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Matrenec R, Oropeza CE, Dekoven E, Matrenec C, Maienschein-Cline M, Chau CS, Green SJ, Kaestner KH, McLachlan A. Foxa deficiency restricts hepatitis B virus biosynthesis through epigenic silencing. J Virol 2024; 98:e0137124. [PMID: 39377604 PMCID: PMC11575325 DOI: 10.1128/jvi.01371-24] [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: 08/05/2024] [Accepted: 09/23/2024] [Indexed: 10/09/2024] Open
Abstract
In the hepatis B virus (HBV) transgenic mouse model of chronic infection, the forkhead box protein A/hepatocyte nuclear factor 3 (Foxa/HNF3) family of pioneer transcription factors are required to support postnatal viral demethylation and subsequent HBV transcription and replication. Liver-specific Foxa-deficient mice with hepatic expression of only Foxa3 do not support HBV replication but display biliary epithelial hyperplasia with bridging fibrosis. However, liver-specific Foxa-deficient mice with hepatic expression of only Foxa1 or Foxa2 also successfully restrict viral transcription and replication but display only minimal alterations in liver physiology. These observations suggest that the level of Foxa activity, rather than the combination of specific Foxa genes, is a key determinant of HBV biosynthesis. Together, these findings suggest that targeting Foxa activity could lead to HBV DNA methylation and transcriptional inactivation, resulting in the resolution of chronic HBV infections that are responsible for approximately one million deaths annually worldwide. IMPORTANCE The current absence of curative therapies capable of resolving chronic hepatis B virus (HBV) infection is a major clinical problem associated with considerable morbidity and mortality. The small viral genome limits molecular targets for drug development, suggesting that the identification of cellular factors essential for HBV biosynthesis may represent alternative targets for therapeutic intervention. Genetic Foxa deficiency in the neonatal liver of HBV transgenic mice leads to the transcriptional silencing of viral DNA by CpG methylation without affecting viability or displaying an obvious phenotype. Therefore, limiting liver Foxa activity therapeutically may lead to the methylation of viral covalently closed circular DNA (cccDNA), resulting in its transcriptional silencing and ultimately the resolution of chronic HBV infection.
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Affiliation(s)
- Rachel Matrenec
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Claudia E. Oropeza
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Eddie Dekoven
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Carly Matrenec
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Mark Maienschein-Cline
- Research Resources Center, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Cecilia S. Chau
- Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, Illinois, USA
| | - Stefan J. Green
- Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, Illinois, USA
| | - Klaus H. Kaestner
- Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Alan McLachlan
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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Kunkel AA, McHugh KJ. Injectable controlled-release systems for the prevention and treatment of infectious diseases. J Biomed Mater Res A 2024; 112:1224-1240. [PMID: 37740704 DOI: 10.1002/jbm.a.37615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 09/03/2023] [Accepted: 09/07/2023] [Indexed: 09/25/2023]
Abstract
Pharmaceutical drugs, including vaccines, pre- and post-exposure prophylactics, and chronic drug therapies, are crucial tools in the prevention and treatment of infectious diseases. These drugs have the ability to increase survival and improve patient quality of life; however, infectious diseases still accounted for more than 10.2 million deaths in 2019 before the COVID-19 pandemic. High mortality can be, in part, attributed to challenges in the availability of adequate drugs and vaccines, limited accessibility, poor drug bioavailability, the high cost of some treatments, and low patient adherence. A majority of these factors are logistical rather than technical challenges, providing an opportunity for existing drugs and vaccines to be improved through formulation. Injectable controlled-release drug delivery systems are one class of formulations that have the potential to overcome many of these limitations by releasing their contents in a sustained manner to reduce the need for frequent re-administration and improve clinical outcomes. This review provides an overview of injectable controlled drug delivery platforms, including microparticles, nanoparticles, and injectable gels, detailing recent developments using these systems for single-injection vaccination, long-acting prophylaxis, and sustained-release treatments for infectious disease.
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Affiliation(s)
- Alyssa A Kunkel
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Kevin J McHugh
- Department of Bioengineering, Rice University, Houston, Texas, USA
- Department of Chemistry, Rice University, Houston, Texas, USA
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Sharifi M, Nourani N, Sanaie S, Hamedeyazdan S. The effect of Oenothera biennis (Evening primrose) oil on inflammatory diseases: a systematic review of clinical trials. BMC Complement Med Ther 2024; 24:89. [PMID: 38360611 PMCID: PMC10867995 DOI: 10.1186/s12906-024-04378-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 01/24/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Evening primrose oil (EPO), extracted from the seeds of Oenothera biennis, has gained attention for its therapeutic effects in various inflammatory conditions. METHOD We performed a systematic search in multiple databases and defined the inclusion criteria based on the following PICOs: P: Patients with a form of inflammatory condition, I: EPO, C: Placebo or other therapeutic interventions, O: changes in inflammatory markers or patients' symptoms; S: randomized controlled trials. The quality of the RCTs was evaluated using Cochrane's RoB tool. RESULTS Several conditions were investigated in the literature. In rheumatoid arthritis, mixed results were observed, with some studies reporting significant improvements in symptoms while others found no significant impact. EPO showed some results in diabetes mellitus, atopic eczema, menopausal hot flashes, and mastalgia. However, it did not demonstrate effectiveness in chronic hand dermatitis, tardive dyskinesia, psoriatic arthritis, cystic fibrosis, hepatitis B, premenstrual syndrome, contact lens-associated dry eyes, acne vulgaris, breast cyst, pre-eclampsia, psoriasis, or primary Sjogren's syndrome. Some results were reported from multiple sclerosis after EPO consumption. Studies in healthy volunteers indicated no significant effect of EPO on epidermal atrophy, nevertheless, positive effects on the skin regarding hydration and barrier function were achieved. CONCLUSION Some evidence regarding the potential benefits of EPO in inflammatory disorders were reported however caution is due to the limitations of the current survey. Overall, contemporary literature is highly heterogeneous and fails to provide strong recommendations regarding the efficacy of EPO on inflammatory disorders. Further high-quality studies are necessitated to draw more definite conclusions and establish O. biennis oil effectiveness as an assuring treatment option in alleviating inflammatory conditions.
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Affiliation(s)
- Melika Sharifi
- Student Research Committee, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasim Nourani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarvin Sanaie
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Sanaz Hamedeyazdan
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
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He CQ, Sun BH, Yu WT, An SY, Qiao BJ, Wu W. Evaluating the impact of COVID-19 outbreak on hepatitis B and forecasting the epidemiological trend in mainland China: a causal analysis. BMC Public Health 2024; 24:47. [PMID: 38166922 PMCID: PMC10763123 DOI: 10.1186/s12889-023-17587-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 12/26/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND It is uncertain how COVID-19 outbreak influences the hepatitis B epidemics. This study aims to evaluate the effects on hepatitis B owing to the COVID-19 outbreak and forecast the hepatitis B epidemiological trend in mainland China to speed up the course of the "End viral hepatitis Strategy". METHODS We estimated the causal impacts and created a forecast through adopting monthly notifications of hepatitis B each year from 2005 to 2020 in mainland China using the Bayesian structural time series (BSTS) method. RESULTS The hepatitis B epidemics fluctuates irregularly during the period 2005-2007(APC = 8.7, P = 0.246) and 2015-2020(APC = 1.7, P = 0.290), and there is a downturn (APC=-3.2, 95% CI -5.2 to -1.2, P = 0.006) from 2007 to 2015 in mainland China. The COVID-19 outbreak was found to have a monthly average reduction on the hepatitis B epidemics of 26% (95% CI 18-35%) within the first three months in 2020,17% (95% CI 7.7-26%) within the first six months in 2020, and 10% (95% CI19-22%) all year as a result of the COVID-19 outbreak, (probability of causal effect = 96.591%, P = 0.034) and the forecasts showed an upward trend from 2021 to 2025 (annual percentage change = 4.18, 95% CI 4.0 to 4.3, P < 0.001). CONCLUSION The COVID-19 has a positive effect on the decline of hepatitis B cases. And the potential of BSTS model to forecast the epidemiological trend of the hepatitis B can be applied in automatic public health policymaking in mainland China.
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Affiliation(s)
- Chao-Qun He
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Bai-Hong Sun
- Liaoning Provincial Centers for Disease Control and Prevention, Shenyang, Liaoning, China
| | - Wang-Tao Yu
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, China
| | - Shu-Yi An
- Liaoning Provincial Centers for Disease Control and Prevention, Shenyang, Liaoning, China
| | - Bao-Jun Qiao
- Liaoning Provincial Centers for Disease Control and Prevention, Shenyang, Liaoning, China
| | - Wei Wu
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, China.
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Kumar S, Ansari S, Narayanan S, Ranjith-Kumar CT, Surjit M. Antiviral activity of zinc against hepatitis viruses: current status and future prospects. Front Microbiol 2023; 14:1218654. [PMID: 37908540 PMCID: PMC10613677 DOI: 10.3389/fmicb.2023.1218654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 09/28/2023] [Indexed: 11/02/2023] Open
Abstract
Viral hepatitis is a major public health concern globally. World health organization aims at eliminating viral hepatitis as a public health threat by 2030. Among the hepatitis causing viruses, hepatitis B and C are primarily transmitted via contaminated blood. Hepatitis A and E, which gets transmitted primarily via the feco-oral route, are the leading cause of acute viral hepatitis. Although vaccines are available against some of these viruses, new cases continue to be reported. There is an urgent need to devise a potent yet economical antiviral strategy against the hepatitis-causing viruses (denoted as hepatitis viruses) for achieving global elimination of viral hepatitis. Although zinc was known to mankind for a long time (since before Christ era), it was identified as an element in 1746 and its importance for human health was discovered in 1963 by the pioneering work of Dr. Ananda S. Prasad. A series of follow up studies involving zinc supplementation as a therapy demonstrated zinc as an essential element for humans, leading to establishment of a recommended dietary allowance (RDA) of 15 milligram zinc [United States RDA for zinc]. Being an essential component of many cellular enzymes and transcription factors, zinc is vital for growth and homeostasis of most living organisms, including human. Importantly, several studies indicate potent antiviral activity of zinc. Multiple studies have demonstrated antiviral activity of zinc against viruses that cause hepatitis. This article provides a comprehensive overview of the findings on antiviral activity of zinc against hepatitis viruses, discusses the mechanisms underlying the antiviral properties of zinc and summarizes the prospects of harnessing the therapeutic benefit of zinc supplementation therapy in reducing the disease burden due to viral hepatitis.
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Affiliation(s)
- Shiv Kumar
- Virology Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Shabnam Ansari
- Virology Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Sriram Narayanan
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - C. T. Ranjith-Kumar
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Milan Surjit
- Virology Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
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Khan T, Rihan FA, Ahmad H. Modelling the dynamics of acute and chronic hepatitis B with optimal control. Sci Rep 2023; 13:14980. [PMID: 37696844 PMCID: PMC10495432 DOI: 10.1038/s41598-023-39582-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/27/2023] [Indexed: 09/13/2023] Open
Abstract
This article examines hepatitis B dynamics under distinct infection phases and multiple transmissions. We formulate the epidemic problem based on the characteristics of the disease. It is shown that the epidemiological model is mathematically and biologically meaningful of its well-posedness (positivity, boundedness, and biologically feasible region). The reproductive number is then calculated to find the equilibria and the stability analysis of the epidemic model is performed. A backward bifurcation is also investigated in the proposed epidemic problem. With the help of two control measures (treatment and vaccination), we develop control strategies to minimize the infected population (acute and chronic). To solve the proposed control problem, we utilize Pontryagin's Maximum Principle. Some simulations are conducted to illustrate the investigation of the analytical work and the effect of control analysis.
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Affiliation(s)
- Tahir Khan
- Department of Mathematical Sciences, College of Science, UAE University, 15551, Al-Ain, United Arab Emirates
| | - Fathalla A Rihan
- Department of Mathematical Sciences, College of Science, UAE University, 15551, Al-Ain, United Arab Emirates.
| | - Hijaz Ahmad
- Department of Mathematics, Faculty of Science, Islamic University of Madinah, Medina, 42210, Saudi Arabia.
- Near East University, Operational Research Center in Healthcare, TRNC Mersin 10, Nicosia, 99138, Turkey.
- Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon.
