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Zhang B, Yu L, Cheng M, Zhang Q, Wu J, Yang J, Liu Q, Lu S, Zhao X, Deng K, Liu Y, Wang J, Zhao P. Hepatitis B virus genotype is an independent prognostic factor of telbivudine and tenofovir treatment in hepatitis B surface antigen-positive pregnant women. Food Sci Nutr 2022; 10:3-11. [PMID: 35035905 PMCID: PMC8751444 DOI: 10.1002/fsn3.2619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 11/06/2022] Open
Abstract
To investigate whether HBV genotype influences the effect of tenofovir and telbivudine on HBV DNA and RNA levels in HBsAg-positive pregnant women. This was a retrospective study of 74 HBsAg-positive pregnant women in Guizhou of China. All patients were treated with telbivudine or tenofovir from 12 weeks of pregnancy and HBV infection to the date of delivery. Blood samples were collected at 12-24, 28-32, and 36-40 weeks of pregnancy for the measurement of genotype, HBsAg, hepatitis B e antigen (HBeAg), HBV DNA, HBV RNA, and liver function, including alanine transaminase, aspartate transaminase, total bilirubin, total bile acids, cholinesterase, alkaline phosphatase (ALP), and gamma-glutamyl transferase. All women with HBsAg were followed up. The HBV genotype was B in 64.9% and C in 35.1%. There were 37 patients of telbivudine and tenofovir group respectively. The telbivudine and tenofovir groups showed no differences in demographic and clinical characteristics, including liver function tests, HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA). Compared with baseline (12-24 weeks), telbivudine group showed a significant increase in ALP and significant reductions in HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36-40 weeks (p < .05). Tenofovir group exhibited a significant increase in ALP and significant reductions in HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36-40 weeks, compared with baseline (p < .05). HBV genotype (B vs. C) was independently associated with HBV DNA change after therapy (p = .005). In telbivudine group, log10 (HBV DNA) increased from 3.38 (2.00-7.30) to 7.43 (4.68-8.70). In tenofovir group, log10 (HBV DNA) decreased from 7.52 (3.32-8.70) to 2.98 (2.00-5.01). HBV genotype was independently associated with HBV DNA change response to telbivudine or tenofovir in pregnant women with hepatitis B. These findings might be helpful for risk assessment regarding vertical transmission of HBV in HBeAg-positive mothers treated with nucleos(t)ide analogues.
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Affiliation(s)
- Baofang Zhang
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Lei Yu
- Prenatal Diagnosis CenterGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Mingliang Cheng
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Quan Zhang
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Jun Wu
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Jing Yang
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Qin Liu
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Shuang Lu
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Xueke Zhao
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - KaiSheng Deng
- The Affliated HospitalGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Yongmei Liu
- LaboratoryGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Jun Wang
- Clinical Research CenterGuizhou Medical UniversityGuiyang, GuizhouChina
| | - Peiling Zhao
- LaboratoryGuizhou Medical UniversityGuiyang, GuizhouChina
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Krueger J, Rudd CE, Taylor A. Glycogen synthase 3 (GSK-3) regulation of PD-1 expression and and its therapeutic implications. Semin Immunol 2020; 42:101295. [PMID: 31604533 DOI: 10.1016/j.smim.2019.101295] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 08/01/2019] [Indexed: 12/14/2022]
Abstract
The past few years have witnessed exciting progress in the application of immune check-point blockade (ICB) for the treatment of various human cancers. ICB was first used against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to demonstrate durable anti-tumor responses followed by ICB against programmed cell death-1 (PD-1) or its ligand, PD-L1. Present approaches involve the use of combinations of blocking antibodies against CTLA-4, PD-1 and other inhibitory receptors (IRs) such as TIM3, TIGIT and LAG3. Despite this success, most patients are not cured by ICB therapy and there are limitations to the use of antibodies including cost, tumor penetration, the accessibility of receptors, and clearance from the cell surface as well as inflammatory and autoimmune complications. Recently, we demonstrated that the down-regulation or inhibition of glycogen synthase kinase 3 (GSK-3) down-regulates PD-1 expression in infectious diseases and cancer (Taylor et al., 2016 Immunity 44, 274-86; 2018 Cancer Research 78, 706-717; Krueger and Rudd 2018 Immunity 46, 529-531). In this Review, we outline the use of small molecule inhibitors (SMIs) that target intracellular pathways for co-receptor blockade in cancer immunotherapy.
