|
1
|
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.
Collapse
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.)
| |
Collapse
|
|
2
|
Zhao S, Dong C, Chang C, Zhang J, Li J, Zhang X, Ren W, Zhang Y, Nan Y. Association between intrahepatic cccDNA and the severity of liver inflammation in chronic hepatitis B virus infection patients. Front Med (Lausanne) 2025; 11:1519686. [PMID: 39927273 PMCID: PMC11802545 DOI: 10.3389/fmed.2024.1519686] [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: 10/30/2024] [Accepted: 12/16/2024] [Indexed: 02/11/2025] Open
Abstract
Background and aims This research aimed to examine the association between hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and liver inflammation in chronic hepatitis B (CHB) infection patients. Methods From August 2013 to June 2022, CHB patients at Hebei Medical University Third Hospital (Hebei, China) were recruited. Intrahepatic cccDNA was quantified and its association with liver inflammation was analyzed. Liver inflammation was assessed using the Ishak-modified histological activity index (HAI). Biochemical and viral indicators as well as hepatic inflammation biomarkers were monitored. Results In total, 55 CHB patients were enrolled. The average HBV-cccDNA level was markedly elevated in HBeAg+ patients compared to HBeAg patients. Intrahepatic cccDNA levels differed significantly in different liver inflammation groups and showed a positive correlation with the HAI score for hepatic inflammation. Conclusion HBV-cccDNA level was associated with liver inflammation.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital, the Key Laboratory of Hepatic Fibrosis Mechanisms of Chronic Liver Diseases in Hebei Province, Hebei International Science and Technology Cooperation Base – Hebei International Joint Research Center for Molecular Diagnosis of Liver Cancer, Shijiazhuang, China
| |
Collapse
|
|
3
|
Kim KS, Iwamoto M, Kitagawa K, Park H, Hayashi S, Tsukuda S, Matsui T, Atsukawa M, Matsuura K, Chuaypen N, Tangkijvanich P, Allweiss L, Nishiyama T, Nakamura N, Fujita Y, Kawakami E, Nakaoka S, Muramatsu M, Aihara K, Wakita T, Perelson AS, Dandri M, Watashi K, Iwami S, Tanaka Y. Prediction of cccDNA dynamics in hepatitis B patients by a combination of serum surrogate markers. PLoS Comput Biol 2025; 21:e1012615. [PMID: 39787253 PMCID: PMC11753647 DOI: 10.1371/journal.pcbi.1012615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 01/22/2025] [Accepted: 11/04/2024] [Indexed: 01/12/2025] Open
Abstract
Quantification of intrahepatic covalently closed circular DNA (cccDNA) is a key for evaluating an elimination of hepatitis B virus (HBV) in infected patients. However, quantifying cccDNA requires invasive methods such as a liver biopsy, which makes it impractical to access the dynamics of cccDNA in patients. Although HBV RNA and HBV core-related antigens (HBcrAg) have been proposed as surrogate markers for evaluating cccDNA activity, they do not necessarily estimate the amount of cccDNA. Here, we employed a recently developed multiscale mathematical model describing intra- and intercellular viral propagation and applied it in HBV-infected patients under treatment. We developed a model that can predict intracellular HBV dynamics by use of extracellular viral markers, including HBsAg, HBV DNA, and HBcrAg in peripheral blood. Importantly, the model prediction of the amount of cccDNA in patients over time was confirmed to be well correlated with the data for quantified cccDNA by paired liver biopsy. Thus, our method combining classic and emerging surrogate markers enables us to predict the decay dynamics of cccDNA in patients undergoing treatment.
Collapse
Affiliation(s)
- Kwang Su Kim
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- Department of Scientific Computing, Pukyong National University, Busan, South Korea
| | - Masashi Iwamoto
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kosaku Kitagawa
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Hyeongki Park
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Sanae Hayashi
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Senko Tsukuda
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Masanori Atsukawa
- Department of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Lena Allweiss
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner sites, Germany
| | - Takara Nishiyama
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Naotoshi Nakamura
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Yasuhisa Fujita
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Eiryo Kawakami
- Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
- Medical Sciences Innovation Hub Program; RIKEN, Yokohama, Kanagawa, Japan
| | - Shinji Nakaoka
- Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kazuyuki Aihara
- International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Alan S. Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Maura Dandri
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba, Japan
| | - Shingo Iwami
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan
- Institute of Mathematics for Industry, Kyushu University,; Fukuoka, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
- NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Interdisciplinary Theoretical and Mathematical Sciences (iTHEMS), RIKEN, Wako, Japan
- Science Groove Inc., Fukuoka, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
4
|
Mahajan A, Kharawala S, Desai S, Kendrick S, Das J, Gielen V. Association of Hepatitis B Surface Antigen Levels With Long-Term Complications in Chronic Hepatitis B Virus Infection: A Systematic Literature Review. J Viral Hepat 2024; 31:746-759. [PMID: 39150061 DOI: 10.1111/jvh.13988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 07/09/2024] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.
Collapse
Affiliation(s)
| | | | | | | | - Joyeta Das
- Research and Development, GSK, Brentford, Middlesex, UK
| | - Vera Gielen
- Research and Development, GSK, Brentford, Middlesex, UK
| |
Collapse
|
|
5
|
Mak LY, Boettler T, Gill US. HBV Biomarkers and Their Role in Guiding Treatment Decisions. Semin Liver Dis 2024; 44:474-491. [PMID: 39442530 DOI: 10.1055/a-2448-4157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Over 300 million individuals worldwide are chronically infected with hepatitis B virus and at risk for progressive liver disease. Due to the lack of a therapy that reliably achieves viral elimination and the variability of liver disease progression, treatment decisions are guided by the degree of liver disease and viral biomarkers as the viral life-cycle is well characterized and largely conserved between individuals. In contrast, the immunological landscape is much more heterogeneous and diverse and the measurement of its components is less well standardized. Due to the lack of a universal and easily measurable set of biomarkers, clinical practice guidelines remain controversial, aiming for a balance between simplifying treatment decisions by reducing biomarker requirements and using all available biomarkers to avoid overtreatment of patients with low risk for disease progression. While approved therapies such as nucleos(t)ide analogs improve patient outcomes, the inability to achieve a complete cure highlights the need for novel therapies. Since no treatment candidate has demonstrated universal efficacy, biomarkers will remain important for treatment stratification. Here, we summarize the current knowledge on virological and immunological biomarkers with a specific focus on how they might be beneficial in guiding treatment decisions in chronic hepatitis B.
Collapse
Affiliation(s)
- Lung-Yi Mak
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tobias Boettler
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Upkar S Gill
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| |
Collapse
|
|
6
|
Begré L, Boyd A, Plissonnier ML, Testoni B, Salazar-Vizcaya L, Suter-Riniker F, Scholtès C, Béguelin C, Rockstroh JK, Günthard HF, Calmy A, Cavassini M, Hirsch HH, Schmid P, Bernasconi E, Levrero M, Wandeler G, Zoulim F, Rauch A. Circulating HBV RNA and Hepatitis B Core-Related Antigen Trajectories in Persons With HIV/HBV Coinfection and Hepatitis B Surface Antigen Loss During Tenofovir Therapy. J Infect Dis 2024; 230:e954-e963. [PMID: 38626170 PMCID: PMC11481342 DOI: 10.1093/infdis/jiae189] [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: 11/02/2023] [Revised: 02/28/2024] [Accepted: 04/25/2024] [Indexed: 04/18/2024] Open
Abstract
BACKGROUND We evaluated long-term trajectories of circulating hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) in persons with and without hepatitis B surface antigen (HBsAg) loss during tenofovir therapy in the Swiss HIV Cohort Study. METHODS We included 29 persons with HIV with HBsAg loss and 29 matched persons with HIV without HBsAg loss. We compared HBV RNA and HBcrAg decline and assessed the cumulative proportions with undetectable HBV RNA and HBcrAg levels during tenofovir therapy using Kaplan-Meier estimates. RESULTS HBsAg loss occurred after a median of 4 years (IQR, 1-8). All participants with HBsAg loss achieved suppressed HBV DNA and undetectable HBV RNA preceding undetectable quantitative HBsAg levels, whereas 79% achieved negative HBcrAg. In comparison, 79% of participants without HBsAg loss achieved undetectable HBV-RNA and 48% negative HBcrAg. After 2 years of tenofovir therapy, an HBV RNA decline ≥1 log10 copies/mL had 100% sensitivity and 36.4% specificity for HBsAg loss, whereas an HBcrAg decline ≥1 log10 U/mL had 91.0% sensitivity and 64.5% specificity. CONCLUSIONS HBV RNA suppression preceded undetectable quantitative HBsAg levels and had high sensitivity but low specificity for HBsAg loss during tenofovir therapy in persons with HIV. HBcrAg remained detectable in approximately 20% of persons with HBsAg loss and 50% of persons without HBsAg loss.
Collapse
Affiliation(s)
- Lorin Begré
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, Switzerland
| | - Anders Boyd
- Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, The Netherlands
- Stichting hiv monitoring Amsterdam, The Netherlands
- Department of Infectious Diseases, Amsterdam UMC location University of Amsterdam, The Netherlands
- Department of Infectious Diseases, Amsterdam Institute for Infection and Immunity, The Netherlands
| | - Marie-Laure Plissonnier
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
| | - Barbara Testoni
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
| | - Luisa Salazar-Vizcaya
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | | | - Caroline Scholtès
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- Laboratoire de Virologie, Institut des Agents Infectieux, Hospices Civils de Lyon, France
| | - Charles Béguelin
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | | | - Huldrych F Günthard
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Switzerland
| | - Alexandra Calmy
- Division of Infectious Diseases, HIV Unit, Geneva University Hospitals, University of Geneva, Switzerland
| | - Matthias Cavassini
- Division of Infectious Diseases, Lausanne University Hospital, University of Lausanne, Switzerland
| | - Hans H Hirsch
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Switzerland
| | - Patrick Schmid
- Division of Infectious Diseases, Infection Prevention and Travel Medicine, Cantonal Hospital St. Gallen, Switzerland
| | - Enos Bernasconi
- Division of Infectious Diseases, Ente Ospedaliero Cantonale Lugano, University of Geneva and University of Southern Switzerland, Lugano, Switzerland
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1 (UCBL1), Lyon, France
- Department of Hepatology, Hospices Civils de Lyon, Lyon, France
| | - Gilles Wandeler
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Fabien Zoulim
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1 (UCBL1), Lyon, France
- Department of Hepatology, Hospices Civils de Lyon, Lyon, France
| | - Andri Rauch
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Switzerland
| |
Collapse
|
|
7
|
Li Y, Wang L, Cheng H, Chi X, Huang Q, Lv P, Zhang W, Niu J, Wen X, Liu Z. ELISA genotyping of hepatitis B virus in China with antibodies specific for genotypes B and C. Sci Rep 2024; 14:23884. [PMID: 39396069 PMCID: PMC11470951 DOI: 10.1038/s41598-024-76023-7] [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: 05/13/2024] [Accepted: 10/09/2024] [Indexed: 10/14/2024] Open
Abstract
Hepatitis B virus (HBV) causes hepatitis B (HB) and distinct HBV genotypes can lead to different prognoses. However, HBV genotyping is rarely done in clinics, because the traditional method by PCR-based DNA sequencing is impractical for clinical diagnosis with tedious process and low success rate. Herein, we have established an ELISA-based genotyping method to quickly determine the HBV genotypes of HB patients in China. First, two commercial antibodies, 16D12 and 6H3 specific for HBV genotypes B and C respectively, are chosen as capture antibodies, since these two genotypes dominate in China. Then two home-made genotype-specific antibodies, B19 and C04, are used as the detection antibodies for genotypes B and C in sandwiched ELISA. The ELISA kit shows high sensitivity (> 95%) and specificity (> 95%) in detecting genotypes B and C of Chinese HB patients. Moreover, the ELISA kit has demonstrated higher success rate (98.7%) than PCR-based DNA sequencing (93.5%) and a commercial PCR-based genotyping kit (92.2%) for sera with HBV DNA ≥ 1000 IU/mL and HBsAg ≥ 250 IU/mL. Such an advantage is more obvious for the sera with HBV DNA < 1000 IU/mL. The kappa analysis between the ELISA and PCR-based DNA sequencing results exhibits a kappa of 0.836, indicating a good correlation.
