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Kosaka M, Fujino H, Tsuge M, Yamaoka K, Fujii Y, Uchikawa S, Ono A, Murakami E, Kawaoka T, Miki D, Hayes CN, Kashiyama S, Mokuda S, Yamazaki S, Oka S. Usefulness of serum HBV RNA levels for predicting antiviral response to entecavir treatment in patients with chronic hepatitis B. J Gastroenterol 2025; 60:469-478. [PMID: 39841247 PMCID: PMC11922970 DOI: 10.1007/s00535-025-02211-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 01/01/2025] [Indexed: 01/23/2025]
Abstract
BACKGROUND Hepatitis B virus (HBV) RNA is an important serum biomarker of hepatic covalently closed circular DNA (cccDNA) transcriptional activity; however, its clinical characteristics remain unclear. This study evaluated the clinical utility of HBV RNA levels in patients with chronic hepatitis B (CHB). METHODS We studied 87 CHB patients with serum HBV DNA levels ≥ 5.0 log IU/mL who initiated entecavir (ETV) treatment between 2000 and 2018. Serum HBV RNA levels were measured at three-time points: before ETV treatment, at 12 weeks, and at 48 weeks after starting ETV treatment. Clinical markers associated with the antiviral effects of ETV treatment were analyzed. RESULTS Serum HBV RNA levels decreased in both HBeAg-positive and -negative patients during the observation period. In HBeAg-positive patients, multivariable analysis showed that lower HBV RNA levels at 48 weeks of ETV treatment were independently associated with HBeAg seroconversion. Additionally, lower baseline HBV RNA levels significantly predicted virologic response in those patients. In contrast, among HBeAg-negative patients, lower HBV core-related antigen (HBcrAg) levels and the FIB-4 index were independently associated with virologic response. In HBeAg-positive patients, those with higher baseline HBV RNA levels showed a more significant reduction in hepatitis B surface antigen levels. CONCLUSION Serum HBV RNA levels predicted HBeAg seroconversion and early HBV DNA reduction in HBeAg-positive patients, while HBcrAg was significantly associated with virologic response in HBeAg-negative patients. These findings highlight the different predictive roles of HBV RNA and HBcrAg based on HBeAg status, which may provide individualized treatment strategies.
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Affiliation(s)
- Masanari Kosaka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Masataka Tsuge
- Liver Center, Hiroshima University Hospital, Hiroshima, Japan.
| | - Kenji Yamaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Seiya Kashiyama
- Section of Clinical Laboratory, Department of Clinical Practice and Support, Hiroshima University Hospital, Hiroshima, Japan
| | - Sho Mokuda
- Division of Laboratory Medicine, Hiroshima University Hospital, Hiroshima, Japan
| | - Shinichi Yamazaki
- Department of Clinical Practice and Support, Hiroshima University Hospital, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Paturel A, Casuscelli di Tocco F, Bousquet D, Plissonnier ML, Grand X, Tak H, Berby F, Scholtès C, Testoni B, Zoulim F, Levrero M. A molecular standard for circulating HBV RNA detection and quantification assays in patients with chronic hepatitis B. JHEP Rep 2024; 6:101124. [PMID: 39328324 PMCID: PMC11424956 DOI: 10.1016/j.jhepr.2024.101124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 05/16/2024] [Accepted: 05/23/2024] [Indexed: 09/28/2024] Open
Abstract
Background & Aims Circulating HBV RNAs have been proposed as a biomarker that reflects the transcriptional activity of covalently closed circular DNA (cccDNA) and may help to evaluate HBV treatment activity. Different research assays have been proposed and, although two PCR-based research use only investigational assays have been developed, the lack of standardized protocols represents an important limitation. Here we have designed and generated a stable clonal cell line producing an RNA-based standard for the calibration of PCR-based circulating HBV RNA assays. Methods HBV RNA-producing Huh7-derived stable cell lines were generated by transfecting pTriEX plasmids containing 1.1 unit length HBV DNA genomes carrying mutations in the catalytic site (YMAA mutation) and the TP domain (Y63F) of the polymerase, and the ε-loop of the pregenomic (pg)RNA (mutation A1G). Results The clonal cell line (Huh7-3D29), carrying a double YMAA and Y63F mutation, displayed, and maintained over several passages in culture, a high RNA secretion phenotype with negligible residual secreted HBV DNA. Density gradient centrifugation showed that most of the secreted HBV RNA from Huh7-3D29 cells was detected in naked capsid and virion-like particles and only a minority in small extracellular vescicles. Nanopore sequencing of 5'RACE products shows that the majority of the Huh7-3D29-secreted HBV RNAs start at the 5' end of pgRNA and pgRNA-derived spliced RNAs. Finally, Huh7-3D29 cells showed a high and up-scalable secreted RNA yield allowing 1,300 standard curves in 9 days from one flask. Conclusion We generated a clonal cell line that produces high quantities of HBV RNAs with very low quantities of contaminating HBV DNAs, representing a stable source of RNA standard for HBV RNA assay calibration. Impact and implications Several investigational assays and two research use only assays have been developed to detect and quantify circulating HBV RNAs, an emerging biomarker of covalently closed circular DNA transcriptional activity and target engagement by new HBV treatments. The lack of a unique molecular standard for circulating HBV RNA quantification represents an important limitation. Here we describe the generation of a stable clonal cell line producing and secreting an RNA-based standard containing all the HBV RNA species found in HBV patients' sera (e.g. pgRNA, HBx transcripts). This new RNA standard can be used to calibrate all PCR-based assays for circulating HBV RNA quantification to evaluate, in a non-invasive manner, the size of the transcriptionally active cccDNA pool and the activity of novel strategies aimed at curing HBV infection.
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Affiliation(s)
- Alexia Paturel
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
| | - Francesca Casuscelli di Tocco
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
| | - Delphine Bousquet
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
| | - Marie-Laure Plissonnier
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
| | - Xavier Grand
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
| | - Hyosun Tak
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
| | - Françoise Berby
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Department of Hepatology, Hospices Civils de Lyon, France
| | - Caroline Scholtès
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
- Laboratoire de Virologie, Institut des Agents Infectieux, Hospices Civils de Lyon, Lyon, France
| | - Barbara Testoni
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
| | - Fabien Zoulim
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
- Department of Hepatology, Hospices Civils de Lyon, France
| | - Massimo Levrero
- IHU Lyon, Lyon Hepatology Institute, Lyon, France
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
- University of Lyon, University Claude Bernard Lyon 1, 69008 Lyon, France
- Department of Hepatology, Hospices Civils de Lyon, France
- Department of Internal Medicine, SCIAC and the IIT Center for Life Nanoscience, Sapienza University, Rome, Italy
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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.
