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Ding L, Huang J, Huang S. The significance of antibody to hepatitis B surface antigen in infection and clearance of hepatitis B virus. Hum Vaccin Immunother 2025; 21:2445283. [PMID: 39754388 DOI: 10.1080/21645515.2024.2445283] [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: 09/24/2024] [Revised: 11/30/2024] [Accepted: 12/17/2024] [Indexed: 01/06/2025] Open
Abstract
One of the key features of chronic hepatitis B virus (HBV) infection is the inability to mount sufficient and coordinated adaptive immune responses against HBV. Recent studies on HBV-specific B cells and antibody to hepatitis B surface antigen (anti-HBs) have shed light on their role in the pathogenesis of chronic hepatitis B (CHB). Anti-HBs is recognized as a protective immune marker, both for HBV infection clearance and following vaccination, and it is also considered an important indicator of functional cure for CHB. Notably, functional impairment of HBV-specific B cells may be reversible. The restoration of HBV-specific B cell function, along with the induction of an anti-HBs antibody response, is regarded as pivotal for terminating chronic HBV infection and achieving functional cure. This article reviews the significance of anti-HBs in both the infection and clearance of HBV, and discusses the potential of neutralizing antibodies and therapeutic vaccines as promising future strategies.
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Affiliation(s)
- Ling Ding
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuaiwen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Pu Z, Ji Z, Su H, Fu T, Shao Z, Yan Y. HBsAg and anti-HBs coexistence in patients with HBV in acute and chronic phases. Virus Res 2025; 355:199567. [PMID: 40174727 PMCID: PMC12001098 DOI: 10.1016/j.virusres.2025.199567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/05/2025] [Accepted: 03/29/2025] [Indexed: 04/04/2025]
Abstract
HBsAg and anti-HBs coexistence represents an unusual serological pattern in hepatitis B virus (HBV) infection. However, its natural course remains unclear. This study investigated the occurrence of this serological pattern in patients with HBV in acute and chronic phases and estimated the associated risks. Of the 215 adult patients diagnosed with acute-phase HBV, 19 (8.84 %) cases demonstrated HBsAg and anti-HBs coexistence. In the chronic phase, 54 new cases of HBsAg and anti-HBs coexistence were identified during a median follow-up of 14 months (interquartile range: 14-28) among 4593 HBsAg-positive patients. The average annual incidence of coexistence was 1.41 % ± 0.28 %. The cumulative risk of HBsAg and anti-HBs coexistence in chronic phase patients was higher in those aged ≥ 50 years (risk ratio [RR]: 1.79, 95 % confidence interval [CI]: 1.04-3.09, P = 0.035), with positive HBeAg (RR: 3.43, 95 % CI: 1.91-6.19, P < 0.001), baseline alanine transaminase abnormalities (RR: 3.62, 95 % CI: 1.93-6.79, P < 0.001), and higher HBV DNA levels (RR: 1.97, 95 % CI: 1.12-3.49, P = 0.017). The quasispecies heterogeneity of the "a" determinant mutation demonstrated no significant change during the occurrence of coexistence with HBsAg and anti-HBs in HBV infection. Therefore, HBsAg and anti-HBs coexistence may be the intermediate process in the natural history of HBV infection, unrelated to "a" determinant mutation but associated with the disease phase.
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Affiliation(s)
- Zhongshu Pu
- Department of Epidemiology, School of Public Health, Air Force Medical University, Xi'an, PR China; Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an, PR China
| | - Zhaohua Ji
- Department of Epidemiology, School of Public Health, Air Force Medical University, Xi'an, PR China; Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an, PR China
| | - Haixia Su
- Department of Epidemiology, School of Public Health, Air Force Medical University, Xi'an, PR China; Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an, PR China
| | - Ting Fu
- Department of Epidemiology, School of Public Health, Air Force Medical University, Xi'an, PR China; Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an, PR China
| | - Zhongjun Shao
- Department of Epidemiology, School of Public Health, Air Force Medical University, Xi'an, PR China; Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an, PR China.
| | - Yongping Yan
- Department of Epidemiology, School of Public Health, Air Force Medical University, Xi'an, PR China; Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an, PR China.
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Shechter O, Sausen DG, Dahari H, Vaillant A, Cotler SJ, Borenstein R. Functional Cure for Hepatitis B Virus: Challenges and Achievements. Int J Mol Sci 2025; 26:3633. [PMID: 40332208 PMCID: PMC12026623 DOI: 10.3390/ijms26083633] [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: 02/24/2025] [Revised: 03/31/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025] Open
Abstract
The Hepatitis B Virus (HBV) presents a formidable global health challenge, impacting hundreds of millions worldwide and imposing a considerable burden on healthcare systems. The elusive nature of the virus, with its ability to establish chronic infection and evade immune detection, and the absence of curative agents have prompted efforts to develop novel therapeutic approaches beyond current antiviral treatments. This review addresses the challenging concept of a functional cure for HBV, a state characterized by the suppression of HBV and HBsAg, mitigating disease progression and transmission without a complete cure. We provide an overview of HBV epidemiology and its clinical impact, followed by an exploration of the current treatment landscape and its limitations. The immunological basis of a functional cure is then discussed, exploring the intricate interplay between the virus and the host immune response. Emerging therapeutic approaches, such as RNA interference-based interventions, entry inhibitors, nucleic acid polymers, and therapeutic vaccines, are discussed with regard to their success in achieving a functional cure. Lastly, the review underscores the urgent need for innovative strategies to achieve a functional cure for HBV.
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Affiliation(s)
- Oren Shechter
- Eastern Virginia Medical School, Norfolk, VA 23501, USA;
| | | | - Harel Dahari
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Andrew Vaillant
- Replicor Inc., 6100 Royalmount Ave., Montreal, QC H4P 2R2, Canada;
| | - Scott J. Cotler
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Ronen Borenstein
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
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Liang H, Wang H, Liang M, Zhang X, Dai M, Li H, Li X, Yin X, Liu X, Yao J, Guan Z, Qiu Y. The prognosis and immune repertoire characteristics of HBsAg and anti-HBs double positive chronic hepatitis B patients. Clin Exp Med 2025; 25:32. [PMID: 39775320 PMCID: PMC11711149 DOI: 10.1007/s10238-024-01537-3] [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: 08/14/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025]
Abstract
Coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) has been observed in some chronic hepatitis B (CHB) patients (DP patients), but the clinical outcomes and comprehensive characterization of immune micro-environmental changes for this specific population remain inconclusive. In this study, we retrospectively analyze the prognosis of 305 patients in Foshan City, Guangdong Province, China, and also investigated the molecular immunology changes in HBsAg and anti-HBs double positive CHB patients (DP group), CHB patients who had recovered from IFN-ɑ treatment (RP group), and healthy controls (HC group) using T cell receptor (TCR) and B cell receptor (BCR) immune repertoire sequencing. Our findings revealed that 22.30% of DP patients were diagnosed with severe liver disease. Immune repertoire sequencing revealed significant skewing in the diversities of T cell receptor β-chain (TRB) and immunoglobulin heavy chain (IGH) in the DP group compared to the RP group. Unique V(D)J gene combinations, such as IGHV1-18/IGHD3-22/IGHJ5, IGHV1-8/IGHD6-13/IGHJ3, and IGHV1-8/IGHD6-19/IGHJ3, as well as TRBV12-3/TRBD1/TRBJ1-5 and TRBV11-2/TRBD2/TRBJ2-1, exhibited distinct utilization patterns in the DP group. Moreover, the top ten most utilized amino acid motifs in the complementarity determining region 3 (CDR3) of TRB in the DP group showed significant differences from those in the RP group. Notably, motifs such as "xxxYDSSGYx" and "AREx" in the IGH CDR3s were selectively prevalent in the DP group. These findings are expected to provide evidence supporting the poor clinical prognosis of DP patients and offer new insights into the distinct immune micro-environmental changes of this group.
