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1
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Wu L, Yang Z, Zheng M. Biogenesis of serum HBV RNA and clinical phenomena of serum HBV RNA in chronic hepatitis B patients before and after receiving nucleos(t)ide analogues therapy. J Viral Hepat 2024; 31:255-265. [PMID: 38332479 DOI: 10.1111/jvh.13926] [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: 10/13/2023] [Revised: 12/20/2023] [Accepted: 01/17/2024] [Indexed: 02/10/2024]
Abstract
There are estimated 300 million people afflicted with chronic hepatitis B (CHB) worldwide. The risk of liver cirrhosis and hepatocellular carcinoma (HCC) increases considerably with chronic hepatitis B infection. While current therapeutics are effective in controlling hepatitis B virus (HBV) infection and disease progression, a cure for HBV infection remains unattainable due to an intranuclear replicative intermediate known as covalently closed circular DNA (cccDNA). It has recently been shown that serum HBV RNA is a non-invasive biomarker that reflects cccDNA transcriptional activity. This review provides a comprehensive overview and the latest updates on the molecular characteristics and clinical significance of serum HBV RNA, such as species of serum HBV RNA, forms of serum HBV RNA carriers and predictive value for relapses in CHB patients after nucleos(t)ide analogues (NAs) discontinuation and development of liver fibrosis and HCC. Furthermore, we summarize standardized assays for testing serum HBV RNA, the dynamic changes of serum HBV RNA levels in treatment-naïve CHB patients and those under NAs therapy, as well as the host and viral influencing factors of serum HBV RNA levels. Finally, we discuss the future perspectives in studies of serum HBV RNA.
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Affiliation(s)
- Liandong Wu
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhenggang Yang
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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2
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Lin J, Jiang S, Chen X, Zhu M, Zhang H. The significance of detecting HBV pgRNA and HBcrAg in HBV patients treated with NAs. Medicine (Baltimore) 2024; 103:e37752. [PMID: 38579047 PMCID: PMC10994503 DOI: 10.1097/md.0000000000037752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 03/08/2024] [Indexed: 04/07/2024] Open
Abstract
The value of detecting hepatitis B virus (HBV), pregenomic RNA (pgRNA), and hepatitis B core-related antigen (HBcrAg), both separately and jointly, in the management of HBV patients undergoing treatment with Nucleotide Analog was investigated. A total of 149 HBV patients who were being treated with Nucleotide Analog were enrolled in this study. The quantitative levels of HBV pgRNA and HBcrAg in the sera of these patients were determined, aiming to comprehend their replication levels and expression during the course of antiviral therapy. The patients were separated into 3 groups based on treatment duration: treatment time ≤ 12 months, treatment time ranging from 12 months to <60 months, and treatment time ≥ 60 months. Significantly different levels of HBcrAg and HBV pgRNA were observed among 3 groups (P < .05). In the group of patients with positive hepatitis B e antigen, both HBcrAg and pgRNA levels were higher compared to the group with negative hepatitis B e antigen, and this difference between the 2 groups was found to be statistically significant. Stratified analysis based on levels of hepatitis B surface antigen (HBsAg) revealed that the group with HBsAg levels < 100 IU/mL had lower levels of both HBcrAg and pgRNA compared to the group with HBsAg levels ≥ 100 IU/mL (P < .001). Following antiviral therapy, various degrees of transcription of covalently closed circular DNA continue to exist within the liver of HBV patients. The levels of serum HBcrAg and HBV pgRNA vary among patients with different treatment durations, indicating their efficacy in evaluating disease conditions during antiviral therapy.