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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
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Yuen MF, Chuang WL, Peng CY, Jeng WJ, Su WW, Chang TT, Chen CY, Hsu YC, De La Rosa G, Ahmad A, Luo E, Conery AL. Phase 1 trial of the safety, pharmacokinetics, and antiviral activity of EDP-514 in untreated viremic chronic hepatitis B patients. Clin Mol Hepatol 2024; 30:375-387. [PMID: 38528825 PMCID: PMC11261219 DOI: 10.3350/cmh.2023.0535] [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: 12/16/2023] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND/AIMS Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics, and antiviral activity of three doses of EDP-514 in treatment-naive viremic patients with HBeAgpositive or -negative chronic HBV infection. METHODS Patients with HBsAg detectable at screening and at least 6 months previously were eligible. HBeAg-positive and -negative patients had a serum/plasma HBV DNA level ≥20,000 and ≥2,000 IU/mL, respectively. Twenty-five patients were randomized to EDP-514 200 (n=6), 400 (n=6) or 800 mg (n=7) or placebo (n=6) once daily for 28 days. RESULTS A dose-related increase in EDP-514 exposure (AUClast and Cmax) was observed across doses. At Day 28, mean reductions in HBV DNA were -2.9, -3.3, -3.5 and -0.2 log10 IU/mL with EDP-514 200 mg, 400 mg, 800 mg, and placebo groups, respectively. The corresponding mean change from baseline for HBV RNA levels was -2.9, -2.4, -2.0, and -0.02 log10 U/mL. No virologic failures were observed. No clinically meaningful changes from baseline were observed for HBsAg, HBeAg or HBcrAg. Nine patients reported treatment emergent adverse events of mild or moderate severity with no discontinuations, serious AEs or deaths. CONCLUSION In treatment-naïve viremic patients, oral EDP-514 was generally safe and well-tolerated, displayed PK profile supportive of once-daily dosing, and markedly reduced HBV DNA and HBV RNA.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Wen Su
- Department of Gastroenterology and Hepatology, Changhua Christian Hospital, Changhua, Taiwan
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Yi Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Yao-Chun Hsu
- Center for Liver Diseases and School of Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Guy De La Rosa
- Formerly Enanta Pharmaceuticals, Inc., Watertown, MA, USA
- Currently at Curevo Vaccine, Bothell, Washington, USA
| | - Alaa Ahmad
- Enanta Pharmaceuticals, Inc., Watertown, MA, USA
| | - Ed Luo
- Enanta Pharmaceuticals, Inc., Watertown, MA, USA
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Suzuki T, Matsuura K, Inoue T, Sasada K, Ogawa S, Watanabe T, Kawamura H, Fujiwara K, Kataoka H, Tanaka Y. Clinical performance of Circulating HBV RNA and iTACT-HBcrAg Assays in HBeAg-negative and HBsAg-cleared Chronic Hepatitis B Patients. J Med Virol 2024; 96:e29816. [PMID: 39015036 DOI: 10.1002/jmv.29816] [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: 02/15/2024] [Revised: 05/29/2024] [Accepted: 07/09/2024] [Indexed: 07/18/2024]
Abstract
Hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) have been reported to reflect the transcriptional activity of covalently closed circular HBV DNA. We retrospectively investigated the proportions of quantifiable serum HBV RNA and immunoassay for total antigen including complex via pretreatment-hepatitis B core-related antigen (iTACT-HBcrAg) in chronic hepatitis B patients negative for hepatitis B e antigen (HBeAg) and/or with hepatitis B surface antigen (HBsAg) seroclearance. This study included 246 HBeAg-negative HBV-infected patients, who comprised 13 with liver cirrhosis (LC, the LC group), 118 chronic hepatitis (CH, the CH group), and 115 inactive carriers (IC, the IC group), and 44 patients with HBsAg seroclearance. iTACT-HBcrAg and HBV RNA levels were determined using stored serum samples. Higher proportions of the patients had quantifiable iTACT-HBcrAg than HBV RNA in all groups of HBeAg-negative patients (iTACT-HBcrAg: 84.6%, 90.7%, 35.7%, HBV RNA: 23.1%, 26.3%, 14.8%, for the LC, CH, IC groups). With HBsAg seroclearance (HBsAg <0.05 IU/mL), the proportions of quantifiable samples for HBV RNA were also lower than iTACT-HBcrAg (0% for HBV RNA). Thus, iTACT-HBcrAg was more often detectable than circulating HBV RNA in this study population. Further long-term prospective evaluation of iTACT-HBcrAg is desirable for its utilization in clinical practice.
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Affiliation(s)
- Takanori Suzuki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Keiko Sasada
- Department of Central Inspection, Kumamoto University, Kumamoto, Japan
| | - Shintaro Ogawa
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
| | - Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
| | - Hayato Kawamura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kei Fujiwara
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Central Inspection, Kumamoto University, Kumamoto, Japan
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
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Liu J, Yu Y, Zhao H, Guo L, Yang W, Yan Y, Lv J. Latest insights into the epidemiology, characteristics, and therapeutic strategies of chronic hepatitis B patients in indeterminate phase. Eur J Med Res 2024; 29:343. [PMID: 38902822 PMCID: PMC11191257 DOI: 10.1186/s40001-024-01942-0] [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: 05/18/2023] [Accepted: 06/17/2024] [Indexed: 06/22/2024] Open
Abstract
As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.
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Affiliation(s)
- Junye Liu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Heping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Wenjuan Yang
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yuzhu Yan
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China.
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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.
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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
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8
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Wu L, Yang Z, Zheng M. Biogenesis of serum HBV RNA and clinical phenomena of serum HBV RNA in chronic hepatitis B patients before and after receiving nucleos(t)ide analogues therapy. J Viral Hepat 2024; 31:255-265. [PMID: 38332479 DOI: 10.1111/jvh.13926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/20/2023] [Accepted: 01/17/2024] [Indexed: 02/10/2024]
Abstract
There are estimated 300 million people afflicted with chronic hepatitis B (CHB) worldwide. The risk of liver cirrhosis and hepatocellular carcinoma (HCC) increases considerably with chronic hepatitis B infection. While current therapeutics are effective in controlling hepatitis B virus (HBV) infection and disease progression, a cure for HBV infection remains unattainable due to an intranuclear replicative intermediate known as covalently closed circular DNA (cccDNA). It has recently been shown that serum HBV RNA is a non-invasive biomarker that reflects cccDNA transcriptional activity. This review provides a comprehensive overview and the latest updates on the molecular characteristics and clinical significance of serum HBV RNA, such as species of serum HBV RNA, forms of serum HBV RNA carriers and predictive value for relapses in CHB patients after nucleos(t)ide analogues (NAs) discontinuation and development of liver fibrosis and HCC. Furthermore, we summarize standardized assays for testing serum HBV RNA, the dynamic changes of serum HBV RNA levels in treatment-naïve CHB patients and those under NAs therapy, as well as the host and viral influencing factors of serum HBV RNA levels. Finally, we discuss the future perspectives in studies of serum HBV RNA.
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Affiliation(s)
- Liandong Wu
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhenggang Yang
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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9
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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.
