028817 DOI: 10.3748/wjg.v22.i35.8041] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/24/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the associations of different types of pre-S deletions with hepatitis B virus (HBV) genotypes.
METHODS The sequences of the pre-S region, basal core promoter (BCP) mutation, and precore (PC) mutation were examined through direct DNA sequencing or clonal analysis and sequencing in 273 HBV carriers, namely 55 asymptomatic carriers, 55 carriers with chronic hepatitis (CH), 55 with liver cirrhosis (LC), 53 with liver cirrhotic hepatocellular carcinoma (LC-HCC), and 55 with noncirrhotic HCC. A total of 126 HBV carriers (46.2%) harbored pre-S deletions. The DNA sequences of pre-S deletion mutants from 43 age-matched genotype B (HBV/B)-infected carriers and 43 age-matched genotype C (HBV/C)-infected carriers were further examined, aligned, and compared.
RESULTS No significant difference was observed in the mean age distribution (P = 0.464), male sex (P = 0.805), viral load (P = 0.635), or BCP mutation (P = 0.117) between the HBV/B and HBV/C groups. However, the rate of PC mutation was significantly higher in the HBV/B-infected carriers than in the HBV/C-infected carriers (P = 0.003). Both genotypes exhibited a high rate of deletion in the C-terminal half of the pre-S1 region and N-terminus of the pre-S2 region (86.0% and 79.1% in the HBV/B group; 69.8% and 72.1% in the HBV/C group, respectively). Epitope mapping showed that deletion in several epitope sites was frequent in both genotypes, particularly pS1-BT and pS2-B2. Conversely, the rate of pS2-B1 deletion was significantly higher in the HBV/B group (72.1% vs 37.2%, P = 0.002), and the rate of pS2-T deletion was significantly higher in the HBV/C group (48.8% vs 25.6%, P = 0.044). Functional mapping showed that the rate of deletion in three functional sites (the nucleocapsid binding site, start codon of M, and site for viral secretion) located in the N-terminus of the pre-S2 region was significantly higher in the HBV/B group (P < 0.05). One type of N-terminus pre-S1 deletion mutant with deletion of the start codon of the L protein was frequently observed in the HBV/C group (20.9% vs 9.3%, P = 0.228), particularly in the LC patients (42.9% vs 12.5%). Different patterns of pre-S deletions were also found between the HBV/B and HBV/C groups according to different clinical outcomes. In CH patients, deletion in the site for polymerized human serum albumin was more frequent in the HBV/B group (88.9% vs 36.4%, P = 0.028). In the LC-HCC patients, the rate of deletion in the pre-S2 region was significantly higher in the HBV/B group than in the HBV/C group (P < 0.05).
CONCLUSION HBV/B- and HBV/C-infected carriers exhibit different patterns of pre-S deletion, which may be associated with the progression of liver diseases.
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Ni YH, Chang MH, Jan CF, Hsu HY, Chen HL, Wu JF, Chen DS. Continuing Decrease in Hepatitis B Virus Infection 30 Years After Initiation of Infant Vaccination Program in Taiwan. Clin Gastroenterol Hepatol 2016; 14:1324-30. [PMID: 27155556 DOI: 10.1016/j.cgh.2016.04.030] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 04/08/2016] [Accepted: 04/15/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Taiwan began a universal hepatitis B virus (HBV) vaccination program for infants in July 1984. The seroprevalence of hepatitis B surface antigen (HBsAg) decreased from 9.8% before the vaccination program to less than 1% by 25 years afterward. We continued to monitor HBV infections in this population. METHODS We conducted a series of serologic and epidemiologic surveys in the Taipei metropolitan area every 5 years from 1984 through 2014. From January 1 through December 31 of 2014, we collected serum samples from 4605 apparently healthy individuals (ages: 287 were <3 y, 405 were 3-6 y, 675 were 7-12 y, 686 were 13-18 y, 468 were 18-22 y, and 2084 were 22-50 y). All subjects were tested for HBsAg, its antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). We performed genotype and viral load analyses for patients who tested positive for anti-HBc. RESULTS Of vaccinated participants (age, <30 y; n = 3299), 0.5% tested positive for HBsAg, 47.4% tested positive for anti-HBs, and 4.5% tested positive for anti-HBc. Of unvaccinated participants (age, 30-50 y, n = 1306), 6.7% tested positive for HBsAg (P < .0001), 69.4% tested positive for anti-HBs, and 44.1% tested positive for anti-HBc. One occult HBV infection was found in each age group. Among subjects positive for HBsAg younger than age 30, 77% were born to mothers positive for HBsAg. CONCLUSIONS Based on a series of serologic and epidemiologic surveys performed in the Taipei metropolitan area, 6.7% of persons born before the universal HBV vaccination program were positive for HBsAg, compared with 0.5% of those born afterward. Most subjects positive for HBsAg younger than age 30 were born to mothers positive for HBsAg.
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Affiliation(s)
- Yen-Hsuan Ni
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Hepatitis Research Center, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Mei-Hwei Chang
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Hepatitis Research Center, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chyi-Feng Jan
- Department of Family Medicine, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ding-Shinn Chen
- Hepatitis Research Center, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Genomics Research Center, Academica Sinica, Taipei, Taiwan
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27
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Hsu CS, Hsu SJ, Liu WL, Chen DS, Kao JH. Association of SCARB1 Gene Polymorphisms with Virological Response in Chronic Hepatitis C Patients Receiving Pegylated Interferon plus Ribavirin Therapy. Sci Rep 2016; 6:32303. [PMID: 27561198 PMCID: PMC4999819 DOI: 10.1038/srep32303] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 08/05/2016] [Indexed: 12/26/2022] Open
Abstract
The scavenger receptor type B class I(SR-BI) is a receptor for high-density lipoproteins(HDL) and one of entry factors for hepatitis C virus(HCV). We examined the association of single nucleotide polymorphisms(SNPs) of the SCARB1 gene, which encodes SR-BI, with virologic responses to pegylated interferon-based treatment in Asian chronic hepatitis C(CHC) patients. Human genomic and clinical data were collected from 156 consecutive Taiwanese HCV genotype 1 or 2 patients who received pegylated interferon plus ribavirin therapy and 153 non-HCV healthy subjects. Three SNPs(rs10846744, rs5888, and rs3782287) of the SCARB1 gene that have been linked to humans diseases were investigated. rs10846744 rather than rs5888 or rs3782287 was associated with serum HCV RNA level and sustained virologic response(SVR) to pegylated interferon plus ribavirin therapy in CHC patients(GG vs. non-GG genotype, Adjusted Odds Ratio, 95% CI: 0.32, 0.11–0.95, P = 0.039). Among patients with IL28B rs8099917 non-TT genotypes, those with rs10846744 non-GG genotype had a higher SVR rate than those with GG genotypes. In addition, patients with GG genotype had a higher fasting blood glucose level than those with CC genotype. In conclusion, SCARB1 gene polymorphisms may serve as a potential predictor of treatment responses in CHC patients receiving interferon-based therapy. (ClinicalTrials.gov number, NCT02714712).