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Affiliation(s)
- Huijun Liang
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China
| | - Haifang Wang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Minfeng Liang
- Department of Infectious Diseases, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Xiaobin Zhang
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China
| | - Meifen Dai
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China
| | - Haixia Li
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xin Li
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaofeng Yin
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xinyao Liu
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiaqi Yao
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ziyun Guan
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China.
| | - Yurong Qiu
- Guangzhou Huayin Health Medical Group Co., Ltd, Guangzhou, 510515, China.
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Xu Y, Li S, OuYang W, Yao Z, Lai X, Gu Y, Yang M, Ye L, Li S, Peng S. Clinical and virological characteristics of coexistent hepatitis B surface antigen and antibody in treatment-naive children with chronic hepatitis B virus infection. Front Public Health 2024; 12:1380771. [PMID: 38952725 PMCID: PMC11215143 DOI: 10.3389/fpubh.2024.1380771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/27/2024] [Indexed: 07/03/2024] Open
Abstract
Serological pattern of simultaneous positivity for hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) is considered a specific and atypical phenomenon among patients with chronic hepatitis B virus (HBV) infection, especially in pediatric patients. Unfortunately, there is limited understanding of the clinical and virological characteristics among children having chronic HBV infection and the coexistence of HBsAg and anti-HBs. Hence, our objective was to determine the prevalence of coexistent HBsAg and anti-HBs and to explore the associated clinical and virological features in this patient population. The researchers conducted a retrospective cohort study on the 413 pediatric patients with chronic HBV infection from December 2011 to June 2022. The patients were stratified into two groups based on their anti-HBs status. Demographic, serum biochemical and virological parameters of two group were compared. Of the total 413 enrolled subjects, 94 (22.8%) were tested positive for both HBsAg and anti-HBs. Patients with anti-HBs were younger and demonstrated significantly higher ratio of albumin to globulin (A/G), elevated serum levels of alanine transaminase (ALT), lower ratio of aspartate transaminase (AST)/ALT (AST/ALT) and reduced serum levels of globulin, HBsAg and HBV DNA, Additionally, these patients were more likely to show coexistent HBeAg and anti-HBe when compared to patients without anti-HBs. The results of multivariate logistical analysis revealed that AST/ALT, serum levels of globulin and HBsAg were negatively associated with coexistence of HBsAg and anti-HBs. Our data demonstrated a considerable prevalence of coexisting HBsAg and anti-HBs in pediatric patients. Children with this specific serological pattern were commonly of a younger age, seemly predisposing them to early liver impairment and lower HBV replication activity.
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Affiliation(s)
- Yi Xu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - ShuangJie Li
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha, China
| | - WenXian OuYang
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha, China
| | - Zhenzhen Yao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xin Lai
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yingping Gu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Meng Yang
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Ling Ye
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Sisi Li
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Songxu Peng
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
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Ali MJ, Shah PA, Rehman KU, Kaur S, Holzmayer V, Cloherty GA, Kuhns MC, Lau DTY. Immune-Escape Mutations Are Prevalent among Patients with a Coexistence of HBsAg and Anti-HBs in a Tertiary Liver Center in the United States. Viruses 2024; 16:713. [PMID: 38793596 PMCID: PMC11125813 DOI: 10.3390/v16050713] [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: 03/21/2024] [Revised: 04/21/2024] [Accepted: 04/27/2024] [Indexed: 05/26/2024] Open
Abstract
The concurrent seropositivity of HBsAg and anti-HBs has been described among patients with chronic hepatitis B (CHB), but its prevalence is variable. HBV S-gene mutations can affect the antigenicity of HBsAg. Patients with mutations in the 'α' determinant region of the S gene can develop severe HBV reactivation under immunosuppression. In this study at a tertiary liver center in the United States, we evaluated the frequency and virological characteristics of the HBsAg mutations among CHB patients with the presence of both HBsAg and anti-HBs. In this cohort, 45 (2.1%) of 2178 patients were identified to have a coexistence of HBsAg and anti-HBs, and 24 had available sera for the genome analysis of the Pre-S1, Pre-S2, and S regions. The frequency of mutations in the S gene was significantly higher among those older than 50 years (mean 8.5 vs. 5.4 mutations per subject, p = 0.03). Twelve patients (50%) had mutations in the 'α' determinant region of the S gene. Mutations at amino acid position 126 were most common in eight subjects. Three had a mutation at position 133. Only one patient had a mutation at position 145-the classic vaccine-escape mutation. Despite the universal HBV vaccination program, the vaccine-escape mutant is rare in our cohort of predominantly Asian patients.
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Affiliation(s)
- Mukarram Jamat Ali
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
- Howard University Hospital, Howard University College of Medicine, Washington, DC 20060, USA
| | - Pir Ahmed Shah
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
| | - Khalil Ur Rehman
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
| | - Satinder Kaur
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
| | - Vera Holzmayer
- Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL 60064, USA; (V.H.); (G.A.C.); (M.C.K.)
| | - Gavin A. Cloherty
- Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL 60064, USA; (V.H.); (G.A.C.); (M.C.K.)
| | - Mary C. Kuhns
- Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL 60064, USA; (V.H.); (G.A.C.); (M.C.K.)
| | - Daryl T. Y. Lau
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
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Gu Y, Li S, Yao Z, Lai X, Yang M, Xu Y, Peng S. Characteristics and clinical treatment outcomes of chronic hepatitis B children with coexistence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg. BMC Med 2024; 22:77. [PMID: 38378606 PMCID: PMC10877877 DOI: 10.1186/s12916-024-03294-2] [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: 10/16/2023] [Accepted: 02/12/2024] [Indexed: 02/22/2024] Open
Abstract
BACKGROUND The coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) represents an uncommon serological pattern observed in patients with hepatitis B virus (HBV) infection, and its underlying mechanism and clinical significance have not been well established. The aim of this study was to investigate the association between this serological profile and clinical treatment outcomes in children with chronic hepatitis B (CHB). METHODS This retrospective cohort study included 372 treatment-naïve CHB children from the Hunan Children's Hospital. The participants were categorized into HBsAb-positive group and HBsAb-negative group. The associations between HBsAb positive status to clinical outcomes were assessed using Cox proportional hazard regression. Receiver operating characteristic curve was conducted to evaluate the prediction ability in HBsAg loss. RESULTS The coexistence of HBsAg and HBsAb accounted for 23.39% (87/372) of the participants. The crude incidence rates of HBsAg loss, hepatitis B e antigen (HBeAg) clearance, and HBV-DNA undetectability were higher in the HBsAb-positive group compared with the HBsAb-negative group (37.46 vs. 17.37, 49.51 vs. 28.66, 92.11 vs. 66.54 per 100 person-years, respectively, all P < 0.05). The Cox regression analysis revealed a significant association between this serological profile and an increased likelihood of HBsAg loss (HR = 1.78, P = 0.001), and HBeAg clearance (HR = 1.78, P = 0.001). In addition, a combination of HBsAb ≥ 0.84 log10 IU/L and age ≤ 5 years can help identify patients likely to achieve HBsAg loss after antiviral therapy, with an AUC of 0.71. CONCLUSIONS Children who are positive for both HBsAg and HBsAb demonstrate a higher probability of favorable outcomes after antiviral treatment. Thus, children with HBsAb-positive CHB should be actively treated to achieve functional cure.