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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
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Yi S, Ren G, Zhu Y, Cong Q. Correlation analysis of hepatic steatosis and hepatitis B virus: a cross-sectional study. Virol J 2024; 21:22. [PMID: 38243304 PMCID: PMC10799397 DOI: 10.1186/s12985-023-02277-8] [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] [Accepted: 12/24/2023] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND The co-occurrence of chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) has drawn considerable attention due to its impact on disease outcomes. This study aimed to investigate the association between hepatic steatosis and hepatitis B virus (HBV) and analyzed the influence of hepatic steatosis on hepatitis B virology in patients with CHB. METHODS In this cross-sectional study, 272 patients infected with HBV who were treatment-naïve or had ceased antiviral treatment for > 6 months were categorized into the CHB group (n = 128) and CHB + MAFLD group (n = 144). Furthermore, based on whether HBV DNA was higher than 2000 IU/mL, patients were categorized into the high-level HBV DNA group (n = 129) and the low-level HBV DNA group (n = 143). The impact of hepatic steatosis on hepatitis B virology was analyzed within the CHB cohort. Multivariate logistic regression analysis was employed to identify independent factors influencing pre-genomic RNA (pgRNA) levels below the lower limit of detection (LLD) in patients with CHB. RESULTS Among the 272 patients, compared with CHB group, HBV DNA levels (4.11 vs. 3.62 log10 IU/mL, P = 0.045), hepatitis B surface antigen (HBsAg) levels (3.52 vs. 3.20 log10 IU/mL, P = 0.008) and the hepatitis B e antigen (HBeAg) positive rate (33.6% vs. 22.2%, P = 0.036) were significantly decreased in the CHB + MAFLD group; In 143 low-level HBV DNA patients, the CHB + MAFLD group exhibited decreased levels of pgRNA and HBsAg compared to the CHB group. However, in 129 high-level HBV DNA patients, a more significant decrease was observed in pgRNA (3.85 vs 3.35 log10 copies/mL, P = 0.044) and HBsAg (3.85 vs 3.59 log10 IU/mL, P = 0.033); Spearman correlation analysis revealed a negative correlation between hepatic steatosis and pgRNA (r = - 0.529, P < 0.001), HBV DNA (r = - 0.456, P < 0.001), HBsAg (r = - 0.465, P < 0.001) and HBeAg (r = - 0.339, P < 0.001) levels; Multivariate logistic regression analysis identified HBV DNA (odds ratio [OR] = 0.283, P < 0.001), HBsAg (OR = 0.300, P < 0.001), and controlled attenuation parameter (CAP) values (OR = 1.013, P = 0.038) as independent factors influencing pgRNA levels below the LLD in patients with CHB. CONCLUSIONS This study establishes a negative correlation between hepatic steatosis and hepatitis B virology, demonstrating decreased HBV expression in patients with CHB + MAFLD.
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Affiliation(s)
- Sitong Yi
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Guanghui Ren
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Ying Zhu
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Qingwei Cong
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
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Xu Z, Xu Y, Wu Z, Wang S, Zhang M, Jiang Y, Gong G. HBV-miR-3 is closely related to HBV replication and strongly predictive of HBeAg seroconversion in PegIFN-α treated patients. Sci Rep 2024; 14:1502. [PMID: 38233602 PMCID: PMC10794194 DOI: 10.1038/s41598-024-52060-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 01/12/2024] [Indexed: 01/19/2024] Open
Abstract
HBV-miR-3 is encoded by HBV and takes part in pathogenesis of HBV-related liver disease. Whether HBV-miR-3 has a relationship with HBV replication and is predictive of PegIFN-α treatment response is still unknown. HBV-miR-3 quantification is based on qRT-PCR. The relationship of HBV-miR-3 and HBV replication, and predictive value of HBV-miR-3 were evaluated in a cohort of 650 HBeAg positive patients from a multi-center, randomized phase III clinical trial for the study of PegIFN-a2b. HBV-miR-3 is significantly positively related to HBVDNA, HBVpgRNA, HBeAg and HBsAg at baseline and at all the different time points during PegIFN-α treatment. Both univariate regression analyses and multivariate logistic regression analyses showed HBV-miR-3 is a predictor of HBeAg seroconversion in the patients treated with PegIFN-α at weeks of 0, 12, and 24. 70.0% of patients with HBV-miR-3 < 3log at week 12 achieved HBeAg seroconversion, otherwise, with HBV-miR-3 > 6log at week 12 no patient obtained HBeAg seroconversion. Conbination of HBV-miR-3 and HBeAg is more strongly predictive of HBeAg seroconversion (83.64%) at week 12. HBV-miR-3 is new biomarker for HBV replication and positively correlated to HBV replication. HBV-miR-3 is also an early predictor of HBeAg seroconversion in the patients treated with PegIFN-α.
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Affiliation(s)
- Zhenyu Xu
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Yun Xu
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Zhenyu Wu
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Sujuan Wang
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Min Zhang
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
| | - Yongfang Jiang
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
- FuRong Laboratory, Changsha, Hunan, China.
- Clinical Medical Research Center for Viral Hepatitis in Hunan Province, Hunan, China.
| | - Guozhong Gong
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
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Xu Q, Ding H, Bai T, Huang R, Wang J, Zhang J, Luan H, Wang J, Yang Y, Chen Y. Serum HBV RNA levels among untreated adults with chronic hepatitis B in distinct immune phases and liver histopathology statuses. J Mol Histol 2023; 54:739-749. [PMID: 37843699 DOI: 10.1007/s10735-023-10162-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 09/21/2023] [Indexed: 10/17/2023]
Abstract
HBV RNA is a novel serum biomarker that reflects intrahepatic HBV covalently closed circular DNA (cccDNA) transcription activity. Serum HBV RNA levels among treatment-naïve adults during the natural history of chronic hepatitis B (CHB) and distinct liver histopathology statuses remain elusive. In our study, we include a total of 411 treatment-naïve CHB patients, among which 43 patients were HBeAg-positive immune-tolerant [IT(e+)], 84 patients were HBeAg-positive immune active [IA(e+)], 65 patients in HBeAg-negative immune active phases [IA(e-)], 149 patients were HBeAg-negative inactive phases [IC(e-)], and 70 patients were in Gray Zone (GZ). HBV RNA was measured in this cohort and its potential correlation with traditional serological markers and liver histopathology were analyzed. Our data showed that HBV RNA was strongly correlated with HBV DNA, HBeAg, HBsAg and ALT. Further subgroup analysis revealed a close correlation between HBV RNA and HBV DNA in patients in the IA (e+) and IA (e-) phases, but neither in IT(e+) nor IC(e-) phase. HBV RNA levels were consistently increased with the advanced degrees of hepatic inflammation, but not hepatic fibrosis. Of note, HBV RNA from HBeAg-positive patients negatively correlated with liver fibrosis, whereas HBV RNA from HBeAg-negative patients was weakly associated with liver inflammation. To sum up, serum HBV RNA shows a distinct profile among CHB patients in different immune statuses and hepatic histopathology stages/grades. Simultaneous testing of HBV RNA and traditional indicators might provide a comprehensive clinical assessment of CHB patients.
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Affiliation(s)
- Qin Xu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
- Department of Laboratory Medicine, Jurong Hospital Affiliated to Jiangsu University, Jurong, China
| | - Hai Ding
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Tao Bai
- Department of Infectious Diseases, Wuhan Jinyintan Hospital, Hubei Clinical Research Center for Infectious Diseases, Tongji Medical College of Huazhong University of Science and Technology, Hubei, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jun Zhang
- Department of Laboratory Medicine, Jurong Hospital Affiliated to Jiangsu University, Jurong, China
| | - Hewei Luan
- Department of Laboratory Medicine, Jurong Hospital Affiliated to Jiangsu University, Jurong, China
| | - Jun Wang
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
| | - Yue Yang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China.