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Affiliation(s)
- Ching-Sheng Hsu
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan.,School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Shih-Jer Hsu
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin County, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wei-Liang Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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28
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A fast and low-cost genotyping method for hepatitis B virus based on pattern recognition in point-of-care settings. Sci Rep 2016; 6:28274. [PMID: 27306485 PMCID: PMC4910285 DOI: 10.1038/srep28274] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 06/01/2016] [Indexed: 12/18/2022] Open
Abstract
A fast and low-cost method for HBV genotyping especially for genotypes A, B, C and D was developed and tested. A classifier was used to detect and analyze a one-step immunoassay lateral flow strip functionalized with genotype-specific monoclonal antibodies (mAbs) on multiple capture lines in the form of pattern recognition for point-of-care (POC) diagnostics. The fluorescent signals from the capture lines and the background of the strip were collected via multiple optical channels in parallel. A digital HBV genotyping model, whose inputs are the fluorescent signals and outputs are a group of genotype-specific digital binary codes (0/1), was developed based on the HBV genotyping strategy. Meanwhile, a companion decoding table was established to cover all possible pairing cases between the states of a group of genotype-specific digital binary codes and the HBV genotyping results. A logical analyzing module was constructed to process the detected signals in parallel without program control, and its outputs were used to drive a set of LED indicators, which determine the HBV genotype. Comparing to the nucleic acid analysis to HBV viruses, much faster HBV genotyping with significantly lower cost can be obtained with the developed method.
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29
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Wu FY, Liao YW, Wu JF, Chen HL, Hsu HY, Chang MH, Ni YH. A Simple and Rapid Test-card Method to Detect Hepatitis B Surface Antigen and Antibody: Potential Application in Young Children and Infants. Pediatr Neonatol 2016; 57:219-24. [PMID: 26560182 DOI: 10.1016/j.pedneo.2015.07.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/25/2015] [Accepted: 07/16/2015] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were conventionally determined by enzyme immunoassays. We aimed to apply a rapid, simple, and accurate method to detect HBsAg and its antibody. METHODS We collected 1463 serum samples from healthy volunteers, hepatitis B carriers, and children of HBsAg-positive mothers. The test card that we examined is a chromatographic immunoassay for the qualitative detection of either HBsAg or anti-HBs. We then compared the results of the test card to the results of the conventional enzyme-immunoassay method, which is regarded as a standard. RESULTS In the use of the test card to check HBsAg, the sensitivity was 88.8% and the specificity was 100%. The median hepatitis B virus viral load was significantly higher in the true-positive group [10(3.71) copies/mL (range, 10(2)-10(9.03) copies/mL)] than in the false-negative group [10(2) copies/mL (range, 10(2)-10(3.26) copies/mL)] (p = 0.005). In those who were younger than 2 years, the diagnostic accuracy of the HBsAg test card was 100%. Then, 1272 samples were tested for anti-HBs rapid test card. The sensitivity was 91.8% and the specificity was 96.5%. The median anti-HBs titer was significantly higher in the true-positive group (295.8 mIU/mL) than in the false-negative group (42.3 mIU/mL; p < 0.001). CONCLUSION Because of (1) the limited amount of blood sample required and (2) most of the young hepatitis B virus carriers having high viremia, and no concerns of false negativity, the test card is a good rapid screening tool for the detection of HBsAg and anti-HBs in pediatric group.
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Affiliation(s)
- Fu-Yu Wu
- Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan
| | - Yu-Wun Liao
- Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan.
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30
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Yu YM, Chao TY, Chang WC, Chang MJ, Lee MF. Thymol reduces oxidative stress, aortic intimal thickening, and inflammation-related gene expression in hyperlipidemic rabbits. J Food Drug Anal 2016; 24:556-563. [PMID: 28911561 PMCID: PMC9336656 DOI: 10.1016/j.jfda.2016.02.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 01/19/2016] [Accepted: 02/15/2016] [Indexed: 02/06/2023] Open
Abstract
Atherosclerosis plays a key role in the development of cardiovascular diseases, and is often associated with oxidative stress and local inflammation. Thymol, a major polyphenolic compound in thyme, exhibits antioxidant and anti-inflammatory properties. In this study, we measured the in vitro antioxidant activity of thymol, and investigated the effect of thymol on high-fat-diet-induced hyperlipidemia and atherosclerosis. New Zealand white rabbits were fed with regular chow, high-fat and high-cholesterol diet (HC), T3, or T6 (HC with thymol supplementation at 3 mg/kg/d or 6 mg/kg/d, respectively) for 8 weeks. Aortic intimal thickening, serum lipid parameters, multiple inflammatory markers, proinflammatory cytokines, and atherosclerosis-associated indicators were significantly increased in the HC group but decreased upon thymol supplementation. In summary, thymol exhibits antioxidant activity, and may suppress the progression of high-fat-diet-induced hyperlipidemia and atherosclerosis by reducing aortic intimal lipid lesion, lowering serum lipids and oxidative stress, and alleviating inflammation-related responses.
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Affiliation(s)
- Ya-Mei Yu
- Department of Nutrition and Health Sciences, Chang Jung Christian University, Tainan, Taiwan
| | - Tzu-Yu Chao
- Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan
| | - Weng-Cheng Chang
- Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan
| | - Margaret J Chang
- Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan
| | - Ming-Fen Lee
- Department of Nutrition and Health Sciences, Chang Jung Christian University, Tainan, Taiwan.