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Affiliation(s)
- Yingping Gu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha, Hunan, 410078, China
| | - Shuangjie Li
- Liver Disease Center, Hunan Children's Hospital, Changsha, 410000, China
| | - Zhenzhen Yao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha, Hunan, 410078, China
| | - Xin Lai
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha, Hunan, 410078, China
| | - Meng Yang
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha, Hunan, 410078, China
| | - Yi Xu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha, Hunan, 410078, China
| | - Songxu Peng
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha, Hunan, 410078, China.
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Roca TP, Villar LM, Nogueira Lima FS, Vasconcelos MPA, Borzacov LMP, Silva EDCE, do Lago BV, da Silva MTL, Botelho Souza LF, Salcedo JMV, dos Santos ADO, Vieira DS. Genomic Variability of Hepatitis B Virus Circulating in Brazilian Western Amazon. Viruses 2022; 14:v14102100. [PMID: 36298655 PMCID: PMC9611064 DOI: 10.3390/v14102100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 12/02/2022] Open
Abstract
The emergence of clinically relevant mutations in the hepatitis B virus (HBV) genome has been a matter of great debate because of the possibility of escape from the host’s immune system, the potential to cause more severe progression of liver diseases and the emergence of treatment-resistant variants. Here we characterized the circulating variants of HBV in Rondônia State, in the north of Brazil. Serum samples of 62 chronic HBV carriers were subjected to PCR assays and clinical data were collected. Mutations and genotypes were characterized through direct sequencing. The findings show the presence of subgenotypes A1 (54.83%, 34/62), D3 (16.13%, 10/62), F2 (16.13%, 10/62), A2 (4.84%, 3/62), D2 (3.23%, 2/62), D1 (1.61%, 1/62), D4 (1.61%, 1/62) and F4 (1.61%, 1/62). Deletions in the pre-S2 region were found in 13.79% (8/58) of the samples, mutations in the S gene in 59.68% (37/62) and RT mutations in 48.39% (30/62). We found a variable genotypic distribution in different locations and important mutations related to immune escape and drug resistance in Western Amazonia, which contributed to genetic surveillance and provided important information to help control the disease.
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Affiliation(s)
- Tárcio Peixoto Roca
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Correspondence: (T.P.R.); (L.M.V.)
| | - Livia Melo Villar
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
- Correspondence: (T.P.R.); (L.M.V.)
| | - Felipe Souza Nogueira Lima
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
| | | | | | | | - Bárbara Vieira do Lago
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
| | - Mayara Torquato Lima da Silva
- Laboratory of Biotechnology and Structural Bioengineering, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | | | - Juan Miguel Villalobos Salcedo
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Tropical Medicine Research Center of Rondônia—CEPEM/RO, Porto Velho 76812-329, Brazil
| | | | - Deusilene Souza Vieira
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Tropical Medicine Research Center of Rondônia—CEPEM/RO, Porto Velho 76812-329, Brazil
- Postgraduate Program in Experimental Biology, Federal University of Rondônia—PGBIOEXP/UNIR, Porto Velho 76801-059, Brazil
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9
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Zhan Q, Chang L, Wu J, Zhang Z, Xu J, Yu Y, Feng Z, Zeng Z. T-Cell Receptor β Chain and B-Cell Receptor Repertoires in Chronic Hepatitis B Patients with Coexisting HBsAg and Anti-HBs. Pathogens 2022; 11:727. [DOI: https:/doi.org/10.3390/pathogens11070727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023] Open
Abstract
Antibodies in response to antigens are related to the immune repertoire of T- and B-cell receptors. However, some patients with chronic hepatitis B (CHB) have coexisting HBsAg and anti-HBsAg antibodies (anti-HBs) that cannot neutralize HBV. We attempted to investigate the repertoires that produce this response in CHB patients. The T-cell receptor β chain (TRB) and B-cell receptor (BCR) repertoires of peripheral blood genomic DNA were analyzed using MiXCR. T-cell receptor (TCR) cluster analysis was carried out by clusTCR, and motifs prediction was selected by Multiple Em for Motif Elicitation (MEME). A total of 76 subjects were enrolled, including 26 HBsAg and anti-HBs coexisting patients with CHB (DP group), 25 anti-HBs single-positive healthy people (SP group), and 25 CHB patients (CHB group). The clone length of BCR in 39, 90 was significantly different among these groups (p = 0.005, 0.036). The motif “CASSLG” in the DP group was significantly higher than SP and CHB groups and may relate to coexistence, and the motif “GAGPLT” was only shown in the SP group and may relate to anti-HB expression. These provide important insights into vaccine development and CHB treatment.
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Affiliation(s)
- Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Le Chang
- Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China
| | - Jian Wu
- MyGenostics Inc., Beijing 101318, China
| | | | - Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Zhenru Feng
- Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
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Zhan Q, Chang L, Wu J, Zhang Z, Xu J, Yu Y, Feng Z, Zeng Z. T-Cell Receptor β Chain and B-Cell Receptor Repertoires in Chronic Hepatitis B Patients with Coexisting HBsAg and Anti-HBs. Pathogens 2022; 11:727. [PMID: 35889974 PMCID: PMC9318409 DOI: 10.3390/pathogens11070727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 11/17/2022] Open
Abstract
Antibodies in response to antigens are related to the immune repertoire of T- and B-cell receptors. However, some patients with chronic hepatitis B (CHB) have coexisting HBsAg and anti-HBsAg antibodies (anti-HBs) that cannot neutralize HBV. We attempted to investigate the repertoires that produce this response in CHB patients. The T-cell receptor β chain (TRB) and B-cell receptor (BCR) repertoires of peripheral blood genomic DNA were analyzed using MiXCR. T-cell receptor (TCR) cluster analysis was carried out by clusTCR, and motifs prediction was selected by Multiple Em for Motif Elicitation (MEME). A total of 76 subjects were enrolled, including 26 HBsAg and anti-HBs coexisting patients with CHB (DP group), 25 anti-HBs single-positive healthy people (SP group), and 25 CHB patients (CHB group). The clone length of BCR in 39, 90 was significantly different among these groups (p = 0.005, 0.036). The motif "CASSLG" in the DP group was significantly higher than SP and CHB groups and may relate to coexistence, and the motif "GAGPLT" was only shown in the SP group and may relate to anti-HB expression. These provide important insights into vaccine development and CHB treatment.
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Affiliation(s)
- Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; (Q.Z.); (J.X.)
| | - Le Chang
- Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China;
| | - Jian Wu
- MyGenostics Inc., Beijing 101318, China; (J.W.); (Z.Z.)
| | - Zhiyuan Zhang
- MyGenostics Inc., Beijing 101318, China; (J.W.); (Z.Z.)
| | - Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; (Q.Z.); (J.X.)
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; (Q.Z.); (J.X.)
| | - Zhenru Feng
- Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China;
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; (Q.Z.); (J.X.)