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Song G, Yang R, Jin Q, Liu J, Rao H, Feng B, Xie Y. HBV pregenome RNA as a predictor of spontanous HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients. BMC Gastroenterol 2023; 23:381. [PMID: 37946120 PMCID: PMC10634007 DOI: 10.1186/s12876-023-03023-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Previous studies have indicated that HBV pregenome RNA (HBV pgRNA) could predict HBeAg seroconversion among the chronic hapatitis B (CHB) patients treated with pegylated interferon (Peg-IFN) or nucleos(t)ide analogues (NAs). However, the data about the prediction of HBV pgRNA for spontaneous HBeAg seroconversion is limited. METHODS One hundred thirteen CHB patients with HBeAg-positive in the immune active phase were followed up for 76 weeks without antiviral treatment. Based on the laboratory test results of liver function, HBeAg, anti-HBe, and HBV DNA at week 76, patients were assigned to two groups: spontaneous HBeAg seroconversion (group A, n = 18) and non-spontaneous HBeAg seroconversion group. Among the latter group, 36 patients were selected as controls (group B, n = 36). RESULTS At week 12, between group A and group B, there was a significant difference in the level of HBV pgRNA (group A 6.35 ± 1.24 log10 copies/ml and group B 7.52 ± 0.79 log10 copies/ml, P = 0.001), and the difference enlarged at week 28. The receiver operating characteristic curves (AUROCs) of the HBV pgRNA level and the ∆HBV pgRNA at week 28 were 0.912 (P = 0.001, 95% CI: 0.830-0.994), and 0.934 (P = 0.001, 95% CI: 0.872-0.996), respectively. The optimal cutoffs of HBV pgRNA and the reduction from baseline (∆HBV pgRNA) at week 28 for spontaneous HBeAg seroconversion prediction were 5.63 log10 copies/ml and 1.85 log10 copies/ml, respectively. The positive predictive value and negative predictive value of HBV pgRNA and ∆HBV pgRNA at week 28 were 86.7% and 87.2%, 87.5% and 89.5%, respectively. And the combination of the HBV pgRNA level and the HBV pgRNA decreased could provide better prediction. CONCLUSIONS HBV pgRNA is a sound predictor for spontaneous HBeAg seroconversion among the CHB patients in immune active phase. Dynamic monitoring of HBV pgRNA is helpful for clinical treatment decision.
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Affiliation(s)
- Guangjun Song
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Ruifeng Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Qian Jin
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Juan Liu
- Research Center for Technologies in Nucleic Acid-Based Diagnostics, Changsha, Hunan, China
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Bo Feng
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Yandi Xie
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, No.11 Xizhimen South Street, Beijing, 100044, China.
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Hu X, Zhao L, Ou M, Chen Y, Wei H, Xia Y, Xu H, Li M, Wang J. Evaluation of reverse transcription-polymerase chain reaction and simultaneous amplification and testing for quantitative detection of serum hepatitis B virus RNA. Heliyon 2023; 9:e18557. [PMID: 37560627 PMCID: PMC10407120 DOI: 10.1016/j.heliyon.2023.e18557] [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: 06/05/2023] [Revised: 07/14/2023] [Accepted: 07/20/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is one of the common infectious diseases in the world. HBV covalently closed circular DNA (cccDNA) is the initial template of HBV replication, which can exist in human hepatocytes for a long time and is difficult to be completely removed. It has been shown that HBV RNA can directly respond to the levels and transcriptional activity of cccDNA in hepatocytes and can be used as a surrogate marker of cccDNA transcriptional activity. At present, the detection techniques used for quantitative HBV RNA mainly include reverse transcription quantitative polymerase chain reaction (RT-qPCR) and simultaneous amplification and testing (SAT). METHODS In this study, we verified the performance of the SAT method for detecting HBV RNA and the clinical effectiveness of SAT and RT-qPCR, and compared the correlation and consistency of the two detection methods for HBV RNA detection. RESULTS The results showed that the limit of detection for HBV RNA by SAT method was 50 copies/mL, with a linear range of 1 × 102-1 × 108 copies/mL. There was no difference in HBV RNA levels detected by the two methods. The correlation and consistency of the results were good, with the coefficient of determination of 0.7787 in HBeAg positive group and 0.8235 in HBeAg negative group. CONCLUSIONS Therefore, this study confirmed that the SAT method and RT-qPCR for detecting HBV RNA have good agreement, which are both reliable methods to detect HBV RNA and can replace each other.
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Affiliation(s)
- Xiaohan Hu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
| | - Liwei Zhao
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
| | - Mingrong Ou
- Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, China
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
| | - Hongxia Wei
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
| | - Yanyan Xia
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
| | - Hongpan Xu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
| | - Miao Li
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
| | - Jun Wang
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, China
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15
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Thompson AJ, Jackson K, Bonanzinga S, Hall SA, Hume S, Burns GS, Sundararajan V, Ratnam D, Levy MT, Lubel J, Nicoll AJ, Strasser SI, Sievert W, Desmond PV, Ngu MC, Sinclair M, Meredith C, Matthews G, Revill PA, Littlejohn M, Bowden DS, Canchola JA, Torres J, Siew P, Lau J, La Brot B, Kuchta A, Visvanathan K. Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants. Hepatol Commun 2023; 7:e0188. [PMID: 37459199 PMCID: PMC10351945 DOI: 10.1097/hc9.0000000000000188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/11/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND AND AIMS HBV RNA in peripheral blood reflects HBV cccDNA transcriptional activity and may predict clinical outcomes. The prospective Melbourne HBV-STOP trial studied nucleot(s)ide analog discontinuation in HBeAg-negative non-cirrhotic participants with long-term virological suppression. Ninety-six weeks after stopping treatment, the proportion of participants with virological relapse (HBV DNA > 2000 IU/mL), biochemical relapse (ALT > 2 × ULN and HBV DNA > 2000 IU/mL), or hepatitis flare (ALT > 5 × ULN and HBV DNA > 2000 IU/mL) was 89%, 58%, and 38%, respectively. We evaluated the ability of serum HBV RNA levels to predict these outcomes. APPROACH RESULTS HBV RNA levels were measured using the Roche cobas 6800/8800 HBV RNA Investigational Assay. Sixty-five participants had baseline and longitudinal off-treatment specimens available for RNA testing. HBV RNA was detectable at baseline in 25% of participants and was associated with a higher risk of biochemical relapse (81% vs. 51%, p value 0.04) and hepatitis flare (63% vs. 31%, p value 0.04). Participants who had undetectable serum HBV RNA as well as HBsAg ≤ 100 IU/mL at baseline were less likely to experience virological relapse (4 of 9, 44%) than participants with detectable HBV RNA and HBsAg level > 100 IU/mL (15/15, 100%; p value 0.0009). Off-treatment levels of HBV RNA were correlated with HBV DNA and were associated with the risk of hepatitis flare. CONCLUSIONS Serum HBV RNA may be a useful biomarker for guiding clinical decision-making before stopping nucleot(s)ide analog therapy. Baseline HBV RNA and HBsAg levels are associated with the risk of clinical relapse, hepatitis flare, and disease remission off-treatment.