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Affiliation(s)
- Jie Lin
- Department of Infectious Diseases, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Shiyao Jiang
- Department of Infectious Diseases, The Third People’s Hospital of Deqing, Huzhou, Zhejiang, P.R. China
| | - Xiangyu Chen
- Department of Infectious Diseases, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Min Zhu
- Department of Infectious Diseases, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Haifeng Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
- Infection Management Office, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
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3
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Lin CL, Kao JH. Precision Management of Patients with HBV Infection. CURRENT HEPATOLOGY REPORTS 2024; 23:22-31. [DOI: 10.1007/s11901-024-00632-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/02/2024] [Indexed: 01/03/2025]
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Ahmed Y, El-Kassas M. Interpreting Serogical Markers in Hepatitis B Virus Infection. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2023; 31. [DOI: 10.1097/ipc.0000000000001322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
Abstract
Hepatitis B virus (HBV) is considered a global health-related problem. The World Health Organization estimates an incidence of approximately 1.5 million new cases annually despite an available effective vaccine, and approximately 296 million people worldwide are living with chronic hepatitis B. This large number of patients require continuous monitoring of the treatment efficacy, disease progression, and screening for the HBV-related liver complications. Recently, it has become more evident that we need better predictive markers to allow treatment cessation when there is a reduced risk of viral reactivation, in addition to the present need to predict disease outcome and improve the management of people living with chronic hepatitis B. Novel HBV biomarkers are focused on in this minireview. These new markers include quantification of serum HBV RNA, hepatitis B core–related antigen, quantitative hepatitis B surface antigen, quantitative anti–hepatitis B core antigen, and detection of HBV nucleic acid–related antigen. The target of finding new markers for HBV replication is to provide crucial clinical data in a noninvasive way for detecting the replicative and transcriptional activity of the virus. This may support better management of patients compared with the criterion-standard invasive marker for detecting the intrahepatic replication and transcription of HBV, which is the quantification of covalently closed circular DNA.
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Affiliation(s)
- Yasmeen Ahmed
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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Wang CR, Liu XQ, Li H, Zhang Q, Zhong GC, Tang Q, Chang Y, Wang JS, Duan YQ, Hu P. PgRNA kinetics predict HBsAg reduction in pregnant chronic hepatitis B carriers after treatment cessation. Front Cell Infect Microbiol 2022; 12:1055774. [PMID: 36579348 PMCID: PMC9791257 DOI: 10.3389/fcimb.2022.1055774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 10/28/2022] [Indexed: 12/14/2022] Open
Abstract
Background Pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) play significant roles in predicting discontinuing treatment outcomes. However, their role in pregnancy has rarely been reported. We aimed to evaluate the performance of pgRNA and HBcrAg kinetics in predicting HBeAg seroconversion and HBsAg reduction postpartum in HBeAg-positive pregnant women. Methods Pregnant HBeAg-positive patients receiving antiviral prophylaxis and ceasing treatment postpartum were included. PgRNA and HBcrAg levels were measured before treatment, at 32 weeks of gestation, and at treatment withdrawal postpartum. Other virological and biochemical parameters were regularly examined until 96 weeks postpartum. Results Of 76 pregnant chronic hepatitis B (CHB) carriers with a median treatment duration of 18.1 weeks, HBeAg seroconversion and HBsAg reduction >0.3 log10 IU/mL at 96 weeks postpartum occurred in 8 (10.5%) and 13 (17.1%) patients, respectively. HBsAg correlated most strongly with pgRNA, while HBeAg correlated most strongly with HBcrAg. Multivariable regression analysis revealed that postpartum pgRNA decline and peak ALT levels were independent predictors of HBsAg reduction. The area under the curve of the regression model was 0.79 and reached as high as 0.76 through bootstrapping validation. The calibration plot showed that the nomogram had a performance similar to that of the ideal model. A decision tree was established to facilitate application of the nomogram. In addition, HBcrAg kinetics, as an independent predictor, performed poorly in predicting HBeAg seroconversion. Conclusions Postpartum pgRNA decline together with peak ALT levels may identify patients with a higher probability of HBsAg reduction after treatment cessation postpartum among pregnant CHB carriers receiving antiviral prophylaxis.