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31
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Yang WT, Wu LW, Tseng TC, Chen CL, Yang HC, Su TH, Wang CC, Kuo SFT, Liu CH, Chen PJ, Chen DS, Liu CJ, Kao JH. Hepatitis B Surface Antigen Loss and Hepatocellular Carcinoma Development in Patients With Dual Hepatitis B and C Infection. Medicine (Baltimore) 2016; 95:e2995. [PMID: 26962809 PMCID: PMC4998890 DOI: 10.1097/md.0000000000002995] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Revised: 01/19/2016] [Accepted: 02/10/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are 2 major causes of chronic viral hepatitis. It is still unclear how HCV coinfection affects HBV replication and clinical outcomes in HBV/HCV coinfected patients.We conducted a longitudinal study, which enrolled 111 patients with HBV/HCV coinfection and 111 propensity score-matched controls with HBV monoinfection. Both groups had comparable baseline age, sex, fibrosis stage, levels of HBV DNA, and HBV surface antigen (HBsAg). The HCV coinfection and other host/viral factors were correlated with various outcomes, including HBsAg loss and cirrhosis/hepatocellular carcinoma (HCC) development.After a 10-year follow-up, we found that HCV coinfection itself was not associated with HBsAg loss. However, coinfected patients with alanine aminotransferase (ALT) level >80 U/L had a higher chance of HBsAg loss than those with ALT level ≤80 U/L [hazard ratio (95% confidence interval): 4.41 (1.75-11.15)] or matched controls with HBV monoinfection [hazard ratio (95% confidence interval): 3.40 (1.54-7.50)]. Besides, both HCV coinfection and higher ALT levels were associated with higher HCC risks and the HCC risks remained even after HBsAg loss in HBV/HCV con-infected patient.HCV coinfection is not associated with HBsAg loss. A higher ALT level is a major determinant of HBsAg loss in patients with HBV/HCV coinfection. Both HCV coinfection and a higher ALT level were independent risk factors of HCC.
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Affiliation(s)
- Wan-Ting Yang
- From the Division of Gastroenterology (T-CT, C-CW), Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation; Division of Gastroenterology (H-CY, T-HS, C-HL, P-JC, C-JL, J-HK), Department of Internal Medicine; Graduate Institute of Clinical Medicine (C-LC, T-HS, C-HL, C-JL, J-HK); Hepatitis Research Center (W-TY, C-HL, J-HK); Department of Medical Research (J-HK); Department of Microbiology (H-CY), National Taiwan University College of Medicine and National Taiwan University Hospital; Master of Public Health Degree Program (W-TY), National Taiwan University, Taipei; Division of Gastroenterology (L-WW), Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei; School of Medicine (T-CT, C-CW), Tzu Chi University, Hualien; Genomics Research Center Academia Sinica (D-SC), Taipei, Taiwan; St Vincent's Hospital (SF-TK), Melbourne VIC, Australia; and Taiwan Liver Disease Consortium (TLC) (C-JL), Taipei, Taiwan
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32
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Wu JF, Chiu YC, Chang KC, Chen HL, Ni YH, Hsu HY, Chang MH. Predictors of hepatitis B e antigen-negative hepatitis in chronic hepatitis B virus-infected patients from childhood to adulthood. Hepatology 2016; 63:74-82. [PMID: 26389515 DOI: 10.1002/hep.28222] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 09/14/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED Hepatitis B e antigen (HBeAg)-negative hepatitis is a clinical indicator of poor outcome for chronic hepatitis B viral (HBV) infection. This long-term prospective cohort study aimed to elucidate the predictors of developing HBeAg-negative hepatitis in chronic HBV-infected subjects followed from childhood to adulthood. We followed 434 HBeAg-positive chronic HBV-infected patients from a median age of 7.22 years (interquartile range 4.31-10.21 years). Spontaneous HBeAg seroconversion occurred in 359 subjects at a median age of 13.93 years (interquartile range 8.76-20.59 years), and 75 subjects developed HBeAg seroconversion after antiviral therapy. These patients were followed for a median of 14.40 years (interquartile range 6.14-22.02 years) after HBeAg seroconversion. Clinical data were analyzed to delineate the predictors of developing HBeAg-negative hepatitis. The HBV basal core promoter and precore/core gene sequences were also evaluated in subjects with and without HBeAg-negative hepatitis. The overall annual incidence of HBeAg-negative hepatitis was 0.37% (95% confidence internal 0.35-0.39) in spontaneous HBeAg seroconverters. The overall annual incidence of HBeAg-negative hepatitis increased to 2.64% in lamivudine-treated subjects but did not increase in those treated with interferon-alpha (0.58%). Male gender (hazard ratio = 3.15), HBV genotype C (hazard ratio = 4.40), HBeAg seroconversion after 18 years of age (hazard ratio = 2.46), and lamivudine therapy prior to HBeAg seroconversion (hazard ratio = 1.42) were predictors of HBeAg-negative hepatitis in HBeAg seroconverters (P < 0.05). HBeAg-negative hepatitis subjects carried more A1762T/G1764A, C2063A, and A2131C HBV gene mutations than those without HBeAg-negative hepatitis. CONCLUSIONS HBeAg seroconversion during childhood predicts a lower risk of HBeAg-negative hepatitis in later life. Interferon-alpha therapy may be an effective antiviral therapy beneficial in chronic HBV-infected children with severe inflammation that facilitates HBeAg seroconversion in earlier life.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University, Taipei, Taiwan
| | - Yu-Chun Chiu
- Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University, Taipei, Taiwan.,Department of Medical Education, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Kai-Chi Chang
- Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University, Taipei, Taiwan.,Department of Emergency, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University, Taipei, Taiwan.,Department of Genetics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Children Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
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33
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Angione SL, Croote D, Leung JW, Mermel LA, Tripathi A. Single fluorophore melting curve analysis for detection of hypervirulent Clostridium difficile. J Med Microbiol 2015; 65:62-70. [PMID: 26516039 DOI: 10.1099/jmm.0.000199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
This study demonstrates a novel detection assay able to identify and subtype strains of Clostridium difficile. Primers carefully designed for melting curve analysis amplify DNA from three C. difficile genes, tcdB, tcdC and cdtB, during quantitative (q)PCR. The tcdB gene allows for confirmation of organism presence, whilst the tcdC and cdtB genes allow for differentiation of virulence status, as deletions in the tcdC gene and the concurrent presence of the cdtB gene, which produces binary toxin, are associated with hypervirulence. Following qPCR, subtyping is then achieved by automated, inline melting curve analysis using only a single intercalating dye and verified by microchip electrophoresis. This assay represents a novel means of distinguishing between toxigenic and hypervirulent C. difficile strains NAP1/027/BI and 078 ribotype, which are highly prevalent hypervirulent strains in humans. This methodology can help rapidly detect and identify C. difficile strains that impose a significant health and economic burden in hospitals and other healthcare settings.