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Affiliation(s)
- Alexander J. Thompson
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sara Bonanzinga
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sam A.L. Hall
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Simon Hume
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Gareth S. Burns
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Vijaya Sundararajan
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
- Department of Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Dilip Ratnam
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
- Monash University, Melbourne, Victoria, Australia
| | - Miriam T. Levy
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, Australia
| | - John Lubel
- Department of Gastroenterology, Alfred Health, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, The Alfred Centre, Melbourne, Victoria, Australia
| | - Amanda J. Nicoll
- Gastroenterology Department of Eastern Health, Melbourne, Victoria, Australia
| | - Simone I. Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
- University of Sydney, Sydney, Australia
| | - William Sievert
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
- Monash University, Melbourne, Victoria, Australia
| | - Paul V. Desmond
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
| | - Meng C. Ngu
- Department of Gastroenterology, Concord Repatriation General Hospital, Sydney, Australia
| | - Marie Sinclair
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Victoria, Australia
| | | | - Gail Matthews
- Department of Infectious Disease, St Vincent’s Hospital Sydney, Sydney, Australia
| | - Peter A. Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - D. Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | | | - Jason Torres
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Philip Siew
- Roche Diagnostics, Pty Ltd, North Ryde, Australia
| | - Jasmin Lau
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | | | - Alison Kuchta
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Kumar Visvanathan
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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17
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Wang L, Zhu Q, Zhang JD, Zhang Y, Ni X, Xiang K, Jiang J, Li B, Yu Y, Hu H, Zhang M, Wu W, Zeng J, Yan Z, Dai J, Sun K, Zhang X, Chen D, Feng S, Sach-Peltason L, Young JAT, Gao L. Discovery of a first-in-class orally available HBV cccDNA inhibitor. J Hepatol 2023; 78:742-753. [PMID: 36587899 DOI: 10.1016/j.jhep.2022.12.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/25/2022] [Accepted: 12/13/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS The persistence of covalently closed circular DNA (cccDNA) in infected hepatocytes is the major barrier preventing viral eradication with existing therapies in patients with chronic hepatitis B. Therapeutic agents that can eliminate cccDNA are urgently needed to achieve viral eradication and thus HBV cure. METHODS A phenotypic assay with HBV-infected primary human hepatocytes (PHHs) was employed to screen for novel cccDNA inhibitors. A HBVcircle mouse model and a uPA-SCID (urokinase-type plasminogen activator-severe combined immunodeficiency) humanized liver mouse model were used to evaluate the anti-HBV efficacy of the discovered cccDNA inhibitors. RESULTS Potent and dose-dependent reductions in extracellular HBV DNA, HBsAg, and HBeAg levels were achieved upon the initiation of ccc_R08 treatment two days after the HBV infection of PHHs. More importantly, the level of cccDNA was specifically reduced by ccc_R08, while it did not obviously affect mitochondrial DNA. Additionally, ccc_R08 showed no significant cytotoxicity in PHHs or in multiple proliferating cell lines. The twice daily oral administration of ccc_R08 to HBVcircle model mice, which contained surrogate cccDNA molecules, significantly decreased the serum levels of HBV DNA and antigens, and these effects were sustained during the off-treatment follow-up period. Moreover, at the end of follow-up, the levels of surrogate cccDNA molecules in the livers of ccc_R08-treated HBVcircle mice were reduced to below the lower limit of quantification. CONCLUSIONS We have discovered a small-molecule cccDNA inhibitor that reduces HBV cccDNA levels. cccDNA inhibitors potentially represent a new approach to completely cure patients chronically infected with HBV. IMPACT AND IMPLICATIONS Covalently closed circular DNA (cccDNA) persistence in HBV-infected hepatocytes is the root cause of chronic hepatitis B. We discovered a novel small-molecule cccDNA inhibitor that can specifically reduce cccDNA levels in HBV-infected hepatocytes. This type of molecule could offer a new approach to completely cure patients chronically infected with HBV.
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Affiliation(s)
- Li Wang
- Infectious Disease Discovery
| | | | | | | | | | | | | | | | | | - Hui Hu
- Infectious Disease Discovery
| | | | | | | | | | | | | | - Xin Zhang
- Preclinical Chemistry Manufacturing and Controls
| | | | | | - Lisa Sach-Peltason
- Data & Analytics, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel
| | | | - Lu Gao
- Infectious Disease Discovery.
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18
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Bian D, Zhao J, Liao H, Wang Y, Ren Y, Jiang Y, Liu S, Chen X, Hu Z, Duan Z, Lu F, Zheng S. Serum HBV RNA is associated with liver fibrosis regression in HBeAg-positive chronic hepatitis B patients treated with nucleos(t)ide analogues. J Viral Hepat 2023; 30:303-309. [PMID: 36533536 DOI: 10.1111/jvh.13790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/28/2022] [Accepted: 12/03/2022] [Indexed: 01/12/2023]
Abstract
Noninvasive methods for assessing hepatic fibrosis are clinically necessary. This study aims to explore HBV markers correlated with liver fibrosis and capable of diagnosing significant fibrosis and predicting fibrosis regression. Seventy-four HBeAg-positive chronic hepatitis B (CHB) patients were enrolled and started on entecavir or adefovir therapy. Serum HBV RNA, HBV DNA, HBsAg and hepatitis B core-related antigen (HBcrAg) levels were measured at baseline and during treatment. Liver fibrosis was assessed at baseline and month 60 by liver biopsy. Fibrosis regression was defined as Ishak fibrosis score decreased ≥1-point. At baseline, HBsAg, HBcrAg and HBV RNA levels had a stronger correlation with Ishak fibrosis score (r = -.441, p = .002; r = -.469, p = .001; r = -.398, p = .001) than APRI and FIB-4 (r = .321 p = .006; r = .371, p = .001). HBsAg >4 log10 IU/ml plus HBcrAg >7 log10 IU/ml or HBsAg >4 log10 IU/ml plus HBV RNA >5 log10 copies/ml exhibited the same excellent diagnostic ability for significant fibrosis with the AUROC of 0.857. After 60 months of antiviral treatment, 66.7% of patients who suffered significant fibrosis at baseline achieved fibrosis regression, and an HBV RNA decline from baseline to month 6 greater than 0.63 log10 copies/ml could predict the fibrosis regression at month 60. In conclusion, serum HBsAg, HBcrAg and HBV RNA are potential markers for predicting significant liver fibrosis. HBV RNA measurement would be particularly useful for monitoring hepatic fibrosis changes in HBeAg-positive CHB patients.
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Affiliation(s)
- Dandan Bian
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.,Department of Infectious Diseases, Electric Power Teaching Hospital, Capital Medical University, Beijing, China
| | - Jing Zhao
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Hao Liao
- Department of Microbiology and Infectious Disease Center, Peking University Health Science Center, Beijing, China.,Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Yang Wang
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yan Ren
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yingying Jiang
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Shuang Liu
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongjie Hu
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, Peking University Health Science Center, Beijing, China
| | - Sujun Zheng
- Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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19
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Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis. Int J Mol Sci 2023; 24:ijms24054964. [PMID: 36902395 PMCID: PMC10003785 DOI: 10.3390/ijms24054964] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx-nuclear-, cytoplasmic- or mitochondria-associated-this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
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20
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Zhang S, Zhang X, Jin H, Dou Y, Li L, Yuan X, Dong C, Hou M, Nan YM, Shang J. Adverse Effect of Nonalcoholic Fatty Liver Disease on the Therapeutic Response in Patients with Chronic Hepatitis B. J Clin Transl Hepatol 2023; 11:67-75. [PMID: 36406311 PMCID: PMC9647108 DOI: 10.14218/jcth.2022.00066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/15/2022] [Accepted: 04/18/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS The impact of nonalcoholic fatty liver disease (NAFLD) on the treatment outcome of chronic hepatitis B (CHB) is undefined and deserves an in-depth investigation. METHODS Histologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD, and followed up at six monthly intervals. Therapeutic response related data were recorded and compared at multiple time points. Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response (CVR). RESULTS We enrolled 267 patients (CHB: 164; CHB with NAFLD: 103) with comparable follow-up durations. They were also comparable in baseline HBV DNA levels and HBeAg positivity. Patients with concomitant NAFLD showed less significant decline in HBV DNA, qHBsAg, pgRNA, and liver enzyme levels over time; moreover, their cumulative incidences of CVR were significantly lower and that of low-level viremia (LLV) were significantly higher at 6, 12, 18, 24 months. First CVR of CHB was delayed with the presence NAFLD (11.0 vs. 7.0 months, p<0.001) and further prolonged with higher grade of liver steatosis (Grade 2-3 vs. 1: 13.0 vs. 9.0 months). On multivariate analysis, HBeAg positivity (HR: 0.650, p=0.036), grade of steatosis (G2 [HR: 0.447, p=0.004]; G3 [HR: 0.085, p=0.002]) and HBV DNA (log10 IU/mL) (HR: 0.687, p<0.001) were significantly associated with delayed CVR, whereas grade of necroinflammation (HR: 1. 758, p<0.001) accelerated the CVR. CONCLUSIONS In CHB patients receiving initial antiviral therapy, NAFLD was associated with higher levels of HBV DNA, pgRNA, and liver enzymes, and higher incidence of LLV and delayed CVR.