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11
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Wang J, Ding W, Liu J, Liu Y, Yan X, Xia J, Wu W, Jia B, Chen Y, Gao D, Hong S, Wang X, Wang L, Tong X, Yin S, Zhang Z, Li J, Huang R, Wu C. Association of Coexistent Hepatitis B Surface Antigen and Antibody With Severe Liver Fibrosis and Cirrhosis in Treatment-Naive Patients With Chronic Hepatitis B. JAMA Netw Open 2022; 5:e2216485. [PMID: 35696167 PMCID: PMC9194671 DOI: 10.1001/jamanetworkopen.2022.16485] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
IMPORTANCE Coexistence of hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) constitutes an atypical serological profile in chronic hepatitis B virus infection, and the association between coexistent HBsAg and anti-HBs with severe liver fibrosis and cirrhosis in patients with chronic hepatitis B (CHB) remains unclear. OBJECTIVE To investigate the association of coexistent HBsAg and anti-HBs with severe liver fibrosis and cirrhosis in patients with CHB. DESIGN, SETTING, AND PARTICIPANTS Consecutive treatment-naive patients with CHB from 2 medical institutions in China were enrolled between January 10, 2015, and March 31, 2021. Severe liver fibrosis and cirrhosis were identified using the aspartate transaminase (AST) to platelet ratio index (APRI), the fibrosis index based on 4 factors (FIB-4; factors comprise age, AST level, alanine aminotransferase [ALT] level, and platelet count), transient elastography, or ultrasonography. Data were analyzed from August 1, 2021, to April 15, 2022. MAIN OUTCOMES AND MEASURES The primary outcomes were rates of severe liver fibrosis and cirrhosis among patients with vs patients without coexistant HBsAg and anti-HBs. Severe liver fibrosis was defined as an APRI score of 1.5 or higher, a FIB-4 score of 3.25 or higher, or a liver stiffness measurement of 8 kPa or higher; cirrhosis was defined as an APRI score of 2.0 or higher, a FIB-4 score of 6.5 or higher, a liver stiffness measurement of 11 kPa or higher, or ultrasonographic findings suggestive of cirrhosis. RESULTS Of 6534 enrolled patients, 4033 patients (61.7%) were male, and the median (IQR) age was 41.0 (33.0-52.0) years. A total of 277 patients (4.2%) had coexistent HBsAg and anti-HBs. Patients with vs without anti-HBs were older (median [IQR], 46.0 [33.0-55.5] years vs 41.0 [33.0-52.0] years) and had a higher proportion of hepatitis B e antigen (HBeAg) positivity (123 of 277 patients [44.4%] vs 2115 of 6257 patients [33.8%]; P < .001), higher ALT levels (median [IQR], 45.1 [24.6-119.0] U/L vs 36.7 [22.0-77.0] U/L; P = .001) and AST levels (median [IQR], 35.0 [23.5-68.4] U/L vs 28.3 [21.6-51.0] U/L; P < .001), and lower platelet counts (median [IQR], 173.0 × 103/μL [129.0-212.5 × 103/μL] vs 185.0 × 103/μL [141.0-224.0 × 103/μL]; P = .004), albumin levels (median [IQR], 4.37 [4.11-4.56] g/dL vs 4.43 [4.17-4.61] g/dL; P = .02), and HBsAg levels (median [IQR], 2.8 log10 [1.6-3.4 log10] IU/mL vs 3.3 log10 [2.6-3.9 log10] IU/mL; P < .001). Compared with patients without anti-HBs, those with anti-HBs had higher APRI scores (median [IQR], 0.5 [0.3-1.4] vs 0.4 [0.3-0.9]; P < .001), FIB-4 scores (median [IQR], 1.4 [0.9-2.6] vs 1.1 [0.7-2.1]; P < .001), and liver stiffness values (median [IQR], 7.5 [6.2-9.8] kPa vs 6.3 [5.2-8.1] kPa; P = .003). Patients with anti-HBs also had higher proportions of severe liver fibrosis (102 of 277 patients [36.8%] vs 1397 of 6207 patients [22.5%]; P < .001) and cirrhosis (87 of 277 patients [31.4%] vs 1194 of 6213 patients [19.2%]; P < .001) compared with patients without anti-HBs. The coexistence of HBsAg and anti-HBs was independently associated with severe liver fibrosis (odds ratio [OR], 2.29; 95% CI, 1.56-3.38; P < .001) and cirrhosis (OR, 1.73; 95% CI, 1.12-2.68; P = .01) in the multivariate analysis. However, the association of coexistent HBsAg and anti-HBs with cirrhosis was only observed in patients with HBeAg negativity (OR, 1.66; 95% CI, 1.05-2.62; P = .03) and not in patients with HBeAg positivity (OR, 1.45; 95% CI, 0.87-2.43; P = .16). CONCLUSIONS AND RELEVANCE In this cross-sectional study, the coexistence of HBsAg and anti-HBs was unusual in hepatitis B virus infection and was associated with more advanced liver diseases, such as severe liver fibrosis and cirrhosis, especially among patients with HBeAg negativity. These results suggest that close monitoring for liver fibrosis and cirrhosis is warranted in patients with CHB who have this serological profile.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yong Liu
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Weihua Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Bei Jia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Dongmei Gao
- Community Work Office, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China
| | - Shuqin Hong
- Hospital Grade Creation Office, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China
| | - Xiaohong Wang
- Department of Surgery, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China
| | - Li Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Zhaoping Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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12
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Xu R, Song D, Wang M, Huang J, Liao Q, Shan Z, Rong X, Fu Y. Molecular Epidemiological Characteristics and Risk Factors for Acquiring HBV Among Li Ethnic in Baisha County, Hainan Island-Subgenotype D3 Was First Discovered in China. Front Microbiol 2022; 13:837746. [PMID: 35197959 PMCID: PMC8859303 DOI: 10.3389/fmicb.2022.837746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 01/14/2022] [Indexed: 12/02/2022] Open
Abstract
The residents of Baisha, a county of Hainan Island, mainly composed of Li ethnic population and relatively closed living environment with its unique geographical location. Our previous study showed that Li ethnic population of Baisha is an endemic center for hepatitis C virus, with significantly higher rates than in other parts of China. However, the epidemiology of HBV in this region remains unclear. Therefore, we conducted a comprehensive epidemiological survey of HBV in Baisha County, including 1,682 Li ethnic residents. The total seropositive rate for HBsAg was 10.2% and was higher than other parts of China. HBV-positive status was associated with the 20–40-year-old group (OR = 1.27, 95%CI 1.04–1.39, P < 0.01) and alcohol consumption (OR = 2.17, 95%CI 1.58–2.99, P < 0.01). Phylogenetic analysis showed that HBV subgenotype D3 was predominant in Baisha County which was first discovered in China, followed by C5, C1, B2, and undetermined subgenotypes which were significantly different from other geographical distribution of main genotypes in China. The most recent common ancestor (tMRCA) of the HBV genotype C in the Li ethnic of Baisha County was 1846 (95%CI: 1739–1932), and Baisha-C5 was earlier than Baisha-C1 and Baisha-C2. Most Baisha-D3 sequences were concentrated in one bundle and unrelated to those D3 genome sequences elsewhere in the world. According to the phylogenetic tree, D3 was introduced into Baisha County in 1884 (95%CI: 1816–1993) and became a local endemic virus. In conclusion, HBV infection in the Li ethnic group is characterized by a high prevalence rate in 20–40-year-old individuals and a unique genotype distribution which were significantly different from other geographical distribution of main genotypes in China, and subgenotype D3 was first discovered in China.