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Affiliation(s)
- Stephanie L Angione
- Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA
| | - Derek Croote
- Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA
| | - Joshua W Leung
- Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA
| | - Leonard A Mermel
- Division of Infectious Diseases, Department of Medicine, Rhode Island Hospital, , Providence, RI, USA.,Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Anubhav Tripathi
- Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA
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34
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Ma C, Han D, Deng M, Wang J, Shi C. Single primer-triggered isothermal amplification for double-stranded DNA detection. Chem Commun (Camb) 2015; 51:553-6. [PMID: 25412213 DOI: 10.1039/c4cc07845d] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Here we have devised a new generation of isothermal double-stranded DNA (dsDNA) detection method, termed single primer-triggered isothermal amplification (SAMP). It is very simple only requiring one primer and a few copies of dsDNA in less than an hour are detectable with multiple signal amplification steps.
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Affiliation(s)
- Cuiping Ma
- Shandong Provincial Key Laboratory of Biochemical Analysis, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China.
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35
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Chen CL, Yang JY, Lin SF, Sun CA, Bai CH, You SL, Chen CJ, Kao JH, Chen PJ, Chen DS. Slow decline of hepatitis B burden in general population: Results from a population-based survey and longitudinal follow-up study in Taiwan. J Hepatol 2015; 63:354-63. [PMID: 25795588 DOI: 10.1016/j.jhep.2015.03.013] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 03/05/2015] [Accepted: 03/10/2015] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Hepatitis B virus (HBV) infection poses a global public health threat. HBV vaccination has proven highly effective in preventing the infection; however, its long-term impact on the general population has not been addressed. We conducted analysis to determine the total and changing burden of chronic HBV infection and evaluate the serological status between vaccinated and unvaccinated in Taiwan. METHODS Participants in "The Taiwanese Survey on Prevalence of Hyperglycemia, Hyperlipidemia and Hypertension" in 2002 (n=6602), and 4088 with follow-up survey in 2007 were included. HBsAg (including titers), anti-HBs, anti-HBc, HBeAg, anti-HBe, HBV genotypes and viral loads were assayed. Prevalence and evolving patterns of these seromarkers was compared between vaccinated and unvaccinated cohorts and predictors of persistent HBsAg positivity and negativity were examined. RESULTS The overall prevalence of chronic HBV infection was 13·7% (95% CI, 12.9% to 14.5%) and about two thirds had past exposure (anti-HBc: 68·46%) in 2002. The vaccinated cohort tended to have lower prevalence of HBsAg and anti-HBc, and a higher proportion of anti-HBs and HBeAg positivity, genotype C and high viral load. The majority (85·42%) were consistently HBsAg negative while 12·65% were consistently positive, and 8·98% achieved seroclearance in a five-year period. In the vaccinated cohort, no subjects had acquired new exposure and became HBsAg positive, and only one (0.54%) cleared HBsAg, demonstrating the durability of vaccination through teenage and young adulthood. CONCLUSIONS This comprehensive, population-representative-survey shows that 20 years after universal vaccination, the backlog still composed a substantial burden of chronic HBV infections in Taiwan.
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Affiliation(s)
- Chi-Ling Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | | | | | - Chien-An Sun
- School of Public Health, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Chyi-Huey Bai
- Department of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
| | - San-Lin You
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chien-Jen Chen
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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36
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Song LW, Wang YB, Fang LL, Wu Y, Yang L, Chen JY, Ge SX, Zhang J, Xiong YZ, Deng XM, Min XP, Zhang J, Chen PJ, Yuan Q, Xia NS. Rapid Fluorescent Lateral-Flow Immunoassay for Hepatitis B Virus Genotyping. Anal Chem 2015; 87:5173-80. [DOI: 10.1021/ac504832c] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Liu-Wei Song
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Ying-Bin Wang
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Lin-Lin Fang
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Yong Wu
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Lin Yang
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Jie-Yu Chen
- Xiamen Innovax Biotech Company, Ltd., Xiamen 361022, China
| | - Sheng-Xiang Ge
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Jing Zhang
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - You-Zheng Xiong
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
- School
of Information Science and Engineering, Computer Science Department, Xiamen University, Xiamen 361005, China
| | - Xiu-Mei Deng
- Xiamen Innovax Biotech Company, Ltd., Xiamen 361022, China
| | - Xiao-Ping Min
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
- School
of Information Science and Engineering, Computer Science Department, Xiamen University, Xiamen 361005, China
| | - Jun Zhang
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Pei-Jer Chen
- National
Taiwan University College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Quan Yuan
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
| | - Ning-Shao Xia
- National
Institute of Diagnostics and Vaccine Development in Infectious Diseases,
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,
School of Life Sciences, Xiamen University, Xiamen 361102, China
- School
of Public Health, Xiamen University, Xiamen 361102, China
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37
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Tseng TC, Liu CJ, Chen CL, Yang WT, Yang HC, Su TH, Wang CC, Kuo SFT, Liu CH, Chen PJ, Chen DS, Kao JH. Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection. Aliment Pharmacol Ther 2015; 41:949-960. [PMID: 25809540 DOI: 10.1111/apt.13170] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/18/2014] [Accepted: 03/02/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clearance of hepatitis B surface antigen (HBsAg) indicates clinical control of hepatitis B virus (HBV) infection. However, little is known about the impact of viral genomic variations on HBsAg loss. METHODS We explored the association between viral genomic factors and HBsAg loss in 2121HBeAg-negative patients. HBV pre-core stop codon (1896) and basal core promoter (BCP) (1762/1764) sequences were determined in patients with HBV DNA ≥200 IU/mL (N = 1693). The effect of HBV genotype on HBsAg loss was further validated in the whole cohort of 3445 HBsAg carriers. RESULTS The cumulative lifetime (age 28-75 years) incidence of HBsAg loss was 50.4% in 2121 HBeAg-negative patients. We found that genotype C, but not pre-core stop codon or BCP mutants, was associated with HBsAg loss. Compared to genotype B patients, genotype C patients had higher lifetime chance of HBsAg loss, with hazard ratio of 1.8 (95% confidence interval: 1.4-2.4). Multivariable analysis showed that male sex, elevated ALT levels, lower serum HBV DNA and HBsAg levels, and genotype C infection were associated with higher chance of HBsAg loss independently. We then performed sensitivity analysis, which re-included HBeAg-positive, cirrhotic and treatment-experienced patients, and confirmed the robustness of our results in 3445 HBsAg carriers. CONCLUSION Genotype C infection, compared to genotype B, is associated with a higher lifetime chance of HBsAg loss in Asian HBV carriers.