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Affiliation(s)
- Siyu Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
| | - Xiaoxiao Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
| | - Huiming Jin
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Yao Dou
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
| | - Lu Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
| | - Xiwei Yuan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
| | - Chen Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
| | - Mengmeng Hou
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
| | - Yue-min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang, Hebei, China
- Correspondence to: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei 050051, China. ORCID: https://orcid.org/0000-0003-4192-099X. Tel: +86-311-66781226, Fax: +86-311-66781289, E-mail: ; Jia Shang, Department of Infectious Diseases, Henan Provincial People’s Hospital, 7 Weiwu Road, Zhengzhou, Henan 450003, China. ORCID: https://orcid.org/0000-0001-9197-8773. Tel/Fax: +86-371-65580879, E-mail:
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
- Correspondence to: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei 050051, China. ORCID: https://orcid.org/0000-0003-4192-099X. Tel: +86-311-66781226, Fax: +86-311-66781289, E-mail: ; Jia Shang, Department of Infectious Diseases, Henan Provincial People’s Hospital, 7 Weiwu Road, Zhengzhou, Henan 450003, China. ORCID: https://orcid.org/0000-0001-9197-8773. Tel/Fax: +86-371-65580879, E-mail:
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21
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End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2023; 56:31-39. [PMID: 35941076 DOI: 10.1016/j.jmii.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 05/01/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND/PURPOSE(S) Since ALT flares after therapy withdrawal are associated with adverse outcomes, risk stratification is of major importance. We aimed to study whether off-treatment flares are related with virological outcomes, and if serum levels of novel biomarkers at end-of-treatment (EOT) can predict flares. METHODS Chronic hepatitis B patients who participated in three global randomised trials of peginterferon-based therapy were studied (99-01, PARC, ARES). HBV RNA, HBsAg and HBcrAg were quantified at EOT. Associations between EOT biomarker levels and flares were assessed as continuous data and after categorisation. Flares were defined as ALT ≥5xULN during six months after therapy cessation. RESULTS We included 344 patients; 230 HBeAg-positive and 114 HBeAg-negative. Patients were predominantly Caucasian (77.0%) and had genotype A/B/C/D in 23.3/7.3/13.4/52.3%. Flares were observed in 122 patients (35.5%). Flares were associated with lower rates of sustained response (3.5% vs 26.8% among patients with and without a flare; p < 0.001). Higher HBsAg (OR 1.586, 95%CI 1.231-2.043), HBV RNA (OR 1.695, 95%CI 1.371-2.094) and HBcrAg (OR 1.518, 95%CI 1.324-1.740) levels were associated with higher risk of flares (p < 0.001). Combinations of biomarkers further improved risk stratification, especially HBsAg + HBV RNA. Findings were consistent in multivariate analysis adjusted for potential predictors including HBeAg-status and EOT-response (HBV DNA <200 IU/mL). CONCLUSION Off-treatment ALT flares were not associated with favourable virological outcomes. Higher EOT serum HBsAg, HBcrAg and HBV RNA were associated with a higher risk of flares after therapy withdrawal. These findings can be used to guide decision-making regarding therapy discontinuation and off-treatment follow-up. TRIAL REGISTRATION ClinicalTrials.gov: NCT00114361, NCT00146705, NCT00877760.
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22
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Janssen HLA, Hou J, Asselah T, Chan HLY, Zoulim F, Tanaka Y, Janczewska E, Nahass RG, Bourgeois S, Buti M, Lampertico P, Lenz O, Verbinnen T, Vandenbossche J, Talloen W, Kalmeijer R, Beumont M, Biermer M, Shukla U. Randomised phase 2 study (JADE) of the HBV capsid assembly modulator JNJ-56136379 with or without a nucleos(t)ide analogue in patients with chronic hepatitis B infection. Gut 2023:gutjnl-2022-328041. [PMID: 36697207 DOI: 10.1136/gutjnl-2022-328041] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 12/22/2022] [Indexed: 01/27/2023]
Abstract
OBJECTIVE We present the final analysis results of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956). DESIGN 232 patients with chronic hepatitis B (CHB) not currently treated at study start (NCT) at study start or virologically suppressed were randomised to receive 75 mg (part 1) or 250 mg (part 2) JNJ-56136379, a hepatitis B virus (HBV)-capsid assembly modulator, one time per day or placebo with nucleos(t)ide analogue (NA) (tenofovir disoproxil fumarate/entecavir) or JNJ-56136379 alone (NCT-only) for ≥24 and ≤48 weeks. RESULTS In patients who are NCT hepatitis B e-antigen (HBeAg) positive, JNJ-56136379 75 mg+NA and 250 mg+NA showed limited mean (SE) hepatitis B surface antigen (HBsAg) declines (0.14 (0.10) and 0.41 (0.15), respectively) from baseline at Week 24 (primary endpoint; placebo+NA: 0.25 (0.11) log10 international unit (IU)/mL).In patients who are NCT HBeAg positive, mean (SE) HBV DNA declines at Week 24 were 5.53 (0.23) and 5.88 (0.34) for JNJ-56136379 75 mg+NA and 250 mg+NA, respectively, versus 5.21 (0.42) log10 IU/mL for placebo+NA. In NCT patients, mean (SE) HBV RNA declines were 2.96 (0.23) and 3.15 (0.33) versus 1.33 (0.32) log10 copies/mL, respectively.Patients with HBsAg declines had HBeAg and hepatitis B core-related antigen (HBcrAg) declines and some early on-treatment isolated alanine aminotransferase flares. Viral breakthrough occurred with JNJ-56136379 monotherapy with the emerging resistant-variant T33N, but not with JNJ-56136379+NA. JNJ-56136379 treatment beyond Week 24 had a generally small additional effect on viral markers.No study treatment-related serious adverse events or clinically significant changes in laboratory parameters occurred. CONCLUSIONS In patients with non-cirrhotic CHB, JNJ-56136379+NA showed pronounced reductions in HBV DNA and HBV RNA, limited HBsAg or HBeAg declines in patients who are NCT HBeAg positive, and was well tolerated, but no clear benefit with regards to efficacy of JNJ-56136379 over NA was observed.