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Affiliation(s)
- Chun-Rui Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-qin Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hu Li
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guo-Chao Zhong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiao Tang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunan Chang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jin-Song Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan-qin Duan
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China,*Correspondence: Peng Hu, ;
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6
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Yu G, Chen R, Zheng S, Liu Y, Zou J, Gu Z, Jiang B, Gao Q, Dai L, Peng J, Wang J, Lu F. A standardized assay for the quantitative detection of serum HBV RNA in chronic hepatitis B patients. Emerg Microbes Infect 2022; 11:775-785. [PMID: 35220917 PMCID: PMC8920369 DOI: 10.1080/22221751.2022.2045874] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/08/2022] [Accepted: 02/19/2022] [Indexed: 01/05/2023]
Abstract
Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is a surrogate marker for reflecting the transcriptional activity of covalently closed circular DNA. However, there is still no standardized assay for the quantitative detection of serum HBV RNA in chronic hepatitis B patients. In this study, quantitative polymerase chain reactions for detecting the preC/C-RNA (preC/C region HBV pgRNA), SF-RNA (splicing variants-free pgRNA) and XR-RNA (X region remained pgRNA) regions were set up. The dynamic changes of serum pgRNA splicing variants and 3' terminal truncations were analysed in three retrospective cohorts: 35 treatment-naive chronic HBV-infected patients (cohort A), 52 chronic hepatitis B (CHB) patients who received nucleos(t)ide analogs (NAs) therapy for 48 weeks (cohort B) and eight CHB patients who are under long-term NAs treatment (cohort C). The accuracy and sensitivity of HBV RNA detection were assessed by the National Standard of HBV RNA. We confirmed that high proportions of pgRNA splicing variants and 3' terminal truncations were present and significantly affect the quantitative detection of serum HBV RNA in both treatment-naive and NAs-treated CHB patients. To achieve the higher accuracy and sensitivity on the detection of HBV RNA level, the primers and probes should be designed at the 5' terminal region of HBV genome and outside the mainly spliced sequence of pgRNA, especially for CHB patients under long-term NAs treatment. This study would help to better understand the significance of the pgRNA splicing variants and 3' terminal truncations, and further guide the clinical detection of serum HBV RNA.
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Affiliation(s)
- Guangxin Yu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Ran Chen
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Sujun Zheng
- Hepatology Center Department, Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Yanna Liu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Jun Zou
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Zhiqiang Gu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Bei Jiang
- Tianjin Institute of Hepatology, Tianjin Second People’s Hospital, Tianjin, People’s Republic of China
| | - Qi Gao
- Beijing Hotgen Biotech Co., Ltd., Beijing, People’s Republic of China
| | - Lizhong Dai
- Sansure Biotechnology Corporation, Changsha, People’s Republic of China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jie Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Fengmin Lu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
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7
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Ceesay A, Bouherrou K, Tan BK, Lemoine M, Ndow G, Testoni B, Chemin I. Viral Diagnosis of Hepatitis B and Delta: What We Know and What Is Still Required? Specific Focus on Low- and Middle-Income Countries. Microorganisms 2022; 10:2096. [PMID: 36363693 PMCID: PMC9694472 DOI: 10.3390/microorganisms10112096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/11/2022] [Accepted: 10/18/2022] [Indexed: 01/25/2023] Open
Abstract
To achieve the World Health Organization's (WHO) goals of eradicating viral hepatitis globally by 2030, the regional prevalence and epidemiology of hepatitis B virus (HBV) and hepatitis delta virus (HDV) coinfection must be known in order to implement preventiveon and treatment strategies. HBV/HDV coinfection is considered the most severe form of vira l hepatitis due to it's rapid progression towards cirrhosis, hepatocellular carcinoma, and liver-related death. The role of simplified diagnosticsis tools for screening and monitoring HBV/HDV-coinfected patients is crucial. Many sophisticated tools for diagnoses have been developed for detection of HBV alone as well as HBV/HDV coinfection. However, these advanced techniques are not widely available in low-income countries and there is no standardization for HDV detection assays, which are used for monitoring the response to antiviral therapy. More accessible and affordable alternative methods, such as rapid diagnostic tests (RDTs), are being developed and validated for equipment-free and specific detection of HBV and HDV. This review will provide some insight into both existing and diagnosis tools under development, their applicability in developing countries and how they could increase screening, patient monitoring and treatment eligibility.