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Affiliation(s)
- Janna Krueger
- Division of Immunology-Oncology, Research Center Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Christopher E Rudd
- Division of Immunology-Oncology, Research Center Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
| | - Alison Taylor
- Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James's University Hospital, LEEDS LS9 7TF, United Kingdom.
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Clemente MG, Vajro P. An update on the strategies used for the treatment of chronic hepatitis B in children. Expert Rev Gastroenterol Hepatol 2017; 10:649-58. [PMID: 26752166 DOI: 10.1586/17474124.2016.1139450] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic hepatitis B (CHB) in children shows a variety of clinical presentations, which influence its natural course and treatment options. This report provides an overview of the ongoing strategies in pediatric CHB management. Interferon-α represents the first choice of treatment in children showing HBV replication and hepatic inflammation (immune active CHB), while the recommendation is to monitor inactive/immune-tolerant children (normal transaminases and low/absent viral replication). When circumstances preclude the use of Interferon-α and in cases of compensated/decompensated cirrhosis, entecavir for children above 2 years of age or tenofovir for children above 12 years of age are the nucleos(t)ide analogues recommended by the most recent guidelines.
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Affiliation(s)
- Maria Grazia Clemente
- a Pediatric Clinic, Department of Surgical, Microsurgical and Medical Sciences , University of Sassari , Sassari , Italy
| | - Pietro Vajro
- b Pediatrics Unit, Department of Medicine and Surgery , University of Salerno , Baronissi (Salerno) , Italy
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Sarkar N, Pal A, Das D, Saha D, Biswas A, Bandopadhayay B, Chakraborti M, Ghosh M, Chakravarty R. Virological Characteristics of Acute Hepatitis B in Eastern India: Critical Differences with Chronic Infection. PLoS One 2015; 10:e0141741. [PMID: 26571502 PMCID: PMC4646492 DOI: 10.1371/journal.pone.0141741] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 10/12/2015] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) manifests high genetic variability and is classifiable into ten genotypes (A-J). HBV infection can lead to variable clinical outcomes, ranging from self-limiting acute hepatitis to active chronic hepatitis, cirrhosis and hepatocellular carcinoma. The present study characterizes HBV strains circulating among patients with acute (AHB) and chronic HBV infection (CHB). Among a total of 653 HBsAg positive cases, 40 manifested acute infection. After sequencing the surface(S), basal core promoter/pre-core(BCP/PC) and the X gene regions, phylogenetic tree was constructed using MEGA4 by neighbor-joining method. Statistical robustness was established with bootstrap analysis. Nucleotide diversity was determined by Shannon entropy per site using the Entropy program of the Los Alamos National Laboratories. Analyses of acute patients revealed that HBV/D2 is the major circulating sub-genotype and commonly associated with sexual promiscuity and the age group between15-30 years. Comparison of AHB and CHB patients revealed that HBeAg positivity, ALT levels and genotype D were significantly high in AHB, whereas CHB patients were predominantly male, had a high viral load, and were commonly associated with genotype C. The frequencies of mutations in the S, BCP/PC, and X gene were low in AHB as compared to CHB. Drug resistant mutations were not detectable in the polymerase gene of AHB. Average nucleotide diversity in AHB was considerably low as compared to CHB. Further, the highest average ΔH (average difference in entropy between chronic and acute infection) was observed in the BCP/PC region implying that this region was most vulnerable to mutations upon HBV persistence, especially in case of genotype C. Additionally, among all substitutions, the A1762T and G1764A BCP mutations were the strongest indicators of chronicity. In conclusion, the study exhibits a general portrait of HBV strains circulating among acute hepatitis B patients in Eastern India and their intricate differences with chronic patients which should be useful from the clinical point of view.