Collapse
Affiliation(s)
- Yumin Li
- Key Laboratory of Bionic Engineering (Ministry of Education), Jilin University, Changchun, 130022, China
| | - Li Wang
- Key Laboratory of Bionic Engineering (Ministry of Education), Jilin University, Changchun, 130022, China
| | - Huanyi Cheng
- Beijing Abace Biotechnology, Beijing, 100176, China
| | - Xiumei Chi
- Core Facility, The First Hospital of Jilin University, Jilin University, Changchun, 130021, China
| | | | - Pinxin Lv
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Jilin University, 130033, Changchun, China
| | - Wenyi Zhang
- Beijing Abace Biotechnology, Beijing, 100176, China
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, 130021, Changchun, China
| | - Xiaoyu Wen
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, 130021, Changchun, China.
| | - Zhenning Liu
- Key Laboratory of Bionic Engineering (Ministry of Education), Jilin University, Changchun, 130022, China.
| |
Collapse
|
|
8
|
Ringlander J, Malmström S, Eilard A, Strömberg LG, Stenbäck JB, Andersson ME, Larsson SB, Kann M, Nilsson S, Hellstrand K, Rydell GE, Lindh M. Hepatitis B virus particles in serum contain minus strand DNA and degraded pregenomic RNA of variable and inverse lengths. Liver Int 2024; 44:1775-1780. [PMID: 38709598 DOI: 10.1111/liv.15955] [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: 07/21/2023] [Revised: 02/01/2024] [Accepted: 04/16/2024] [Indexed: 05/08/2024]
Abstract
This study utilized digital PCR to quantify HBV RNA and HBV DNA within three regions of the HBV genome. Analysis of 75 serum samples from patients with chronic infection showed that HBV RNA levels were higher in core than in S and X regions (median 7.20 vs. 6.80 and 6.58 log copies/mL; p < .0001), whereas HBV DNA levels showed an inverse gradient (7.71 vs. 7.73 and 7.77 log copies/mL, p < .001). On average 80% of the nucleic acid was DNA by quantification in core. The core DNA/RNA ratio was associated with viral load and genotype. In individual patients, the relations between RNA levels in core, S and X were stable over time (n = 29; p = .006). The results suggest that pregenomic RNA is completely reverse transcribed to minus DNA in ≈75% of the virus particles, whereas the remaining 25% contain both RNA and DNA of lengths that reflect variable progress of the polymerase.
Collapse
Affiliation(s)
- Johan Ringlander
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sebastian Malmström
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Anders Eilard
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Lucia Gonzales Strömberg
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Joakim B Stenbäck
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Maria E Andersson
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Simon B Larsson
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Addiction and Dependency, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Michael Kann
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Staffan Nilsson
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Kristoffer Hellstrand
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Gustaf E Rydell
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Lindh
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| |
Collapse
|
|
9
|
Lai X, OuYang W, Li S, Qiu J, Zhang H, Jiang T, Qin X, Tang L, Gu Y, Yao Z, Peng S. Predictive role of early treatment dynamics of HBV RNA and HBcrAg for HBeAg seroconversion in children with chronic hepatitis B. J Med Virol 2024; 96:e29670. [PMID: 38773810 DOI: 10.1002/jmv.29670] [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: 11/26/2023] [Revised: 04/27/2024] [Accepted: 05/05/2024] [Indexed: 05/24/2024]
Abstract
This study aimed to assess the predictive capacity of emerging serological markers, serum HBV RNA and HBcrAg, for HBeAg seroconversion in children with HBeAg-positive chronic hepatitis B (CHB). Treatment-naïve HBeAg-positive CHB children who admitted to the Liver Disease Center of Hunan Children's Hospital between April 2021 and September 2022 and received treatment with the combined entecavir and interferon-alpha treatment were recruited. Serum HBV RNA and HBcrAg were measured at baseline and Weeks 12, 24, and 48 of treatment. Our study showed that serum HBV RNA (HR = 0.71, 95% CI: 0.56-0.91, p = 0.006), HBcrAg (HR = 0.60, 95% CI: 0.43-0.84, p = 0.003), and HBsAg (HR = 0.49, 95%CI: 0.36-0.69, p < 0.001) at Week 12 were independent predictors of HBeAg seroconversion. ROC curve analysis presented that serum HBV RNA decline value (ΔHBV RNA) at Week 36 and HBcrAg decline value (ΔHBcrAg) at Week 12 (AUC = 0.871, p = 0.003 and AUC = 0.810, p = 0.003, respectively) could effectively predict HBeAg seroconversion. Furthermore, the optimal critical values were determined and the children with ΔHBV RNA > 3.759 log10 copies/mL at Week 36 or ΔHBcrAg >0.350 log10 U/mL at Week 12 more likely to achieve HBeAg seroconversion. The serum HBV RNA and HBcrAg provide new insights into the treatment of CHB in children. Early assessment of serum HBV RNA and HBcrAg during treatment can assist clinical decision-making and optimize individualized therapeutic approaches.
Collapse
Affiliation(s)
- Xin Lai
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
- The Affiliated Women and Children's Hospital of Xiamen University, Xiamen, China
| | - Wenxian OuYang
- Liver Disease Center, Hunan Children's Hospital, Changsha, China
| | - Shuangjie Li
- Liver Disease Center, Hunan Children's Hospital, Changsha, China
| | - Jun Qiu
- Liver Disease Center, Hunan Children's Hospital, Changsha, China
| | - Hui Zhang
- Liver Disease Center, Hunan Children's Hospital, Changsha, China
| | - Tao Jiang
- Liver Disease Center, Hunan Children's Hospital, Changsha, China
| | - Xiaomei Qin
- Liver Disease Center, Hunan Children's Hospital, Changsha, China
| | - Lian Tang
- Liver Disease Center, Hunan Children's Hospital, Changsha, China
| | - Yingping Gu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Zhenzhen Yao
- 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
| |
Collapse
|
|
10
|
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.
Collapse
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
| |
Collapse
|
|
11
|
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.
Collapse
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
| |
Collapse
|
|
12
|
阎 岩, Davgadorj C, 吕 春, 陆 忠, 俞 萍. [Predictive Value of Baseline Serum Marker Levels for the Effect of Interferon Therapy in Patients With Chronic Hepatitis B]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2024; 55:383-390. [PMID: 38645851 PMCID: PMC11026883 DOI: 10.12182/20240360105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Indexed: 04/23/2024]
Abstract
Objective To study the changes in the serum markers in chronic hepatitis B patients who have had previous treatment with long-acting interferon therapy of nucleoside and those who have not and to assess the value of the serum markers for clinical prognosis evaluation. Methods The clinical data of 411 cases of chronic hepatitis B were collected. All cases were given the additional treatment of long-acting interferon between October 2019 to April 2022. The cases were divided into two groups, a previously treated group consisting of patients who had been treated with nucleoside and nucleotide analogues (NAs) for more than 6 months after they became infected with hepatitis B virus (HBV) for over 6 months and an initial treatment group, or treatment naïve group, consisting of patients who had HBV infection for over 6 months and received no treatment or patients who have stopped NAs therapy for more than 6 months. The serum marker levels of the previously treated group and the initial treatment group, i.e., the previously treatment-naïve patients, were compared, and the receiver operating characteristics (ROC) curve was used to evaluate the value of the baseline levels of hepatitis B surface antigen (HBsAg) and HBV pregenomic RNA (pgRNA) for predicting the rate of cured cases in the two groups. Results There was no significant difference in the rate of cured cases between the previously treated group and the initial treatment group. The baseline HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg) levels of the cured cases in both groups were significantly lower than those in the uncured cases (P<0.0001). After 48 weeks of treatment, the serum HBsAb levels (mIU/mL) of the cured cases in both the previously treated and initial treatment groups were significantly higher than those of the uncured cases in the two groups (previously treated group: 78.97±22.57 vs. 0.99±0.38, P<0.0001; initial treatment group: 235.50±175.00 vs. 1.32±0.88, P<0.0001). The serum HBsAb levels (mIU/mL) of the cured cases in the initial treatment groups were significantly higher than that of cured cases in the previously treated group (235.50±175.00 vs. 78.97±22.57, P<0.0001). Within 0 to 60 weeks of treatment, HBV pgRNA levels of cured cases in both groups were significantly lower than those of the the uncured cases in both groups (P<0.0001). Multivariate logistic regression and ROC curve analysis showed that baseline serum HBsAg was the influencing factor and predictor of interferon efficacy in both the previously treated cases and the initial treatment cases, with the area under the curve (AUC) being 0.80 (95% confidence interval [CI]: 0.7423-0.8615, P<0.0001) and 0.74 (95% CI: 0.6283-0.8604, P=0.0079), respectively, and the optimal cut-off values being 244.60 IU/mL and 934.40 IU/mL, respectively. However, the baseline serum HBV pgRNA level of under 1340.00 copies/mL in the initial treatment cases led to better sensitivity and better specificity in efficacy prediction, with the AUC of the baseline HBV pgRNA being 0.9649 (95% CI: 0.9042-1.0000, P<0.0001). Conclusion Among the previously treated cases and the initial treatment cases, patients who achieve clinical cure have lower levels of HBV DNA, HBsAg, and HBeAg at baseline, lower level of HBV pgRNA over the course of their treatment, and higher level of HBsAb at week 48. Baseline HBsAg levels can be used to effectively predict the clinical cure outcomes in previously treated cases and initial treatment cases. Baseline HBV pgRNA levels also exhibit a high predictive value for treatment outcomes in initial treatment cases.
Collapse
Affiliation(s)
- 岩 阎
- 无锡市第五人民医院 感染与免疫实验室 （无锡 214016）Laboratory for Infection and Immunity, The Fifth People's Hospital of Wuxi, Wuxi 214016, China
| | - Chantsalmaa Davgadorj
- 无锡市第五人民医院 感染与免疫实验室 （无锡 214016）Laboratory for Infection and Immunity, The Fifth People's Hospital of Wuxi, Wuxi 214016, China
| | - 春燕 吕
- 无锡市第五人民医院 感染与免疫实验室 （无锡 214016）Laboratory for Infection and Immunity, The Fifth People's Hospital of Wuxi, Wuxi 214016, China
| | - 忠华 陆
- 无锡市第五人民医院 感染与免疫实验室 （无锡 214016）Laboratory for Infection and Immunity, The Fifth People's Hospital of Wuxi, Wuxi 214016, China
| | - 萍 俞
- 无锡市第五人民医院 感染与免疫实验室 （无锡 214016）Laboratory for Infection and Immunity, The Fifth People's Hospital of Wuxi, Wuxi 214016, China
| |
Collapse
|
|
13
|
Yu X, Pfefferkorn M, van Bömmel F, Zhang X, Berg T. Clinical applications of circulating HBV RNA as a potential surrogate biomarker for intrahepatic cccDNA transcriptional activity. Gut 2024; 73:563-566. [PMID: 38123992 DOI: 10.1136/gutjnl-2023-331217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 11/30/2023] [Indexed: 12/23/2023]
Affiliation(s)
- Xiaoqi Yu
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
| | - Maria Pfefferkorn
- Division of Hepatology, Department of Medicine II, University of Leipzig Medical Center, Leipzig, Germany
| | - Florian van Bömmel
- Division of Hepatology, Department of Medicine II, University of Leipzig Medical Center, Leipzig, Germany
| | - Xinxin Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Clinical Research Center, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, University of Leipzig Medical Center, Leipzig, Germany
| |
Collapse
|
|
14
|
Testoni B, Scholtès C, Plissonnier ML, Paturel A, Berby F, Facchetti F, Villeret F, Degasperi E, Scott B, Hamilton A, Heil M, Lampertico P, Levrero M, Zoulim F. Quantification of circulating HBV RNA expressed from intrahepatic cccDNA in untreated and NUC treated patients with chronic hepatitis B. Gut 2024; 73:659-667. [PMID: 37879886 PMCID: PMC10958289 DOI: 10.1136/gutjnl-2023-330644] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/26/2023] [Indexed: 10/27/2023]
Abstract
OBJECTIVE A convenient, reproducible biomarker of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) transcriptional activity is lacking. We measured circulating HBV RNA (cirB-RNA) in untreated and nucleos(t)ide analogues (NUC) treated chronic hepatitis B (CHB) patients to define its correlation with intrahepatic viral markers and HBV core-related antigen (HBcrAg). DESIGN Paired liver biopsy and serum samples were collected from 122 untreated and 30 NUC-treated CHB patients. We measured cirB-RNA, HBV DNA, hepatitis B surface antigen (HBsAg), HBcrAg and alanine aminotransferase levels. cirB-RNA was quantified using an investigational HBV RNA assay for use on the cobas 6800 system. The test detects a region spanning the HBV canonical polyadenylation site. cccDNA and 3.5 kb RNA in liver tissue were assessed by quantitative PCR and droplet digital PCR. RESULTS cirB-RNA was detectable in 100% of HBeAg(+) chronic hepatitis (CH), 57% and 14% of HBeAg(-) CH and chronic infection untreated patients and 47% of NUC-treated patients. cirB-RNA undetectability was associated with lower intrahepatic cccDNA transcriptional activity, as well as serum HBcrAg, but no significant differences in HBsAg, in both untreated and treated patients. In untreated HBeAg(-) patients, cirB-RNA correlated with intrahepatic 3.5 kb RNA and cccDNA transcriptional activity, serum HBV DNA and HBcrAg, but not with HBsAg or total cccDNA levels. Combined undetectability of both cirB-RNA and HBcrAg detection in untreated HBeAg(-) patients identified a subgroup with the lowest levels of intrahepatic transcriptionally active cccDNA. CONCLUSION Our results support the usefulness of quantification of circulating HBV RNA expressed from cccDNA as an indicator of intrahepatic active viral reservoir in both untreated and NUC-treated CHB patients. TRIAL REGISTRATION NUMBER NCT02602847.