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Affiliation(s)
- Amie Ceesay
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
- Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine, Atlantic Boulevard, Fajara P.O. Box 273, Banjul, The Gambia
- School of Arts and Sciences, University of The Gambia, Serrekunda P.O. Box 3530, Banjul, The Gambia
| | - Khaled Bouherrou
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
| | - Boun Kim Tan
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
- Department of Intensive Care Unit, Hôpital Lyon Sud, Hospices Civils de Lyon, 165, Chemin du Grand Revoyet, 69310 Pierre-Bénite, France
| | - Maud Lemoine
- Division of Digestive Diseases, Section of Hepatology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W2 1NY, UK
| | - Gibril Ndow
- Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine, Atlantic Boulevard, Fajara P.O. Box 273, Banjul, The Gambia
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
| | - Isabelle Chemin
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
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8
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Xu L, Li X, Lu L, Liu X, Song X, Li Y, Han Y, Zhu T, Cao W, Li T. HBV pgRNA profiles in Chinese HIV/HBV coinfected patients under pre- and posttreatment: a multicentre observational cohort study. J Viral Hepat 2022; 29:616-626. [PMID: 35582838 PMCID: PMC9541493 DOI: 10.1111/jvh.13704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/30/2022] [Accepted: 05/10/2022] [Indexed: 12/09/2022]
Abstract
Data on hepatitis B virus (HBV) pregenomic (pgRNA) levels in HIV/HBV coinfected patients pre- and post-combined antiretroviral therapy (cART) are limited. This study aimed to evaluate the distribution of HBV pgRNA levels in treatment-naive coinfected patients and explore the changes that occur after the initiation of cART by examining patients from multicentre cohort studies performed in China. We included HIV/HBV coinfected subjects from the China AIDS Clinical Trial cohorts established from 2008 to 2014. Clinical and serological markers of HIV and HBV infection and biochemical data were acquired at baseline and after 96 and 240-480 weeks of cART. The correlations between HBV pgRNA and HBV DNA levels as well as HBsAg levels were calculated using Spearman's bivariate correlation analysis, and multivariate regression analysis was performed to determine factors associated with undetectable HBV pgRNA levels before cART and HBeAg loss after cART. A total of 132 HIV/HBV coinfected patients were enrolled, and 100 individuals were HBeAg-negative. A total of 34.4% (32/93) of patients were positive for HBV pgRNA, and the median HBV pgRNA level was 4.92 (IQR: 4.21-6.12) log10 copies/mL before cART. The median HBV pgRNA level was significantly lower in HBeAg-negative individuals than in HBeAg-positive individuals (4.22 (IQR: 2.70-4.84) log10 copies/mL vs. 5.77 (IQR: 4.63-6.55) log10 copies/mL, p = 0.002). HBV pgRNA was moderately correlated with HBsAg (r = 0.594, p = 0.001), and positively associated with HBV DNA (r = 0.445, p = 0.011). The factors independently associated with undetectable HBV pgRNA level before cART were HBV DNA (OR: 5.61, 95% CI: 1.50-20.96, p = 0.01) and HBeAg status (OR: 5.95, 95% CI: 1.52-23.25, p = 0.01). A total of 87.5% (28/32) of patients were followed for a median duration of 138 (IQR: 54-240) weeks, and the HBV pgRNA levels became undetectable in seven patients. The 132 patients were observed for 695.5 person-years, and no HBsAg loss occurred. Thirteen individuals achieved HBeAg loss, four patients had undetectable levels of HBV pgRNA pre-cART, and the level of six individuals became undetectable during the 48-week (IQR: 48-264) follow-up period. HBeAg status was significantly associated with HBV pgRNA level in HIV/HBV coinfected patients pre- and post-cART. Additionally, undetectable HBV pgRNA level may be associated with HBeAg loss after cART.