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Affiliation(s)
- Neelakshi Sarkar
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Ananya Pal
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Dipanwita Das
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Debraj Saha
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Avik Biswas
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Bhaswati Bandopadhayay
- Department of Virology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
| | - Mandira Chakraborti
- Department of Virology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
| | - Mrinmoy Ghosh
- Department of Medicine, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Runu Chakravarty
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
- * E-mail:
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Feng C, Cao LJ, Song HF, Xu P, Chen H, Xu JC, Zhu XY, Zhang XG, Wang XF. Expression of PD-L1 on CD4+CD25+Foxp3+ Regulatory T Cells of Patients with Chronic HBV Infection and Its Correlation with Clinical Parameters. Viral Immunol 2015; 28:418-24. [PMID: 26266813 DOI: 10.1089/vim.2015.0062] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Regulatory T cells (Tregs) play a pivotal role in suppressing specific antiviral immune responses during the progression of chronic hepatitis B virus infection (CHB) as well as tumorigenesis. Programmed death-1 ligand-1 (PD-L1) expressed on Tregs can transduce an inhibitory signal into effector T cells through interacting with programmed death-1 (PD-1). However, in CHB patients, the clinical significance of PD-L1 expression on Tregs has not been clearly described. This study investigated the frequency of circulating Tregs and PD-L1 expression on Tregs and analyzed their correlations with clinical parameters. The data show that both the frequency of CD4+CD25+FoxP3+ Tregs and PD-L1 expression on Tregs in the peripheral blood increased significantly in CHB patients when compared with healthy controls. At the same time, it is shown that PD-L1 expression on Tregs was positively correlated with the percentage of Tregs in CHB patients. Moreover, the results demonstrated that both Treg frequency and PD-L1 expression on Tregs positively correlated with the levels of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST), both of which are indicators of the extent of liver injury. Taken together, these findings suggest that PD-L1 on Tregs might contribute to progression of hepatitis B virus infection through mediating the inhibitory function of Tregs. Thereby, blockade of interaction between Treg-expressing PD-L1 and PD-1 on effector T cells may be adopted as a potential therapeutic approach in CHB.
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Affiliation(s)
- Chao Feng
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
| | - Li-Juan Cao
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
| | - Hua-Feng Song
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China .,2 Central Laboratory, The Affiliated Infectious Hospital of Soochow University , Suzhou, China .,3 Key Laboratory of Infection and Immunity of Suzhou City , Suzhou, China
| | - Ping Xu
- 2 Central Laboratory, The Affiliated Infectious Hospital of Soochow University , Suzhou, China .,3 Key Laboratory of Infection and Immunity of Suzhou City , Suzhou, China
| | - Hui Chen
- 2 Central Laboratory, The Affiliated Infectious Hospital of Soochow University , Suzhou, China .,3 Key Laboratory of Infection and Immunity of Suzhou City , Suzhou, China
| | - Jun-Chi Xu
- 2 Central Laboratory, The Affiliated Infectious Hospital of Soochow University , Suzhou, China .,3 Key Laboratory of Infection and Immunity of Suzhou City , Suzhou, China
| | - Xiao-Yan Zhu
- 2 Central Laboratory, The Affiliated Infectious Hospital of Soochow University , Suzhou, China .,3 Key Laboratory of Infection and Immunity of Suzhou City , Suzhou, China
| | - Xue-Guang Zhang
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China .,4 The First Affiliated Hospital of Soochow University , Suzhou, China
| | - Xue-Feng Wang
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
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Xu HZ, Liu YP, Guleng B, Ren JL. Hepatitis B Virus-Related Hepatocellular Carcinoma: Pathogenic Mechanisms and Novel Therapeutic Interventions. Gastrointest Tumors 2014; 1:135-45. [PMID: 26676160 DOI: 10.1159/000365307] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Infection with the hepatitis B virus (HBV) is one of most important risk factors for hepatocellular carcinoma (HCC). Indeed, HBV is considered a group 1 human carcinogen and is a highly oncogenic agent. HBV cannot be effectively controlled or completely eliminated, so chronic HBV infection is a public health challenge worldwide. SUMMARY It is now believed that HBV-induced HCC involves a complex interaction between multiple viral and host factors. Many factors contribute to HBV-associated HCC, including products of HBV, viral integration and mutation, and host susceptibility. This review outlines the main pathogenic mechanisms with a focus on those that suggest novel targets for the prevention and treatment of HCC. KEY MESSAGE HBV infection is an important risk factor for HCC. Understanding the interaction between viral and host factors in HBV-induced HCC will reveal potential targets for future therapies. PRACTICAL IMPLICATIONS The two main therapeutic strategies consist of antiviral agents and immunotherapy-based approaches. Dendritic cell-based immunotherapy is promising for restoring the T cell-mediated antiviral immune response. Another approach is the specific expansion of the host's pool of HBV-specific T cells. Stimulation of the Toll-like receptors (TLRs), particularly TLR9, provides another means of boosting the antiviral response. Combination therapy with cytokines (interferon gamma and tumor necrosis factor alpha) plus lamivudine is more effective than these agents used alone. Therapeutic vaccines are being developed as an alternative to long-term antiviral treatment or as an adjunct.