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Ghany MG, Saraswat VA. Patients With Compensated Hepatitis B Virus-Related Cirrhosis and Low-Level Viremia: Treat or Not to Treat? Am J Gastroenterol 2023; 118:970-971. [PMID: 36940387 PMCID: PMC10238665 DOI: 10.14309/ajg.0000000000002224] [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: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 03/22/2023]
Abstract
ABSTRACT Patients with hepatitis B virus-related cirrhosis and low-level viremia represent a special group that might benefit from treatment because of their higher risk of complications. Evidence for the benefit of treatment in this population is lacking. The current study, which analyzed data of a historical cohort of 627 patients from a single Korean center with hepatitis B virus-related compensated cirrhosis, reported a 2.4-fold increased hepatocellular carcinoma risk among patients with low-level viremia compared with those with undetectable viremia provides indirect evidence in support of treatment for this population. The study underscores the importance of treating patients before the development of cirrhosis and the need for finite duration curative therapy.
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Affiliation(s)
- Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Vivek A Saraswat
- Department of Hepatology and Liver Transplantation, Mahatma Gandhi Medical College, Sitapura, Jaipur, India
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Kumar M, Pahuja S, Khare P, Kumar A. Current Challenges and Future Perspectives of Diagnosis of Hepatitis B Virus. Diagnostics (Basel) 2023; 13:368. [PMID: 36766473 PMCID: PMC9914745 DOI: 10.3390/diagnostics13030368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
It is estimated that approximately 260 million people worldwide are infected with the hepatitis B virus (HBV), which is one of the leading causes of liver disease and liver cancer throughout the world. Compared with developed countries, low-income and middle-income countries have limited access to resources and advanced technologies that require highly specialized staff for HBV diagnosis. In spite of the heavy burden caused by hepatitis B virus, 90% of people are still undiagnosed. The World Health Organization (WHO) goal of eliminating hepatitis B by 2030 seems very difficult to achieve due to the existing diagnostic infrastructure in low-resource regions. The majority of diagnostic laboratories still use hepatitis B surface antigen (HBsAg)-based tests. WHO's elimination plan is at risk of derailment due to phases like the window period, immune control, and occult HBV infection (OBI) not being detected by standard tests. Here, in this article, we are focusing on various diagnostic platforms for the better diagnosis of HBV. The aim of the elimination of HBV can only be achieved by detecting all phases of HBV infection, which can be executed by a combined approach of using new marker assays along with advanced pretesting and testing methods.
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Affiliation(s)
- Manoj Kumar
- National Institute of Biologicals, Noida 201309, India
| | - Sangeeta Pahuja
- Department of Immunohaematology and Blood Transfusion, Lady Hardinge Medical College and Associated Hospitals, New Delhi 110001, India
| | - Prashant Khare
- Center for Advanced Biotechnology Research, Xenesis Institute, 5th Floor, Plot 68, Sector 44, Gurugram 122003, India
| | - Anoop Kumar
- National Institute of Biologicals, Noida 201309, India
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Harris AM, Schillie S. Hepatitis B and Hepatitis D Viruses. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2023:1125-1133.e4. [DOI: 10.1016/b978-0-323-75608-2.00213-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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[Natural history and disease progression of chronic hepatitis B virus infection]. BEIJING DA XUE XUE BAO. YI XUE BAN = JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2022; 54. [PMID: 36241234 PMCID: PMC9568401 DOI: 10.19723/j.issn.1671-167x.2022.05.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To better understand and revise the natural history and disease progression of chronic hepatitis B virus (HBV) infection through analysis of a single-center large-scale cohort of indivi-duals with chronic HBV infection. METHODS Patients with chronic HBV infection who had undergone liver biopsy in the Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital from January 2014 to October 2020 were retrospectively recruited. Based on patient's hepatitis B e antigen (HBeAg) states and pathologic diagnosis, they were categorized into four disease progression statuses (or phases according to the old-terminology in the updated guidelines of chronic hepatitis B (CHB), such as European Association for the Study of the Liver (EASL) 2017, Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection: HBeAg-positive chronic HBV infection (immune tolerance), HBeAg-positive CHB (immune active HBeAg positive), HBeAg-negative chronic HBV infection (inactive carrier), and HBeAg-negative CHB (immune reactive HBeAg negative). Then the demographic, laboratory tests and liver histological results of the patients in different disease progression stages were compared. Age differences between the two groups were evaluated using Mann-Whitney U test. RESULTS A total of 760 eligible patients with a median age of 29 (interquartile range: 16-39) years were enrolled. Among them, 197 were underage individuals (age < 18 years) and 563 were adults; and 456 were males and 304 females. According to the pathological diagnosis, the patients were classified, and in each of the above four natural disease phases there were 173, 329, 95, and 163 individuals, respectively. Further comparison of the ages of the patients of the four disease progression statuses revealed that patients of HBeAg-negative CHB had a median age at 37 years, which was reasonably higher than those with HBeAg-positive CHB in immune active phase (37 vs. 24 years, P < 0.001), but was relatively younger than those with HBeAg-negative chronic HBV infection (37 vs. 39 years, P= 0.240). CONCLUSION According to this study, it could be speculated that HBeAg-negative CHB patients probably not all reactivate from individuals of HBeAg-negative chronic HBV infection. Instead, certain HBeAg-negative CHB patients may also come from HBeAg-positive CHB patients who have undergone HBeAg clearance or seroconversion and still remain in the immune active state.
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Zhang Z, Lu W, Huang D, Zhou X, Ding R, Li X, Wang Y, Lin W, Zeng D, Feng Y. Capabilities of hepatitis B surface antigen are divergent from hepatitis B virus DNA in delimiting natural history phases of chronic hepatitis B virus infection. Front Immunol 2022; 13:944097. [PMID: 35958621 PMCID: PMC9359073 DOI: 10.3389/fimmu.2022.944097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveQuantitative hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA in the natural history of chronic HBV infection have not been rationally evaluated. This study aimed to re-characterize quantitative HBsAg and HBV DNA in the natural history phases.MethodsA total of 595 and 651 hepatitis B e antigen (HBeAg)-positive patients and 485 and 705 HBeAg-negative patients were assigned to the early and late cohorts, respectively. Based on the ‘S-shape’ receiver operating characteristic (ROC) curves, the HBeAg-positive sub-cohorts with possibly high HBV replication (PHVR) and possibly low HBV replication (PLVR) and the HBeAg-negative sub-cohorts with possibly high HBsAg expression (PHSE) and possibly low HBsAg expression (PLSE) were designated.ResultsThe areas under the ROC curve (AUCs) of HBsAg and HBV DNA in predicting HBeAg-positive significant hepatitis activity (SHA) in the early cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.655 and 0.541, 0.720 and 0.606, and 0.553 and 0.725, respectively; those in the late cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.646 and 0.501, 0.798 and 0.622, and 0.603 and 0.674, respectively. The AUCs of HBsAg and HBV DNA in predicting HBeAg-negative SHA in the early cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.508 and 0.745, 0.573 and 0.780, and 0.577 and 0.729, respectively; those in the late cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.503 and 0.761, 0.560 and 0.814, and 0.544 and 0.722, respectively. The sensitivity and specificity of HBsAg ≤4.602 log10 IU/ml in predicting HBeAg-positive SHA in the early cohort were 82.6% and 45.8%, respectively; those in the late cohort were 87.0% and 44.1%, respectively. The sensitivity and specificity of HBV DNA >3.301 log10 IU/ml in predicting HBeAg-negative SHA in the early cohort were 73.4% and 60.8%, respectively; those in the late cohort were 73.6% and 64.1%, respectively.ConclusionQuantitative HBsAg and HBV DNA are valuable, but their capabilities are divergent in delimiting the natural history phases.
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Affiliation(s)
- Zhanqing Zhang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- *Correspondence: Zhanqing Zhang,
| | - Wei Lu
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Dan Huang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xinlan Zhou
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Rongrong Ding
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiufen Li
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yanbing Wang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Weijia Lin
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Dong Zeng
- Department of Clinical Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yanling Feng
- Department of Clinical Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
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Kim HJ, Kim JH, Yeon JE, Seo YS, Jang JW, Cho YK, Jang BK, Han BH, Lee C, Lee JH, Yoon JH, Kim KM, Kim MY, Kim DY, Park NH, Cho EY, Lee JS, Lee JW, Kim IH, Song BC, Lee BS, Kwon OS. A Multi-Center, Double-Blind Randomized Controlled Phase III Clinical Trial to Evaluate the Antiviral Activity and Safety of DA-2802 (Tenofovir Disoproxil Orotate) and Viread (Tenofovir Disoproxil Fumarate) in Chronic Hepatitis B Patients. J Korean Med Sci 2022; 37:e92. [PMID: 35315603 PMCID: PMC8938614 DOI: 10.3346/jkms.2022.37.e92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/20/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF, Viread®) had been used as a standard treatment option of chronic hepatitis B (CHB). This clinical trial was conducted to evaluate the efficacy and safety of DA-2802 (tenofovir disoproxil orotate) compared to TDF. METHODS The present study was a double blind randomized controlled trial. Patients with CHB were recruited from 25 hospitals in Korea and given DA-2802 at a dose of 319 mg once daily or Viread® at a dose of 300 mg once daily for 48 weeks from March 2017 to January 2019. Change in hepatitis B virus (HBV) DNA level at week 48 after dosing compared to baseline was the primary efficacy endpoint. Secondary efficacy endpoints were proportions of subjects with undetectable HBV DNA, those with normal alanine aminotransferase (ALT) levels, and those with loss of hepatitis B envelop antigen (HBeAg), those with loss of hepatitis B surface antigen (HBsAg). Adverse events (AEs) were also investigated. RESULTS A total of 122 patients (DA-2802 group: n = 61, Viread® group: n = 61) were used as full analysis set for efficacy analysis. Mean age, proportion of males, laboratory results and virologic characteristics were not different between the two groups. The change in HBV DNA level at week 48 from baseline was -5.13 ± 1.40 in the DA-2802 group and -4.97 ± 1.40 log10 copies/mL in the Viread® group. The analysis of primary endpoint using the nonparametric analysis of covariance showed statistically significant results (P < 0.001), which confirmed non-inferiority of DA-2802 to Viread® by a prespecified noninferiority margin of 1. The proportion of undetectable HBV DNA was 78.7% in the DA-2802 group and 75.4% in the Viread® group (P = 0.698). The proportion of subjects who had normal ALT levels was 75.4% in the DA-2802 group and 73.3% in the Viread® group (P = 0.795). The proportion of those with HBeAg loss was 8.1% in the DA-2802 group and 10.8% in the Viread® group (P = 1.000). No subject showed HBsAg loss. The frequency of AEs during treatment was similar between the two groups. Most AEs were mild to moderate in severity. CONCLUSION DA-2802 is considered an effective and safe treatment for patients with CHB. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02967939.
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Affiliation(s)
- Hyung Joon Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Ju Hyun Kim
- Department of Internal Medicine, Division of Gastroenterology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Jong Eun Yeon
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jeong Won Jang
- Department of Internal Medicine, Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yong Kyun Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Byung Hoon Han
- Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Changhyeong Lee
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Eun Young Cho
- Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Korea
| | - June Sung Lee
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - In Hee Kim
- Department of Gastroenterology, Jeonbuk National University Hospital, Jeonju, Korea
| | - Byung-Cheol Song
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
| | - Byung-Seok Lee
- Department of Internal Medicine, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Oh Sang Kwon
- Department of Internal Medicine, Division of Gastroenterology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.
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Premkumar M, Chawla YK. Should We Treat Immune Tolerant Chronic Hepatitis B? Lessons from Asia. J Clin Exp Hepatol 2022; 12:144-154. [PMID: 35068795 PMCID: PMC8766700 DOI: 10.1016/j.jceh.2021.08.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/22/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) remains a public health burden, with more than 257 million persons living with hepatitis B virus globally. Despite the availability of a safe and efficacious vaccine, access to immunization remains poor. As per current estimates, if Asian countries rely only on immunization to reduce the burden of disease, the timelines for HBV elimination will be extended to 2060-2090, a far cry from the World Health Organization's clarion call for viral hepatitis elimination by 2030. METHODS Currently, all practice guidelines lay stress on immunization, prevention of mother-to-child transmission and treatment of immune active disease or cirrhosis. In this review, we critically examine the data from the Asian cohorts, clinical and public health rationale of early treatment, risk of HCC, and assess the need for revision of guidelines. DISCUSSION Patients in the immune tolerant phase (IT) remain untreated till they meet variable age, transaminase, or fibrosis criteria, are often lost to follow up and continue transmitting the infection. With global migration patterns, immunization programmes alone cannot prevent the complications of HBV like cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). In addition, data from Asian cohorts from Taiwan and Korea suggest that HBV DNA levels are directly associated with increased risk of HCC. Histological evidence of advanced fibrosis or immune reactive T cell subsets in the IT phase also raises doubts about the viability of current guidelines that focus on age, alanine transaminase levels, and liver stiffness as markers of risk of inflammation and fibrosis. Current practice does not take into account the histological subsets with minimal inflammation, HBV genome integration or risk of HCC with high viral loads. CONCLUSION New data from Asian cohorts argue the case of expanding access to care to IT-CHB from public health and clinical perspective.