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Affiliation(s)
- Ling Xu
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Department of Infectious Diseases and Clinical MicrobiologyBeijing Chao‐yang Hosipital, Capital Medical UniversityBeijingChina
| | - Xiaodi Li
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Lianfeng Lu
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Xiaosheng Liu
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Xiaojing Song
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yanling Li
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yang Han
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Ting Zhu
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Wei Cao
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Taisheng Li
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Center for AIDS ResearchChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina,Tsinghua University Medical CollegeBeijingChina
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9
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Loggi E, Gitto S, Gabrielli F, Franchi E, Seferi H, Cursaro C, Andreone P. Virological Treatment Monitoring for Chronic Hepatitis B. Viruses 2022; 14:1376. [PMID: 35891357 PMCID: PMC9319170 DOI: 10.3390/v14071376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/07/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open
Abstract
More than 250 million people worldwide are currently infected with hepatitis B, despite the effectiveness of vaccination and other preventive measures. In terms of treatment, new therapeutic approaches are rapidly developing, promising to achieve the elimination of infected cells and the complete cure of infection. The on-treatment monitoring of these innovative antiviral treatments will require the implementation of new virological tools. Therefore, new biomarkers are being evaluated besides the traditional virological and serological assays in order to obtain information on different steps of the viral replication cycle and to monitor response to therapy more accurately. The purpose of this work is to describe both standard and innovative tools for chronic hepatitis B treatment monitoring, and to analyse their potential and feasibility.
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Affiliation(s)
- Elisabetta Loggi
- Hepatology Unit, Department of Medical & Surgical Sciences, University of Bologna, 40126 Bologna, Italy;
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
| | - Filippo Gabrielli
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
- Department of Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Elena Franchi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
| | - Hajrie Seferi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
| | - Carmela Cursaro
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy;
| | - Pietro Andreone
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy;
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Medicina Interna Metabolico-Nutrizionale, Ospedale Civile di Baggiovara, Via Pietro Giardini 1355, 41126 Modena, Italy
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10
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Wang Y, Liao H, Deng Z, Liu Y, Bian D, Ren Y, Yu G, Jiang Y, Bai L, Liu S, Liu M, Zhou L, Chen Y, Duan Z, Lu F, Zheng S. Serum HBV RNA predicts HBeAg clearance and seroconversion in patients with chronic hepatitis B treated with nucleos(t)ide analogues. J Viral Hepat 2022; 29:420-431. [PMID: 35274400 PMCID: PMC9311425 DOI: 10.1111/jvh.13671] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 01/29/2022] [Accepted: 02/22/2022] [Indexed: 12/12/2022]
Abstract
This study evaluated the predictive value of serum HBV DNA, HBV RNA, HBcrAg, HBsAg, intrahepatic HBV DNA and cccDNA for HBeAg clearance and seroconversion during long-term treatment with nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). A single centre, prospective cohort of CHB patients was used for this study. Serum HBV RNA levels were retrospectively measured at baseline, 6, 12, 24, 36, 48, 60, 72 and 84 months post-NAs treatment. Serum HBsAg and HBcrAg levels were quantified at baseline, month 6, 60 and 72. Histological samples from liver biopsy at baseline and month 60 were analysed for intrahepatic HBV DNA and cccDNA. Eighty-three HBeAg-positive patients were enrolled with a median follow-up time of 108 months (range 18-138 months). Of them, 53 (63.86%) patients achieved HBeAg clearance, and 37 (44.58%) achieved HBeAg seroconversion. Cox multivariate analysis showed that only baseline HBV RNA was independently associated with HBeAg clearance and seroconversion (<5.45 log10 copies/mL, HR = 5.06, 95% CI: 1.87-13.71, p = .001; HR = 3.38, 95% CI: 1.28-8.91, p = .01). The independent association with HBeAg clearance and seroconversion remained for HBV RNA levels at month 6 (<4.72 log10 copies/mL, HR = 4.16, 95% CI: 1.61-10.72, p = .003; HR = 6.52, 95% CI: 1.85-22.94, p = .003) and month 12 (<4.08 log10 copies/mL, HR = 3.68, 95% CI: 1.96-6.90, p < .001; HR = 2.79, 95% CI: 1.31-5.94, p = .008). The AUCs of baseline HBV RNA for predicting the HBeAg clearance (0.83, 95% CI: 0.70-0.96, 0.83, 95% CI: 0.70-0.96 and 0.82, 95% CI: 0.69-0.95 respectively) and seroconversion (0.89, 95% CI: 0.77-1.00; 0.81, 95% CI: 0.66-0.95 and 0.84, 95% CI: 0.71-0.98 respectively) at month 36, 60 and 84 were higher than those of HBV DNA, HBsAg and HBcrAg. In conclusion, lower serum HBV RNA at baseline, month 6 and 12 post-NAs treatment could predict HBeAg clearance and seroconversion during long-term NAs treatment.