Collapse
Affiliation(s)
- Barbara Testoni
- INSERM U1052, Cancer Research Center of Lyon, Lyon, France
- University of Lyon, UMR_S1052, CRCL, Lyon, France
| | - Caroline Scholtès
- INSERM U1052, Cancer Research Center of Lyon, Lyon, France
- University of Lyon, UMR_S1052, CRCL, Lyon, France
- Department of Virology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | | | - Alexia Paturel
- INSERM U1052, Cancer Research Center of Lyon, Lyon, France
- University of Lyon, UMR_S1052, CRCL, Lyon, France
| | | | - Floriana Facchetti
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - François Villeret
- INSERM U1052, Cancer Research Center of Lyon, Lyon, France
- University of Lyon, UMR_S1052, CRCL, Lyon, France
- Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Beth Scott
- Roche Molecular Diagnostics, Pleasanton, California, USA
| | - Aaron Hamilton
- Roche Molecular Diagnostics, Pleasanton, California, USA
| | - Marintha Heil
- Roche Molecular Diagnostics, Pleasanton, California, USA
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Massimo Levrero
- INSERM U1052, Cancer Research Center of Lyon, Lyon, France
- University of Lyon, UMR_S1052, CRCL, Lyon, France
- Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
- Department of Internal Medicine-DMISM and the IIT Center for Life Nanoscience (CLNS), Sapienza University, Rome, Italy
| | - Fabien Zoulim
- INSERM U1052, Cancer Research Center of Lyon, Lyon, France
- University of Lyon, UMR_S1052, CRCL, Lyon, France
- Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| |
Collapse
|
|
15
|
Ghany MG, King WC, Hinerman AS, Lok ASF, Lisker-Melman M, Chung RT, Terrault N, Janssen HL, Khalili M, Lee WM, Lau DT, Cloherty GA, Sterling RK. Use of HBV RNA and to predict change in serological status and disease activity in CHB. Hepatology 2023; 78:1542-1557. [PMID: 37074026 PMCID: PMC11165989 DOI: 10.1097/hep.0000000000000413] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 03/28/2023] [Indexed: 04/20/2023]
Abstract
BACKGROUND AND AIMS Predicting changes in disease activity and serological endpoints is necessary for the management of patients with chronic hepatitis B (CHB). We examined whether HBV RNA and hepatitis B core-related antigen (HBcrAg), two specialized virological markers proposed to reflect the activity of covalently closed circular DNA, may improve the ability to predict not sustained inactive carrier phase, spontaneous alanine aminotransferase (ALT) flare, HBeAg loss, and HBsAg loss. APPROACH AND RESULTS Among eligible participants enrolled in the North American Hepatitis B Research Network Adult Cohort Study, we evaluated demographic, clinical, and virologic characteristics, including HBV RNA and HBcrAg, to predict not sustained inactive carrier phase, ALT flare, HBeAg loss, and HBsAg loss through a series of Cox proportional hazard or logistic regression models, controlling for antiviral therapy use. Among the study population, 54/103 participants experienced not sustained inactive carrier phase, 41/1006 had a spontaneous ALT flare, 83/250 lost HBeAg, and 54/1127 lost HBsAg. HBV RNA or HBcrAg were predictive of all 4 events. However, their addition to models of the readily available host (age, sex, race/ethnicity), clinical (ALT, use of antiviral therapy), and viral factors (HBV DNA), which had acceptable-excellent accuracy (e.g., AUC = 0.72 for ALT flare, 0.92 for HBeAg loss, and 0.91 for HBsAg loss), provided only small improvements in predictive ability. CONCLUSION Given the high predictive ability of readily available markers, HBcrAg and HBV RNA have a limited role in improving the prediction of key serologic and clinical events in patients with CHB.
Collapse
Affiliation(s)
- Marc G. Ghany
- Liver Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
| | - Wendy C. King
- Graduate School of Public Health University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Amanda S. Hinerman
- Department of Epidemiology, Graduate School of Public Health University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anna SF. Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Mauricio Lisker-Melman
- Washington University School of Medicine and John Cochran VA Medical Center, St. Louis, Missouri, USA
| | | | - Norah Terrault
- Division of Gastrointestinal and Liver Diseases, Keck Medicine of University of Southern California, Los Angeles, California, USA
| | - Harry L.A. Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Mandana Khalili
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - William M. Lee
- Meredith Mosle Chair in Liver Disease, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Daryl T.Y. Lau
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Gavin A. Cloherty
- Head of Infectious Disease Research, Abbott Diagnostics, Abbott Park, Illinois, USA
| | - Richard K. Sterling
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| |
Collapse
|
|
16
|
Zaiets I, Gunewardena S, Menne S, Weinman SA, Gudima SO. Sera of Individuals Chronically Infected with Hepatitis B Virus (HBV) Contain Diverse RNA Types Produced by HBV Replication or Derived from Integrated HBV DNA. J Virol 2023; 97:e0195022. [PMID: 36877036 PMCID: PMC10062156 DOI: 10.1128/jvi.01950-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/11/2023] [Indexed: 03/07/2023] Open
Abstract
This study aimed to better characterize the repertoire of serum hepatitis B virus (HBV) RNAs during chronic HBV infection in humans, which remains understudied. Using reverse transcription-PCR (RT-PCR), real-time quantitative PCR (RT-qPCR), RNA-sequencing, and immunoprecipitation, we found that (i) >50% of serum samples bore different amounts of HBV replication-derived RNAs (rd-RNAs); (ii) a few samples contained RNAs transcribed from integrated HBV DNA, including 5'-HBV-human-3' RNAs (integrant-derived RNAs [id-RNAs]) and 5'-human-HBV-3' transcripts, as a minority of serum HBV RNAs; (iii) spliced HBV RNAs were abundant in <50% of analyzed samples; (iv) most serum rd-RNAs were polyadenylated via conventional HBV polyadenylation signal; (v) pregenomic RNA (pgRNA) was the major component of the pool of serum RNAs; (vi) the area of HBV positions 1531 to 1739 had very high RNA read coverage and thus should be used as a target for detecting serum HBV RNAs; (vii) the vast majority of rd-RNAs and pgRNA were associated with HBV virions but not with unenveloped capsids, exosomes, classic microvesicles, or apoptotic vesicles and bodies; (viii) considerable rd-RNAs presence in the circulating immune complexes was found in a few samples; and (ix) serum relaxed circular DNA (rcDNA) and rd-RNAs should be quantified simultaneously to evaluate HBV replication status and efficacy of anti-HBV therapy with nucleos(t)ide analogs. In summary, sera contain various HBV RNA types of different origin, which are likely secreted via different mechanisms. In addition, since we previously showed that id-RNAs were abundant or predominant HBV RNAs in many of liver and hepatocellular carcinoma tissues as compared to rd-RNAs, there is likely a mechanism favoring the egress of replication-derived RNAs. IMPORTANCE The presence of integrant-derived RNAs (id-RNAs) and 5'-human-HBV-3' transcripts derived from integrated hepatitis B virus (HBV) DNA in sera was demonstrated for the first time. Thus, sera of individuals chronically infected with HBV contained both replication-derived and integrant-transcribed HBV RNAs. The majority of serum HBV RNAs were the transcripts produced by HBV genome replication, which were associated with HBV virions and not with other types of extracellular vesicles. These and other above-mentioned findings advanced our understanding of the HBV life cycle. In addition, the study suggested a promising target area on the HBV genome to increase sensitivity of the detection of serum HBV RNAs and supported the idea that simultaneous detection of replication-derived RNAs (rd-RNAs) and relaxed circular DNA (rcDNA) in serum provides more adequate evaluation of (i) the HBV genome replication status and (ii) the durability and efficiency of the therapy with anti-HBV nucleos(t)ide analogs, which could be useful for improvement of the diagnostics and treatment of HBV-infected individuals.
Collapse
Affiliation(s)
- Igor Zaiets
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University, Washington, DC, USA
| | - Steven A. Weinman
- Department of Internal Medicine, Division of Gastroenterology, Liver Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Severin O. Gudima
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| |
Collapse
|
|
17
|
Guo Y, Han J, Zhang Y, Jin C, Zhang Y, He J, Chen S, Guo Y, Lin Y, Li F, Yang F, Shen Z, Mao R, Zhu H, Zhang J. End-of-treatment anti-HBs levels and HBeAg status identify durability of HBsAg loss after PEG-IFN discontinuation. Front Cell Infect Microbiol 2023; 13:1120300. [PMID: 36909726 PMCID: PMC9998526 DOI: 10.3389/fcimb.2023.1120300] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 02/02/2023] [Indexed: 03/14/2023] Open
Abstract
Background Hepatitis B surface antigen (HBsAg) loss, namely, the functional cure, can be achieved through the pegylated interferon (PEG-IFN)-based therapy. However, it is an unignorable fact that a small proportion of patients who achieved functional cure develop HBsAg reversion (HRV) and the related factors are not well described. Methods A total of 112 patients who achieved PEG-IFN-induced HBsAg loss were recruited. HBV biomarkers and biochemical parameters were examined dynamically. HBV RNA levels were assessed in the cross-sectional analysis. The primary endpoint was HRV, defined as the reappearance of HBsAg after PEG-IFN discontinuation. Results HRV occurred in 17 patients during the follow-up period. Univariable analysis indicated that hepatitis B e antigen (HBeAg) status, different levels of hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) at the end of PEG-IFN treatment (EOT) were significantly associated with the incidence of HRV through using the log-rank test. Additionally, time-dependent receiver operating characteristic (ROC) analysis showed that the anti-HBs was superior to anti-HBc in predictive power for the incidence of HRV during the follow-up period. Multivariable Cox proportional hazard analysis found that anti-HBs ≥1.3 log10IU/L (hazard ratio (HR), 0.148; 95% confidence interval (CI), 0.044-0.502) and HBeAg negativity (HR, 0.183; 95% CI, 0.052-0.639) at EOT were independently associated with lower incidence of HRV. Cross-sectional analysis indicated that the HBV RNA levels were significantly correlated with the HBsAg levels in patients with HRV (r=0.86, p=0.003). Conclusions EOT HBeAg negativity and anti-HBs ≥1.3 log10IU/L identify the low risk of HRV after PEG-IFN discontinuation.
Collapse
Affiliation(s)
- Yifei Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiajia Han
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yongmei Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chengmeng Jin
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Fudan University, Shanghai, China
| | - Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingjing He
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Shiqi Chen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yue Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yanxue Lin
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhongliang Shen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- *Correspondence: Haoxiang Zhu, ; Jiming Zhang,
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Infectious Diseases, Jing’An Branch of Huashan Hospital, Fudan University, Shanghai, China
- *Correspondence: Haoxiang Zhu, ; Jiming Zhang,
| |
Collapse
|
|
18
|
Deng R, Liu S, Shen S, Guo H, Sun J. Circulating HBV RNA: From biology to clinical applications. Hepatology 2022; 76:1520-1530. [PMID: 35342969 DOI: 10.1002/hep.32479] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 01/01/2023]
Abstract
Chronic HBV infection can hardly be cured due to the persistence of an intrahepatic pool of viral covalently closed circular DNA (cccDNA) transcription template, which is refractory to current antivirals. The direct analyses of cccDNA quantity and transcriptional activity require an invasive biopsy. Recently, circulating HBV RNA has been identified as a promising noninvasive surrogate marker of cccDNA and can be used for monitoring disease progression and predicting prognosis of patients with chronic HBV infection. To better understand this surrogate biomarker of cccDNA, we reviewed the current knowledge about the molecular characteristics and potential clinical applications of circulating HBV RNA. Specifically, we summarized the reported species and existing forms of circulating HBV RNA and discussed their biogenesis and the capacity of de novo infection by RNA virions. Moreover, we described the potential applications of circulating HBV RNA in different clinical scenarios, such as classifying the phases of chronic HBV infection, analyzing sustained on-treatment and off-treatment outcomes of treated patients, as well as predicting HCC development. Perspectives on future research of circulating HBV RNA were also proposed in this review.