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Affiliation(s)
- Harry L A Janssen
- Toronto General Hospital, Toronto, Ontario, Canada.,Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands
| | - Jinlin Hou
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tarik Asselah
- Université de Paris Cité, INSERM UMR1149, Hôpital Beaujon AP-HP, Clichy, France
| | - Henry L Y Chan
- The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Fabien Zoulim
- Hospices Civils de Lyon and Lyon University & INSERM U1052-Cancer Research Institute of Lyon, Lyon, France
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
| | - Ewa Janczewska
- Faculty of Health Sciences in Bytom, Medical University of Silesia, Katowice, Poland
| | | | | | - Maria Buti
- Hospital Universitario Vall d'Hebrón and CIBERHED del Instituto Carlos III, Barcelona, Spain
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, CRC 'A. M. and A. Migliavacca' Center for Liver Disease, University of Milan, Milan, Italy
| | | | | | | | | | | | - Maria Beumont
- Janssen Pharmaceuticals R&D, Titusville, New Jersey, USA
| | | | - Umesh Shukla
- Janssen Pharmaceuticals R&D, Titusville, New Jersey, USA
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23
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Affiliation(s)
- Geoffrey Dusheiko
- From University College London (G.D.), Kings College Hospital London (G.D., K.A.), Kings College London (K.A.), and the Institute of Immunity and Transplantation, University College London (M.K.M.) - all in London
| | - Kosh Agarwal
- From University College London (G.D.), Kings College Hospital London (G.D., K.A.), Kings College London (K.A.), and the Institute of Immunity and Transplantation, University College London (M.K.M.) - all in London
| | - Mala K Maini
- From University College London (G.D.), Kings College Hospital London (G.D., K.A.), Kings College London (K.A.), and the Institute of Immunity and Transplantation, University College London (M.K.M.) - all in London
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24
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Chung RT, King WC, Ghany MG, Lisker-Melman M, Hinerman AS, Khalili M, Sulkowski M, Jain MK, Choi EYK, Nalesnik MA, Bhan AK, Cloherty G, Wong DK, Sterling RK. A Prospective Cohort Study of Novel Markers of Hepatitis B Virus Replication in Human Immunodeficiency Virus Coinfection. Clin Gastroenterol Hepatol 2023; 21:125-135.e8. [PMID: 34973459 PMCID: PMC9240105 DOI: 10.1016/j.cgh.2021.12.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The contribution of the novel biomarkers, hepatitis B virus (HBV) RNA and HBV core-related antigen (HBcrAg), to characterization of HBV-human immunodeficiency virus (HIV) coinfection is unclear. We evaluated the longitudinal dynamics of HBV RNA and HBcrAg and their association with classical HBV serum biomarkers and liver histology and viral staining. METHODS HBV-HIV co-infected adults from 8 North American centers entered a National Institutes of Health-funded prospective cohort study. Demographic, clinical, serological, and virological data were collected at entry and every 24 to 48 weeks for up to 192 weeks. Participants with HBV RNA and HBcrAg measured ≥2 times (N = 95) were evaluated; 56 had paired liver biopsies obtained at study entry and end of follow-up. RESULTS Participants had a median age of 50 years; 97% were on combination anti-viral therapy. In hepatitis B e antigen (HBeAg)+ participants, there were significant declines in HBV RNA and HBcrAg over 192 weeks that tracked with declines in HBeAg, hepatitis B surface antigen, HBV DNA, and hepatitis B core antigen (HBcAg) hepatocyte staining grade (all P < .05). In HBeAg- participants, there were not significant declines in HBV RNA (P = .49) and HBcrAg (P = .63), despite modest reductions in hepatitis B surface antigen (P < .01) and HBV DNA (P = .03). HBV serum biomarkers were not significantly related to change in hepatic activity index, Ishak fibrosis score, or hepatocyte HBcAg loss (all P > .05). CONCLUSIONS In HBV-HIV coinfected adults on suppressive dually active antiviral therapy, the use of novel HBV markers reveals continued improvement in suppression of HBV transcription and translation over time. The lack of further improvement in HBV serum biomarkers among HBeAg- patients suggests limits to the benefit of combination anti-viral therapy and provide rationale for additional agents with distinct mechanisms of action.
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Affiliation(s)
- Raymond T Chung
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Wendy C King
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Mauricio Lisker-Melman
- Washington University School of Medicine and John Cochran VA Medical Center, St. Louis, Missouri
| | - Amanda S Hinerman
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Mandana Khalili
- University of California San Francisco, San Francisco, California
| | | | - Mamta K Jain
- University of Texas Southwestern Medical Center and Parkland Health & Hospital System, Dallas, Texas
| | | | | | - Atul K Bhan
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - David K Wong
- University Health Network, Toronto, Ontario, Canada
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25
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Chang S, Hedskog C, Parhy B, Martin R, Mo H, Maiorova E, Zoulim F. Sequence characterization of extracellular HBV RNA in patient plasma. J Viral Hepat 2023; 30:29-38. [PMID: 36208116 DOI: 10.1111/jvh.13760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 09/27/2022] [Accepted: 10/02/2022] [Indexed: 12/09/2022]
Abstract
Antiviral nucleos(t)ide analogue therapies inhibit HBV replication and suppress the HBV DNA levels in patients with chronic HBV infection. Since HBV RNAs are expressed from cccDNA or HBV integrated sequences, independently of viral genome replication, levels of HBV RNAs in plasma may remain high following treatment with nucleos(t)ide analogue. Thus, HBV RNAs have been proposed to be used as a viral biomarker for treatment outcome and disease progression. Recent investigations of plasma HBV RNAs described the presence of full length as well as subgenomic forms of RNA. To support the usage of plasma HBV RNAs as a viral biomarker, further understanding of HBV RNA composition in clinical samples is needed. Here, sequence of extracellular HBV RNAs was characterized in plasma samples of patients with chronic HBV infection using two independent RNA amplification methods that do not use HBV-specific primers for amplification: total RNA (NuGEN RNAseq) and mRNA (TruSeq RNAseq). Sequencing coverage was obtained across the full length of HBV genome for both methods, confirming the presence of full-length HBV RNA in plasma. The sequence of HBV RNA was nearly identical to plasma HBV DNA sequence in each sample with only 0-14 (median 4) mismatches over 3 kb. Thus, sequence of HBV RNA plasma reflects the intrahepatic viral reservoir and can be used for monitoring of sequence variants such as resistance in clinical trials. Additionally, RNA splice forms, different polyA tails start positions and presence of HBV-human chimeric transcript were identified.
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Affiliation(s)
- Silvia Chang
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | - Ross Martin
- Gilead Sciences, Inc., Foster City, California, USA
| | - Hongmei Mo
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- Hospices Civils de Lyon (HCL), Lyon, France
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26
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Mak LY, Wong D, Kuchta A, Hilfiker M, Hamilton A, Chow N, Mao X, Seto WK, Yuen MF. Hepatitis B virus pre-genomic RNA and hepatitis B core-related antigen reductions at week 4 predict favourable hepatitis B surface antigen response upon long-term nucleos(t)ide analogue in chronic hepatitis B. Clin Mol Hepatol 2023; 29:146-162. [PMID: 35989092 PMCID: PMC9845664 DOI: 10.3350/cmh.2022.0172] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/12/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND/AIMS We investigated the dynamics of serum HBV pre-genomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) in patients receiving nucleos(t)ide analogues (NAs) and their predictability for favourable suppression of serum hepatitis B surface antigen (HBsAg). METHODS Serum viral biomarkers were measured at baseline, weeks 4, 12, 24, 36, and 48 of treatment. Patients were followed up thereafter and serum HBsAg level was measured at end of follow-up (EOFU). Favourable HBsAg response (FHR) was defined as ≤100 IU/mL or HBsAg seroclearance upon EOFU. RESULTS Twenty-eight hepatitis B e antigen (HBeAg)-positive and 36 HBeAg-negative patients (median, 38.2 years old; 71.9% male) were recruited with median follow-up duration of 17.1 years (interquartile range, 12.8-18.2). For the entire cohort, 22/64 (34.4%) achieved FHR. For HBeAg-positive patients, serum HBV pgRNA decline at week 4 was significantly greater for patients with FHR compared to non-FHR (5.49 vs. 4.32 log copies/mL, respectively; P=0.016). The area under the receiver-operating-characteristic curve (AUROC) for week 4 HBV pgRNA reduction to predict FHR in HBeAg-positive patients was 0.825 (95% confidence interval [CI], 0.661-0.989). For HBeAg-negative patients, instead of increase in serum HBcrAg in non-FHR patients, FHR patients had median reduction in HBcrAg at week 4 (increment of 1.75 vs. reduction of 2.98 log U/mL; P=0.023). The AUROC for week 4 change of HBcrAg to predict FHR in HBeAg-negative patients was 0.789 (95% CI, 0.596-0.982). CONCLUSION Early on-treatment changes of serum HBV pgRNA and HBcrAg at 4 weeks predict HBsAg seroclearance or ≤100 IU/mL in NA-treated CHB patients upon long-term FU.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Danny Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | | | | | | | - Ning Chow