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Affiliation(s)
- T-C Tseng
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan
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Hsu HY, Chang MH, Ni YH, Chiang CL, Wu JF, Chen HL. Universal infant immunization and occult hepatitis B virus infection in children and adolescents: a population-based study. Hepatology 2015; 61:1183-91. [PMID: 25501911 DOI: 10.1002/hep.27650] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 12/08/2014] [Indexed: 12/22/2022]
Abstract
UNLABELLED To determine whether universal infant immunization affects occult hepatitis B virus (HBV) infection (OBI), serum samples from hepatitis B surface antigen (HBsAg)-negative subjects <18 years enrolled during six sequential seroepidemiological surveys conducted between 1984 (just before universal infant immunization) and 2009 were analyzed. Study subjects were divided into unvaccinated cohorts (born before 1984) and vaccinated cohorts (born after 1984). HBV-DNA positivity was determined by positivity of nested polymerase chain reaction in at least two of three regions (pre-S, S, and pre-core/core genes). OBI frequency was lower in vaccinated than unvaccinated antibody to hepatitis B core antigen (anti-HBc)-negative subjects (0 of 392 [0%] vs. 4 of 218 [1.8%]; P = 0.007), tended to be higher in vaccinated than unvaccinated anti-HBc-positive subjects (16 of 334 [4.8%] vs. 3 of 181 [1.7%]; P = 0.072), and was higher in vaccinated than unvaccinated subjects seropositive for both antibody to hepatitis B surface antigen (anti-HBs) and anti-HBc (13 of 233 [5.6%] vs. 3 of 170 [1.8%]; P = 0.025). By using known anti-HBc seropositivity rate in children in our serosurveys, the estimated OBI frequency per 10(4) HBsAg-negative subjects declined from 160.7 in unvaccinated cohorts to 11.5 in vaccinated cohorts. In vaccinated cohorts, OBI frequency was higher in anti-HBc-positive subjects than in anti-HBc-negative subjects (16 of 334 [4.8%] vs. 0 of 392 [0%]; P < 0.001). Subjects with OBI had much lower viral load (P < 0.001) and a trend of higher mutation rates in "a" determinant of HBsAg than age-comparable, HBsAg-positive subjects. CONCLUSIONS Reduction of OBI in immunized subjects complements the well-documented universal infant immunization-related benefit of markedly reduced overt HBV infection. Breakthrough infections in immunized subjects seem to associate with more occurrence of OBI than natural infections in unvaccinated subjects. In the postvaccination era, anti-HBc seropositivity is a useful marker for OBI screening in HBsAg-negative subjects, and a very-low-level viral replication and HBsAg expression is the major mechanism underlying OBI.
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Affiliation(s)
- Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Primary Care Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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Hsu CS, Liu WL, Chao YC, Lin HH, Tseng TC, Wang CC, Chen DS, Kao JH. Adipocytokines and liver fibrosis stages in patients with chronic hepatitis B virus infection. Hepatol Int 2015; 9:231-42. [DOI: 10.1007/s12072-015-9616-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 02/17/2015] [Indexed: 12/17/2022]
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Chyuan IT, Tsai HF, Tzeng HT, Sung CC, Wu CS, Chen PJ, Hsu PN. Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model. Cell Mol Immunol 2015; 12:317-25. [PMID: 25661729 DOI: 10.1038/cmi.2015.01] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 01/02/2015] [Accepted: 01/03/2015] [Indexed: 12/25/2022] Open
Abstract
Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-α blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-α blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-α blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose- and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-α blockage therapy occurred at early time points after HBV infection. In addition, TNF-α blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1(high)CD127(low) exhausted T cells. Furthermore, TNF-α blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-α blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-α blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-α-blocking agents.
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Affiliation(s)
- I-Tsu Chyuan
- 1] Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, China [2] Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China
| | - Hwei-Fang Tsai
- 1] Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan, China [2] Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, China
| | - Horng-Tay Tzeng
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China
| | - Chi-Chang Sung
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China
| | - Chien-Sheng Wu
- Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan, China
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China
| | - Ping-Ning Hsu
- 1] Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China [2] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, China
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41
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Tseng TC, Liu CJ, Yang HC, Chen CL, Yang WT, Tsai CS, Kuo SFT, Verbree FC, Su TH, Wang CC, Liu CH, Chen PJ, Chen DS, Kao JH. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut 2015; 64:292-302. [PMID: 24763132 DOI: 10.1136/gutjnl-2014-306977] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND OBJECTIVE Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis. METHODS 251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case-control study, which included 184 patients with biopsy-proven liver fibrosis stages. RESULTS In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant ≥45% compared to <45% in the longitudinal cohort; this finding was validated by the case-control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67). CONCLUSIONS A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Master of Public Health Degree Program, National Taiwan University, Taipei, Taiwan
| | - Cheng-Shiue Tsai
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
| | | | | | - Tung-Hung Su
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Genomics Research Center, Academia Sinica, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Ansari N, Makvandi M, Samarbaf-Zadeh AR. Hepatitis B virus Genotyping Among Patients With Cirrhosis. Jundishapur J Microbiol 2015; 8:e14571. [PMID: 25964845 PMCID: PMC4417903 DOI: 10.5812/jjm.14571] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 01/22/2014] [Accepted: 03/15/2014] [Indexed: 12/11/2022] Open
Abstract
Background: Hepatitis B virus (HBV) infection is a worldwide public health problem. Nine HBV genotypes (A-I) have been already discovered. HBV genotypes are important both in the clinical manifestation of disease and treatment response. Moreover, HBV DNA without HBs (Hepatitis B surface)-antigenemia was detected in some patients with chronic hepatitis (occult hepatitis). There is little information about HBV genotypes and its relation to occult infection despite the importance of this infection in Khuzestan Province. Objectives: This study aimed to determine both occult hepatitis B infection and HBV genotypes among cirrhotic patients. Patients and Methods: Thirty-eight patients with liver cirrhosis, including 11 (28.9%) HBsAg-positive patients and 27 (71.1%) patients with cryptogenic cirrhosis participated in this study. The mean age of the patients at the time of cirrhosis diagnosis was 54.85 years (range 26-75 years). All patients were anti-HCV and anti-HIV negative. For all the samples, the serological Enzyme-Linked Immunosorbent Assay (ELISA) was performed for HBV markers including HBsAg, HBcAb, HBeAg, HBeAb tests. The common primer of S region of HBV was used for Nested PCR. The PCR products of the positive individuals were sequenced for genotyping and subtyping of HBV. Results: Eleven (40.7%) out of 27 HBV cryptogenic cirrhosis and all 11 HBsAg-positive patients were positive for HBV DNA. The seroprevalences of Hepatitis B virus HBe antigen, anti-HBe and anti-HBc antibodies among the cryptogenic cirrhosis patients were 5 (18.5%), 1 (3.7%), and 5 (20.83), and among HBsAg-positive patients were 6 (54.5%), 5 (45.5%), and 7 (63.6%), respectively. Conclusions: In our study, only HBV genotype D was found among all the positive HBsAg and occult HBV infection. Moreover, high prevalence (40.7%) of occult HBV infection was determined among patients suffered from cryptogenic cirrhosis.