Collapse
Affiliation(s)
- Rui Deng
- 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
| | - Sheng Shen
- 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.,Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Haitao Guo
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - 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
| |
Collapse
|
|
19
|
Mazzaro C, Adinolfi LE, Pozzato G, Nevola R, Zanier A, Serraino D, Andreone P, Fenoglio R, Sciascia S, Gattei V, Roccatello D. Extrahepatic Manifestations of Chronic HBV Infection and the Role of Antiviral Therapy. J Clin Med 2022; 11:6247. [PMID: 36362478 PMCID: PMC9657147 DOI: 10.3390/jcm11216247] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/27/2022] [Accepted: 10/12/2022] [Indexed: 08/30/2023] Open
Abstract
The hepatitis B virus (HBV) infection leads to chronic hepatitis, cirrhosis, and hepatocarcinoma. However, about 20% of patients experience extrahepatic manifestations such as polyarteritis nodosa, non-rheumatoid arthritis, non-Hodgkin lymphoma, cryoglobulinemic vasculitis, and glomerulonephritis. These influence the patient's morbidity, quality of life and mortality. The treatment of an HBV infection is based on nucleotide analogues (NAs) which are safe and effective for the suppression of HBV-DNA in almost 100% of cases. A few studies have shown that NAs induce a viral response and an improvement of extrahepatic diseases. There is a lack of a thorough analysis of the available treatments for extrahepatic HBV manifestations. In 90% to 100% of cases, the NAs stop the HBV replication, and they produce a clinical response in the majority of patients with mild to moderate extrahepatic signs/symptoms. Arthritis can definitely disappear after the HBV elimination and, in some cases, the HBV eradication following NAs therapy appears to improve the renal function in HBV-related nephropathies. Plasma exchange can be used in subjects who are suffering from the most aggressive forms of cryoglobulinemic vasculitis and glomerulonephritis, progressive peripheral neuropathy, and life-threatening cases, and this can be combined with glucocorticosteroids and antiviral agents. In selected refractory patients, the use of rituximab in conjunction with NAs therapy can be considered. The review provides an update on extrahepatic conditions that are linked to HBV and the impact of treating HBV with NAs.
Collapse
Affiliation(s)
- Cesare Mazzaro
- Clinical of Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Luigi Elio Adinolfi
- Unit Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, 80138 Naples, Italy
| | - Gabriele Pozzato
- Department of Clinical and Surgical Sciences, Maggiore Hospital University of Trieste, 34149 Trieste, Italy
| | - Riccardo Nevola
- Unit Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, 80138 Naples, Italy
| | - Ada Zanier
- Department of Internal Medicine, Pordenone General Hospital, 33170 Pordenone, Italy
| | - Diego Serraino
- Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Pietro Andreone
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Roberta Fenoglio
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) CMID-Nephrology and Dialysis Unit, San Giovanni Bosco Hub Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy
| | - Savino Sciascia
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) CMID-Nephrology and Dialysis Unit, San Giovanni Bosco Hub Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy
| | - Valter Gattei
- Clinical of Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Dario Roccatello
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) CMID-Nephrology and Dialysis Unit, San Giovanni Bosco Hub Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy
| |
Collapse
|
|
20
|
Lok J, Dusheiko G, Carey I, Agarwal K. Review article: novel biomarkers in hepatitis B infection. Aliment Pharmacol Ther 2022; 56:760-776. [PMID: 35770458 DOI: 10.1111/apt.17105] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Chronic hepatitis B remains a global health problem with an estimated 296 million people affected worldwide. Individuals are at risk of serious complications such as cirrhosis and hepatocellular carcinoma and accurately predicting these clinical endpoints has proven difficult. However, several viral biomarkers have recently been developed, including quantitative HBV surface antigen (qHBsAg), hepatitis B RNA (HBV RNA) and core-related antigen (HBcrAg), and shown promise in a range of clinical settings. AIMS To critically appraise these novel biomarkers, exploring their potential uses, availability of assays and areas for future development. METHODS We performed a literature search of PubMed, identifying articles published in the field of hepatitis B biomarkers between 2010 and 2022. RESULTS Novel biomarkers such as HBcrAg, HBV RNA and qHBsAg may be useful in predicting treatment outcomes, stratifying the risk of future complications and estimating off-treatment viral reactivation. Furthermore, HBV RNA and HBcrAg titres may accurately reflect cccDNA transcriptional activity, and this is particularly informative in the context of nucleoside analogue therapy. On a cautionary note, most studies have been performed in Caucasian or Asian populations, and methods for detecting HBV RNA lack standardisation. CONCLUSION Novel viral biomarkers have the potential to provide additional insights into the natural history of infection and allow a more bespoke, cost-effective framework of care. However, access remains limited, and further efforts are needed to validate their use in ethnically diverse populations, confirm predictive cut-off values, and establish their role in the era of novel antiviral therapies.
Collapse
Affiliation(s)
- James Lok
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
| |
Collapse
|
|
21
|
Zhang Q, Huang H, Sun A, Liu C, Wang Z, Shi F, Duan W, Sun X, Wang Q, Sun P, Pu C, Zhang Y. Change of Cytokines in Chronic Hepatitis B Patients and HBeAg are Positively Correlated with HBV RNA, Based on Real-world Study. J Clin Transl Hepatol 2022; 10:390-397. [PMID: 35836760 PMCID: PMC9240249 DOI: 10.14218/jcth.2021.00160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/20/2021] [Accepted: 08/17/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS The natural course of chronic hepatitis B virus (HBV) infection is widely studied; however, follow-up studies of the same patients are scanty. Here, we studied the dynamic changes of serum HBV RNA and cytokines in hepatitis B virus e antigen (HBeAg)-positive patients treated with entecavir (ETV) to explore the relationship between the HBV serum viral nucleic acids and host immunity. METHODS Thirty-three chronic hepatitis B patients who are HBeAg-positive, with high virus load (HBV DNA >20,000 IU/mL), and received standard nucleos(t)ide analogue (NA) antiviral therapy (ETV) for more than 48 weeks were included. The serum levels of HBV nucleic acids and selected cytokines were measured at 0, 12, 24, and 48 weeks respectively. RESULTS Serum HBV RNA could still be detected while serum HBV DNA had fallen below the detection limit in patients treated with ETV. There was a strong positive correlation between HBV RNA and HBeAg, with a concomitant decrease in the secretion of cytokines from type 1 helper T (Th1)/type 2 helper T (Th2)/interleukin (IL)-17 producing T (Th17) cells. IL-4 and IL-10 were the main cytokines negatively associated with serum HBV RNA. CONCLUSIONS HBeAg can be used to reflect the load of HBV RNA indirectly, because serum HBV RNA has not been widely used in clinical practice. Meanwhile, serum IL-4 and IL-10 might be explored in combination with HBV RNA in guiding future clinical antiviral therapy.
Collapse
Affiliation(s)
- Qiqi Zhang
- Department of Biobank, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hui Huang
- Department of Biobank, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Aijun Sun
- Outpatient Department of Hepatitis, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chunyan Liu
- Department of Biobank, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Zhidong Wang
- Department of Pathology, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Feifan Shi
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Wei Duan
- School of Medicine, Deakin University, Victoria, Australia
| | - Xueying Sun
- Department of Biobank, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qi Wang
- Department of Pathology, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Ping Sun
- Department of Pathology, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chunwen Pu
- Department of Biobank, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yong Zhang
- Outpatient Department of Hepatitis, The Sixth Affiliated People's Hospital of Dalian Medical University, Dalian, Liaoning, China
| |
Collapse
|
|
22
|
Hawkins C, Kang M, Bhattacharya D, Cloherty G, Kuhns M, Matining R, Thio C, Samaneka W, Chinula L, Mulinda N, Badal-Faesen S, Sugandhavesa P, Lama J, Gaseitsiwe S, Holzmayer V, Anderson M, Murphy R, Peters M. Hepatitis B surface antigen and hepatitis B RNA changes in HIV/hepatitis B virus co-infected participants receiving hepatitis B virus-active antiretroviral therapy. AIDS 2022; 36:975-984. [PMID: 35165216 PMCID: PMC9167724 DOI: 10.1097/qad.0000000000003193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION With advances in hepatitis B virus (HBV) therapies, there is a need to identify serum biomarkers that assess the HBV covalently closed circular DNA (cccDNA) reservoir and predict functional cure in HIV/HBV co-infection. METHODS In this retrospective study, combining samples from HIV/HBV co-infected participants enrolled in two ACTG interventional trials, proportions achieving HBsAg less than 0.05 log10 IU/ml and HBV RNA less than log10 1.65 U/ml or not detected (LLoQ/NEG) in response to DUAL [tenofovir TDF+emtricitabine (FTC)] vs. MONO [FTC or lamivudine (3TC)] HBV-active ART, were measured. Predictors of qHBsAg less than 0.05 log10 IU/ml were evaluated in logistic regression models. RESULTS There were 88 participants [58% women, median age 34; 47 on DUAL vs. 41 on MONO HBV-active ART]. Twenty-one percent achieved HBsAg less than 0.05 log10 IU/ml (30% DUAL vs. 10% MONO). Time to HBsAg less than 0.05 log10 IU/ml was lower (P = 0.02) and the odds of achieving HBsAg less than 0.05 log10 IU/ml were higher (P = 0.07) in DUAL participants. HBV RNA became less than LLoQ/NEG in 47% (DUAL 60% vs. MONO 33%). qHBsAg less than 3 log10 IU/ml was the strongest predictor of HBsAg less than 0.05 log10 IU/ml. CONCLUSION This study supports current recommendations of TDF-based DUAL-HBV active ART for initial use in HIV/HBV co-infection. HBV RNA could be a useful marker of treatment response in HIV/HBV co-infected patients on HBV-active ART.
Collapse
Affiliation(s)
- Claudia Hawkins
- Department of Medicine, Feinberg School of Medicine, Northwestern University CRS, Chicago, Illinois
| | - Minhee Kang
- Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Debika Bhattacharya
- David Geffen School of Medicine, Division of Infectious Diseases, University of California, Los Angeles (UCLA), California
| | - Gavin Cloherty
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Mary Kuhns
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Roy Matining
- Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Chloe Thio
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Lameck Chinula
- UNC Project Malawi CRS, UNC Department of Obstetrics and Gynecology's Division of Global Women's Health, Chapel Hill, North Carolina, USA
| | | | - Sharlaa Badal-Faesen
- Clinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | | | - Javier Lama
- Asociacion Civil Impacta Salud y Educacion, Lima, Peru, and Botswana Harvard School of Public Health AIDS Initiative Partnership, Botswana
| | - Simani Gaseitsiwe
- Clinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Vera Holzmayer
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Mark Anderson
- Infectious Diseases Research, Abbott, Abbott Park, Illinois
| | - Robert Murphy
- Department of Medicine, Feinberg School of Medicine, Northwestern University CRS, Chicago, Illinois
| | - Marion Peters
- Department of Medicine, Feinberg School of Medicine, Northwestern University CRS, Chicago, Illinois
| |
Collapse
|
|
23
|
Peña‐Asensio J, Calvo H, Miquel J, Sanz‐de‐Villalobos E, González‐Praetorius A, Torralba M, Larrubia J. Model to predict on-treatment restoration of functional HBV-specific CD8 + cell response foresees off-treatment HBV control in eAg-negative chronic hepatitis B. Aliment Pharmacol Ther 2022; 55:1545-1559. [PMID: 35224746 PMCID: PMC9305412 DOI: 10.1111/apt.16850] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/12/2022] [Accepted: 02/14/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV)-specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off-treatment HBV control in e-antigen-negative chronic hepatitis B (CHBe(-)). AIM To predict this response with variables involved in T-cell exhaustion for use as a treatment stopping tool. METHODS In NUC-treated CHBe(-) patients, we considered a functional response in cases with HBV-specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off-treatment follow-up according to LRM likelihood. RESULTS We developed an LRM that predicted the presence of a proliferative type I cytokine-secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off-treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability. CONCLUSIONS Short-term low-level antigen exposure and early long-term NUC treatment influence the restoration of a functional HBV-specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off-treatment HBV control and HBsAg decline and loss.