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Affiliation(s)
- Yang Wang
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Hao Liao
- Department of Microbiology and Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
- Intervention and Cell Therapy CenterPeking University Shenzhen HospitalShenzhen Peking University‐The Hong Kong University of Science and Technology Medical CenterShenzhenChina
| | - Zhongping Deng
- Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina
- Hunan Provincial Key Laboratory of Gene Diagnostic TechnologyChangshaChina
| | - Yanna Liu
- Department of Microbiology and Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Dandan Bian
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Yan Ren
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Guangxin Yu
- Department of Microbiology and Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Yingying Jiang
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Li Bai
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Shuang Liu
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Mei Liu
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Li Zhou
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Yu Chen
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Zhongping Duan
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Sujun Zheng
- Liver Disease CenterBeijing YouAn HospitalCapital Medical UniversityBeijingChina
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & ResearchBeijing YouAn HospitalCapital Medical UniversityBeijingChina
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11
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Pan J, Tian Y, Xu J, Luo H, Tan N, Han Y, Kang Q, Chen H, Yang Y, Xu X. Dynamics of Hepatitis B Virus Pregenomic RNA in Chronic Hepatitis B Patients With Antiviral Therapy Over 9 Years. Front Med (Lausanne) 2022; 9:851717. [PMID: 35572978 PMCID: PMC9099358 DOI: 10.3389/fmed.2022.851717] [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: 01/10/2022] [Accepted: 04/12/2022] [Indexed: 12/03/2022] Open
Abstract
Serum hepatitis B virus pregenomic RNA (HBV pgRNA) is a potential biomarker that is correlated with covalently closed circular DNA. The long-term dynamics of HBV pgRNA in patients with chronic hepatitis B need to be explored. One hundred naïve nucleos(t)ide analog-treated patients with chronic hepatitis B were enrolled to analyze the dynamics of HBV pgRNA over 9 years. The positive rates of HBV pgRNAs declined gradually and showed biphasic kinetics. Serum HBV pgRNA levels in patients treated with entecavir became negative later than those treated with adefovir or lamivudine. Patients who remain positive for HBV pgRNA after 9 years of treatment may have higher viral transcription efficiencies. The reverse transcription efficiency of hepatitis B e-antigen (HBeAg)-positive patients was higher than that of HBeAg-negative patients at baseline and showed no difference after 24-week nucleos(t)ide analog treatment. The trajectory of serum HBV pgRNA-negative transformation differs in patients with different characteristics. Long-term dynamic monitoring of serum HBV pgRNA levels has significance in hepatitis B treatment.
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Affiliation(s)
- Jiali Pan
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Yu Tian
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Hao Luo
- Department of Gastroenterology, National Center of Gerontology, Beijing Hospital, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ning Tan
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Yifan Han
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Qian Kang
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Hongyu Chen
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Yuqing Yang
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
- *Correspondence: Xiaoyuan Xu,
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Xia M, Chi H, Wu Y, Hansen BE, Li Z, Liu S, Liao G, Zhang X, Zhou B, Hou J, Sun J, Janssen HLA, Peng J. Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment. Aliment Pharmacol Ther 2021; 54:709-714. [PMID: 34275138 DOI: 10.1111/apt.16538] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/04/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Nucleos(t)ide analogue (NA) discontinuation may be attempted in carefully selected patients with chronic hepatitis B (CHB) infection. AIM To investigate whether a novel serum marker of quantitative hepatitis B virus (HBV) RNA levels could predict biochemical relapse after NA discontinuation. METHODS We prospepctively followed non-cirrhotic Asian patients with CHB who stopped NA according to pre-specified stopping criteria. The primary endpoint was biochemical relapse (HBV DNA >2000 IU/mL and alanine transaminase >2x upper limit of normal), which were also the re-treatment criteria. RESULTS Biochemical relapse occurred in 50 patients (48.3% at year 6). Multivariable analysis showed that higher HBV RNA levels (HR 1.34; P < 0.001) at the time of NA discontinuation were associated with increased biochemical relapse risk. The area under the curve of HBV RNA at the time of NA discontinuation for the incidence of biochemical relapse was 0.760 at 6 years. Six years after treatment discontinuation, all patients with HBV RNA levels ≥20 000 copies/mL at the end of treatment developed a biochemical relapse compared with 23.8% of patients with HBV RNA levels<1000 copies/mL (P < 0.001). More patients with HBV RNA levels <1000 copies/mL at end of treatment achieved loss of hepatitis B surface antigen than patients with higher levels (30.9% vs 1.6%; P = 0.027). CONCLUSIONS The HBV RNA level at end of treatment predicted biochemical relapse after treatment discontinuation and may be used to guide decisions on treatment discontinuation.