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Affiliation(s)
- Ru Xu
- Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, China
| | - Dandan Song
- Department of Clinical Laboratory, The Fifth People’s Hospital of Zhuhai, Zhuhai, China
| | - Min Wang
- Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, China
| | - Jieting Huang
- Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, China
| | - Qiao Liao
- Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, China
| | - Zhengang Shan
- Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, China
| | - Xia Rong
- Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, China
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
- *Correspondence: Xia Rong,
| | - Yongshui Fu
- Institute of Clinical Blood Transfusion, Guangzhou Blood Center, Guangzhou, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, China
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
- Zhujiang Hospital of Southern Medical University, Guangzhou, China
- Yongshui Fu,
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13
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Sarowar A, Hirode G, Janssen HLA, Feld JJ. Controversies in Treating Chronic Hepatitis B Virus Infection: Discordant Serologic Results. Clin Liver Dis 2021; 25:805-816. [PMID: 34593154 DOI: 10.1016/j.cld.2021.06.007] [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] [Indexed: 02/07/2023]
Abstract
Despite effective vaccines and approved therapeutic agents, hepatitis B virus (HBV) remains a prevalent global health problem. Current guidelines rely on a combination of serologic, virological, and biochemical markers to identify the phase in the natural history of chronic HBV infection. Discordant serologic results can occur, which may lead to misclassification. Commonly encountered results that differ from the typical profiles seen in chronic HBV infection are described. For each scenario, the frequency of occurrence, possible explanations, and recommendations for clinical management are discussed. Recognition of discordant serologic findings is crucial for optimal clinical decision.
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Affiliation(s)
- Arif Sarowar
- Toronto Centre for Liver Disease, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Grishma Hirode
- Toronto Centre for Liver Disease, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
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14
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Jiang X, Chang L, Yan Y, Wang L. Paradoxical HBsAg and anti-HBs coexistence among Chronic HBV Infections: Causes and Consequences. Int J Biol Sci 2021; 17:1125-1137. [PMID: 33867835 PMCID: PMC8040313 DOI: 10.7150/ijbs.55724] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B surface antigen (HBsAg) and Hepatitis B surface antibody (anti-HBs) were reported simultaneously among Hepatitis B virus (HBV) infections. HBsAg is a specific indicator of acute or chronic HBV infections, while anti-HBs is a protective antibody reflecting the recovery and immunity of hosts. HBsAg and anti-HBs coexist during seroconversion and then form immune complex, which is rare detected in clinical cases. However, with the promotion of vaccination and the application of various antiviral drugs, along with the rapid development of medical technology, the coexistence of HBsAg and anti-HBs has become more prevalent. Mutations in the viral genomes, immune status and genetic factors of hosts may contribute to the coexistence. Novel HBsAg assays, with higher sensitivity and ability to detect mutations or immune complexes, can also yield HBsAg/anti-HBs coexistence. The discovery of coexistence has shattered the idea of traditional serological patterns and raised questions about the effectiveness of vaccines. Worth noting is that HBsAg/anti-HBs double positivity is strongly associated with progressive liver diseases, especially hepatocellular carcinoma. In conclusion, viral mutations, host factors, and methodology impacts can all lead to the coexistence of HBsAg and anti-HBs. This coexistence is not an indicator of improvement, as an increased risk of adverse clinical outcomes still exists.
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Affiliation(s)
- Xinyi Jiang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Le Chang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Ying Yan
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Lunan Wang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China
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15
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Hou W, Huo Z, Du Y, Wang C, Syn WK. Characteristics of amino acid substitutions within the "a" determinant region of hepatitis B virus in chronically infected patients with coexisting HBsAg and anti-HBs. Clin Res Hepatol Gastroenterol 2020; 44:923-931. [PMID: 31624004 DOI: 10.1016/j.clinre.2019.08.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/06/2019] [Accepted: 08/09/2019] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Simultaneous positivity for both hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) is an atypical serological profile in chronic hepatitis B (CHB) patients. The exact mechanisms underlying the uncommon profile remains unclear. The aim of this study was to analyze the characteristics of amino acid substitutions within the "a" determinant region in a large cohort of CHB patients with coexistence of HBsAg and anti-HBs. METHODS In total 8687 CHB patients, of which 505 had coexisting HBsAg and anti-HBs, were enrolled in this study. Mutations within the "a" determinant region in 131 HBsAg+/anti-HBs+ patients and 150 age and gender matched HBsAg+/anti-HBs- patients were determined by direct sequencing and the characteristics of amino acid substitutions were analyzed. RESULTS The prevalence of coexistence of HBsAg and anti-HBs in the CHB patients was 5.81%. Compared to the control subjects, there were more amino acid substitutions in HBsAg+/anti-HBs+ patients (30.5% vs. 12.7%, P<0.001), especially within the first loop of the "a" determinant region. The most frequent amino acid substitution was located at position s126 and the predominant substitution was sI126T in HBsAg+/anti-HBs+ patients with genotype C. The frequency of additional N-glycosylation sites in HBsAg+/anti-HBs+ patients and the control subjects was 3.8% and 0.6%, respectively. CONCLUSIONS The accumulation and diversity of amino acid variations within "a" determinant region might contribute to the coexistence of HBsAg and anti-HBs. These findings extend understanding of the genetic mechanism of this atypical serological profile in CHB patients.
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Affiliation(s)
- Wei Hou
- Tianjin Second People's Hospital and Tianjin Institute of Hepatology, Tianjin, China; Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
| | - Zhixiao Huo
- Tianjin Second People's Hospital and Tianjin Institute of Hepatology, Tianjin, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China
| | - Cindy Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Section of Gastroenterology, Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
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16
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Lee WM, King WC, Schwarz KB, Rule J, Lok ASF. Prevalence and clinical features of patients with concurrent HBsAg and anti-HBs: Evaluation of the hepatitis B research network cohort. J Viral Hepat 2020; 27:922-931. [PMID: 32364641 DOI: 10.1111/jvh.13312] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 03/06/2020] [Accepted: 03/23/2020] [Indexed: 12/15/2022]
Abstract
The prevalence of concurrent HBsAg and anti-HBs in plasma of persons with chronic hepatitis B virus (HBV) infection is variable and its clinical significance enigmatic. We examined the prevalence and clinical and virological features of concurrent HBsAg and anti-HBs in children and adults with chronic HBV infection living in North America. A total of 1462 HBsAg positive participants in the Hepatitis B Research Network paediatric and adult cohorts were included (median age 41 (range 4-80) years, 48% female, 11% white, 13% black, 73% Asians). Only 18 (1.2%) were found to be anti-HBs positive (≥10 mIU/mL) at initial study evaluation. Distributions of sex, race, HBV genotype and ALT were similar between participants with and without concurrent anti-HBs. Those who were anti-HBs positive appeared to be older (median age 50 vs 41 years, P = .06), have lower platelet counts (median 197 vs 222 × 103/mm3 , P = .07) and have higher prevalence of HBeAg (44% vs 26%, P = .10). They also had lower HBsAg levels (median 2.0 vs 3.5 log10 IU/mL, P = .02). Testing of follow-up samples after a median of 4 years (range 1-6) in 12 of the 18 participants with initial concurrent anti-HBs showed anti-HBs became undetectable in 6, decreased to <10 mIU/mL in 1 and remained positive in 5 participants. Two patients lost HBsAg during follow-up. In conclusion, prevalence of concurrent HBsAg and anti-HBs was low at 1.2%, with anti-HBs disappearing in some during follow-up, in this large cohort of racially diverse children and adults with chronic HBV infection living in North America. Presence of concurrent HBsAg and anti-HBs did not identify a specific phenotype of chronic hepatitis B, nor did it appear to affect clinical outcomes.