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Affiliation(s)
- Hong-Zhi Xu
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China
| | - Yun-Peng Liu
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China
| | - Bayasi Guleng
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China ; Medical College of Xiamen University, Xiamen, China
| | - Jian-Lin Ren
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China
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Sunbul M. Hepatitis B virus genotypes: Global distribution and clinical importance. World J Gastroenterol 2014; 20:5427-5434. [PMID: 24833873 PMCID: PMC4017058 DOI: 10.3748/wjg.v20.i18.5427] [Citation(s) in RCA: 274] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 11/20/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
At least 600000 individuals worldwide annually die of hepatitis B virus (HBV)-related diseases, such as chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Many viral factors, such as viral load, genotype, and specific viral mutations, are known to affect disease progression. HBV reverse transcriptase does not have a proofreading function, therefore, many HBV genotypes, sub-genotypes, mutants, and recombinants emerge. Differences between genotypes in response to antiviral treatment have been determined. To date, 10 HBV genotypes, scattered across different geographical regions, have been identified. For example, genotype A has a tendency for chronicity, whereas viral mutations are frequently encountered in genotype C. Both chronicity and mutation frequency are common in genotype D. LC and progression to HCC are more commonly encountered with genotypes C and D than the other genotypes. Pathogenic differences between HBV genotypes explain disease intensity, progression to LC, and HCC. In conclusion, genotype determination in CHB infection is important in estimating disease progression and planning optimal antiviral treatment.
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Wang L, Zou ZQ, Liu CX, Liu XZ. Immunotherapeutic interventions in chronic hepatitis B virus infection: a review. J Immunol Methods 2014; 407:1-8. [PMID: 24747918 DOI: 10.1016/j.jim.2014.04.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 02/20/2014] [Accepted: 04/02/2014] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a public health challenge worldwide. Antiviral agents (nucleos(t)ide analogues, NAs) and immune-based therapies (IFN-α or Pegylated-IFN-α) are two therapeutic approaches available currently against chronic hepatitis B (CHB). However, these approaches are associated with the development of acquired drug resistance or poor response rates and are accompanied by numerous side effects. Furthermore, due to defective innate and adaptive immune responses, HBV cannot be effectively controlled or completely eliminated, which may ultimately result in liver decompensation and hepatocelluar carcinoma. The imperative for development of new approaches targeting CHB cannot be overstated. Various immunotherapeutic interventions have been tried as adjuvants to inhibit HBV replication. In this paper, we will review immunotherapeutic interventions in the treatment of CHB.
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Affiliation(s)
- Li Wang
- Infectious Disease Hospital of Yantai, Huanshan Road 62, Zhifu District, 264001, Yantai, Shandong, China.
| | - Zhi Qiang Zou
- Infectious Disease Hospital of Yantai, Huanshan Road 62, Zhifu District, 264001, Yantai, Shandong, China
| | - Cheng Xia Liu
- Digestive Department, Affiliated Hospital of Binzhou Medical College, Huanghe Second Road 661, 256603, Shandong, China
| | - Xiang Zhong Liu
- Infectious Disease Hospital of Yantai, Huanshan Road 62, Zhifu District, 264001, Yantai, Shandong, China
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