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Key Words
- ALT, alanine transaminase
- CHB, chronic hepatitis B
- HBV Elimination in India
- HBV RNA
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- IA, immune active
- IT, immune tolerant
- MTCT, mother-to-child transmission
- NA, nucleos(t)ide analogs
- PWID, persons who inject drugs
- WHO, World Health Organization
- cccDNA
- chronic hepatitis B
- hepatocellular carcinoma
- immune tolerant phase
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Affiliation(s)
- Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Yogesh K. Chawla
- Emeritus Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, India
- Address for correspondence: Prof. Yogesh K Chawla, Ex-Director (PGIMER), Former Prof, & Head, Department of Hepatology, PGIMER, Chandigarh, 160012, India.
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Sun X, Zhu Y, Tang F, Deng X, Wang Z, Liu Y. Analysis of epidemiological serosurvey of hepatitis B virus among people under 29 years of age in Jiangsu Province, China. Hum Vaccin Immunother 2021; 17:3729-3734. [PMID: 34096830 DOI: 10.1080/21645515.2021.1928461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Background: The purpose of this paper was to analyze the prevalence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core anti-body (anti-HBc)in1-29 years old living in the most populous eastern province of China,22 years after introduction of hepatitis B vaccine (HepB) vaccination of infants and provide provincial baseline data for developping a better prevention and control plan for hepatitis B virus (HBV)in Jiangsu Province, ChinaMethods: The incidence rates of HBV in Jiangsu province from 2004 to 2014 were obtained from the National Notifiable Disease Reporting System (NNDRS). A stratified cluster random sampling method was used to select 3,002 participants aged 1-29 years across 13 HBV monitoring points throughout the province, which had been classified as either urban or rural. HBV serological markers were measured by Abbott microparticle enzyme immunoassay (MEIA) kits (Abbott Laboratories, Chicago, Illinois).Results: The incidence of hepatitis B decreased by approximately 71.44% in Jiangsu province between 2004 and 2014. Serological assessments showed that the prevalence of the HBsAg, anti-HBc, and anti-HBsin the 1-29 age group were 1.20%, 5.33%,and 66.89%, respectively. There was a significantly lower prevalence of HepB who were vaccinated than in unvaccinated subjects (0.46% vs 14.93%, p < .0001). Among these the ages of 1-29, the coverage rate drops from 97.7% to 56.6% with age,andthe timely rate among people aged 1-14 years was 90.93%.Conclusions: Since the HepB was integrated into the immunization programme in Jiangsu province,the rate of hepatitis B reported and the prevalence of HBsAg decreased significantly, and the coverage of HepB and the vaccination rate within 24 hours after birth have played an important role in reducing HBV infection.
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Affiliation(s)
- Xiang Sun
- Department of Expanded Program on Immunization, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Yuanyuan Zhu
- Department of Expanded Program on Immunization, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Fenyang Tang
- Department of Expanded Program on Immunization, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Xiuying Deng
- Department of Expanded Program on Immunization, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Zhiguo Wang
- Department of Expanded Program on Immunization, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Yuanbao Liu
- Department of Expanded Program on Immunization, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
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15
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Mahamat G, Kenmoe S, Akazong EW, Ebogo-Belobo JT, Mbaga DS, Bowo-Ngandji A, Foe-Essomba JR, Amougou-Atsama M, Monamele CG, Mbongue Mikangue CA, Kame-Ngasse GI, Magoudjou-Pekam JN, Zemnou-Tepap C, Meta-Djomsi D, Maïdadi-Foudi M, Touangnou-Chamda SA, Daha-Tchoffo AG, Selly-Ngaloumo AA, Nayang-Mundo RA, Yéngué JF, Taya-Fokou JB, Fokou LKM, Kenfack-Momo R, Tchami Ngongang D, Atembeh Noura E, Tazokong HR, Demeni Emoh CP, Kengne-Ndé C, Bigna JJ, Boyomo O, Njouom R. Global prevalence of hepatitis B virus serological markers among healthcare workers: A systematic review and meta-analysis. World J Hepatol 2021; 13:1190-1202. [PMID: 34630885 PMCID: PMC8473496 DOI: 10.4254/wjh.v13.i9.1190] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/29/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The hepatitis B virus (HBV) infection is a global public health concern that affects about 2 billion people and causes 1 million people deaths yearly. HBV is a blood-borne disease and healthcare workers (HCWs) are a high-risk group because of occupational hazard to patients' blood. Different regions of the world show a highly variable proportion of HCWs infected and/or immunized against HBV. Global data on serologic markers of HBV infection and immunization in HCWs are very important to improve strategies for HBV control. AIM To determine the worldwide prevalence of HBV serological markers among HCWs. METHODS In this systematic review and meta-analyses, we searched PubMed and Excerpta Medica Database (Embase) to identify studies published between 1970 and 2019 on the prevalence of HBV serological markers in HCWs worldwide. We also manually searched for references of relevant articles. Four independent investigators selected studies and included those on the prevalence of each of the HBV serological markers including hepatitis B surface antigen (HBsAg), hepatitis e antigen (HBeAg), immunoglobulin M anti-HBc, and anti-HBs. Methodological quality of eligible studies was assessed and random-effect model meta-analysis resulted in the pooled prevalence of HBV serological markers HBV infection in HCWs. Heterogeneity (I²) was assessed using the χ² test on Cochran's Q statistic and H parameters. Heterogeneity' sources were explored through subgroup and metaregression analyses. This study is registered with PROSPERO, number CRD42019137144. RESULTS We reviewed 14059 references, out of which 227 studies corresponding to 448 prevalence data among HCWs (224936 HCWs recruited from 1964 to 2019 in 71 countries) were included in this meta-analysis. The pooled seroprevalences of current HBsAg, current HBeAg, and acute HBV infection among HCWs were 2.3% [95% confidence interval (CI): 1.9-2.7], 0.2% (95%CI: 0.0-1.7), and 5.3% (95%CI: 1.4-11.2), respectively. The pooled seroprevalences of total immunity against HBV and immunity acquired by natural HBV infection in HCWs were 56.6% (95%CI: 48.7-63.4) and 9.2% (95%CI: 6.8-11.8), respectively. HBV infection was more prevalent in HCWs in low-income countries, particularly in Africa. The highest immunization rates against HBV in HCWs were recorded in urban areas and in high-income countries including Europe, the Eastern Mediterranean and the Western Pacific. CONCLUSION New strategies are needed to improve awareness, training, screening, vaccination, post-exposure management and treatment of HBV infection in HCWs, and particularly in low-income regions.
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Affiliation(s)
- Gadji Mahamat
- Department of Microbiology, The University of Yaounde I, Yaoundé 00237, Cameroon
| | - Sebastien Kenmoe
- Virology Department, Centre Pasteur of Cameroon, Yaoundé 00237, Cameroon
| | - Etheline W Akazong
- Department of Biochemistry, University of Dschang, Dschang 00237, Cameroon
| | - Jean Thierry Ebogo-Belobo
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé 00237, Cameroon
| | - Donatien Serge Mbaga
- Department of Microbiology, The University of Yaounde I, Yaoundé 00237, Cameroon
| | - Arnol Bowo-Ngandji
- Department of Microbiology, The University of Yaounde I, Yaoundé 00237, Cameroon
| | | | - Marie Amougou-Atsama
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institut de Recherches Médicales et d'Etudes des Plantes Médicinales, Yaoundé 00237, Cameroon
| | | | | | - Ginette Irma Kame-Ngasse
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé 00237, Cameroon
| | | | - Cromwel Zemnou-Tepap
- Department of Biochemistry, The University of Yaounde I, Yaoundé 00237, Cameroon
| | - Dowbiss Meta-Djomsi
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institut de Recherches Médicales et d'Etudes des Plantes Médicinales, Yaoundé 00237, Cameroon
| | - Martin Maïdadi-Foudi
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institut de Recherches Médicales et d'Etudes des Plantes Médicinales, Yaoundé 00237, Cameroon
| | | | | | | | | | | | | | - Lorraine K M Fokou
- Department of Biochemistry, The University of Yaounde I, Yaoundé 00237, Cameroon
| | - Raoul Kenfack-Momo
- Department of Biochemistry, The University of Yaounde I, Yaoundé 00237, Cameroon
| | | | - Efietngab Atembeh Noura
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé 00237, Cameroon
| | - Hervé Raoul Tazokong
- Department of Microbiology, The University of Yaounde I, Yaoundé 00237, Cameroon
| | | | - Cyprien Kengne-Ndé
- Evaluation and Research Unit, National AIDS Control Committee, Yaoundé 00237, Cameroon
| | - Jean Joel Bigna
- Department of Epidemiology and Public Health, Centre Pasteur of Cameroon, Yaoundé 00237, Cameroon
| | - Onana Boyomo
- Department of Microbiology, The University of Yaounde I, Yaoundé 00237, Cameroon
| | - Richard Njouom
- Virology Department, Centre Pasteur of Cameroon, Yaoundé 00237, Cameroon.
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16
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Liu Y, Zhu P, Wang W, Tan X, Liu C, Chen Y, Pei R, Cheng X, Wu M, Guo Q, Liang H, Liang Z, Liu J, Xu Y, Wu X, Weng X. Mucosal-Associated Invariant T Cell Dysregulation Correlates With Conjugated Bilirubin Level in Chronic HBV Infection. Hepatology 2021; 73:1671-1687. [PMID: 33080074 DOI: 10.1002/hep.31602] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 09/09/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Mucosal-associated invariant T (MAIT) cells are nonconventional T cells restricted to major histocompatibility complex class I-related protein 1 (MR1). They are highly abundant in human liver and activated by T-cell receptor (TCR)-dependent and TCR-independent mechanisms to exhibit rapid, innate-like effector responses. However, the roles of MAIT cells in chronic HBV infection are still open for study. This study aims to test their antiviral potential and investigate their dynamic changes and regulating factors during chronic HBV infection. APPROACH AND RESULTS Blood samples from 257 chronic HBV-infected patients were enrolled, and nontumor liver specimens were collected from 58 HBV-infected HCC patients. Combining cell-culture experiments and human data, we showed that MAIT cells had strong cytotoxicity against HBV-transfected hepatocytes in an MR1-dependent way. However, circulating and hepatic MAIT cells in HBV-infected patients decreased significantly compared to controls. Correlation analysis suggested that MAIT cell frequency was associated with disease progression and inversely correlated with serum-conjugated bilirubin level. In particular, conjugated bilirubin not only directly promoted MAIT cell activation and apoptosis, but also impaired TCR-induced proliferation and expansion of MAIT cells, which could be partially rescued by IL-2 in the absence of conjugated bilirubin. Despite that MAIT cells from patients with high conjugated bilirubin levels showed decreased cytokine-producing capacity, the increased TCR-dependent antiviral cytokine production suggested MAIT cells as an important guardian of chronic HBV with high conjugated bilirubin. CONCLUSIONS We reveal the MR1-dependent, anti-HBV potential of MAIT cells and identify conjugated bilirubin as a major factor dysregulating its frequency and function in chronic HBV-infected patients, suggesting a therapeutic target for MAIT-cell-based immunity against chronic HBV infection.