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Affiliation(s)
- Nastaran Ansari
- Department of Virology, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Nastaran Ansari, Department of Virology, Tehran University of Medical Sciences, Tehran, IR Iran. Tel: +98-218112677819, E-mail:
| | - Manochehr Makvandi
- Department of Virology, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Ali Reza Samarbaf-Zadeh
- Department of Virology, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahvaz, IR Iran
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Liu CJ, Chen TC, Chen PJ, Wang HY, Tseng TC, Cheng HR, Liu CH, Chen DS, Kao JH. Micro-evolution of the hepatitis B virus genome in hepatitis B e-antigen-positive carriers: comparison of genotypes B and C at various immune stages. J Gastroenterol Hepatol 2015; 30:172-177. [PMID: 25040688 DOI: 10.1111/jgh.12654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/12/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Patients with hepatitis B virus (HBV) genotype B infection experience hepatitis B e-antigen (HBeAg) seroconversion at an earlier stage than do patients with genotype C infection. Therefore, this study investigated whether the differential phenotypes are related to HBV genomic evolution. METHODS Thirty-three HBeAg-positive patients with a mean follow-up of 3.1 years were enrolled: 16 at the immune tolerance stage (group I) and 17 at the immune clearance stage (group II). The evolution rates of paired viral genomes at enrollment and at the final follow-up in the full-length genome (μf), nonoverlapping regions (synonymous [μs] and nonsynonymous [μa]), and overlapping regions (μ) were calculated. The evolution rates were then compared according to serum alanine aminotransferase (ALT) levels and HBV genotype. RESULTS The overall μf evolution rate was lower in group I than in group II (1.4 × 10(-5) ± 3.3 × 10(-5) vs 1.2 × 10(-3) ± 1.2 × 10(-3) nucleotide substitution/site/year, P < 0.001). We observed similar results for the μs, μa, and μ evolution rates. All evolution parameters were comparable between genotypes B and C. We determined a positive correlation between μa/y and the area under the average ALT time curve in genotype B (R(2) = 0.6935, P < 0.0001), but not in genotype C (R(2) = 0.1606, P = 0.124). CONCLUSION The evolution rate of the HBV genome is higher at the immune clearance stage than at the immune tolerance stage. Host immune selection might play a role in triggering evolution of genotype B.
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Affiliation(s)
- Chun-Jen Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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Wu JF, Hsu HY, Chiu YC, Chen HL, Ni YH, Chang MH. The effects of cytokines on spontaneous hepatitis B surface antigen seroconversion in chronic hepatitis B virus infection. THE JOURNAL OF IMMUNOLOGY 2014; 194:690-6. [PMID: 25505294 DOI: 10.4049/jimmunol.1401659] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We examined the role of human cytokines in the natural course of hepatitis B surface Ag (HBsAg) seroconversion in chronic hepatitis B virus (HBV) infection. The clinical course of spontaneous HBsAg seroconversion was assessed in 296 chronically HBV-infected patients. Single nucleotide polymorphisms (SNPs) in IL-1β, IL-2, IL-4, IL-10, IL-12β, IL-13, IL-27, and IFN-γ genes were examined in 296 chronically HBV-infected patients and another 193 HBV recoverers. The HBsAg a determinant sequence of chronically HBV-infected subjects with and without HBsAg seroconversion was also analyzed. The start of the immune-clearance phase (serum alanine aminotransferase levels > 30 IU/l) before the age of 48 mo and hepatitis B e Ag (HBeAg) seroconversion before the age of 10 y predicted spontaneous HBsAg seroconversion in chronically HBV-infected patients (odds ratios 17.7 and 5.0; p < 0.001 and p < 0.002, respectively). The A-allele of IL-10 SNP rs1800872 was associated with higher IL-10 serum levels, and the G-allele of IL-12β SNP rs3212217 was associated with sustained high serum IL-12p70 levels during the immune-clearance phase. Both were predictors of spontaneous HBsAg seroconversion and HBV recovery (odds ratios 4.0 and 26.3; p = 0.002 and p < 0.001, respectively). Spontaneous HBsAg seroconversion was not related to sex, HBV genotype, or HBsAg a determinant mutation. The start of immune-clearance phase, age at HBeAg seroconversion, and serum IL-10 and IL-12 levels are associated with the course of the immune-clearance phase in chronic HBV infection, and are predictive of spontaneous HBsAg seroconversion and HBV recovery.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan
| | - Yu-Chun Chiu
- Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei 10041, Taiwan; and
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan; Department of Genetics, National Taiwan University Hospital, Taipei 10041, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei 10041, Taiwan; and
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Song LW, Liu PG, Liu CJ, Zhang TY, Cheng XD, Wu HL, Yang HC, Hao XK, Yuan Q, Zhang J, Kao JH, Chen DS, Chen PJ, Xia NS. Quantitative hepatitis B core antibody levels in the natural history of hepatitis B virus infection. Clin Microbiol Infect 2014; 21:197-203. [PMID: 25658546 DOI: 10.1016/j.cmi.2014.10.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 07/17/2014] [Accepted: 10/05/2014] [Indexed: 02/06/2023]
Abstract
We previously demonstrated that pretreatment quantitative anti-hepatitis B core protein (qAnti-HBc) levels can predict the treatment response for both interferon and nucleoside analogue therapy, but the characteristics of qAnti-HBc during chronic hepatitis B virus (HBV) infection remain poorly understood. To understand this issue, the qAnti-HBc levels were evaluated in individuals with past HBV infection, occult HBV infection and chronic HBV infection in the immune tolerance phase, immune clearance phase, low-replicative phase and hepatitis B e antigen (HBeAg)-negative hepatitis phase. Individuals with hepatitis B surface antigen (n = 598, 3.74 ± 0.90 log10 IU/mL) had significantly higher (p < 0.001, approximately 1000-fold) serum qAnti-HBc levels than those who had occult HBV, and serum qAnti-HBc levels were significantly higher in the occult HBV group than in the past HBV infection group (p < 0.001). qAnti-HBc levels were positively correlated with alanine aminotransferase levels (R = 0.663, p < 0.001), and subjects with an abnormal alanine aminotransferase level had a higher qAnti-HBc level (p < 0.001). Serum qAnti-HBc level varied in different phases of HBV infection, as determined by host immune status. Serum qAnti-HBc level is strongly associated with hepatitis activity in subjects with chronic HBV infection.