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Affiliation(s)
- William M Lee
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Wendy C King
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kathleen B Schwarz
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jody Rule
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
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17
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Long-term outcomes of HBsAg/anti-HBs double-positive versus HBsAg single-positive patients with chronic hepatitis B. Sci Rep 2019; 9:19417. [PMID: 31857656 PMCID: PMC6923451 DOI: 10.1038/s41598-019-56015-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 12/05/2019] [Indexed: 12/15/2022] Open
Abstract
The coexistence of HBsAg and anti-HBs has been reported in some chronic hepatitis B patients; however, the long-term outcomes of this serological profile have not been elucidated. We aimed to evaluate the long-term outcomes of HBsAg/anti-HBs double-positive chronic hepatitis B patients. Chronic hepatitis B patients who underwent baseline abdominal ultrasonography and follow-up (HBsAg/anti-HBs assessment and abdominal ultrasonography) at our healthcare center were included. The "coexistence group" included patients positive for both HBsAg and anti-HBs and the "control group" included patients positive for only HBsAg during follow-up. The outcomes were hepatocellular carcinoma (HCC) incidence, HBsAg seroclearance and overall mortality. Kaplan-Meier and Cox proportional hazard regression analyses were performed. Of the 2,341 eligible patients, 166 (7.1%) were in the coexistence group. The total follow-up duration was 5.4 years. The coexistence group had a 3.08-fold higher risk of HCC than the control group [hazard ratio (HR) 3.08, 95% confidence interval(CI) 1.26-7.55, P = 0.014] in multivariate analysis. The coexistence group had more HBsAg seroclearance than the control group (HR 1.43, 95% CI 1.01-2.03, P = 0.046). However, overall mortality did not significantly differ between the 2 groups. The coexistence group is heterogeneous and includes subjects with unfavorable outcomes (incidence of HCC) and favorable outcomes (more HBsAg seroclearance).
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Jin ZZ, Jin FF, Liu X, Liu N, Wen F, Lou JL. Coexistence of low levels of HBsAg and high levels of anti-HBs may increase risk of hepatocellular carcinoma in chronic hepatitis B patients with high HBV load. Braz J Infect Dis 2019; 23:343-351. [PMID: 31542378 PMCID: PMC9427988 DOI: 10.1016/j.bjid.2019.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/07/2019] [Accepted: 08/23/2019] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE The clinical significance of coexistence of HBsAg/anti-HBs in chronic hepatitis B (CHB) patients remains controversial. This study was aimed to assess the association of this serological pattern with hepatocellular carcinoma (HCC) in patients with CHB. METHODS In this cross-section study, 206 CHB patients with coexistence of HBsAg/anti-HBs and 206 CHB patients with HBsAg alone were included to evaluate the risk of HCC development by logistic regression analysis. In addition, a retrospective cohort of 260 patients with CHB was recruited to estimate the cumulative incidence of HCC by Kaplan-Meier analysis. RESULTS The serological pattern of coexistence of HBsAg/anti-HBs, with high levels of ("High") HBsAg/low levels of ("Low") anti-HBs, were considered as independent risk factors for HCC. In particular, patients with "High" HBsAg/"High" anti-HBs [odds ratio (OR), 4.295; 95% confidence interval (CI), 1.104-16.699; p = 0.035] and "Low" HBsAg/ "High" anti-HBs (OR, 3.207; 95%CI, 1.299-7.919; p = 0.012) exhibited significantly higher risk for HCC development. However, only "Low" HBsAg /"High" anti-HBs might increase risk of HCC in CHB patients with high HBV load (logrank p < 0.001) in our cohort study. CONCLUSION The coexistence of "Low" HBsAg /"High" anti-HBs might increase the risk of HCC development in CHB patients with high HBV load, which reflected that the long-term interaction between immune response and virus might lead to the development of HCC. The identification of the patients with poor prognosis will help clinicians to refine the therapeutic decisions and individualize follow-up strategies.
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Affiliation(s)
- Zi-Zheng Jin
- Capital Medical University, Beijing You an Hospital, Center for clinical laboratory, Beijing, People's Republic of China
| | - Fang-Fang Jin
- Capital Medical University, Beijing You an Hospital, Center for clinical laboratory, Beijing, People's Republic of China
| | - Xin Liu
- Capital Medical University, Beijing You an Hospital, Center for clinical laboratory, Beijing, People's Republic of China
| | - Ning Liu
- Capital Medical University, Beijing You an Hospital, Center for clinical laboratory, Beijing, People's Republic of China
| | - Feng Wen
- Capital Medical University, Beijing You an Hospital, Center for clinical laboratory, Beijing, People's Republic of China
| | - Jin-Li Lou
- Capital Medical University, Beijing You an Hospital, Center for clinical laboratory, Beijing, People's Republic of China.
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19
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Wang S, Wang J, Fan M, Li T, Pan H, Wang X, Liu H, Lin Q, Zhang J, Guan L, Zhernakova DV, O'Brien SJ, Feng Z, Chang L, Dai E, Lu J, Xi H, Zeng Z, Yu Y, Wang B. Identified OAS3 gene variants associated with coexistence of HBsAg and anti-HBs in chronic HBV infection. J Viral Hepat 2018; 25:904-910. [PMID: 29582521 PMCID: PMC6105377 DOI: 10.1111/jvh.12899] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 02/22/2018] [Indexed: 12/20/2022]
Abstract
The underlying mechanism of coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antigen antibody (anti-HBs) is still controversial. To identify the host genetic factors related to this unusual clinical phenomenon, a two-stage study was conducted in the Chinese Han population. In the first stage, we performed a case-control (1:1) age- and gender-matched study of 101 cases with concurrent HBsAg and anti-HBs and 102 controls with negative HBsAg and positive anti-HBs using whole exome sequencing. In the second validation stage, we directly sequence the 16 exons on the OAS3 gene in two dependent cohorts of 48 cases and 200 controls. Although, in the first stage, a genome-wide association study of 58,563 polymorphism variants in 101 cases and 102 controls found no significant loci (P-value ≤ .05/58563), and neither locus achieved a conservative genome-wide significance threshold (P-value ≤ 5e-08), gene-based burden analysis showed that OAS3 gene rare variants were associated with the coexistence of HBsAg and anti-HBs. (P-value = 4.127e-06 ≤ 0.05/6994). A total of 16 rare variants were screened out from 21 cases and 3 controls. In the second validation stage, one case with a stop-gained rare variant was identified. Fisher's exact test of all 149 cases and 302 controls showed that the rare coding sequence mutations were more frequent in cases vs controls (P-value = 7.299e-09, OR = 17.27, 95% CI [5.01-58.72]). Protein-coding rare variations on the OAS3 gene are associated with the coexistence of HBsAg and anti-HBs in patients with chronic HBV infection in Chinese Han population.