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Affiliation(s)
- Yu Liu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,School of Nursing, Nanchang University, Nanchang, China
| | - Peng Zhu
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaosheng Tan
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Yingshan Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Rongjuan Pei
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Xue Cheng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mi Wu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Guo
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongmei Liang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihui Liang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Science and Technology, Wuhan, China
| | - Yang Xu
- Department of Microbiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiongwen Wu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiufang Weng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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17
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Ben Dhifallah I, Ayouni K, Jmel H, Kammoun W, Hamzaoui K, Sadraoui A, Triki H. Strong association of functional polymorphism in IL-12B with susceptibility to chronic hepatitis B in Tunisia. J Med Virol 2021; 93:4949-4956. [PMID: 33739474 DOI: 10.1002/jmv.26946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The chronicity or clearance of hepatitis B virus (HBV) infection depends on viral and genetic variables. The immune response against HBV is thought to be responsible for viral persistence or clearance. Cytokines such as interleukin 1-2B (IL1-2B) involved in the T-helper 1 system are key mediators in the defence mechanisms against viral infection and play a role in the regulation of HBV clearance during infection. We aimed to examine whether the polymorphic variant TaqI polymorphism in the 3'-untranslated region (3'-UTR; rs3212227) suspected to modulate interleukin-levels of IL-12B has an influence on the risk of development of chronicity after HBV exposure. METHODS Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method for 236 patients with chronic hepatitis B (CHB) and 240 controls from different cities of Tunisia recruited in the Pasteur Institute of Tunisia between January 2017 and December 2018. RESULTS We found that the IL-12B polymorphism was associated with a significantly increased risk of CHB in patients (p = 1 × 10-3 ; χ 2 = 10.31 and odds ratio [OR] = 2.14; 95% confidence interval [CI] = 1.30-3.52) when AC/CC variant genotypes were compared with the wild-type AA homozygote. Statistical significance was found when CHB-males were compared with CHB-females (p = 2 × 10-7 ; χ 2 = 26.62 and p = 1 × 10-3 ; χ 2 = 10.36, for genotypic and allelic frequencies, respectively). Also, CHB-patients carrying C-allele less than 50-years were at an increased risk of developing chronic HBV infection than patients more than 50-years (p = 6.1 × 10-5 ; χ 2 = 16.07). CONCLUSIONS These results suggest that the C-allele would affect susceptibility to chronicity after HBV exposure in Tunisian patients especially for males less than 50-years. Age and sex have an influence on this polymorphism in CHB Tunisian patients.
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Affiliation(s)
- Imène Ben Dhifallah
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Kaouther Ayouni
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia.,Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Haifa Jmel
- Laboratory of Biomedical Genomics and Oncogenetics, Pasteur Institute Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Wafa Kammoun
- Laboratory of Biomedical Genomics and Oncogenetics, Regional Training Center supported by WHO-TDR for East Mediterranean Region (EMR), Pasteur Institute, Tunis, Tunisia
| | - Kamel Hamzaoui
- Department of Basic Sciences Histology, Immunology and cell Biology, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Amel Sadraoui
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Henda Triki
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
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18
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:819-837.e6. [DOI: 10.1016/b978-0-323-67293-1.00075-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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19
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Kouenkam JPII, Mbang J, Emvudu Y. Global dynamics of a model of hepatitis B virus infection in a sub-Saharan African rural area. INT J BIOMATH 2020. [DOI: 10.1142/s1793524520500540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We formulate and systematically study a deterministic compartmental model of Hepatitis B. This model has some important and novel features compared with the well-known basic model in the literature. Specifically, it takes into account the differential susceptibility that follows the vaccine formulation employing three-doses schedule. It points up the HbeAg status of carriers, their levels of viral replication, the fact that treatment being not curative is recommended only to a small proportion of chronic carriers, and finally the fact that only inactive carriers are able to recover from disease. The model has simple dynamical behavior which has a globally asymptotically stable disease-free equilibrium when the basic reproduction number [Formula: see text] and an endemic equilibrium when [Formula: see text]. By the use of Lyapunov functions, when it exists, we prove the global asymptotic stability of the endemic equilibrium under some conditions. Using data from Tokombere, a rural area in Cameroon, numerical simulations are performed. These numerical simulations first confirm analytical results, second they suggest that a policy based on treatment could not significantly impact the course of the infection. Third, they show as it is well known that vaccination is a very effective measure to control the infection. Furthermore, they show that neonatal vaccination influences more the course of infection than mass vaccination strategy. Nevertheless, they picture how much loss between consecutive doses of vaccine could be harmful. Finally, it is suggested that for a Sub-saharan African rural area, two-thirds of expected incidence of Hepatitis B virus infection and one third of expected prevalence of chronic carriers could be averted by 2030 if the birth dose vaccination becomes systematic and if mass vaccination rate increases to up 10%.
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Affiliation(s)
- Jean Pierre II Kouenkam
- Department of Mathematics, Faculty of Science, University of Yaounde I, P. O. Box 812 Yaounde, Cameroon
| | - Joseph Mbang
- Department of Mathematics, Faculty of Science, University of Yaounde I, P. O. Box 812 Yaounde, Cameroon
- UMI 209 IRD/UPMC UMMISCO, Bondy, Projet MASAIE INRIA Grand Est, France and Projet GRIMCAPE, LIRIMA, Cameroun
| | - Yves Emvudu
- Department of Mathematics, Faculty of Science, University of Yaounde I, P. O. Box 812 Yaounde, Cameroon
- UMI 209 IRD/UPMC UMMISCO, Bondy, Projet MASAIE INRIA Grand Est, France and Projet GRIMCAPE, LIRIMA, Cameroun
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20
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KHAN MUHAMMADALTAF, SHAH SYEDAZHARALI, ULLAH SAIF, OKOSUN KAZEEMOARE, FAROOQ MUHAMMAD. OPTIMAL CONTROL ANALYSIS OF THE EFFECT OF TREATMENT, ISOLATION AND VACCINATION ON HEPATITIS B VIRUS. J BIOL SYST 2020. [DOI: 10.1142/s0218339020400057] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Hepatitis B infection is a serious health issue and a major cause of deaths worldwide. This infection can be overcome by adopting proper treatment and control strategies. In this paper, we develop and use a mathematical model to explore the effect of treatment on the dynamics of hepatitis B infection. First, we formulate and use a model without control variables to calculate the basic reproduction number and to investigate basic properties of the model such as the existence and stability of equilibria. In the absence of control measures, we prove that the disease free equilibrium is locally asymptotically stable when the basic reproduction number is less than unity. Also, using persistent theorem, it is shown that the infection is uniformly persistent, whenever the basic reproduction number is greater than unity. Using optimal control theory, we incorporate into the model three time-dependent control variables and investigate the conditions required to curtail the spread of the disease. Finally, to illustrate the effectiveness of each of the control strategies on disease control and eradication, we perform numerical simulations. Based on the numerical results, we found that the first two strategies (treatment and isolation strategy) and (vaccination and isolation strategy) are not very effective as a long term control or eradication strategy for HBV. Hence, we recommend that in order to effectively control the disease, all the control measures (isolation, vaccination and treatment) must be implemented at the same time.
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Affiliation(s)
- MUHAMMAD ALTAF KHAN
- Informetrics Research Group, Ton Duc Thang University, Ho Chi Minh City, Vietnam
- Faculty of Mathematics and Statistics, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - SYED AZHAR ALI SHAH
- Department of Mathematics, University of Peshawar, Khyber Pakhtunkhwa, Pakistan
| | - SAIF ULLAH
- Department of Mathematics, University of Peshawar, Khyber Pakhtunkhwa, Pakistan
| | | | - MUHAMMAD FAROOQ
- Department of Mathematics, University of Peshawar, Khyber Pakhtunkhwa, Pakistan
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21
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Ben Dhifallah I, Ayouni K, Najjar G, Chelbi H, Sadraoui A, Hammami W, Touzi H, Triki H. Interleukin IL-1B gene polymorphism in Tunisian patients with chronic hepatitis B infection: Association with replication levels. Microbiol Immunol 2020; 64:512-519. [PMID: 31944355 DOI: 10.1111/1348-0421.12774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/16/2019] [Accepted: 01/10/2020] [Indexed: 12/20/2022]
Abstract
Approaches based on association studies have proven useful in identifying genetic predictors for many diseases, including susceptibility to chronic hepatitis B. In this study we were interested by the IL-1B genetic variants that have been involved in the immune response and we analyzed their role in the susceptibility to develop chronic hepatitis B in the Tunisian population. IL-1B is a potent proinflammatory cytokine that plays an important role in inflammation of the liver. Polymorphic gene IL-1 (-511, +3954) was analyzed in a total of 476 individuals: 236 patients with chronic hepatitis B from different cities of Tunisia recruited in Pasteur Institute between January 2017 and December 2018 and 240 controls. Genomic DNA was obtained using the standard salting-out method and genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism. For -511C>T polymorphism a significant association was found between patients and controls when comparing the genotypic (P = 0.007; χ2 = 9.74 and odds ratio [OR] = 0.60; confidence interval [CI] = 0.41-0.89) and allelic (P = 0.001; χ2 = 10.60) frequencies. When the viral load was taken into account a highly significant difference was found (P = 9 × 10-4 ; χ2 = 10.89). For +3954C>T polymorphism a significant association was found between patients and controls when comparing genotypic (P = 0.0058; χ2 = 7.60 and OR = 1.67; CI = 1.14-2.46) and allelic (P = 0.0029; χ2 = 8.81) frequencies. T allele can be used as a strong marker for hepatitis B virus disease for both polymorphisms.
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Affiliation(s)
- Imen Ben Dhifallah
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Kaouther Ayouni
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia.,Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Ghofrane Najjar
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Hanene Chelbi
- Medical Parasitology, Biotechnology and Biomolecules, Pasteur Institute of Tunis, Tunis, Tunisia
| | - Amel Sadraoui
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Walid Hammami
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Henda Touzi
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Henda Triki
- Laboratory of Clinical Virology, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia
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22
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Fu B, Ji Y, Hu S, Ren T, Bhuva MS, Li G, Yang H. Efficacy and safety of anti-viral therapy for Hepatitis B virus-associated glomerulonephritis: A meta-analysis. PLoS One 2020; 15:e0227532. [PMID: 31940324 PMCID: PMC6961902 DOI: 10.1371/journal.pone.0227532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 12/21/2019] [Indexed: 12/14/2022] Open
Abstract
Objectives To assess the potency of anti-viral treatment for hepatitis B virus-associated glomerulonephritis (HBV-GN). Method: We searched for controlled clinical trials on anti-viral therapy for HBV-GN in MEDLINE, Embase, the Cochrane Library, and PubMed from inception to March 11th 2019. Seven trials, including 182 patients met the criteria for evaluating. The primary outcome measures were proteinuria and changes in the estimated glomerular filtration rate, and the secondary outcome measure was hepatitis B e-antigen clearance. A fixed or random effect model was established to analyze the data. Subgroup analyses were performed to explore the effects of clinical trial type, anti-viral drug type, age, and follow-up duration. Results The total remission rate of proteinuria (OR = 10.48, 95% CI: 4.60−23.89, I2 = 0%), complete remission rate of proteinuria (OR = 11.64, 95% CI: 5.17−26.21, I2 = 23%) and clearance rate of Hepatitis Be Antigen (HBeAg) were significantly higher in the anti-viral treatment group than in the control group (OR = 27.08, 95% CI: 3.71−197.88, I2 = 63%). However, antiviral therapy was not as effective regarding the eGFR (MD = 5.74, 95% CI: -4.24−15.73). In the subgroup analysis, age and drug type had significant impacts on proteinuria remission, and study type and follow-up duration only slightly affected the heterogeneity. Conclusion Antiviral therapy induced remission of proteinuria and increased HBeAg clearance but failed to improve the eGFR. Pediatric patients were more sensitive to antiviral therapy than adults. IFNs seem more effective but are accompanied by more adverse reactions than NAs.
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Affiliation(s)
- Baohui Fu
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yue Ji
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shouci Hu
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Zhejiang, China
| | - Tong Ren
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Maheshkumar Satishkumar Bhuva
- International Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China
| | - Ge Li
- Public Health Science and Engineering College, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- * E-mail: (HY); (GL)
| | - Hongtao Yang
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- * E-mail: (HY); (GL)
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23
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Yue X, Jiang X, Zou H, Li G, Wang J, Liu Y. Association of hepatocellular carcinoma risk with polymorphisms in tumour necrosis factor alpha gene in a Chinese Han population. Int J Immunogenet 2020; 47:286-293. [PMID: 31943768 DOI: 10.1111/iji.12474] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 12/06/2019] [Accepted: 12/21/2019] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Studies have shown that the tumour necrosis factor alpha (TNF-α) plays an important role in the development of HCC; however, the association between genetic variations of TNF-α and HCC is not yet fully understood. To evaluate the correlation of TNF-α polymorphisms with HCC, we randomly selected 327 HCC patients and 432 healthy controls, all these subjects reported Han nationality. Genotyping of four TNF-α SNPs (rs1799724, rs1800629, rs1799964 and rs1800610) was performed using the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) method. Distributions of rs1799964 genotypes and rs1800610 alleles were found to be significantly different between cases and controls (p = .011, p = .001). The recessive model of rs1799964 significantly increased HCC risk (p = .0015), while the dominant and over-dominant models of rs1800610 significantly reduced HCC risk (p = .0096, p = .014). Haplotype analysis of the four TNF-α SNPs revealed that the TGTA haplotype was associated with a reduced HCC risk (p = .0033, OR = 0.53), while the TGTG haplotype was associated with an increased HCC risk (p = .0032, OR = 9.69). These findings indicated that specific TNF-α polymorphisms may be associated with the susceptibility to HCC.