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Affiliation(s)
- L-W Song
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen, China
| | - P-G Liu
- Zhongshan Hospital, Medical College of Xiamen University, Xiamen, China
| | - C-J Liu
- National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan
| | - T-Y Zhang
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen, China
| | - X-D Cheng
- Center of Clinical Laboratory Medicine of PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - H-L Wu
- National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan
| | - H-C Yang
- National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan
| | - X-K Hao
- Center of Clinical Laboratory Medicine of PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Q Yuan
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen, China; School of Public Health, Xiamen University, Xiamen, China.
| | - J Zhang
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen, China; School of Public Health, Xiamen University, Xiamen, China
| | - J-H Kao
- National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan
| | - D-S Chen
- National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan
| | - P-J Chen
- National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - N-S Xia
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen, China; School of Public Health, Xiamen University, Xiamen, China.
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Constantinescu I, Dinu AA, Boscaiu V, Niculescu M. Hepatitis B virus core promoter mutations in patients with chronic hepatitis B and hepatocellular carcinoma in bucharest, romania. HEPATITIS MONTHLY 2014; 14:e22072. [PMID: 25477976 PMCID: PMC4250966 DOI: 10.5812/hepatmon.22072] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/10/2014] [Accepted: 09/26/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Accurate and personalized molecular virological diagnosis of hepatitis B virus (HBV) infection is crucial for individualized selection of patients for antiviral therapy in Romania. OBJECTIVES We aimed to investigate HBV mutations in Romanian patients with chronic HBV infection, also to match HBV genotypes with HBV mutations identified and clinical outcomes. PATIENTS AND METHODS This was a cross-sectional study. A total of 484 Romanian patients with chronic HBV infection and hepatocellular carcinoma (HCC) were investigated. This was performed in Fundeni Clinical Institute, Bucharest, Romania during January 2005 to August 2010. HBsAg positive patients with chronic HBV infection admitted to Fundeni Clinical Institute were randomly enrolled in the study. Analysis was performed in the Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania. Indirect diagnosis was performed with enhanced chemiluminescence method using Architect i2000SR and HBV-DNA was quantified with COBAS TaqMan HBV PCR. Direct sequencing of the PCR-products was performed with the PCR-product sequencing kit. HBV genotyping was performed with INNO-LiPA DR Amplification and INNO-LiPA HBV precore-core. RESULTS We detected two HBV genotypes; A (8.1%) and D (60.5%), and a mixture of genotypes A and D (31.4%) (P < 0.001). Basal core promoter (BCP) A1762T/G1764A and precore (PC) G1896A mutations were detected in these Romanian patients with chronic HBV infection. HBV chronic carriers had mainly genotype D (54.4%) and HBV WT (64.0%). BCP A1762T, G1764A and PC G1896A were significantly associated with HCC-tissue HBV sequencing (75.3%) (P < 0.001). PC G1896A alone was detected in HCC-serum HBV sequencing group (66.7%). CONCLUSIONS Genotype D was the main genotype detected in Romanian patients with chronic HBV infection. Genotype D presented both BCP and PC mutations more frequently.
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Affiliation(s)
- Ileana Constantinescu
- Immunology of Transplantation Discipline, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Center for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania
- Corresponding Author: Ileana Constantinescu, Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania. Tel: +40-744341984, Fax: +40-213180448, E-mail:
| | - Andrei-Antoniu Dinu
- Center for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania
| | - Voicu Boscaiu
- “Gheorghe Mihoc-Caius Iacob” Institute of Statistics and Applied Mathematics, Bucharest, Romania
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Liu WR, Tian MX, Jin L, Yang LX, Ding ZB, Shen YH, Peng YF, Zhou J, Qiu SJ, Dai Z, Fan J, Shi YH. High levels of hepatitis B surface antigen are associated with poorer survival and early recurrence of hepatocellular carcinoma in patients with low hepatitis B viral loads. Ann Surg Oncol 2014; 22:843-50. [PMID: 25269529 DOI: 10.1245/s10434-014-4043-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Indexed: 12/28/2022]
Abstract
PURPOSE Recurrence is a disastrous outcome in patients with hepatitis-related hepatocellular carcinoma (HCC) who have undergone curative resection, and little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk of HCC recurrence. PATIENTS AND METHODS This retrospective study included 1,360 HBsAg-positive postoperative HCC patients with hepatitis B viral (HBV) DNA levels < 2000 IU/mL, including 298 patients in a training cohort and 1,062 patients in a validation cohort. The prognostic value of the HBsAg level was evaluated using Cox regression and Kaplan-Meier analyses. RESULTS We demonstrated that 1,000 IU/mL, but not 10 or 100 IU/mL, was a meaningful cutoff level for significantly discriminating these patients into an HBsAg(Low) group and an HBsAg(High) group based on correlations between the HBsAg level and liver cirrhosis (p = 0.028), tumor size (p = 0.039), and hepatitis B e antigen level (p < 0.001). The postoperative 1-, 3-, and 5-year overall survival (OS) rates of HCC patients in the HBsAg(Low) group were significantly higher than those of HCC patients in the HBsAg(High) group. Accordingly, the 5-year recurrence-free survival (RFS) rates of patients in the HBsAg(Low) group were markedly higher than those of HCC patients in the HBsAg(High) group. The HBsAg level was a prognostic indicator for OS (p = 0.014) and RFS (p = 0.01). CONCLUSION HBsAg level is correlated with more aggressive tumor behavior and serves as a prognostic indicator in patients with surgically resected HCC with low HBV load.