Collapse
Affiliation(s)
- Julia Peña‐Asensio
- Department of Biology of SystemsUniversity of AlcaláAlcalá de HenaresSpain
| | - Henar Calvo
- Section of GastroenterologyGuadalajara University HospitalGuadalajaraSpain
| | - Joaquín Miquel
- Section of GastroenterologyGuadalajara University HospitalGuadalajaraSpain
| | | | | | - Miguel Torralba
- Service of Internal MedicineGuadalajara University HospitalGuadalajaraSpain,Department of Medicine & Medical SpecialtiesUniversity of AlcaláAlcalá de HenaresSpain
| | - Juan‐Ramón Larrubia
- Section of GastroenterologyGuadalajara University HospitalGuadalajaraSpain,Department of Medicine & Medical SpecialtiesUniversity of AlcaláAlcalá de HenaresSpain
| |
Collapse
|
|
24
|
Wang Y, Liu Y, Liao H, Deng Z, Bian D, Ren Y, Yu G, Jiang Y, Bai L, Liu S, Liu M, Zhou L, Chen Y, Chen X, Duan Z, Lu F, Zheng S. Serum HBV DNA plus RNA reflecting cccDNA level before and during NAs treatment in HBeAg positive CHB patients. Int J Med Sci 2022; 19:858-866. [PMID: 35693741 PMCID: PMC9149645 DOI: 10.7150/ijms.71737] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/20/2022] [Indexed: 11/06/2022] Open
Abstract
Background & Aims: Correlations between serum viral markers and intrahepatic cccDNA in patients undergoing long-term nucleos(t)ide analogues (NAs) treatment haven't been fully explored. In this study, we evaluate the correlation between intrahepatic cccDNA and other serum viral markers and intrahepatic HBV DNA in HBeAg positive chronic hepatitis B (CHB) patients during 60-month treatment with NAs. Methods: Fifty-four HBeAg positive CHB patients received long-term NAs treatment were included in this study. Serial serum samples were regularly collected and quantitatively analyzed for HBsAg, HBV DNA, HBV RNA and HBcrAg. Histological samples from liver biopsy at baseline and month 60 were analyzed for intrahepatic HBV DNA and cccDNA. Results: At baseline, serum HBV DNA plus RNA was positively associated with intrahepatic cccDNA in multivariate regression analysis (β=0.205, P<0.001). In the correlation analysis between cccDNA and serum viral markers, HBV DNA plus RNA had the highest correlation coefficient (r=0.698, P<0.001), followed by serum HBV DNA (r=0.641, P<0.001), HBV RNA (r=0.590, P<0.001), and HBcrAg (r=0.564, P<0.001). At month 60, correlations between these serum viral markers and cccDNA were not observed (P>0.05). Multivariate regression analysis showed that only the decreased HBV DNA plus RNA was positively associated with cccDNA decline (β=0.172, P =0.006). Changes of HBV DNA plus RNA (r=0.525, P=0.001) was better correlated with cccDNA decline as compared to HBV RNA (r=0.384, P=0.008), HBV DNA (r=0.431, P=0.003), and HBsAg (r=0.342, P=0.029). Conclusions: Serum HBV DNA plus RNA better correlated with intrahepatic cccDNA than other viral makers before and during NAs treatment in HBeAg positive CHB patients.
Collapse
Affiliation(s)
- Yang Wang
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yanna Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Hao Liao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Department of Clinical Laboratory, Shenzhen Third People's Hospital, Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, 518112, PR China
| | - Zhongping Deng
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
- Hunan Provincial Key Laboratory of Gene Diagnostic Technology, Changsha 410205, China
| | - Dandan Bian
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yan Ren
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Guangxin Yu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yingying Jiang
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Li Bai
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Shuang Liu
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Mei Liu
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Li Zhou
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yu Chen
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Xinyue Chen
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Zhongping Duan
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Sujun Zheng
- Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| |
Collapse
|
|
25
|
Scholtès C, Hamilton AT, Plissonnier ML, Charre C, Scott B, Wang L, Berby F, French J, Testoni B, Blair A, Subic M, Hoppler M, Lankenau A, Grubenmann A, Levrero M, Heil ML, Zoulim F. Performance of the cobas® HBV RNA Automated Investigational Assay for the Detection and Quantification of Circulating HBV RNA in Chronic HBV Patients. J Clin Virol 2022; 150-151:105150. [DOI: 10.1016/j.jcv.2022.105150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/22/2022] [Accepted: 03/31/2022] [Indexed: 01/02/2023]
|
|
26
|
Tao Y, Wang M, Liao J, Cheng X, He M, Zhang D, Zhou T, Chen J, Chen E, Tang H. Dynamics of Serum Pregenome RNA in Chronic Hepatitis B Patients Receiving 96-Month Nucleos(t)ide Analog Therapy. Front Med (Lausanne) 2022; 9:787770. [PMID: 35295596 PMCID: PMC8918695 DOI: 10.3389/fmed.2022.787770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/25/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Tissue covalently closed circular DNA (cccDNA) can reflect the activity of HBV replication. However, it is impractical to assess intrahepatic cccDNA in every outpatient. Serum pregenome RNA (pgRNA) is transcribed from intrahepatic cccDNA and may reflect the activity of intrahepatic cccDNA. We explored the dynamics and the potential role of serum pgRNA in patients receiving long-term NAs treatment. METHODS Serum pgRNA, HBV DNA, HBsAg, HBeAg, and ALT levels were quantified, and the relationships between serum pgRNA and these common clinical indicators before and after the treatment were investigated. RESULTS Serum pgRNA showed dynamic change during the 96-month NAs therapy, and serum pgRNA levels were positive and detectable in 19 patients with undetectable serum HBV DNA. Serum pgRNA showed strong and positive correlation with serum HBV DNA (r = 0.693, p < 0.001) and serum HBsAg levels (r = 0.621, p < 0.001) at baseline. Patients with HBeAg seroconversion had lower baseline serum pgRNA levels (p = 0.002). The area under the curve (AUC) of baseline serum pgRNA for predicting HBeAg seroconversion was 0.742 (95% CI: 0.606-0.850) with 63.16% sensitivity and 80.56% specificity. The cumulative HBeAg seroconversion rate was higher in patients with low serum pgRNA (p = 0.001). CONCLUSION Serum pgRNA of low level at baseline or great decline at month 6 may independently predict the high incidence of undetectable serum pgRNA at year 4 following NAs therapy, and the baseline serum pgRNA may serve as a novel predictor for HBeAg seroconversion during NAs therapy.
Collapse
Affiliation(s)
- Yachao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Menglan Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Juan Liao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Xing Cheng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Min He
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Dongmei Zhang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Taoyou Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Jie Chen
- Shanghai RenDu Biotechnology Co. Ltd, Shanghai, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| |
Collapse
|
|
27
|
Hayashi S, Isogawa M, Kawashima K, Ito K, Chuaypen N, Morine Y, Shimada M, Higashi-Kuwata N, Watanabe T, Tangkijvanich P, Mitsuya H, Tanaka Y. Droplet digital PCR assay provides intrahepatic HBV cccDNA quantification tool for clinical application. Sci Rep 2022; 12:2133. [PMID: 35136096 PMCID: PMC8826402 DOI: 10.1038/s41598-022-05882-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/13/2022] [Indexed: 12/14/2022] Open
Abstract
The persistence of covalently closed circular DNA (cccDNA) poses a major obstacle to curing chronic hepatitis B (CHB). Here, we used droplet digital PCR (ddPCR) for cccDNA quantitation. The cccDNA-specific ddPCR showed high accuracy with the dynamic range of cccDNA detection from 101 to 105 copies/assay. The ddPCR had higher sensitivity, specificity and precisely than qPCR. The results of ddPCR correlated closely with serum HB core-related antigen and HB surface antigen (HBsAg) in 24 HBV-infected human-liver-chimeric mice (PXB-mice). We demonstrated that in 2 PXB-mice after entecavir treatment, the total cccDNA content did not change during liver repopulation, although the cccDNA content per hepatocyte was reduced after the treatment. In the 6 patients with HBV-related hepatocellular carcinoma, ddPCR detected cccDNA in both tumor and non-tumor tissues. In 13 HBeAg-negative CHB patients with pegylated interferon alpha-2a, cccDNA contents from paired biopsies were more significantly reduced in virological response (VR) than in non-VR at week 48 (p = 0.0051). Interestingly, cccDNA levels were the lowest in VR with HBsAg clearance but remained detectable after the treatment. Collectively, ddPCR revealed that cccDNA content is stable during hepatocyte proliferation and persists at quantifiable levels, even after serum HBsAg clearance.
Collapse
Affiliation(s)
- Sanae Hayashi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Masanori Isogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Keigo Kawashima
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kyoko Ito
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Nobuyo Higashi-Kuwata
- Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan
| | - Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Hiroaki Mitsuya
- Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan
- Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
| |
Collapse
|
|
28
|
Leoni S, Casabianca A, Biagioni B, Serio I. Viral hepatitis: Innovations and expectations. World J Gastroenterol 2022; 28:517-531. [PMID: 35316960 PMCID: PMC8905017 DOI: 10.3748/wjg.v28.i5.517] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/14/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is a significant health problem worldwide, associated with morbidity and mortality. Hepatitis B, C, D, and occasionally E viruses (HBV, HCV, HDV, and HEV) can evolve in chronic infections, whereas hepatitis A virus (HAV) frequently produces acute self-limiting hepatitis. In the last years, different studies have been performed to introduce new antiviral therapies. The most important goal in the treatment of viral hepatitis is to avoid chronic liver disease and complications. This review analyzes currently available therapies, in particular for viruses associated with chronic liver disease. The focus is especially on HBV and HCV therapies, investigating new drugs already introduced in clinical practice and clinical trials. We also describe new entry inhibitors, developed for the treatment of chronic HDV and HBV and currently available treatments for HEV. The last drugs introduced have shown important efficacy in HCV, with achievable target HCV elimination by 2030. Concurrently, renewed interest in curative HBV therapies has been registered; current nucleotide/ nucleoside analogs positively impact liver-related complications, ensuring high safety and tolerability. Novel approaches to HBV cure are based on new antivirals, targeting different steps of the HBV life cycle and immune modulators. The improved knowledge of the HDV life cycle has facilitated the development of some direct-acting agents, as bulevirtide, the first drug conditionally approved in Europe for HDV associated compensated liver disease. Further studies are required to identify a new therapeutic approach in hepatitis E, especially in immunosuppressed patients.
Collapse
Affiliation(s)
- Simona Leoni
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Alberto Casabianca
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Benedetta Biagioni
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Ilaria Serio
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| |
Collapse
|
|
29
|
Yim HJ, Kim W, Ahn SH, Jung YK, Um SH, Sohn JH, Jang JY, Kim DJ, Park ES, Jin SY, Kim KH. Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients. J Gastroenterol Hepatol 2022; 37:378-386. [PMID: 34653281 DOI: 10.1111/jgh.15710] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/15/2021] [Accepted: 10/04/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy. METHODS This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed. RESULTS A total of 46 CHB patients received liver biopsies (BSV, n = 29; TDF, n = 17). After 48 weeks of treatment, virological response rate was comparable between the groups (P = 0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥ 2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% vs 36.4%, P = 0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48 weeks of BSV or TDF treatment (P < 0.001) without intergroup differences (P = 0.349). CONCLUSIONS The BSV therapy improves hepatic histology and decreases intrahepatic cccDNA in CHB patients.