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Affiliation(s)
- Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Yaobo Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bettina E Hansen
- Toronto Centre of Liver Disease, University Health Network, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - Zhandong Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shi Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - GuiChan Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Harry L A Janssen
- Toronto Centre of Liver Disease, University Health Network, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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13
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Wu IC, Liu WC, Chiu YC, Chiu HC, Cheng PN, Chang TT. Clinical Implications of Serum Hepatitis B Virus Pregenomic RNA Kinetics in Chronic Hepatitis B Patients Receiving Antiviral Treatment and Those Achieving HBsAg Loss. Microorganisms 2021; 9:1146. [PMID: 34073483 PMCID: PMC8229518 DOI: 10.3390/microorganisms9061146] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is correlated with covalently closed circular DNA. We aimed to investigate the utility of serum HBV pgRNA in chronic hepatitis B patients receiving nucleos(t)ide analogue treatment and those achieving HBsAg loss. One hundred and eighty-five patients were enrolled for studying long-term HBV pgRNA kinetics during treatment. Twenty patients achieving HBsAg loss after treatment were enrolled for examining HBV pgRNA kinetics around HBsAg loss. HBV pgRNA significantly decreased in the high baseline HBV pgRNA (≥6 log copies/mL) group but significantly increased in the low baseline HBV pgRNA (<4 log copies/mL) group after 3-month entecavir treatment. Among the 20 patients achieving HBsAg loss, 13 (65%) patients had serum HBV pgRNA higher than the limit of detection (LOD, 1466 copies/mL) when they achieved HBsAg loss. Finally, all 20 patients had HBV pgRNA going below the LOD within 3 years after achieving HBsAg loss. In conclusion, baseline serum HBV pgRNA alone is insufficient for predicting the trajectory of HBV pgRNA. Most patients still had HBV pgRNA higher than the LOD when they achieved HBsAg loss. Further studies on HBV pgRNA kinetics around HBsAg loss would provide an enhanced basis for further applications of HBV pgRNA.
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Affiliation(s)
| | | | | | | | | | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan; (I.-C.W.); (W.-C.L.); (Y.-C.C.); (H.-C.C.); (P.-N.C.)
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14
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Vachon A, Osiowy C. Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management. Viruses 2021; 13:951. [PMID: 34064049 PMCID: PMC8224022 DOI: 10.3390/v13060951] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022] Open
Abstract
Even though an approved vaccine for hepatitis B virus (HBV) is available and widely used, over 257 million individuals worldwide are living with chronic hepatitis B (CHB) who require monitoring of treatment response, viral activity, and disease progression to reduce their risk of HBV-related liver disease. There is currently a lack of predictive markers to guide clinical management and to allow treatment cessation with reduced risk of viral reactivation. Novel HBV biomarkers are in development in an effort to improve the management of people living with CHB, to predict disease outcomes of CHB, and further understand the natural history of HBV. This review focuses on novel HBV biomarkers and their use in the clinical setting, including the description of and methodology for quantification of serum HBV RNA, hepatitis B core-related antigen (HBcrAg), quantitative hepatitis B surface antigen (qHBsAg), including ultrasensitive HBsAg detection, quantitative anti-hepatitis B core antigen (qAHBc), and detection of HBV nucleic acid-related antigen (HBV-NRAg). The utility of these biomarkers in treatment-naïve and treated CHB patients in several clinical situations is further discussed. Novel HBV biomarkers have been observed to provide critical clinical information and show promise for improving patient management and our understanding of the natural history of HBV.