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Affiliation(s)
- Wei-Ren Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
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Wu JF, Tsai WY, Tung YC, Chen HL, Ni YH, Hsu HY, Chang MH. Effect of menarche onset on the clinical course in females with chronic hepatitis B virus infection. J Pediatr 2014; 165:534-8. [PMID: 24973292 DOI: 10.1016/j.jpeds.2014.05.049] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Revised: 04/04/2014] [Accepted: 05/08/2014] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To investigate the impact of menarche on the natural course of chronic hepatitis B virus (HBV) infection in women. STUDY DESIGN Young women who are positive for hepatitis B e antigen (HBeAg; n = 101) chronically infected with genotypes B and C HBV were recruited at a mean age of 4.57 ± 3.08 years, and a mean follow-up duration of 23.98 ± 3.77 years. Clinical data, including age at menarche, HBV genotypes, serum HBV viral loads, hepatitis B surface antigen (HBsAg) titers, and serial liver functional profiles were analyzed. RESULTS Women with earlier onset of menarche had earlier spontaneous HBeAg seroconversion than others (hazard ratio, 2.0; P = .02) adjusting for HBV genotype and peak alanine aminotransferase levels before HBeAg seroconversion. The annual decrease in HBsAg titer from 15 to 20 years of age also was greater in the early menarche group compared with the late menarche group (0.11 ± 0.11 vs 0.05 ± 0.11 log10 IU/mL, P = .04). The baseline HBV viral load was also borderline low in female subjects with earlier menarche as compared with others (P = .06). Earlier menarche onset was associated with higher spontaneous HBeAg seroconversion, HBsAg seroclearance, and HBsAg seroconversion rate before 15 years of age in females with chronic HBV infection. CONCLUSIONS Earlier puberty-onset, indicated by menarche-onset, was associated with earlier spontaneous HBeAg seroconversion and greater rate of HBV clearance before 15 years of age in female subjects with chronic HBV infection.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Yu Tsai
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Ching Tung
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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Wu HL, Kao JH, Chen TC, Wu WH, Liu CH, Su TH, Yang HC, Chen DS, Chen PJ, Liu CJ. Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: clinical and mechanistic implications. J Gastroenterol Hepatol 2014; 29:1629-1636. [PMID: 24730549 DOI: 10.1111/jgh.12606] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Acute exacerbation (AE) of chronic hepatitis B virus (HBV) infection is common and negatively impacts the clinical outcome. Although upsurge of viral load always precedes or coincides with AE, the underlying immunological mechanisms remain unclear and were investigated. METHODS We prospectively followed the serum cytokine/chemokine profiles, viral load, and alanine aminotransferase (ALT) levels in 250 patients and identified 44 consecutive patients (male: 72.7%; age: 40.4 ± 9.7 years; hepatitis B e antigen [HBeAg] positivity: 63.6%; genotype B/C: 75%/25%) who developed AE during the follow-up in a medical center. The impact of clinical characteristics (age, gender, HBeAg, ALT, HBV genotype), cytokines (tumor necrosis factor-alpha, interferon gamma, interleukin [IL]-2, IL-4, IL-6, and IL-10), and chemokines (CXCL10/interferon gamma-induced protein [IP]-10, CCL2/MCP-1, CXCL9/MIG, CCL5/RANTES, and CXCL8/IL-8) on the serum HBV DNA dynamics at different time points (baseline, peak of serum HBV DNA level, peak of serum ALT level, and after AE) were analyzed. RESULTS Of 44 patients, serum HBV DNA level surged before the peak of serum ALT level in 23 (52.3%), and coincided with the peak of ALT in 21 (47.7%). The upsurge of serum viral load significantly correlated with the increase of IL-10 (P = 0.0037) and CXCL10/IP-10 (P = 0.0044). Upsurge of serum viral load was preceded by an increase in serum IL-4 (P < 0.05), IL-6 (P < 0.05), and IL-10 (P < 0.05). Combination of HBV genotype, IL-6 level at baseline, and ALT level at the peak of serum HBV DNA reliably predicted subsequent AE pattern (P = 0.0116). CONCLUSIONS Enhanced Th2 activity is likely involved in the surge of HBV DNA level before hepatitis exacerbation.
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Affiliation(s)
- Hui-Lin Wu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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Lee MH, Yang HI, Yuan Y, L’Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus infection. World J Gastroenterol 2014; 20:9270-80. [PMID: 25071320 PMCID: PMC4110557 DOI: 10.3748/wjg.v20.i28.9270] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 03/04/2014] [Accepted: 04/27/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) affects 130-210 million people worldwide and is one of the major risk factors for hepatocellular carcinoma. Globally, at least one third of hepatocellular carcinoma cases are attributed to HCV infection, and 350000 people died from HCV related diseases per year. There is a great geographical variation of HCV infection globally, with risk factors for the HCV infection differing in various countries. The progression of chronic hepatitis C to end-stage liver disease also varies in different study populations. A long-term follow-up cohort enrolling participants with asymptomatic HCV infection is essential for elucidating the natural history of HCV-caused hepatocellular carcinoma, and for exploring potential seromarkers that have high predictability for risk of hepatocellular carcinoma. However, prospective cohorts comprising individuals with HCV infection are still uncommon. The risk evaluation of viral load elevation and associated liver disease/cancer in HCV (REVEAL-HCV) study has followed a cohort of 1095 residents seropositive for antibodies against hepatitis C virus living in seven townships in Taiwan for more than fifteen years. Most of them have acquired HCV infection through iatrogenic transmission routes. As the participants in the REVEAL-HCV study rarely receive antiviral therapies, it provides a unique opportunity to study the natural history of chronic HCV infection. In this review, the prevalence, risk factors and natural history of HCV infection are comprehensively reviewed. The study cohort, data collection, and findings on liver disease progression of the REVEAL-HCV study are described.
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