Collapse
Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Eun-Sook Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - So-Young Jin
- Department of Pathology, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
| | - Kyun-Hwan Kim
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea
| |
Collapse
|
|
30
|
Laras A, Papatheodoridi M, Panopoulou E, Papatheodoridis GV, Hadziyannis SJ, Hadziyannis E. Serum hepatitis B virus RNA detectability, composition and clinical significance in patients with ab initio hepatitis B e antigen negative chronic hepatitis B. Virol J 2022; 19:22. [PMID: 35093105 PMCID: PMC8800272 DOI: 10.1186/s12985-022-01749-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/19/2022] [Indexed: 12/15/2022] Open
Abstract
Background Serum hepatitis B virus (HBV) RNA is a surrogate biomarker for intrahepatic covalently closed circular DNA (cccDNA) transcriptional activity and persistence. In this retrospective study, we investigated its presence, levels and composition in ab initio Hepatitis B e antigen (HBeAg) negative chronically infected patients and examined possible associations with disease activity and the outcome of nucleos(t)ide analogue (NA) discontinuation. Methods We developed a sensitive real time polymerase chain reaction (RT-PCR) for the specific detection of HBV pregenomic RNA (pgRNA) and precore (preC) mRNA and analyzed 220 serum specimens, 160 under NA treatment, from 116 Greek patients initially negative for HBeAg. Results HBV pgRNA was detected in 31% and preC mRNA in 15% of samples, at lower levels representing a small fraction (3.4%) of total core promoter produced transcripts. In the absence of NAs, pgRNA was detected in 57% of samples with median value of 5.19 (2.61–8.35) log10 cp/mL, at lower levels than HBV DNA and correlated significantly with ALT (r = 0.764) and serum HBV DNA (r = 0.906). A wide range of HBV DNA/pgRNA ratio was observed with significant inter- and intra-patient variation. During NA treatment, pgRNA displayed low detectability (22%) and variable levels, median 3.97 (2.30– 8.13) log10 cp/mL, as well as, a significant inverse correlation with the duration of treatment (r = − 0.346, p < 0.01). In 74 events of NA discontinuation, end-of-treatment pgRNA-positive compared to pgRNA-negative cases, experienced more frequently virological (p = 0.016) and clinical (p = 0.011) relapse. Conclusions In genotype D ab initio HBeAg negative patients, serum HBV RNA is primarily composed of pgRNA plus a minor fraction of preC mRNA transcripts. Serum pgRNA is associated with disease activity, suggesting lysis of infected hepatocytes as a possible source of serum HBV RNA in untreated patients and in the early phase of NA treatment. During long term NA treatment, detectable serum pgRNA predicts viral rebound and clinical relapse following treatment discontinuation and may thus serve as a marker for the decision of cessation of therapy.
Collapse
|
|
31
|
Zhang X, Wang Y, Yang G. Research progress in hepatitis B virus covalently closed circular DNA. Cancer Biol Med 2021; 19:j.issn.2095-3941.2021.0454. [PMID: 34931766 PMCID: PMC9088183 DOI: 10.20892/j.issn.2095-3941.2021.0454] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/16/2021] [Indexed: 11/28/2022] Open
Abstract
Hepatitis B virus (HBV) infections are a global public health issue. HBV covalently closed circular DNA (cccDNA), the template for the transcription of viral RNAs, is a key factor in the HBV replication cycle. Notably, many host factors involved in HBV cccDNA epigenetic modulation promote the development of hepatocellular carcinoma (HCC). The HBV cccDNA minichromosome is a clinical obstacle that cannot be efficiently eliminated. In this review, we provide an update on the advances in research on HBV cccDNA and further discuss factors affecting the modulation of HBV cccDNA. Hepatitis B virus X protein (HBx) contributes to HBV cccDNA transcription and the development of hepatocarcinogenesis through modulating host epigenetic regulatory factors, thus linking the cccDNA to hepatocarcinogenesis. The measurable serological biomarkers of continued transcription of cccDNA, the effects of anti-HBV drugs on cccDNA, and potential therapeutic strategies targeting cccDNA are discussed in detail. Thus, this review describes new insights into HBV cccDNA mechanisms and therapeutic strategies for cleaning cccDNA, which will benefit patients with liver diseases.
Collapse
Affiliation(s)
- Xiaodong Zhang
- Department of Gastrointestinal Cancer Biology, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yufei Wang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Guang Yang
- Department of Gastrointestinal Cancer Biology, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| |
Collapse
|
|
32
|
Zhong YW, Shi YM, Chu F, Liu J, Shi C, Xu JJ, Liu P, Bai YJ, Xiao XH, Zhang XC, Zhang M. Prediction for HBsAg seroconversion in children with chronic hepatitis B. BMC Infect Dis 2021; 21:1211. [PMID: 34863101 PMCID: PMC8645145 DOI: 10.1186/s12879-021-06883-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 11/16/2021] [Indexed: 11/17/2022] Open
Abstract
Background To establish a prediction of HBsAg seroconversion in children with chronic hepatitis B (CHB), so as to help clinicians to choose therapeutic strategy. Methods A total of 63 children with HBeAg-positive CHB aged 1 to 17 years, who admitted to the fifth medical center of Chinese PLA general hospital and treated with interferon α (IFNα) 48 weeks were enrolled, the clinical data were measured. Based on the results of HBsAg seroconversion (HBsAg < 0.05 IU/mL and anti-HBsAg > 10 IU/L) at week 48, the patients were divided into HBsAg seroconversion (S) group and non-HBsAg seroconversion (NS) group. Multivariate COX regression was used to identify the impact factors associated with HBsAg seroconversion. A novel prediction index was established and the area under the receiver operating characteristic curve (AUROC) was used to assess the prediction for HBsAg seroconversion. Results The 63 patients were divided into S group (20.6%, 13/63) and NS group (79.4%, 50/63). Univariate and multivariate analysis identified age, baseline intrahepatic cccDNA and serum HBsAg levels were independent impact factors for HBsAg seroconversion. Intrahepatic cccDNA was positively correlated with serum HBsAg (r = 0.464, p = 0.000). AUROC of HBV cccDNA was 0.83 (95% CI 0.71 to 0.95) and AUROC of baseline HBsAg was 0.77 (95% CI 0.61 to 0.92). Intrahepatic cccDNA ≤ 0.08 log10 copies/106 cell is regarded as cutoff value, the positive predictive value(PPV) and negative predictive value(NPV) for HBsAg seroconversion were 86.8% and 60.0%, respectively, with a sensitivity of 92.0% and specificity of 56.2%. HBsAg ≤ 3.68 log10 IU/mL is used as cut off value, the PPV and NPV for HBsAg seroconversion were 91.2% and 56.3%, respectively; the sensitivity and specificity was 86.0% of 69.2%, respectively. There was no statistical difference between them for predicting HBsAg seroconversion (p = 0.146). Conclusions HBsAg seroconversion can be predicted by the baseline serum HBsAg or intrahepatic cccDNA in children with CHB. Using the index, clinicians can choose more reasonable therapeutic strategy and reduce the waste of medical resources.
Collapse
Affiliation(s)
- Yan-Wei Zhong
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China.
| | - Yan-Min Shi
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China
| | - Fang Chu
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China
| | - Jie Liu
- Hebei North University, South Diamond Road No.11, High Tech Zone, Zhangjiakou Province, 075000, Hebei, China
| | - Ce Shi
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China
| | - Jiao-Jiao Xu
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China.,Hebei North University, South Diamond Road No.11, High Tech Zone, Zhangjiakou Province, 075000, Hebei, China
| | - Peng Liu
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China
| | - Yan-Jie Bai
- Peking University Third Hospital, 49 North Garden Rd., Beijing, 100191, China
| | - Xiao-He Xiao
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China.
| | - Xiu-Chang Zhang
- Hebei North University, South Diamond Road No.11, High Tech Zone, Zhangjiakou Province, 075000, Hebei, China.
| | - Min Zhang
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Xisihuan Mid-Road No.100, 100039, Beijing, China.
| |
Collapse
|
|
33
|
Lee JH, Kim HS. Current laboratory tests for diagnosis of hepatitis B virus infection. Int J Clin Pract 2021; 75:e14812. [PMID: 34487586 DOI: 10.1111/ijcp.14812] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/03/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) has a long history in human infectious diseases. HBV infection can progress chronically, leading to cancer. After introduction of a vaccine, the overall incidence rate of HBV infection has decreased, although it remains a health problem in many countries. PURPOSE The aim of this review was to summarise current diagnostic efforts for HBV infection and future HBV diagnosis perspectives. METHODS We reviewed and summarised current laboratory diagnosis related with HBV infection in clinical practice. RESULTS There have been various serologic- and molecular-based methods to diagnose acute or chronic HBV infection. Since intrahepatic covalently closed circular DNAs (cccDNAs) function as robust HBV replication templates, cure of chronic HBV infection is limited. Recently, new biomarkers such as hepatitis B virus core-related antigen (HBcrAg) and HBV RNA have emerged that appear to reflect intrahepatic cccDNA status. These new biomarkers should be validated before clinical usage. CONCLUSION An effective diagnostic approach and current updated knowledge of treatment response monitoring are important for HBV infection management. Brand new ultrasensitive and accurate immunologic methods may pave the way to manage HBV infection in parallel with immunotherapy era.
Collapse
Affiliation(s)
- Jong-Han Lee
- Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Hyon-Suk Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
34
|
Jaroenlapnopparat A, Chayanupatkul M, Tangkijvanich P. Novel viral markers and the prediction of off-treatment relapse in chronic hepatitis B patients: A systematic review. J Gastroenterol Hepatol 2021; 36:2349-2362. [PMID: 33811375 DOI: 10.1111/jgh.15516] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/02/2021] [Accepted: 03/27/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) are novel markers that reflect intrahepatic cccDNA and could be useful in the prediction of relapse after nucleos(t)ide analogues (NA) discontinuation. The aim of the study is to perform a systematic review on this issue. METHODS Medline/Pubmed database was searched using text terms related to HBcrAg, RNA, NAs, discontinuation, and relapse. Included studies were those that enrolled adult patients who had been on NAs for more than 6 months with available information on end-of-treatment (EOT) HBcrAg and/or HBV RNA and relapse rates. RESULTS Sixteen studies were included. Virological and clinical relapse rates ranged from 11% to 100% and 11% to 73%, respectively. Low or undetectable EOT HBcrAg levels were associated with low off-treatment relapse rates in most studies with area under the receiver operating characteristic curve (AUROC) of 0.69-0.70 for predicting virological relapse (VR) and 0.61-0.77 for predicting clinical relapse (CR). Undetectable EOT HBV RNA was associated with a lower risk of off-treatment relapse with AUROC of 0.65-0.76 for predicting VR and 0.66-0.73 for predicting CR. Combined EOT HBcrAg and HBV RNA performed better in predicting off-treatment relapse than either test alone with AUROC of 0.816-0.846 for predicting CR. None of the patients with double-negative HBV RNA and HBcrAg developed CR. CONCLUSION Combining HBcrAg with HBV RNA or HBsAg improved the discriminating abilities in the prediction of off-treatment relapse of each test. Patients with double-negative HBcrAg and HBV RNA at EOT had low risks of relapse and could be considered for NA discontinuation.
Collapse
Affiliation(s)
- Aunchalee Jaroenlapnopparat
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Maneerat Chayanupatkul
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
35
|
Ghosh S, Chakraborty A, Banerjee S. Persistence of Hepatitis B Virus Infection: A Multi-Faceted Player for Hepatocarcinogenesis. Front Microbiol 2021; 12:678537. [PMID: 34526974 PMCID: PMC8435854 DOI: 10.3389/fmicb.2021.678537] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/06/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection has a multi-dimensional effect on the host, which not only alters the dynamics of immune response but also persists in the hepatocytes to predispose oncogenic factors. The virus exists in multiple forms of which the nuclear localized covalently closed circular DNA (cccDNA) is the most stable and the primary reason for viral persistence even after clearance of surface antigen and viral DNA. The second reason is the existence of pregenomic RNA (pgRNA) containing virion particles. On the other hand, the integration of the viral genome in the host chromosome also leads to persistent production of viral proteins along with the chromosomal instabilities. The interferon treatment or administration of nucleot(s)ide analogs leads to reduction in the viral DNA load, but the pgRNA and surface antigen clearance are a slow process and complete loss of serological HBsAg is rare. The prolonged exposure of immune cells to the viral antigens, particularly HBs antigen, in the blood circulation results in T-cell exhaustion, which disrupts immune clearance of the virus and virus-infected cells. In addition, it predisposes immune-tolerant microenvironment, which facilitates the tumor progression. Thus cccDNA, pgRNA, and HBsAg along with the viral DNA could be the therapeutic targets in the early disease stages that may improve the quality of life of chronic hepatitis B patients by impeding the progression of the disease toward hepatocellular carcinoma.