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Affiliation(s)
- Xin Yue
- Department of Radiology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
| | - Hongjiu Zou
- Changchun International Travel Healthcare Center, Changchun, China
| | - Gaokai Li
- Department of Toxicology, School of Public Health, Jilin University, Changchun, China
| | - Jinan Wang
- Department of Radiology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Ying Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun, China
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24
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Dietrich CF, Teufel A, Sirlin CB, Dong Y. Surveillance of hepatocellular carcinoma by medical imaging. Quant Imaging Med Surg 2019; 9:1904-1910. [PMID: 31867241 PMCID: PMC6902144 DOI: 10.21037/qims.2019.10.04] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 10/05/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Christoph F. Dietrich
- Sino-German Tongji-Caritas Research Center of Ultrasound in Medicine, Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Department of Internal Medicine II, Caritas-Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany
| | - Andreas Teufel
- Division of Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, CA, USA
| | - Yi Dong
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200433, China
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25
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Khan T, Ahmad S, Zaman G. Modeling and qualitative analysis of a hepatitis B epidemic model. CHAOS (WOODBURY, N.Y.) 2019; 29:103139. [PMID: 31675818 DOI: 10.1063/1.5111699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/07/2019] [Indexed: 06/10/2023]
Abstract
We develop an epidemic mathematical model for hepatitis B contagious disease, which is one of the major causes of death among various infectious diseases. We prove the existence, positivity, and biological feasibility of the model. We find the threshold quantity of the model and analyze the sensitivity analysis to show the effect of various parameters on the spread of hepatitis B virus. Exploiting the linear stability approach, we find stability conditions to perform the stability analysis. We use the central manifold theory to discuss the existence of backward bifurcation of the proposed model. Finally, we present numerical simulations to verify the analytical calculations and to analyze the sensitivity of parameters.
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Affiliation(s)
- Tahir Khan
- Department of Mathematics, University of Malakand, Chakdara, Dir Lower, Khyber Pakhtunkhawa 18800, Pakistan
| | - Saeed Ahmad
- Department of Mathematics, University of Malakand, Chakdara, Dir Lower, Khyber Pakhtunkhawa 18800, Pakistan
| | - Gul Zaman
- Department of Mathematics, University of Malakand, Chakdara, Dir Lower, Khyber Pakhtunkhawa 18800, Pakistan
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26
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Xie Y, Yi W, Zhang L, Lu Y, Hao HX, Gao YJ, Ran CP, Lu HH, Chen QQ, Shen G, Wu SL, Chang M, Ping-Hu L, Liu RY, Sun L, Wan G, Li MH. Evaluation of a logistic regression model for predicting liver necroinflammation in hepatitis B e antigen-negative chronic hepatitis B patients with normal and minimally increased alanine aminotransferase levels. J Viral Hepat 2019; 26 Suppl 1:42-49. [PMID: 31380591 DOI: 10.1111/jvh.13163] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 05/15/2019] [Indexed: 12/26/2022]
Abstract
Liver necroinflammation is the indicator for treating patients with chronic hepatitis B (CHB) infection. However, there is no suitable non-invasive index for diagnosing liver necroinflammation. This study aimed to create a non-invasive index to predict liver necroinflammation in patients who lack clear-cut clinical inflammation parameters. Patients who were hepatitis B e antigen (HBeAg)-negative and underwent liver histological diagnosis, had a normal or minimally increased alanine aminotransferase (ALT) level were enrolled. Liver necroinflammation was defined as histological active index ≥4. A logistic regression model (LRM) was established based on the parameters independently associated with liver necroinflammation. Of all 550 patients, 36.73% had necroinflammation. In patients with an abnormal ALT level, the rate of necroinflammation was 52.49%. The area under the curve (AUC) of the ALT level for predicting necroinflammation was 0.655 (95% confidence interval [CI], 0.609-0.702), and that of the HBV DNA level ≥2000 IU/mL combined with an abnormal ALT level was 0.618. By using the LRM, the AUC improved to 0.769 (95% CI, 0.723-0.815) with a Youden index of 0.519 and diagnostic accuracy of 75.3%. The cutoff value ≥0.7 in the LRM had a specificity of 97.4% and positive predictive value of 85.0% for predicting necroinflammation. By using the cutoff value <0.15 in the LRM, the presence of necroinflammation could be excluded with a negative predictive value of 90.8%. This study indicated that the LRM can be used to effectively diagnose liver necroinflammation in HBeAg-negative patients with CHB who have normal or minimally elevated ALT levels.
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Affiliation(s)
- Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hong-Xiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuan-Jiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chong-Ping Ran
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hui-Hui Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Qi-Qi Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shu-Ling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ming Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lei Ping-Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Rui-Yu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lei Sun
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Gang Wan
- Medical Records and Statistics Department, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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27
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Paccoud O, Surgers L, Lacombe K. [Hepatitis B virus infection: Natural history, clinical manifestations and therapeutic approach]. Rev Med Interne 2019; 40:590-598. [PMID: 30982550 DOI: 10.1016/j.revmed.2019.03.333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/16/2019] [Accepted: 03/23/2019] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis B infection remains a major public-health problem, with approximately 260 million world-wide cases of infection. Recent advances in the understanding of the natural history of chronic hepatitis B infection have led to progress in the care of infected patients. Sustained viral suppression is now possible for a majority of treated patients and is associated with a decrease in the morbidity and mortality attributable to cirrhosis and hepatocellular carcinoma. Complete cure is however not yet possible, due to the long-term persistence of viral DNA in hepatocytes of treated patients. Assessing the risk of viral reactivation in patients receiving immunosuppressive therapy is an increasingly frequent situation in clinical practice and its management is guided by both the patient's serological status and the potency of the immunosuppressive regimen. This review aims to present the clinical and biological presentations of chronic hepatitis B infection, the modalities of antiviral treatment, and how to assess the risk of viral reactivation in patients receiving immunosuppressive therapy.
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Affiliation(s)
- O Paccoud
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France
| | - L Surgers
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France; Sorbonne université, CIMI équipe 13, Inserm U1135, 75005 Paris, France
| | - K Lacombe
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France; Sorbonne université, Inserm UMR-S1136, IPLESP, 75005 Paris, France.
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28
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Khan T, Zaman G, Chohan MI. The transmission dynamic of different hepatitis B-infected individuals with the effect of hospitalization. JOURNAL OF BIOLOGICAL DYNAMICS 2018; 12:611-631. [PMID: 30047315 DOI: 10.1080/17513758.2018.1500649] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 07/09/2018] [Indexed: 06/08/2023]
Abstract
We propose an epidemic model for the transmission of hepatitis B virus along with the classification of different infection phases and hospitalized class. We formulate the model and discuss its basic mathematical properties, e.g. existence, positivity, and biological feasibility. Exploiting the next generation matrix approach, we find the basic reproductive number of the model. We perform sensitivity analysis to illustrate the effect of various parameters on the transmission of the disease. We investigate stability of the equilibria of the model in terms of the basic reproduction number. Conditions for the stability of the proposed model are obtained using various approaches. Finally, we perform the numerical simulations to discuss sensitivity analysis and to support our analytical work.
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Affiliation(s)
- Tahir Khan
- a Department of Mathematics , University of Malakand , Chakdara , Khyber Pakhtunkhwa , Pakistan
| | - Gul Zaman
- a Department of Mathematics , University of Malakand , Chakdara , Khyber Pakhtunkhwa , Pakistan
| | - Muhammad Ikhlaq Chohan
- b Department of Business Administration and Accounting , Buraimi University College , Al-Buraimi , Oman
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29
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Long JD, Rutledge SM, Sise ME. Autoimmune Kidney Diseases Associated with Chronic Viral Infections. Rheum Dis Clin North Am 2018; 44:675-698. [PMID: 30274630 DOI: 10.1016/j.rdc.2018.06.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autoimmune kidney diseases triggered by viruses are an important cause of kidney disease in patients affected by chronic viral infection. Hepatitis B virus (HBV) infection is associated with membranous nephropathy and polyarteritis nodosa. Hepatitis C virus (HCV) infection is a major cause of cryoglobulinemic glomerulonephritis. Patients with human immunodeficiency virus (HIV) may develop HIV-associated nephropathy, a form of collapsing focal segmental glomerulosclerosis, or various forms of immune-complex-mediated kidney diseases. This article summarizes what is known about the pathogenesis, diagnosis, and management of immune-mediated kidney diseases in adults with chronic HBV, HCV, and HIV infections.
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Affiliation(s)
- Joshua D Long
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, 55 Fruit Street, GRB 7, Boston, MA 02114, USA
| | - Stephanie M Rutledge
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, 55 Fruit Street, GRB 7, Boston, MA 02114, USA
| | - Meghan E Sise
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, 55 Fruit Street, GRB 7, Boston, MA 02114, USA.
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30
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Fung J, Cheung KS, Wong DKH, Mak LY, To WP, Seto WK, Lai CL, Yuen MF. Long-term outcomes and predictive scores for hepatocellular carcinoma and hepatitis B surface antigen seroclearance after hepatitis B e-antigen seroclearance. Hepatology 2018. [PMID: 29534307 DOI: 10.1002/hep.29874] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
UNLABELLED The significance of hepatitis B e-antigen (HBeAg) seroclearance (ESC) in the long term is not well defined. The current study aimed to determine the clinical outcomes, the factors and predictive scores for hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) seroclearance of a large cohort of patients undergoing ESC. Patients with documented ESC were followed up 3- to 6-monthly. Baseline characteristics and longitudinal laboratory results were recorded. Predictive scores for HCC (HCC-ESC) and HBsAg seroclearance (HBsAg-ESC) were derived from multivariate Cox regression models. A total of 723 patients underwent ESC with a median ESC age and follow-up of 36.0 and 18.3 years, respectively. Only 3.5% and 3.0% had persistently normal alanine aminotransferase (ALT) and HBV DNA <2logs IU/mL, respectively, after ESC. For patients with 100%, 100%-90%, 90%-50%, 50%-10%, 10%-0%, and 0% normal ALT after HBeAg seroclearance, the rate of HCC was 4.3%, 2.2%, 3.6%, 3.9%, 17.3%, and 37.2% at 20 years after ESC, respectively (P < 0.001). At 20 years after ESC, the cumulative incidence of HCC and HBsAg seroclearance was 7.9% and 13.5%, respectively, with an overall survival of 91.5%. ESC age, male sex, cirrhosis, hypoalbuminemia, viral load, and ALT were significant factors for HCC, whereas ESC age, male sex, viral load, and antiviral therapy were significant factors for HBsAg seroclearance. The area under receiver operating characteristics for HCC-ESC and HBsAg-ESC scores to predict HCC and HBsAg seroclearance at 20 years after ESC was 0.92 and 0.74, respectively. CONCLUSION Male sex, older age at ESC, ALT, and higher level of HBV DNA were associated with higher rates of HCC after ESC. HCC-ESC and HBsAg-ESC predictive scores can determine the likelihood of developing HCC and achieving HBsAg seroclearance. (Hepatology 2018).