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Affiliation(s)
- Sa Wang
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Jing Wang
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
- Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China
| | - Mengjie Fan
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Tengyan Li
- Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China
| | - Hong Pan
- Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China
| | - Xi Wang
- Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China
| | - Hankui Liu
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Qiongfen Lin
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Jianguo Zhang
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Liping Guan
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Daria V. Zhernakova
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199004, Russia
| | - Stephen J. O'Brien
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199004, Russia
| | - Zhenru Feng
- Department of Laboratory Medicines, Peking University First Hospital, Beijing 100034, China
| | - Le Chang
- Department of Laboratory Medicines, Peking University First Hospital, Beijing 100034, China
| | - Erhei Dai
- the Fifth Hospital of Shijiazhuang, Shijiazhuang 050024, China
| | - Jianhua Lu
- the Fifth Hospital of Shijiazhuang, Shijiazhuang 050024, China
| | - Hongli Xi
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Binbin Wang
- Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China
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20
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Fougère Y, El Houss S, Suris JC, Rouvenaz-Defago S, Miletto D, Von der Weid L, Willen F, Williams-Smith JA, Gehri M, Crisinel PA. High coverage of hepatitis B vaccination and low prevalence of chronic hepatitis B in migrant children dictate a new catch-up vaccination strategy. Vaccine 2018; 36:4501-4506. [PMID: 29907480 DOI: 10.1016/j.vaccine.2018.06.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/03/2018] [Accepted: 06/04/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND Worldwide coverage of hepatitis B (HB) vaccination is increasing. This should be considered when determining the best strategy for catch-up HB vaccination in migrant children, who rarely have written proof of past immunizations. This study aimed to estimate HB vaccine protection, chronic HB prevalence and to identify determinants of vaccine protection. METHODS Newly arrived migrant children at Lausanne University Hospital from October 2014 to July 2017 were prospectively enrolled. Children and adolescents aged 1-18 years were approached for inclusion if they had no proof of past vaccinations and accepted a single dose of injected HB vaccine. HB surface antibody (anti-HBs) serology was performed after 4-6 weeks. Anti-HBs ≥100 IU/L were considered consistent with a booster-type antibody response. Patients with anti-HBs <100 IU/L received additional dose(s) of HB vaccine, after exclusion of chronic HB in children with anti-HBs <10 IU/L. Potential determinants of vaccine response were compared between children with and without booster-type response. RESULTS Two hundred children were available for analysis. Median age was 8.9 years (IQR 4.8-12.9), and 97 (49%) were female. The majority (n = 124, 62%) came from the region classified by the WHO as eastern Mediterranean. One hundred and sixty-one children (81%) had a booster-type antibody response. Only 1 patient (<1%) had chronic HB. In the multivariate analysis, younger age (OR per decreasing-year, 1.28; 95%CI, 1.05-1.57; p = 0.017) and migration from an urban area (OR 1.16; 95%CI, 1.01-1.33; p = 0.043) were the only significant determinants of booster-type response. CONCLUSION Post-vaccine serology may be used to identify a high proportion of individuals in our pediatric migrant population with previous immunization for HB. Our study also showed extremely low prevalence of chronic HB. No variable could definitively determine the results of serology. Post-vaccine serology represents the most effective strategy in this context of high vaccine coverage.
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Affiliation(s)
- Yves Fougère
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland.
| | - Samir El Houss
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
| | - Joan-Carles Suris
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
| | - Sylvie Rouvenaz-Defago
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
| | - Damien Miletto
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
| | - Lucie Von der Weid
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
| | - Fanny Willen
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
| | | | - Mario Gehri
- Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
| | - Pierre Alex Crisinel
- Unit of Pediatric Infectious Diseases and Vaccinology, Department Women-Mother-Child, Lausanne University Hospital, Switzerland
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21
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Su H, Shao Z, Pu Z, Wang Y, Zhang L, Zhang W, Wang B, Wang A, Ji Z, Yan Y, Zhang Y. Overt and occult hepatitis B virus infection among community children in Northwest China. J Viral Hepat 2017; 24:797-803. [PMID: 28342241 DOI: 10.1111/jvh.12709] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 03/17/2017] [Indexed: 12/26/2022]
Abstract
Although a universal newborn hepatitis B (HB) immunization programme has been implemented in China, hepatitis B virus (HBV) breakthrough infection, including HB surface antigen (HBsAg)-positive infection and occult HBV infection (OBI), still occurs during infancy or childhood. Obtaining the actual prevalence of HBV infection in general children is important for preventing and controlling the spread of HB. Accordingly, we investigated the prevalence of overt infection and OBI in community children and compared the serological and virological characteristics of OBI and HBsAg carrier children to clarify the mechanisms related to OBI. In total, 6 706 community children <12 years of age were included from a population-based HBV seroepidemiological investigation in Northwest China. The HBsAg carrier rate in community children was 1.60% (107/6706), and the anti-HBs positive rate was 57.35% (3846/6706). Additionally, 1192 HBsAg-negative children were examined for OBI using nested PCR. The prevalence of OBI in local children was 1.26% (15/1192), and the predominant OBI genotypes were C and D. The 15 OBI children and 29 HBsAg-positive children from the same population did not have a statistical significant difference in age, gender, alanine aminotransferase (ALT), proportion of anti-HBs or anti-HBc, viral genotypes or mutations. Children with chronic overt infection had higher viral loads than OBI children (P=.004). These results suggested that HBV overt and occult infection of children was more serious in underdeveloped north-west regions. HBV neonatal immunization and catch-up programmes should be strengthened and supplemented. None of specific viral mutations or genotypes related to OBI were found. OBI may be a specific stage of HBV infection.
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Affiliation(s)
- H Su
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Z Shao
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Z Pu
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Y Wang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - L Zhang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - W Zhang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - B Wang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - A Wang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Z Ji
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Y Yan
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Y Zhang
- Department of Health Statistics, School of Public Health, The Fourth Military Medical University, Xi'an, China
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22
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Zhou TC, Li X, Li L, Li XF, Zhang L, Wei J. Evolution of full-length genomes of HBV quasispecies in sera of patients with a coexistence of HBsAg and anti-HBs antibodies. Sci Rep 2017; 7:661. [PMID: 28386078 PMCID: PMC5428874 DOI: 10.1038/s41598-017-00694-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/08/2017] [Indexed: 02/07/2023] Open
Abstract
Although the evolutionary changes of viral quasispecies are correlated to the pathological status of a disease, little is known in the coexistence of hepatitis B surface antigen (HBsAg) and antibodies to these antigens (anti-HBs). To examine evolutionary changes in hepatitis B virus (HBV) and their relationship to the coexistence of HBsAg and anti-HBs antibodies, HBV genomes in patients with a coexistence of HBsAg and anti-HBs antibodies (experimental group) and HBsAg positive without anti-HBs (control group) were assessed. Our results showed that quasispecies diversity was significantly higher in the experimental group for large HBsAg (LHBsAg), middle HBsAg (MHBsAg), and HBsAg genes. LHBsAg harbored dN/dS values eight times higher in the experimental group; however, the mean dN/dS ratios in genes HbxAg, Pol and PreC/C of the experimental patients had an opposite trend. Phylogenetic trees in the experimental group were more complex than the control group. More positive selection sites, mutations and deletions were observed in the experimental group in specific regions. Furthermore, several amino acid variants in epitopes were potentially associated with the immune evasion. In conclusion, cumulative evolutionary changes in HBV genome that facilitate immune evasion provide insights into the genetic mechanism of a coexistence of HBsAg and anti-HBs antibodies.
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Affiliation(s)
- Tai-Cheng Zhou
- Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Xiao Li
- Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Long Li
- Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Xiao-Fei Li
- Clinical laboratory, the third people's hospital of Kunming City, Kunming, Yunnan Province, China
| | - Liang Zhang
- Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China.
| | - Jia Wei
- Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China.