Collapse
Affiliation(s)
| | | | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| |
Collapse
|
|
36
|
Shah NJ, Aloysius MM, Sharma NR, Pallav K. Advances in treatment and prevention of hepatitis B. World J Gastrointest Pharmacol Ther 2021. [DOI: 10.4292/wjg.v12.i4.56] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
37
|
Shah NJ, Aloysius MM, Sharma NR, Pallav K. Advances in treatment and prevention of hepatitis B. World J Gastrointest Pharmacol Ther 2021; 12:56-78. [PMID: 34316384 PMCID: PMC8290928 DOI: 10.4292/wjgpt.v12.i4.56] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/22/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) continues to contribute to worldwide morbidity and mortality significantly. Scientists, clinicians, pharmaceutical companies, and health organizations have dedicated substantial Intellectual and monetary resources to finding a cure, increasing immunization rates, and reducing the global burden of CHB. National and international health-related organizations including the center for disease control, the national institute of health, the American Association for the study of liver disease (AASLD), The European association for the study of the Liver (EASL), The Asia Pacific association for the study of the Liver (APASL) and the world health organization release periodic recommendations for disease prevention and treatment. Our review of the most recent guidelines by EASL, AASLD, APASL, and Taiwan Association for the Study of the Liver revealed that an overwhelming majority of cited studies were published before 2018. We reviewed Hepatitis B-related literature published 2018 onwards to identify recent developments and current barriers that will likely direct future efforts towards eradicating hepatitis B. The breakthrough in our understanding of the hepatitis B virus life cycle and resulting drug development is encouraging with significant room for further progress. Data from high-risk populations, most vulnerable to the devastating effects of hepatitis B infection and reactivation remain sparse. Utilization of systems approach, optimization of experimental models, identification and validation of next-generation biomarkers, and precise modulation of the human immune response will be critical for future innovation. Within the foreseeable future, new treatments will likely complement conventional therapies rather than replace them. Most Importantly, pragmatic management of CHB related population health challenges must be prioritized to produce real-world results.
Collapse
Affiliation(s)
- Niraj James Shah
- Department of Internal Medicine, Digestive Disease, University of Mississippi Medical Center, Jackson, MS 39216, United States
| | - Mark M Aloysius
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, United States
| | - Neil Rohit Sharma
- Department of Internal Medicine, Interventional Oncology and Surgical Endoscopy, Parkview Regional Medical Center, Parkview Cancer Institute, Fort Wayne, IN 46845, United States
| | - Kumar Pallav
- Department of Internal Medicine, Interventional Oncology and Surgical Endoscopy, Parkview Regional Medical Center, Parkview Cancer Institute, Fort Wayne, IN 46845, United States
| |
Collapse
|
|
38
|
Mak LY, Cloherty G, Wong DKH, Gersch J, Seto WK, Fung J, Yuen MF. HBV RNA Profiles in Patients With Chronic Hepatitis B Under Different Disease Phases and Antiviral Therapy. Hepatology 2021; 73:2167-2179. [PMID: 33159329 DOI: 10.1002/hep.31616] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Large-scale comprehensive studies on HBV RNA in chronic hepatitis B are lacking. We aimed to study the HBV RNA profile and its correlation with other viral markers in patients with chronic hepatitis B who are treatment-naïve and patients receiving nucleos(t)ide analogues (NA). APPROACH AND RESULTS Biomarkers, including HBV RNA and hepatitis B core-related antigen (HBcrAg), were measured in 388 patients. Of these, 246 were treatment-naïve and were categorized into HBeAg-positive chronic infection (n = 41), HBeAg-positive chronic hepatitis (n = 81), HBeAg-negative chronic infection (n = 39), HBeAg-negative chronic hepatitis (n = 66), and HBsAg seroclearance (n = 19). These biomarkers were also measured in 142 patients who were NA-treated receiving tenofovir or entecavir at baseline, week 48, and week 96. The pattern of serum HBV RNA levels mirrored HBV DNA (1-2 logs higher than HBV RNA) and HBcrAg in patients who were treatment-naïve. HBV RNA correlated best with HBcrAg (r = 0.84) and to a lesser extent with HBV DNA (r = 0.737) (both P < 0.001). In patients with HBsAg seroclearance, 15.8% and 15.8% had detectable serum HBV RNA and HBcrAg, respectively. NA treatment reduced serum HBV RNA by 1.46 logs and 1.77 logs at weeks 48 and 96, respectively. At week 96 of NA therapy, only 19.1% patients who were tenofovir-treated and 25.7% patients who were entecavir-treated had unquantifiable HBV RNA (P > 0.05). In patients who were treated and had undetectable HBV DNA, 77.5% and 30% had quantifiable HBV RNA and HBcrAg, respectively. CONCLUSIONS HBV RNA showed distinct and corresponding profiles in patients with HBV in different disease phases. HBV RNA and HBcrAg could be used to monitor residual transcriptional activities in patients with HBsAg seroclearance. NA led to reduction of serum HBV RNA. Monitoring of viral activities can still be achieved in patients with undetectable HBV DNA by serum HBV RNA.
Collapse
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Gavin Cloherty
- Department of Infectious Diseases, Abbott Laboratories, Chicago, IL
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Jeffrey Gersch
- Department of Infectious Diseases, Abbott Laboratories, Chicago, IL
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| |
Collapse
|
|
39
|
Wang ML, Liao J, Ye F, Tao YC, Wu DB, He M, Tang H, Chen EQ. Distribution and factors associated with serum HBV pregenomic RNA levels in Chinese chronic hepatitis B patients. J Med Virol 2021; 93:3688-3696. [PMID: 32949174 DOI: 10.1002/jmv.26529] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 09/04/2020] [Accepted: 09/17/2020] [Indexed: 02/05/2023]
Abstract
Correlations between serum hepatitus B virus (HBV) pregenomic RNA (pgRNA), hepatitus B surface antigen (HBsAg), and hepatitus B core-related antigen (HBcrAg) levels, and influencing factors of serum HBV pgRNA levels in Chinese chronic hepatitis B (CHB) patients are rarely reported. This was a retrospective cohort study consisting of 204 outpatients with CHB. Serum levels of HBV pgRNA, HBsAg, and HBcrAg were quantitative measured in frozen blood samples. The linear regression and multivariate logistic regression analysis were performed to determine associated factors of serum HBV pgRNA levels. In this cohort, the median serum HBV pgRNA level was 4.12 log10 copies/ml and 33.33% (68/204) of them had serum HBV pgRNA under low limit of detection (LLD) (<500 copies/ml); and the percentage of patients with serum HBV pgRNA under LLD in hepatitis B e antigen (HBeAg)-positive patients was significantly lower than that in HBeAg-negative patients (15.75% [23/46] vs. 77.59% [45/58], p < .001). Overall, serum HBV pgRNA strongly correlated with HBcrAg (r = 0.760, p < .001), and moderately correlated with HBV DNA (r = 0.663, p < .001) and HBsAg (r = 0.670, p < .001). As compared with HBsAg and HBV DNA, only HBcrAg showed stable correlation with serum HBV pgRNA both in HBeAg-positive and HBeAg-negative patients. Serum HBV pgRNA level differed between HBeAg-positive and HBeAg-negative patients; and it had better and more stable correlation with serum HBcrAg than serum HBV DNA and HBsAg, irrespective of HBeAg status.
Collapse
Affiliation(s)
- Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Juan Liao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Feng Ye
- Beijing GenomePrecision Technology Co., Ltd., Beijing, China
| | - Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Dong-Bo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Min He
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
|
40
|
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.
Collapse
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.)
| |
Collapse
|
|
41
|
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.
Collapse
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
| |
Collapse
|
|
42
|
Pan J, Xu J, Luo H, Tan N, Kang Q, Chen H, Cheng R, Han Y, Yang Y, Xu X. Factors and virological significance of hepatitis B virus pregenomic RNA status after 5 years of antiviral therapy. Int J Infect Dis 2021; 105:418-423. [PMID: 33676002 DOI: 10.1016/j.ijid.2021.02.116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/16/2021] [Accepted: 02/24/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES To investigate the factors and virological significance of serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after long-term antiviral therapy with nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). METHODS In total, 51 treatment-naïve patients with CHB were included in the study. Clinical data were collected at baseline, during 5 years and at year 10 of NA treatment. Serum HBV pgRNA status of 51 patients was determined at year 5. RESULTS At year 5, 45% of the patients remained positive for HBV pgRNA. There were significant differences in baseline hepatitis B e antigen (HBeAg) status, HBV DNA load and hepatitis B surface antigen (HBsAg) levels between patients testing positive and negative for HBV pgRNA at year 5. Serum HBV pgRNA status and serum HBV DNA load were correlated after 5 years of NA treatment (r = 0.347, P = 0.013). Being HBV pgRNA positive at year 5 was an independent risk factor for sustainedly undetectable HBV DNA after 10 years of NA treatment (odds ratio 13.638, 95% confidence interval 1.32-140.81; P = 0.028). Furthermore, HBV pgRNA status at year 5 was associated with HBV DNA re-appearance at year 10 (P = 0.009). CONCLUSIONS HBV pgRNA status at year 5 can reveal HBV covalently closed circular DNA (cccDNA) activity, and HBV pgRNA positivity after long-term antiviral therapy may indicate higher transcriptional activity of HBV cccDNA. Long-term dynamic monitoring of HBV pgRNA should be considered.
Collapse
Affiliation(s)
- Jiali Pan
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Hao Luo
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Ning Tan
- 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
| | - Ran Cheng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Yifan Han
- 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.
| |
Collapse
|
|
43
|
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 .
Collapse
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.
| |
Collapse
|
|
44
|
Matsuda S, Maekawa S, Komiyama Y, Nakakuki N, Muraoka M, Suzuki Y, Sato M, Tatsumi A, Miura M, Amemiya F, Shindo H, Takano S, Fukasawa M, Yamaguchi T, Nakayama Y, Inoue T, Sato T, Yamashita A, Moriishi K, Enomoto N. Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy. Hepatol Res 2021; 51:39-50. [PMID: 32961003 DOI: 10.1111/hepr.13574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 09/03/2020] [Accepted: 09/05/2020] [Indexed: 12/29/2022]
Abstract
AIM Recently, serum hepatitis B virus (HBV)-RNA has been reported to be detectable even when HBV particle production is inhibited by nucleot(s)ide analogues (NAs). However, the dynamics of the HBV-RNA sequence compared with those of HBV-DNA during the emergence of antiviral resistance are yet to be elucidated. METHODS First, we quantified serum HBV-RNA in 181 infected patients, and its relationships with clinical characteristics as well as HBV markers were investigated. Next, we undertook simultaneous deep sequencing of HBV-RNA/HBV-DNA and their dynamics among four patients receiving NA therapy who were experiencing viral breakthrough. RESULTS Serum HBV-RNA was detected in 25% (31/123) of cases among patients with HBV without NAs, and the detection rate was significantly high in hepatitis B e antigen-positive cases with high viral activity. In patients with chronic hepatitis, hepatitis B core-related antigen was significantly correlated with serum HBV-RNA irrespective of NA use. In the analysis of the four patients experiencing viral breakthrough, no NA resistance mutation was detected in the serum HBV-RNA immediately before the breakthrough. However, NA-resistant sequences appeared at the rates of 0%, 3%, 14%, and 100%, and the NA-resistant HBV-RNA sequence rate was correlated with the peak HBV-DNA titer multiplied by the HBV-DNA detection duration during the breakthrough (R2 = 0.978) observed before redisappearance of HBV-DNA following the addition of new NA. CONCLUSION Serum HBV-RNA could reflect the transcriptional activity of covalently closed circular DNA and hepatitis B core-related antigen. The dynamics of HBV-RNA could help understanding of the turnover process of HBV covalently closed circular DNA in the liver.
Collapse
Affiliation(s)
- Shuya Matsuda
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yasuyuki Komiyama
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Natsuko Nakakuki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masaru Muraoka
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yuichiro Suzuki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mitsuaki Sato
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Akihisa Tatsumi
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mika Miura
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Fumitake Amemiya
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hiroko Shindo
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinichi Takano
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mitsuharu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Tatsuya Yamaguchi
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yasuhiro Nakayama
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Taisuke Inoue
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Tadashi Sato
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Atsuya Yamashita
- Department of Microbiology, University of Yamanashi, Yamanashi, Japan
| | - Kohji Moriishi
- Department of Microbiology, University of Yamanashi, Yamanashi, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| |
Collapse
|
|
45
|
Limothai U, Chuaypen N, Poovorawan K, Chotiyaputta W, Tanwandee T, Poovorawan Y, Tangkijvanich P. Reverse transcriptase droplet digital PCR vs reverse transcriptase quantitative real-time PCR for serum HBV RNA quantification. J Med Virol 2020; 92:3365-3372. [PMID: 32219874 DOI: 10.1002/jmv.25792] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/27/2020] [Accepted: 03/23/2020] [Indexed: 01/02/2023]
Abstract
Serum hepatitis B virus (HBV) RNA is a novel marker reflecting the activity of covalently closed circular DNA. However, the methodology for detecting HBV RNA has been a technical challenge. In this study, the performance of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) for quantifying HBV RNA was compared with that of reverse transcription quantitative real-time PCR (RT-qPCR) in serum samples collected from treatment-naïve patients with different phases of chronic hepatitis B (CHB). A total of 417 serum samples, including 136 HBeAg-positive CHB and 281 HBeAg-negative CHB were examined. HBV RNA levels measured by RT-ddPCR and RT-qPCR showed a high degree of linearity and quantitative correlation. The limit of detections of RT-ddPCR and RT-qPCR assays were 102 and 103 copies/mL, respectively. Our results also demonstrated that RT-ddPCR was superior to RT-qPCR in terms of its consistency for quantifying HBV RNA across all concentrations. In the HBeAg-positive group, serum HBV RNA levels based on RT-ddPCR were moderately correlated with HBV DNA (r = 0.591, P < .001) and HBsAg (r = 0.502, P < .001). Among patients with HBeAg-negative CHB, serum HBV RNA levels were moderately correlated with HBV DNA (r = 0.603, P < .001) but had weak correlation with HBsAg (r = 0.203, P = .001). In summary, RT-ddPCR could enhance the sensitivity of serum HBV RNA detection, particularly among the HBeAg-negative group with low viral loads. Thus, RT-ddPCR could serve as an optimal method for HBV RNA quantification in clinical practice.