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Affiliation(s)
- James Fung
- Department of Medicine, The University of Hong Kong, Hong Kong SAR.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR
| | - Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Hong Kong SAR.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Wai-Pan To
- Department of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong SAR.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Hong Kong SAR.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong SAR.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR
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31
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Jiang H, Cao F, Cao H, Rao Q, Yang Y. Associations of human leukocyte antigen and interleukin-18 gene polymorphisms with viral load in patients with hepatitis B infection. Medicine (Baltimore) 2018; 97:e11249. [PMID: 30045250 PMCID: PMC6078658 DOI: 10.1097/md.0000000000011249] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
This study aimed to assess the associations of human leukocyte antigen (HLA)-DR and interleukin (IL)-18 gene polymorphisms with hepatitis B virus (HBV).Clinical data were retrospectively reviewed between December 2006 and December 2015 at Xiangyang Central Hospital. HBV patients were assigned to the high and low viral load groups, respectively, according to HBV copies. HLA-DRB1*03 polymorphisms and IL-18 polymorphisms were detected by sequence-specific primer-polymerase chain reaction (PCR-SSP) and PCR-ligase detection reaction (PCR-LDR), respectively. T cell subgroups were identified by flow cytometry, and IL-18, IL-12, interferon-γ (IFN-γ), IL-4, and IL-10 expression levels were assessed by ELISA. A total of 630 subjects were included in the analysis.Compared with healthy controls, the chronic HBV group showed significantly lower IL-18 (P < .001), IL-12 (P < .001), and IFN-γ (P < .001) expression levels, and markedly increased IL-4 (P < .001) and IL-10 (P < .001) amounts. Th2 cytokine expression was high in HLA-DRB1*03 positive (+) HBV patients, with low Th1 cytokine levels. The ratios of CD4+/CD8+ and Th1/Th2 cells decreased with increasing HBV DNA levels. The chronic HBV group showed a relatively high frequency of -137G in the IL-18 gene, while IL-18 expression was low in homozygous GG genotype individuals.Polymorphisms in the HLA-DRB1*03 and IL-18 genes are associated with viral load in HBV. HLA-DRB1 and IL-18 gene polymorphisms are involved in the regulation of the Th1/Th2 balance and expression of relevant cytokines that influence immune responses in HBV.
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Affiliation(s)
| | | | - Hong Cao
- Department of Clinical Laboratory
| | - Qun Rao
- Department of Clinical Laboratory
| | - Ying Yang
- Department of Gastroenterology, Hospital Affiliated to Hubei University of Arts and Science, Xiangyang, Hubei, People's Republic of China
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32
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Hesari A, Ghasemi F, Salarinia R, Biglari H, Tabar Molla Hassan A, Abdoli V, Mirzaei H. Effects of curcumin on NF-κB, AP-1, and Wnt/β-catenin signaling pathway in hepatitis B virus infection. J Cell Biochem 2018; 119:7898-7904. [PMID: 29923222 DOI: 10.1002/jcb.26829] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 02/28/2018] [Indexed: 12/30/2022]
Abstract
Curcumin is a yellow-orange powder derived from the Curcuma longa plant. Curcumin has been used extensively in traditional medicine for centuries. This component is non-toxic and shown different therapeutic properties such as anti-inflammatory, anti-cancer, antiviral, anti-bacterial, anti-fungal, anti-parasites, and anti-oxidant. Hepatitis B virus (HBV) is a small DNA member of the genus Orthohepadnavirus (Hepadnaviridae family) which is a highly contagious blood-borne viral pathogen. HBV infection is a major public health problem with 2 billion people infected throughout the world and 350 million suffering from chronic HBV infection. Increasing evidence indicated that curcumin as a natural product could be employed in the treatment of HBV patients. It has been showed that curcumin exerts its therapeutic effects on HBV patients via targeting a variety of cellular and molecular pathways such as Wnt/β-catenin, Ap1, STAT3, MAPK, and NF-κB signaling. Here, we summarized the therapeutic effects of curcumin on patients who infected with HBV. Moreover, we highlighted main signaling pathways (eg, NF-κB, AP1, and Wnt/β-catenin signaling) which affected by curcumin in HBV infections.
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Affiliation(s)
- AmirReza Hesari
- Faculty of Medicine, Department of Biotechnology, Arak University of Medical Sciences, Arak, Iran
| | - Faezeh Ghasemi
- Faculty of Medicine, Department of Biotechnology, Arak University of Medical Sciences, Arak, Iran
| | - Reza Salarinia
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hamed Biglari
- Department of Environmental Health Engineering, School of Public Health, Gonabad University of Medical Sciences, Gonabad, Iran
| | | | - Vali Abdoli
- Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Hamed Mirzaei
- Department of Biomaterials, Tissue Engineering and Nanotechnology, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Liu W, Guo TF, Jing ZT, Yang Z, Liu L, Yang YP, Lin X, Tong QY. Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway. FASEB J 2018; 32:3033-3046. [PMID: 29401603 DOI: 10.1096/fj.201701144r] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hepatitis B virus core protein (HBc) is expressed preferentially in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). HBc can function as an oncogene arising from its gene regulatory properties, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of HBc during HBV-associated hepatocellular tumorigenesis. HBc increased tumor formation of hepatoma cells. Moreover, expression of HBc specifically promoted proliferation of hepatoma cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal switch from inactive Src to the active form of the kinase by HBc. HBc-mediated sarcoma (Src) kinase activation was associated with down-regulation of C-terminal Src kinase (Csk). In addition, HBc enhances Src expression by activation of alternative Src 1A promoter in an Sp1 transcription factor-dependent manner. Proliferation induced by stable HBc expression was associated with increased G1-S cell cycle progression mediated by Src kinase activation. HBc-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that HBc promotes tumorigenesis of hepatoma cells by enhancing the expression of total Src and the active form of the kinase and subsequently activates Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis.-Liu, W., Guo, T.-F., Jing, Z.-T., Yang, Z., Liu, L., Yang, Y.-P., Lin, X., Tong, Q.-Y. Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway.
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Affiliation(s)
- Wei Liu
- Institute of Digestive Disease, China Three Gorges University, Yichang, China
- Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China; and
| | - Teng-Fei Guo
- Institute of Digestive Disease, China Three Gorges University, Yichang, China
| | - Zhen-Tang Jing
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Zhi Yang
- Institute of Digestive Disease, China Three Gorges University, Yichang, China
- Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China; and
| | - Lei Liu
- Institute of Digestive Disease, China Three Gorges University, Yichang, China
- Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China; and
| | - Yuan-Ping Yang
- Institute of Digestive Disease, China Three Gorges University, Yichang, China
- Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China; and
| | - Xu Lin
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Qiao-Yun Tong
- Institute of Digestive Disease, China Three Gorges University, Yichang, China
- Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China; and
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Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018; 67:1560-1599. [PMID: 29405329 PMCID: PMC5975958 DOI: 10.1002/hep.29800] [Citation(s) in RCA: 2780] [Impact Index Per Article: 397.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 01/11/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Norah A Terrault
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, CA
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Brian J McMahon
- Liver Diseases and Hepatitis Program, Alaska NativeTribal Health Consortium, Anchorage, AK
| | - Kyong-Mi Chang
- Division of Gastroenterology, Corporal Michael J. Crescenz VA Medical Center & University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Jessica P Hwang
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Maureen M Jonas
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | | | - John B Wong
- Division of Clinical Decision Making, Tufts Medical Center, Tufts University School of Medicine, Boston, MA
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Wu Z, Yao J, Bao H, Chen Y, Lu S, Li J, Yang L, Jiang Z, Ren J, Xu KJ, Ruan B, Yang SG, Xie TS, Li Q. The effects of booster vaccination of hepatitis B vaccine on children 5-15 years after primary immunization: A 5-year follow-up study. Hum Vaccin Immunother 2018; 14:1251-1256. [PMID: 29337651 DOI: 10.1080/21645515.2018.1426419] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The aim of this study was to evaluate changes in hepatitis B surface antibody titers (anti-HBs) after booster vaccinations in children aged 5-15 y and to provide suitable immunization strategies. A total of 2208 children were initially enrolled in screening, and 559 children were finally included. The participants were divided into 2 groups according to their pre-booster anti-HBs levels: Group I, <10 mIU/ml and Group II, ≥10 mIU/ml. Group I was administered 3 doses of booster hepatitis B vaccine (0-1-6 months, 10 μg), and Group II was administered 1 dose of booster hepatitis B vaccine (10 μg). The antibody titer changes were examined at 4 time points: 1 month after dose 1 and dose 3, and 1 year and 5 years after dose 3. The protective seroconversion rates at those points were 95.65%, 99.67%, 97.59% and 91.05% (p < 0.001), respectively, in Group I, and 100.00%, 99.87%, 99.66% and 98.21% (χ2 = 6.04, p = 0.11), respectively, in Group II. The GMT in subjects aged 5-9 y were higher than that in subjects aged 10-15 y in both Group I and Group II at 1 month after dose 1, but no difference was observed at the other three time points. This study demonstrates that booster vaccination has a good medium-term effect. A booster dose for subjects with protective antibodies is not necessary but effective, and 3 doses of hepatitis B vaccination are recommended for those who have lost immunological memory. Receiving booster immunization at the age of 10-15 years may be more appropriate for individuals living in HBV high epidemic areas.
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Affiliation(s)
- Zikang Wu
- a School of Medicine , Ningbo University , Ningbo , Zhejiang , China
| | - Jun Yao
- b The National Science and Technology Project , Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou , Zhejiang , China
| | - Hongdan Bao
- a School of Medicine , Ningbo University , Ningbo , Zhejiang , China
| | - Yongdi Chen
- b The National Science and Technology Project , Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou , Zhejiang , China
| | - Shunshun Lu
- c Ningbo Medical Center Lihuili Eastern Hospital , Ningbo , Zhejiang , China
| | - Jing Li
- d Zhejiang Provincial Hospital , Hangzhou , Zhejiang , China
| | - Linna Yang
- d Zhejiang Provincial Hospital , Hangzhou , Zhejiang , China
| | - Zhenggang Jiang
- b The National Science and Technology Project , Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou , Zhejiang , China
| | - Jingjing Ren
- e State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Key Laboratory of Infectious Diseases, the First Affiliated Hospital , School of Medicine, Zhejiang University , Hangzhou , Zhejiang , China
| | - Kai-Jin Xu
- e State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Key Laboratory of Infectious Diseases, the First Affiliated Hospital , School of Medicine, Zhejiang University , Hangzhou , Zhejiang , China
| | - Bing Ruan
- e State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Key Laboratory of Infectious Diseases, the First Affiliated Hospital , School of Medicine, Zhejiang University , Hangzhou , Zhejiang , China
| | - Shi-Gui Yang
- e State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Key Laboratory of Infectious Diseases, the First Affiliated Hospital , School of Medicine, Zhejiang University , Hangzhou , Zhejiang , China
| | - Tian-Sheng Xie
- e State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Key Laboratory of Infectious Diseases, the First Affiliated Hospital , School of Medicine, Zhejiang University , Hangzhou , Zhejiang , China
| | - Qian Li
- b The National Science and Technology Project , Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou , Zhejiang , China
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Collier MG, Schillie S. Hepatitis B and Hepatitis D Viruses. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2018:1107-1114.e4. [DOI: 10.1016/b978-0-323-40181-4.00213-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Heath RD, Tahan V. Natural History of Hepatitis B Virus. VIRAL HEPATITIS: CHRONIC HEPATITIS B 2018:1-10. [DOI: 10.1007/978-3-319-93449-5_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Khan T, Jung IH, Khan A, Zaman G. Classification and sensitivity analysis of the transmission dynamic of hepatitis B. Theor Biol Med Model 2017; 14:22. [PMID: 29202763 PMCID: PMC5716382 DOI: 10.1186/s12976-017-0068-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 10/10/2017] [Indexed: 12/30/2022] Open
Abstract
Background Hepatitis B infection caused by the hepatitis B virus is one of the most serious viral infections and a global health problem. In the transmission of hepatitis B infection, three different phases, i.e. acute infected, chronically infected, and carrier individuals, play important roles. Carrier individuals are especially significant, because they do not exhibit any symptoms and are able to transmit the infection. Here we assessed the transmissibility associated with different infection stages of hepatitis B and generated an epidemic model. Methods To demonstrate the transmission dynamic of hepatitis B, we investigate an epidemic model by dividing the infectious class into three subclasses, namely acute infected, chronically infected, and carrier individuals with both horizontal and vertical transmission. Results Numerical results and sensitivity analysis of some important parameters are presented to show that the proportion of births without successful vaccination, perinatally infected individuals, and direct contact rate are highest risk factors for the spread of hepatitis B in the community. Conclusion Our work provides a coherent platform for studying the full dynamics of hepatitis B and an effective direction for theoretical work.