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Affiliation(s)
- Alicia Vachon
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
| | - Carla Osiowy
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
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15
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Wang X, Chi X, Wu R, Xu H, Gao X, Yu L, Liu L, Zhang M, Tan Y, Niu J, Jin Q. Serum HBV RNA correlated with intrahepatic cccDNA more strongly than other HBV markers during peg-interferon treatment. Virol J 2021; 18:4. [PMID: 33407619 PMCID: PMC7789711 DOI: 10.1186/s12985-020-01471-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/15/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Serum hepatitis B virus RNA (HBV RNA) has been reported to be a surrogate marker of intrahepatic cccDNA during nucleos(t)ide analogs therapy. However, in HBeAg-positive patients treated with peg-interferon (peg-IFN), whether HBV RNA is superior to other HBV markers in reflecting cccDNA profile is still unclear. METHODS Serum HBV RNA, HBcrAg, HBV DNA, and HBsAg were longitudinally assessed among 30 HBeAg-positive patients during 48-week peg-IFN treatment. Besides, intrahepatic cccDNA was detected at baseline and week 48 respectively. Then, the individual correlations between HBV RNA, HBcrAg, HBV DNA, HBsAg, and cccDNA were statistically analyzed. RESULTS HBV RNA levels decreased more rapidly in patients with HBeAg seroconversion than those without HBeAg seroconversion. Among all patients, cccDNA correlated better with HBV RNA than with HBcrAg, HBV DNA, and HBsAg at baseline. After 48 weeks peg-IFN treatment, cccDNA still correlated more strongly with HBV RNA than other HBV markers. Further analysis indicated that in patients with HBeAg seroconversion cccDNA strongly correlated with HBV RNA and HBcrAg, whereas not correlate with HBV DNA and HBsAg. While in patients without HBeAg seroconversion, cccDNA highly correlated with HBV RNA and HBV DNA, moderately correlated with HBcrAg, and not correlated with HBsAg. CONCLUSION Compared to HBcrAg, HBV DNA, and HBsAg, serum HBV RNA correlated more strongly with intrahepatic cccDNA levels before and after 48-week peg-IFN treatment. The level of serum HBV RNA may be a superior surrogate marker in reflecting the intrahepatic cccDNA profile in HBeAg-positive patients during peg-IFN treatment. Trial registration ClinicalTrials, NCT03546530. Registered 1 January 2015. https://clinicaltrials.gov/ct2/results?cond=&term=NCT03546530 .
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Affiliation(s)
- Xiaomei Wang
- Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Xiumei Chi
- Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Ruihong Wu
- Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Xiuzhu Gao
- Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Lei Yu
- Department of Infectious Diseases, The Fourth Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
| | - Longgen Liu
- Department of Infectious Diseases, The Third Hospital of Changzhou, Changzhou, 213001, Jiangsu Province, China
| | - Mingxiang Zhang
- Department of Hepatology, Shenyang Sixth People's Hospital, Shenyang, 110006, Liaoning Province, China
| | - Youwen Tan
- Department of Hepatology, The Third People's Hospital of Zhenjiang, Zhenjiang, 212021, Jiangsu Province, China
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Qinglong Jin
- Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China.
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Balagopal A, Grudda T, Ribeiro RM, Saad YS, Hwang HS, Quinn J, Murphy M, Ward K, Sterling RK, Zhang Y, Perelson AS, Sulkowski MS, Osburn WO, Thio CL. Single hepatocytes show persistence and transcriptional inactivity of hepatitis B. JCI Insight 2020; 5:140584. [PMID: 33004689 PMCID: PMC7566712 DOI: 10.1172/jci.insight.140584] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022] Open
Abstract
There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2–4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure. Single-cell laser capture microdissection integrated with droplet digital PCR was used to study hepatocytes from individuals with chronic hepatitis B.
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Affiliation(s)
- Ashwin Balagopal
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tanner Grudda
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ruy M Ribeiro
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.,Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal
| | - Yasmeen S Saad
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hyon S Hwang
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jeffrey Quinn
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michael Murphy
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kathleen Ward
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Richard K Sterling
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Yang Zhang
- Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Alan S Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Mark S Sulkowski
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - William O Osburn
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Chloe L Thio
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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