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23
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Clinical features and viral quasispecies characteristics associated with infection by the hepatitis B virus G145R immune escape mutant. Emerg Microbes Infect 2017; 6:e15. [PMID: 28325923 PMCID: PMC5378923 DOI: 10.1038/emi.2017.2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/29/2016] [Accepted: 12/30/2016] [Indexed: 12/12/2022]
Abstract
Coexistence of the hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) is an uncommon phenomenon, and the underlying mechanisms remain largely unknown. Amino-acid (aa) substitution from glycine to arginine at aa 145 (G145R), in the major hydrophilic region, has been reported in patients with HBsAg and anti-HBs coexistence. However, there is limited knowledge about the clinical features and viral quasispecies characteristics associated with G145R mutant hepatitis B virus (HBV) infection. We herein describe the dynamic changes in the serological and virological markers in a case of hepatitis B with coexisting HBsAg and anti-HBs, caused by a G145R immune escape mutant (genotype C). Entecavir was administered during the 4th week after admission. Alanine aminotransferase peaked in the 16th week, while both the HBsAg and HBeAg declined rapidly. HBsAg clearance and hepatitis B e antigen (HBeAg)/hepatitis B e antibody (anti-HBe) seroconversion were achieved in the 36th week, and then entecavir was withdrawn. A follow-up of 96 weeks showed that HBV DNA remained undetectable and that anti-HBs was maintained above 100 mIU/mL. The quasispecies characteristics of the G145R mutant HBV were investigated via ultra-deep sequencing. The complexity and genetic distance of the S and RT regions were much higher in the 8th week than at baseline or in the 4th week. Moreover, the frequencies of mutations (L173P, Q181R and A184V) in cytotoxic T lymphocyte epitopes increased before entecavir treatment. These findings extend understanding of the evolution of HBV under host immune pressure and of the clinical outcomes of affected patients.
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24
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Fu X, Chen J, Chen H, Lin J, Xun Z, Li S, Liu C, Zeng Y, Chen T, Yang B, Ou Q. Mutation in the S gene of hepatitis B virus and anti-HBs subtype-nonspecificity contributed to the co-existence of HBsAg and anti-HBs in patients with chronic hepatitis B virus infection. J Med Virol 2017; 89:1419-1426. [PMID: 28198078 DOI: 10.1002/jmv.24782] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 12/25/2016] [Accepted: 01/17/2017] [Indexed: 02/03/2023]
Affiliation(s)
- Xiaochun Fu
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- First Clinical College; Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Jing Chen
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Huijuan Chen
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Jinpiao Lin
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Zhen Xun
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- First Clinical College; Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Shiqi Li
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- First Clinical College; Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Can Liu
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Yongbin Zeng
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Tianbin Chen
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Bin Yang
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
| | - Qishui Ou
- Department of Laboratory Medicine; The First Affiliated Hospital of Fujian Medical University; Fuzhou China
- The Genetic Diagonstic Laboratory; The First Affiliated Hospital of Fujian Medical University; China
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25
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de Campos Albuquerque I, Sousa MT, Santos MDC, Nunes JDC, Moraes MJD, Gomes-Gouvêa MS, Pinho JRR, Carrilho FJ, Fonseca LMB, de Sousa Paiva Ferreira A. Mutation in the S gene a determinant of the hepatitis B virus associated with concomitant HBsAg and anti-HBs in a population in Northeastern Brazil. J Med Virol 2016; 89:458-462. [PMID: 27486854 DOI: 10.1002/jmv.24653] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2016] [Indexed: 12/17/2022]
Abstract
Mutations in the a determinant of S gene may develop co-existence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) in the serum of infected hepatitis B virus (HBV) individuals. Mutations in this region may change the antigenicity of HBsAg, which in turn, lead to escape of neutralizing action of anti-HBs antibodies. This study identified individuals with concomitant HBsAg and anti-HBs serological markers in individuals of Maranhão, Northeastern Brazil. Samples from a population-based study were evaluated for HBsAg, anti-HBs, and anti-HBc, and those that tested positive for simultaneous HBsAg and anti-HBs were submitted to HBV DNA quantification and S gene characterization by Sanger sequencing. Mutations were investigated in the a determinant located in major hydrophilic region (MHR) of the S gene. Among 3,984 samples analyzed, 92 (2.3%) were positive for HBsAg and three had the atypical HBsAg and anti-HBs-positive profile (3.26%). The frequency of HBsAg and anti-HBs co-existence was similar to previous studies. Only one individual harbored mutation in the S gene a determinant associated with this profile. Little is known about this phenomenon; however, studies as ours may contribute for future enlightenment of this important issue. J. Med. Virol. 89:458-462, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
| | - Marinilde Teles Sousa
- Graduate Program of Health Sciences, Federal University of Maranhão, Maranhão, Brazil
| | - Max Diego Cruz Santos
- Department of Gastroenterology, University of Sao Paulo School of Medicine, São Paulo, Brazil
| | | | - Maria Josélia Diniz Moraes
- Maranhão Clinical Research Center, University Hospital of the Federal University of Maranhão, Maranhão, Brazil
| | | | | | - Flair José Carrilho
- Department of Gastroenterology, University of Sao Paulo School of Medicine, São Paulo, Brazil
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26
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Allain JP, Opare-Sem O. Screening and diagnosis of HBV in low-income and middle-income countries. Nat Rev Gastroenterol Hepatol 2016; 13:643-653. [PMID: 27625189 DOI: 10.1038/nrgastro.2016.138] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
HBV testing and diagnosis of HBV-related liver disease in low-income and middle-income countries differs substantially from that in developed countries in terms of access to resources and expensive technologies requiring highly specialized staff. For identification and classification of HBV infection, genomic amplification methods to detect and quantify HBV DNA are often nonexistent or available only in central laboratories of major cities. When samples from peripheral locations do arrive, delays in receiving results generate loss to follow-up. Testing is often limited to measurement of hepatitis B surface antigen (HBsAg), alanine aminotransferase levels, aspartate aminotransferase to platelet ratio index and hepatitis B e antigen (HBeAg) to determine indications for antiviral therapy (AVT). Utilization of AVT is limited by cost and availability, particularly when patients are not covered by health insurance. The natural history of HBV infection is influenced by genotypes B and C in East Asia, where decades of immune tolerance have led to mostly vertical transmission; in sub-Saharan Africa, where genotypes A1 and E predominate, infection is transmitted horizontally between young children, followed by a nonreplicative phase. In both regions, cirrhosis and hepatocellular carcinoma are common and would be considerably ameliorated by AVT. Implementation of the HBV vaccine since the 1990s in Asia and 2000s in Africa has decreased the incidence of HBV, but vaccine failure and insufficiently effective prevention remain concerning issues.
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Affiliation(s)
- Jean-Pierre Allain
- Department of Haematology, University of Cambridge, Science Village, Chesterford Research Park, Little Chesterford CB10 1XL, UK
| | - Ohene Opare-Sem
- Department of Medicine, Kwame Nkrumah University of Science and Technology, University Post Office, Kumasi, Ghana
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27
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Sahebjam F, Hajdu CH, Nortey E, Sigal SH. Direct acting antiviral therapy is curative for chronic hepatitis C/autoimmune hepatitis overlap syndrome. World J Hepatol 2016; 8:632-636. [PMID: 27190580 PMCID: PMC4867421 DOI: 10.4254/wjh.v8.i14.632] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 02/18/2016] [Accepted: 03/14/2016] [Indexed: 02/06/2023] Open
Abstract
Autoimmune phenomena are common in patients with chronic hepatitis C. Management of chronic hepatitis C/autoimmune hepatitis syndrome has until recently been problematic due to the adverse effects of interferon on autoimmune processes and immunosuppression on viral replication. In this report we describe 3 patients with chronic hepatitis C/autoimmune hepatitis overlap syndrome who responded rapidly to direct acting anti-viral therapy. The resolution of the autoimmune process supports a direct viral role in its pathophysiology.
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