Collapse
Affiliation(s)
- Umaporn Limothai
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Watcharasak Chotiyaputta
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
46
|
Ribeiro CRDA, Martinelli KG, de Mello VDM, Baptista BDS, Dias NST, Paiva IA, Lewis-Ximenez LL, Pinto LMDO, de Paula VS. Cytokine, Genotype, and Viral Load Profile in the Acute and Chronic Hepatitis B. Viral Immunol 2020; 33:620-627. [PMID: 33090087 DOI: 10.1089/vim.2020.0176] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Several hepatitis B virus (HBV) factors, including viral load, genotype, genome mutations, and cytokine production, have been reported to be associated with different risks of progression of liver disease. The aim of this study was to verify if there is an association among the levels of cytokines (interleukin [IL]-35, IL-6, IL-17A, interferon [IFN]-γ) in the plasma, viral load, and the different genotypes of HBV in patients with acute or chronic hepatitis B. Methods: 49 serum samples, 20 from acute and 29 from chronic cases, were submitted to a real-time and nested-polymerase chain reaction to quantify, detect, and genotype HBV DNA. The cytokines IL-35, IL-6, IL-17A, and IFN-γ were detected by an enzyme-linked immunosorbent assay (ELISA). The median viral load was 3.15 log10 IU DNA/mL and 2.90 log10 IU DNA/mL for acute and chronic patients, respectively. Genotype A, D, E, and F were identified in chronic carriers of HBV infection, while only genotype A and F were identified in individuals with acute infection. IFN-γ (p = 0.024) and IL-17A (p = 0.046) levels were significantly increased in chronic patients and IL-6 and IL-35 were higher in patients with acute infection, however, without statistical difference. IL-17A and IFN-γ can be modulating proinflammatory effects and inducing hepatocellular damage, in chronic patients, and IL-6 and IL-35 may be involved in viral elimination and protection against chronicity during the acute phase of infection. These results can contribute to understanding of the complex regulatory mechanisms of the host antiviral response related to cytokine production during acute and chronic HBV infection.
Collapse
Affiliation(s)
| | | | | | - Bruna da Silva Baptista
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Natália Spitz Toledo Dias
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Iury Amancio Paiva
- Laboratory of Viral Immunology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Lia Laura Lewis-Ximenez
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - Vanessa Salete de Paula
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| |
Collapse
|
|
47
|
Wang X, Wang Z, Chi X, Wu R, Jin Q, Xu H, Gao X, Yu L, Chen Y, Shang J, Liu L, Zhang S, Jiang Y, Zhang M, Tong Q, Zhang L, Tan Y, Ma A, Dang S, Xu B, Jin Z, Li J, Li X, Lu F, Niu J. Efficacy of a combination of HBV RNA and HBeAg in predicting HBeAg seroconversion in patients treated with entecavir for 144 weeks. Int J Infect Dis 2020; 99:171-178. [PMID: 32721532 DOI: 10.1016/j.ijid.2020.07.031] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/08/2020] [Accepted: 07/18/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND In some previous studies, serum hepatitis B virus RNA (HBV RNA) was proposed as an HBV viral marker during therapy. However, the dynamic change of HBV RNA, the correlation of HBV RNA with cccDNA, and the combination of HBV RNA with known HBV markers in predicting entecavir (ETV) treatment outcome in the same cohort are rarely reported. METHODS A total of 111 HBeAg-positive patients were enrolled in our study. The dynamic changes of serum HBV RNA and the correlation of HBV RNA with other HBV markers were investigated in the early treatment period of 144-week ETV treatment. Intrahepatic cccDNA was detected at baseline and week 48. Receiver operating characteristic analyses were used to identify HBV RNA levels associated with HBeAg seroconversion. RESULTS The serum HBV RNA levels decreased more rapidly in patients with HBeAg seroconversion than those without HBeAg seroconversion. The levels of HBV RNA decreased slower compared with the serum HBV DNA, irrespective of whether the patients achieved HBeAg seroconversion or not. Although the serum HBV RNA was positively correlated with cccDNA at baseline among all patients, no significant correlation was observed in the patients with HBeAg seroconversion at week 48 (r=0.094, P=0.588). The area under the receiver operating characteristic (AUROC) of HBV RNA and HBeAg at week 24 was 0.754 and 0.800, respectively. The AUROC of the HBV RNA and HBeAg combination had a higher value (AUROC=0.821). CONCLUSIONS The level of HBV RNA at week 24 was a powerful predictor of HBeAg seroconversion in HBeAg-positive patients after 144-week ETV treatment, while the combination of HBV RNA and HBeAg was superior to HBV RNA alone in predicting HBeAg seroconversion.
Collapse
Affiliation(s)
- Xiaomei Wang
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Zhongfeng Wang
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Xiumei Chi
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Ruihong Wu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Qinglong Jin
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Hongqin Xu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Xiuzhu Gao
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Lei Yu
- Department of Hepatology, Fourth Hospital of Harbin Medical University, Harbin, China
| | - Yuping Chen
- Department of Hepatology, Baoding Infectious Disease Hospital, Baoding, China
| | - Jia Shang
- Department of Hepatology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Longgen Liu
- Department of Hepatology, Changzhou Third People's Hospital, Changzhou, China
| | - Shuqin Zhang
- Department of Hepatology, Hepatology Hospital of Jilin Province, Changchun, China
| | - Yongfang Jiang
- Department of Hepatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Mingxiang Zhang
- Department of Infectious Disease, Shenyang Sixth People's Hospital, Shenyang, China
| | - Qiaoxia Tong
- Department of Infectious Disease, Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Lunli Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Youwen Tan
- Department of Hepatology, The Third People's Hospital of Zhenjiang, Zhenjiang, China
| | - Anlin Ma
- Department of Infectious Disease, China-Japan Friendship Hospital, Beijing, China
| | - Shuangsuo Dang
- Department of Infectious Disease, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Bin Xu
- Department of Hepatology, Beijing You'an Hoapital, Capital Medical University, Beijing, China
| | - Zhenjing Jin
- Department of Hepatology, the Second Hospital of Jilin University, Changchun, China
| | - Jia Li
- Department of Hepatology, the Second Hospital of Tianjin, Tianjing, China
| | - Xiaobo Li
- Department of Hepatology, Peking University People's Hospital, Beijing, China
| | - Fengmin Lu
- Department of Microbiology, Peking University Health Science Center, Beijing, China.
| | - Junqi Niu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
48
|
Rybicka M, Bielawski KP. Recent Advances in Understanding, Diagnosing, and Treating Hepatitis B Virus Infection. Microorganisms 2020; 8:E1416. [PMID: 32942584 PMCID: PMC7565763 DOI: 10.3390/microorganisms8091416] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects 292 million people worldwide and is associated with a broad range of clinical manifestations including cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Despite the availability of an effective vaccine HBV still causes nearly 900,000 deaths every year. Current treatment options keep HBV under control, but they do not offer a cure as they cannot completely clear HBV from infected hepatocytes. The recent development of reliable cell culture systems allowed for a better understanding of the host and viral mechanisms affecting HBV replication and persistence. Recent advances into the understanding of HBV biology, new potential diagnostic markers of hepatitis B infection, as well as novel antivirals targeting different steps in the HBV replication cycle are summarized in this review article.
Collapse
Affiliation(s)
- Magda Rybicka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland;
| | | |
Collapse
|
|
49
|
Liu Y, Xue J, Liao W, Yan H, Liang X. Serum HBV RNA Dynamic and Drug Withdrawal Predictor Value in Patients With Chronic HBV Infection on Long-term Nucleos(t)ide Analogue (NA) Therapy. J Clin Gastroenterol 2020; 54:e73-e82. [PMID: 32604147 PMCID: PMC7458089 DOI: 10.1097/mcg.0000000000001376] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/10/2020] [Indexed: 02/07/2023]
Abstract
AIMS This study aimed to investigate the dynamic pattern of serum hepatitis B virus (HBV) RNA in chronic hepatitis B (CHB) patients on long-term nucleos(t)ide analogue (NA) therapy and evaluate predictor value of end-of-treatment (EOT) serum HBV RNA status on drug-withdrawal durability. METHODS We carried out a real-life cohort study of 326 CHB patients on NA treatment between February 12, 2016 and February 21, 2018. Thirty of these patients discontinued NA treatment after enrollment, and were included in 2-year off-therapy follow-up. Serum HBV RNA levels were determined using the RNA simultaneous amplification testing method. RESULTS Both serum HBV RNA and DNA levels declined significantly in long-term antiviral progress. When the treatment duration was longer than 3 years, the undetectable rates of HBV RNA and DNA were 55.10% and 97.0%, respectively. The serum HBV RNA-negative rate was 39.5%. The cumulative 2-year off-therapy viral and clinical relapse rate was 40.56%; 95% confidence interval (95% CI), 21.51-59.61 and 31.31%; 95% CI, 11.32-51.29 in all patients, respectively. Patients with EOT hepatitis B surface antigen (HBsAg)≤1000 IU/mL plus HBV RNA negativity had a relatively lower cumulative 2-year off-therapy viral relapse rate (23.01%; 95% CI, 0.17-45.99). EOT HBsAg≤1000 IU/mL plus HBV RNA negativity showed obvious superiority for the EOT HBsAg≤1000 IU/mL single in drug withdrawal durability prediction, with better specificity (18.18% vs. 72.73%, P=0.03), and the positive predictive value and negative predictive value were 76.92% and 47.06%, respectively. CONCLUSIONS In the long-term antiviral process, both serum HBV RNA and DNA levels declined significantly. EOT serum HBV RNA negativity was not an independent drug withdrawal marker, but can complement the HBsAg titer to monitor drug withdrawal in CHB patients on long-term NA therapy.
Collapse
Affiliation(s)
| | | | - Wei Liao
- Departments of Infectious Diseases
| | - Hongli Yan
- Reproductive Medicine Center, Changhai Hospital, Second Military Medical University, Shanghai, China
| | | |
Collapse
|
|
50
|
Mak LY, Seto WK, Fung J, Yuen MF. New Biomarkers of Chronic Hepatitis B. Gut Liver 2020; 13:589-595. [PMID: 30919601 PMCID: PMC6860035 DOI: 10.5009/gnl18425] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 11/12/2018] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis B (CHB) infection leads to clinically heterogeneous disease outcomes. Different viral markers are utilized to monitor treatment effects and predict risk of complications in patients with CHB. Hepatitis B core-related antigen (HBcrAg) is a novel serum composite viral protein whose performance has been proven to be superior to that of existing viral markers. It showed good correlation with intrahepatic covalently closed-circular DNA. Its profile differs drastically in patients in different disease phases, and the level declines with antiviral therapies. HBcrAg may be helpful for predicting hepatocellular carcinoma development and hepatitis B virus (HBV) reactivation in immunosuppressed patients. Another emerging measurable serum marker, HBV RNA, exists in the form of pregenomic RNA-containing virions. Its profile differs between patients in different disease phases in a similar manner to that of HBcrAg. HBV RNA is present in serum at lower levels than HBV DNA in treatment-naïve patients by 1–2 logs. In contrast, its level is higher than HBV DNA in patients receiving nucleos(t)ide analogues (NAs). A significant decline in serum RNA was observed in patients receiving novel antiviral therapies, including core protein allosteric modulators and RIG-1/NOD2 agonists. Both HBcrAg and HBV RNA may be helpful for predicting off-therapy sustained virological control in patients who stop long-term NA treatment.
Collapse
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - James Fung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| |
Collapse
|