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Affiliation(s)
- Tahir Khan
- Department of Mathematics, University of Malakand, Khyber Pakhtunkhawa, Chakdara Dir Lower, Pakistan
| | - Il Hyo Jung
- Department of Mathematics, Pusan National University, Busan, 46241, South Korea.
| | - Amir Khan
- Department of Mathematics, University of Malakand, Khyber Pakhtunkhawa, Chakdara Dir Lower, Pakistan.,Department of Mathematics, University of Swat, Mingora, Swat, Khyber Pakhtunkhawa, Pakistan
| | - Gul Zaman
- Department of Mathematics, University of Malakand, Khyber Pakhtunkhawa, Chakdara Dir Lower, Pakistan
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Khan T, Zaman G, Chohan MI. The transmission dynamic and optimal control of acute and chronic hepatitis B. JOURNAL OF BIOLOGICAL DYNAMICS 2017; 11:172-189. [PMID: 27852159 DOI: 10.1080/17513758.2016.1256441] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
In this article, we present the transmission dynamic of the acute and chronic hepatitis B epidemic problem and develop an optimal control strategy to control the spread of hepatitis B in a community. In order to do this, first we present the model formulation and find the basic reproduction number [Formula: see text]. We show that if [Formula: see text] then the disease-free equilibrium is both locally as well as globally asymptotically stable. Then, we prove that the model is locally and globally asymptotically stable, if [Formula: see text]. To control the spread of this infection, we develop a control strategy by applying three control variables such as isolation of infected and non-infected individuals, treatment and vaccination to minimize the number of acute infected, chronically infected with hepatitis B individuals and maximize the number of susceptible and recovered individuals. Finally, we present numerical simulation to illustrate the feasibility of the control strategy.
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Affiliation(s)
- Tahir Khan
- a Department of Mathematics , University of Malakand, Chakdara Dir (Lower) Khyber Pakhtunkhawa , Pakistan
| | - Gul Zaman
- a Department of Mathematics , University of Malakand, Chakdara Dir (Lower) Khyber Pakhtunkhawa , Pakistan
| | - M Ikhlaq Chohan
- b Department of Business Administration and Accounting , Buraimi University College , Al-Buraimi , Oman
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Luo X, Yu JX, Xie L, Ma WJ, Wang LH. Clinical Analysis of Polyethylene Glycol Interferon-α Treatment in 155 Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B (CHB) Patients. Ann Hepatol 2017; 16:888-892. [PMID: 29055925 DOI: 10.5604/01.3001.0010.5279] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
PURPOSE This study aims to investigate the antiviral effect of polyethylene glycol (PEG)-interferon α-2a and PEG-interferon α-2b treatment on hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) at the 48th week of treatment and the 24th and 48th week after withdrawal, in order to provide guidance on the antiviral treatment of HBeAg-positive CHB patients. MATERIAL AND METHODS Antiviral treatment was performed on 155 HBeAg-positive CHB patients. Among these patients, 66 patients received PEG-interferon α-2a treatment and 89 patients received PEG-interferon α-2b treatment; and these treatments were administered by subcutaneous injection, once per week, which lasted for 48 weeks. Other antiviral and hepatoprotective drugs were not used during the treatment. RESULTS At the 48th week of treatment, ALT recovery rate, HBsAg seroconversion rate, HBeAg seroconversion rate and HBV DNA titers dropped below 200 IU/mL rate were 69.7%, 6.1%, 27.3% and 50.0%, respectively, in the PEG-interferon α-2a group; and were 70.8%, 6.7%, 33.7% and 62.9%, respectively, in the PEG-interferon α-2b group. At the 24th and 48th week of follow-up after withdrawal, HBsAg seroconversion rate in these two groups did not change; and HBeAg seroconversion rate further increased. Furthermore, HBV DNA revealed a low recurrence rate. The difference between these two groups was not significantly significant. CONCLUSIONS PEG-interferon α-2a and PEG-interferon α-2b are effective antiviral drugs for the treatment of HbeAgpositive CHB, which has a HBsAg seroconversion rate of more than 5%. Furthermore, this sustained response effect was maintained at the 24th and 48th week of follow-up after withdrawal.
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Affiliation(s)
- Xin Luo
- Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, China
| | - Ji-Xian Yu
- Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, China
| | - Lei Xie
- Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, China
| | - Wen-Jun Ma
- Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, China
| | - Li-Hong Wang
- Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, China
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Chen C, Zhu X, Xu W, Yang F, Zhang G, Wu L, Zheng Y, Gao Z, Xie C, Peng L. IFNA2 p.Ala120Thr impairs the inhibitory activity of Interferon-α2 against the hepatitis B virus through altering its binding to the receptor. Antiviral Res 2017; 147:11-18. [PMID: 28958921 DOI: 10.1016/j.antiviral.2017.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 09/03/2017] [Accepted: 09/22/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND Our previous study found that a rare genetic mutation IFNA2p.Ala120Thr affects the structure of IFN-α2 and contributes to increased host susceptibility to CHB. However, the way in which the single amino acid residue mutation affects IFN-α2 activity is unclear. The purpose of this research was to investigate the effects and mechanisms of IFNA2p.Ala120Thr on IFN-α2 activity. METHODS Plasmid transfection of BL-21 was used to construct both wild type IFNA2 (wt) and p.Ala120Thr IFNA2 (mut) proteins. The HepG2-NTCP model was established using a lentiviral vector (LV003). Anti-HBV activity of wt and mut were tested on HepG2-NTCP infected cells with HBV, through the detection of HBsAg and HBcAg using immunohistochemistry and by detecting HBV DNA with RT PCR. IF and Co-IP were performed in order to investigate the binding of the IFNA2 protein and its receptor. The changes in IFNAR density and signal molecule phosphorylation were measured with western blotting. We used qPCR to further explore anti-HBV protein expression including APOBEC3, MxA, OAS1, and PKR. RESULTS Cell model experiments confirmed that IFNA2p.Ala120Thr impairs anti-HBV activity of IFN-α2. Co-IP tests indicated that the binding of mut-IFNα to IFNR was weaker in the mut-treated group. IFNR density on the cells surface increased after treatment with wt-IFN-α2. Obvious differences in the STAT phosphorylation profiles were seen between the mut-treated and wt-treated groups. The expression of four main kinds of anti-HBV proteins induced by mut was higher in the HepG2-NTCP cells. Thus, IFNA2p.Ala120Thr affects anti-HBV activity of IFN-α2. CONCLUSION IFNA2p.Ala120Thr impairs the anti-HBV ability of IFN-a2, mainly by reducing its binding to the IFN receptor. Mut IFN-a2 has a very weak binding, barely inducing STAT phosphorylation, and induces the expression of only a low level of related anti-HBV ISG. This is quite different from the effects of wt IFN-a2, implying that modifying the key structural position of IFNa may lead to the modulation of targeted gene expression.
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Affiliation(s)
- Chuming Chen
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Infectious Diseases, Third People's Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Xiang Zhu
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenxiong Xu
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fangji Yang
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Genglin Zhang
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lina Wu
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yongyuan Zheng
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chan Xie
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Liang Peng
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Brar TS, Hilgenfeldt E, Soldevila-Pico C. Etiology and Pathogenesis of Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-3-319-68082-8_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Baldassarre A, Felli C, Prantera G, Masotti A. Circulating microRNAs and Bioinformatics Tools to Discover Novel Diagnostic Biomarkers of Pediatric Diseases. Genes (Basel) 2017; 8:genes8090234. [PMID: 28925938 PMCID: PMC5615367 DOI: 10.3390/genes8090234] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 09/08/2017] [Accepted: 09/12/2017] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level. Current studies have shown that miRNAs are also present in extracellular spaces, packaged into various membrane-bound vesicles, or associated with RNA-binding proteins. Circulating miRNAs are highly stable and can act as intercellular messengers to affect many physiological processes. MicroRNAs circulating in body fluids have generated strong interest in their potential use as clinical biomarkers. In fact, their remarkable stability and the relative ease of detection make circulating miRNAs ideal tools for rapid and non-invasive diagnosis. This review summarizes recent insights about the origin, functions and diagnostic potential of extracellular miRNAs by especially focusing on pediatric diseases in order to explore the feasibility of alternative sampling sources for the development of non-invasive pediatric diagnostics. We will also discuss specific bioinformatics tools and databases for circulating miRNAs focused on the identification and discovery of novel diagnostic biomarkers of pediatric diseases.
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Affiliation(s)
| | - Cristina Felli
- Bambino Gesù Children's Hospital-IRCCS, Research Laboratories, 00146 Rome, Italy.
| | - Giorgio Prantera
- Department of Ecology and Biology, Università della Tuscia, 01100 Viterbo, Italy.
| | - Andrea Masotti
- Bambino Gesù Children's Hospital-IRCCS, Research Laboratories, 00146 Rome, Italy.
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Silva Souza ACD, Souza Marasca GD, Kretzmann-Filho NA, Dall-Bello A, Alexandre Kliemann D, Valle Tovo C, Gorini da Veiga AB. Identification of hepatitis B virus A1762T/G1764A double mutant strain in patients in Southern Brazil. Braz J Infect Dis 2017; 21:525-529. [PMID: 28606415 PMCID: PMC9425463 DOI: 10.1016/j.bjid.2017.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 04/12/2017] [Accepted: 05/11/2017] [Indexed: 01/09/2023] Open
Abstract
Infection by hepatitis B virus (HBV) is a worldwide public health problem. Chronic HBV infection with high viral replication may lead to cirrhosis and/or hepatocellular carcinoma. Mutant HBV strains, such as the HBV A1762T/G1764A double mutant, have been associated with poor prognosis and higher risk of the patient for developing cirrhosis and/or hepatocellular carcinoma. This study analyzed the presence of the HBV A1762T/G1764A double mutant in patients with chronic HBV and its association with clinical parameters such as viral load, aminotransferases, and HBV antigens. A total of 49 patients with chronic hepatitis B were included in the study, and the HBV A1762T/G1764A double mutant strain was detected in four samples (8.16%) by polymerase chain reaction followed by restriction fragment length analysis (PCR-RFLP). The viral load was not significantly different between patients with or without the double mutant strain (p=0.43). On the other hand, carriers of the HBV A1762T/G1764A double mutant had higher levels of ALT (p=0.0028), while AST levels did not differ between groups (p=0.051). In this study, 75% of the samples with the HBV A1762T/G1764A double mutation were HBeAg negative and anti-HBe positive, reflecting seroconversion even though they still displayed high viral loads. Our study has shown that the HBV A1762T/G1764A double mutant strain circulates in Brazilian patients, and is associated with elevated levels of ALT and HBeAg seroconversion.
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Affiliation(s)
- Adaliany Cecília da Silva Souza
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Giórgia de Souza Marasca
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Nélson Alexandre Kretzmann-Filho
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Aline Dall-Bello
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Dimas Alexandre Kliemann
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil; Hospital Nossa Senhora da Conceição (HNSC), Porto Alegre, RS, Brazil
| | - Cristiane Valle Tovo
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil; Hospital Nossa Senhora da Conceição (HNSC), Porto Alegre, RS, Brazil
| | - Ana Beatriz Gorini da Veiga
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil.
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Ganesan K, Jayachandran M, Xu B. A critical review on hepatoprotective effects of bioactive food components. Crit Rev Food Sci Nutr 2017; 58:1165-1229. [DOI: 10.1080/10408398.2016.1244154] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Kumar Ganesan
- Program of Food Science and Technology, Beijing Normal University–Hong Kong Baptist University United International College, Zhuhai, China
| | - Muthukumaran Jayachandran
- Program of Food Science and Technology, Beijing Normal University–Hong Kong Baptist University United International College, Zhuhai, China
| | - Baojun Xu
- Program of Food Science and Technology, Beijing Normal University–Hong Kong Baptist University United International College, Zhuhai, China
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Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects. Hepatol Int 2017; 11:390-400. [PMID: 28560658 DOI: 10.1007/s12072-017-9797-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 04/28/2017] [Indexed: 01/13/2023]
Abstract
BACKGROUND Pradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir. METHODS Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group. RESULTS The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (C max) and area under the curve (AUC)0-48 of serum pradefovir ranged from (21.41 ± 12.98) to (447.33 ± 79.34) ng/mL and (46.10 ± 29.45) to (748.18 ± 134.15) ng h/mL across the dose range, respectively. The C max and AUC0-48 of serum PMEA ranged from 18.10 ± 4.96 to 312.33 ± 114.19 ng/mL and 72.65 ± 28.25 to 1095.48 ± 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)]. CONCLUSIONS The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events. TRIAL REGISTRATION NUMBER CTR20140341.
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Wu DX, Fu XY, Gong GZ, Sun KW, Gong HY, Wang L, Wu J, Tan DM. Novel HBV mutations and their value in predicting efficacy of conventional interferon. Hepatobiliary Pancreat Dis Int 2017; 16:189-196. [PMID: 28381384 DOI: 10.1016/s1499-3872(16)60184-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Accumulating studies assessing the impacts of hot spot mutations on conventional interferon (IFN) efficacy come to discrepant conclusions; studies regarding the mutations in S and RT regions are also unclear. The present study aimed to evaluate the impacts of HBV mutations on the efficacy of conventional IFN. METHODS A total of 126 patients who received conventional IFN treatment for 48 weeks were enrolled. Biochemical and serological parameters were routinely tested. The sequences of HBV from 78 serum samples were amplified by nested-PCR; mutations were identified with sequence scanner V1.0 after ABI 3730xl direct sequencing, HBV genotypes were determined according to RT gene sequences utilizing NCBI Genotyping Tool which was based on phylogenetic analysis. RESULTS The baseline DNA levels of virological response (VR) group were significantly lower than those of no VR group [7.13+/-0.76 vs 7.69+/-0.56 lg (copies/mL), P=0.001]. The baseline ALT levels were significantly higher in the HBeAg clearance group (204.72+/-88.65 vs 162.80+/-85.81 IU/L, P<0.05) and HBeAg seroconversion group (204.89+/-95.68 vs 166.75+/-84.43 IU/L, P<0.05). Females and lower BMI levels (20.01+/-2.33 vs 21.65+/-3.66 kg/m2, P<0.05) were prone to acquired biochemical response (BR). PC-W28STOP (ntG1896A) was significantly higher in the combined response (CR) group than that in the no CR group (91.7% vs 39.7%, P=0.001). Multivariate logistic regression analysis showed that baseline DNA, PC-P159T (ntC2288A), BCP-N118T (ntA1726C) and BCP-L134L (ntA1775C/G/T) influenced VR independently. PC-G182C (ntG2357T), PC-S64A/T (ntT2003G/A) and BMI were independent influence factors for HBeAg clearance, HBeAg seroconversion and BR, respectively. The new predicting model concluded that baseline DNA and new mutations for VR were established successfully, and ROC analysis showed that AUC was 0.842 (P<0.001) with a sensitivity of 0.652 and a specificity of 0.933. CONCLUSIONS PC-P159T (ntC2288A), BCP-N118T (ntA1726C), BCP-L134L (ntA1775C/G/T), PC-G182C (ntG2357T) and PC-S64A/T (ntT2003G/A) were novel identified mutations that impacted IFN therapeutic efficacy. These novel mutations could serve as important predictors before conventional IFN treatment.
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Affiliation(s)
- Da-Xian Wu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Key Laboratory of Viral Hepatitis of Hunan Province, Changsha, China.
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McFadden VC, Shalaby RE, Iram S, Oropeza CE, Landolfi JA, Lyubimov AV, Maienschein-Cline M, Green SJ, Kaestner KH, McLachlan A. Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation. PLoS Pathog 2017; 13:e1006239. [PMID: 28235042 PMCID: PMC5342274 DOI: 10.1371/journal.ppat.1006239] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 03/08/2017] [Accepted: 02/14/2017] [Indexed: 12/17/2022] Open
Abstract
The FoxA family of pioneer transcription factors regulates hepatitis B virus (HBV) transcription, and hence viral replication. Hepatocyte-specific FoxA-deficiency in the HBV transgenic mouse model of chronic infection prevents the transcription of the viral DNA genome as a result of the failure of the developmentally controlled conversion of 5-methylcytosine residues to cytosine during postnatal hepatic maturation. These observations suggest that pioneer transcription factors such as FoxA, which mark genes for expression at subsequent developmental steps in the cellular differentiation program, mediate their effects by reversing the DNA methylation status of their target genes to permit their ensuing expression when the appropriate tissue-specific transcription factor combinations arise during development. Furthermore, as the FoxA-deficient HBV transgenic mice are viable, the specific developmental timing, abundance and isoform type of pioneer factor expression must permit all essential liver gene expression to occur at a level sufficient to support adequate liver function. This implies that pioneer transcription factors can recognize and mark their target genes in distinct developmental manners dependent upon, at least in part, the concentration and affinity of FoxA for its binding sites within enhancer and promoter regulatory sequence elements. This selective marking of cellular genes for expression by the FoxA pioneer factor compared to HBV may offer the opportunity for the specific silencing of HBV gene expression and hence the resolution of chronic HBV infections which are responsible for approximately one million deaths worldwide annually due to liver cirrhosis and hepatocellular carcinoma. This study demonstrates the connection between FoxA expression and gene silencing by DNA methylation in vivo during liver maturation. Insufficient FoxA expression results in selective developmentally regulated hepatitis B virus (HBV) silencing by DNA methylation. To our knowledge, this is the first in vivo demonstration that pioneer factors such as FoxA function by mediating the developmental demethylation of their target genes, leading to their tissue specific gene expression. Furthermore, our results strongly imply that the marking of cellular target genes for subsequent transcription later in development is dependent upon the level and timing of FoxA expression plus its affinity for its target sequences within enhancer and promoter regions. Consequently, these findings suggest that the appropriate control of FoxA activity during development could lead to the transcriptional inactivation of nuclear HBV covalently closed circular DNA by methylation and hence resolution of chronic HBV infection. This represents a clinical goal that current therapies are unable to attain, and hence suggests a potential route to a cure for this chronic infection which kills approximately 1 million individuals annually.
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Affiliation(s)
- Vanessa C. McFadden
- Department of Microbiology and Immunology College of Medicine University of Illinois at Chicago 909 South Wolcott Avenue Chicago, IL, United States of America
| | - Rasha E. Shalaby
- Department of Microbiology and Immunology College of Medicine University of Illinois at Chicago 909 South Wolcott Avenue Chicago, IL, United States of America
| | - Saira Iram
- Department of Microbiology and Immunology College of Medicine University of Illinois at Chicago 909 South Wolcott Avenue Chicago, IL, United States of America
| | - Claudia E. Oropeza
- Department of Microbiology and Immunology College of Medicine University of Illinois at Chicago 909 South Wolcott Avenue Chicago, IL, United States of America
| | - Jennifer A. Landolfi
- Toxicology Research Laboratory Department of Pharmacology College of Medicine University of Illinois at Chicago Chicago, IL, United States of America
| | - Alexander V. Lyubimov
- Toxicology Research Laboratory Department of Pharmacology College of Medicine University of Illinois at Chicago Chicago, IL, United States of America
| | - Mark Maienschein-Cline
- Research Resources Center College of Medicine University of Illinois at Chicago 835 South Wolcott Avenue Chicago, IL, United States of America
| | - Stefan J. Green
- Research Resources Center College of Medicine University of Illinois at Chicago 835 South Wolcott Avenue Chicago, IL, United States of America
| | - Klaus H. Kaestner
- Department of Genetics University of Pennsylvania School of Medicine Philadelphia, PA, United States of America
| | - Alan McLachlan
- Department of Microbiology and Immunology College of Medicine University of Illinois at Chicago 909 South Wolcott Avenue Chicago, IL, United States of America
- * E-mail:
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Sone LHE, Voufo RA, Dimodi HT, Kengne M, Gueguim C, Ngah N, Oben J, Ngondi JL. Prevalence and Identification of Serum Markers Associated with Vertical Transmission of Hepatitis B in Pregnant Women in Yaounde, Cameroon. Int J MCH AIDS 2017; 6:69-74. [PMID: 28798895 PMCID: PMC5547227 DOI: 10.21106/ijma.174] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVE To determine the prevalence of Hepatitis B Virus (HBV) infection in pregnant women and identify markers associated with vertical transmission of HBV. METHODS Prospective and cross-sectional study over 10 months on 298 pregnant women attending antenatal clinics in the Cité Verte and Efoulan District hospitals in Cameroon. A dry tube blood collection was performed on all pregnant women and babies born to HBsAg-positive mothers. Serum from the women was used to test for HBsAg through immunochromatography and then confirmed by ELISA. The test for HBeAg, HBeAb and HBcAb and dosage of transaminases were performed on the serum of HBsAg-positive women. Only HBsAg was tested in babies within 24 hours after birth. RESULTS HBsAg was present in 23 (7.7%) mothers while 275 (92.3%) tested negative. Due to loss to follow-up, we assessed vertical transmission in 20 babies born to20 mothers. In all, eight babies tested HBsAg-positive; six mothers tested positive with HBeAg; 10 mothers with HBeAb and two were simultaneously infected with HBV and HIV. CONCLUSION AND GLOBAL HEALTH IMPLICATIONS HBeAg and increase in liver transaminases were serum markers associated with the vertical transmission of HBV while HBeAb and anti-HIV therapy were protective markers. There is need to systematically screen all pregnant women for hepatitis B, follow up those that are positive, and administer a dose of gammaglobulin anti-HBs to their children to reduce the risks of chronic hepatitis and hepatocellular carcinoma (CHC) and curb mortality and morbidity due to viral hepatitis B.
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Affiliation(s)
- Lucien Honoré Etame Sone
- Institute of Medical Research and Medicinal Plants Studies, P. O. Box 6163, Yaoundé, Cameroon.,The Higher Institute of Medical Technology, Yaounde, Cameroon
| | - Roger Ahouga Voufo
- School of Health Sciences, Catholic University of Central Africa, P. O. Box 1110 Yaoundé, Cameroon
| | | | - Michel Kengne
- School of Health Sciences, Catholic University of Central Africa, P. O. Box 1110 Yaoundé, Cameroon
| | | | - Nnanga Ngah
- Institute of Medical Research and Medicinal Plants Studies, P. O. Box 6163, Yaoundé, Cameroon.,Faculty of Medicine and Biomedical Science, University of Yaounde I, Cameroon
| | - Julius Oben
- Faculty of Science, University of Yaounde I, Cameroon
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Spradling PR, Xing J, Rupp LB, Moorman AC, Gordon SC, Teshale ET, Lu M, Boscarino JA, Schmidt MA, Trinacty CM, Holmberg SD. Distribution of disease phase, treatment prescription and severe liver disease among 1598 patients with chronic hepatitis B in the Chronic Hepatitis Cohort Study, 2006-2013. Aliment Pharmacol Ther 2016; 44:1080-1089. [PMID: 27640985 DOI: 10.1111/apt.13802] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 07/07/2016] [Accepted: 08/25/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND Limited information exists regarding the distribution of disease phases, treatment prescription and severe liver disease among patients with chronic hepatitis B (CHB) in US general healthcare settings. AIM To determine the distribution of disease phases, treatment prescription and severe liver disease among patients with CHB in general US healthcare settings. METHODS We analysed demographic and clinical data collected during 2006-2013 from patients with confirmed CHB in the Chronic Hepatitis Cohort Study, an observational cohort study involving patients from healthcare organisations in Michigan, Pennsylvania, Oregon and Hawaii. CHB phases were classified according to American Association for the Study of Liver Disease guidelines. RESULTS Of 1598 CHB patients with ≥12 months of follow-up (median 6.3 years), 457 (29%) were immune active during follow-up [11% hepatitis B e antigen (HBeAg)-positive, 16% HBeAg-negative, and 2% HBeAg status unknown], 10 (0.6%) were immune tolerant, 112 (7%) were inactive through the duration of follow-up and 886 (55%) were phase indeterminate. Patients with cirrhosis were identified within each group (among 21% of immune active, 3% of inactive and 9% of indeterminate phase patients) except among those with immune-tolerant CHB. Prescription of treatment was 59% among immune active patients and 84% among patients with cirrhosis and hepatitis B virus (HBV) DNA >2000 IU/mL. CONCLUSIONS Approximately, one-third of the cohort had active disease during follow-up; 60% of eligible patients were prescribed treatment. Our findings underscore the importance of ascertainment of fibrosis status in addition to regular assessment of ALT and HBV DNA levels.
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Affiliation(s)
- P R Spradling
- Division of Viral Hepatitis, National Centers for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.
| | - J Xing
- Division of Viral Hepatitis, National Centers for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - L B Rupp
- Henry Ford Health System, Detroit, MI, USA
| | - A C Moorman
- Division of Viral Hepatitis, National Centers for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - S C Gordon
- Henry Ford Health System, Detroit, MI, USA
| | - E T Teshale
- Division of Viral Hepatitis, National Centers for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - M Lu
- Henry Ford Health System, Detroit, MI, USA
| | - J A Boscarino
- Center for Health Research, Geisinger Health System, Danville, PA, USA
| | - M A Schmidt
- The Center for Health Research, Kaiser Permanente-Northwest, Portland, OR, USA
| | - C M Trinacty
- The Center for Health Research, Kaiser Permanente-Hawaii, Honolulu, Hawaii
| | - S D Holmberg
- Division of Viral Hepatitis, National Centers for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
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