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - XianHua Mao
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong,Corresponding author : Man-Fung Yuen Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pokfulam Road, Hong Kong Tel: +852-22553984, Fax: +852-28162863, E-mail:
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong,Corresponding author : Man-Fung Yuen Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pokfulam Road, Hong Kong Tel: +852-22553984, Fax: +852-28162863, E-mail:
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27
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Yu G, Chen R, Zheng S, Liu Y, Zou J, Gu Z, Jiang B, Gao Q, Dai L, Peng J, Wang J, Lu F. A standardized assay for the quantitative detection of serum HBV RNA in chronic hepatitis B patients. Emerg Microbes Infect 2022; 11:775-785. [PMID: 35220917 PMCID: PMC8920369 DOI: 10.1080/22221751.2022.2045874] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is a surrogate marker for reflecting the transcriptional activity of covalently closed circular DNA. However, there is still no standardized assay for the quantitative detection of serum HBV RNA in chronic hepatitis B patients. In this study, quantitative polymerase chain reactions for detecting the preC/C-RNA (preC/C region HBV pgRNA), SF-RNA (splicing variants-free pgRNA) and XR-RNA (X region remained pgRNA) regions were set up. The dynamic changes of serum pgRNA splicing variants and 3′ terminal truncations were analysed in three retrospective cohorts: 35 treatment-naive chronic HBV-infected patients (cohort A), 52 chronic hepatitis B (CHB) patients who received nucleos(t)ide analogs (NAs) therapy for 48 weeks (cohort B) and eight CHB patients who are under long-term NAs treatment (cohort C). The accuracy and sensitivity of HBV RNA detection were assessed by the National Standard of HBV RNA. We confirmed that high proportions of pgRNA splicing variants and 3′ terminal truncations were present and significantly affect the quantitative detection of serum HBV RNA in both treatment-naive and NAs-treated CHB patients. To achieve the higher accuracy and sensitivity on the detection of HBV RNA level, the primers and probes should be designed at the 5′ terminal region of HBV genome and outside the mainly spliced sequence of pgRNA, especially for CHB patients under long-term NAs treatment. This study would help to better understand the significance of the pgRNA splicing variants and 3′ terminal truncations, and further guide the clinical detection of serum HBV RNA.
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Affiliation(s)
- Guangxin Yu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
| | - Ran Chen
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.,Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Sujun Zheng
- Hepatology Center Department, Beijing YouAn Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yanna Liu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
| | - Jun Zou
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
| | - Zhiqiang Gu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
| | - Bei Jiang
- Tianjin Institute of Hepatology, Tianjin Second People's Hospital, Tianjin, People's Republic of China
| | - Qi Gao
- Beijing Hotgen Biotech Co., Ltd., Beijing, People's Republic of China
| | - Lizhong Dai
- Sansure Biotechnology Corporation, Changsha, People's Republic of China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jie Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
| | - Fengmin Lu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China
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28
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Feld JJ, Lawitz E, Nguyen T, Lalezari J, Hassanein T, Martin P, Han SH, Dieterich D, Giard JM, De La Rosa G, Ahmad A, Luo E, Conery AL, Adda N. EDP-514 in healthy subjects and nucleos(t)ide reverse transcriptase inhibitor-suppressed patients with chronic hepatitis B. Antivir Ther 2022; 27:13596535221127848. [DOI: 10.1177/13596535221127848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB. Methods In Part 1, 82 subjects received placebo or EDP-514 in fed or fasted state as single ascending doses of 50–800 mg and multiple ascending doses of 200–800 mg for 14 days. In Part 2, 24 HBV DNA-suppressed, nucleos(t)ide (NUC)-treated (i.e., NUC-suppressed) CHB patients received EDP-514 200–800 mg or placebo for 28 days. Results EDP-514 was well tolerated in healthy subjects and CHB patients with most adverse events of mild intensity. In Part 1, EDP-514 exposure increased in an approximately dose proportional manner up to 600 mg after single doses and up to 400 mg after 14-day dosing. In Part 2, EDP-514 exposure increased linearly with dose on Day 1 and Day 28, with some accumulation for Day 28 and median trough concentrations (Ctrough) approximately 20-fold above the protein-adjusted 50% effective concentration (EC50) for the dose range. Mean change in HBV RNA from baseline to Day 28 was −2.03, −1.67, −1.87, and −0.58 log U/mL in the 200 mg, 400 mg, 800 mg, and placebo CHB groups, respectively. Conclusions EDP-514 was well tolerated, had a PK profile supporting once daily dosing, and reduced HBV RNA levels in NUC-suppressed CHB patients.
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Affiliation(s)
- Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Eric Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Tuan Nguyen
- Gastroenterology and Hepatology, San Diego, CA, USA
| | | | | | - Paul Martin
- Gastroenterology, University of Miami, Coral Gables, FL, USA
| | - Steven-Huy Han
- University of California, Los Angeles, Los Angeles, CA, USA
| | - Douglas Dieterich
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Alaa Ahmad
- Enanta Pharmaceuticals, Inc., Watertown, MA, USA
| | - Ed Luo
- Enanta Pharmaceuticals, Inc., Watertown, MA, USA
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29
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Kramvis A, Chang KM, Dandri M, Farci P, Glebe D, Hu J, Janssen HLA, Lau DTY, Penicaud C, Pollicino T, Testoni B, Van Bömmel F, Andrisani O, Beumont-Mauviel M, Block TM, Chan HLY, Cloherty GA, Delaney WE, Geretti AM, Gehring A, Jackson K, Lenz O, Maini MK, Miller V, Protzer U, Yang JC, Yuen MF, Zoulim F, Revill PA. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol 2022; 19:727-745. [PMID: 35859026 PMCID: PMC9298709 DOI: 10.1038/s41575-022-00649-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/16/2022] [Indexed: 12/13/2022]
Abstract
Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.
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Affiliation(s)
- Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Hamburg, Germany
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dieter Glebe
- National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Giessen, Germany
| | - Jianming Hu
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Philadelphia, PA, USA
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Daryl T Y Lau
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Capucine Penicaud
- Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Teresa Pollicino
- Laboratory of Molecular Hepatology, Department of Human Pathology, University Hospital "G. Martino" of Messina, Messina, Italy
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Florian Van Bömmel
- Department of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Ourania Andrisani
- Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
| | | | | | - Henry L Y Chan
- Chinese University of Hong Kong, Shatin, Hong Kong
- Union Hospital, Shatin, Hong Kong
| | | | | | - Anna Maria Geretti
- Roche Pharma Research & Early Development, Basel, Switzerland
- Department of Infectious Diseases, Fondazione PTV, Faculty of Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Adam Gehring
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | | | - Mala K Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | | | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Fabien Zoulim
- INSERM Unit 1052 - Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
- Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
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30
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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.
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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
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31
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Papatheodoridi M, Papachristou E, Moschidis Z, Hadziyannis E, Rigopoulou E, Zachou K, Villeret F, Magiorkinis G, Lyberopoulou A, Gatselis N, Vlachogiannakos I, Manolakopoulos S, Dalekos GN, Zoulim F, Paraskevis D, Papatheodoridis GV. Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy. J Viral Hepat 2022; 29:948-957. [PMID: 35789515 DOI: 10.1111/jvh.13729] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/13/2022] [Accepted: 06/20/2022] [Indexed: 12/30/2022]
Abstract
HBV RNA is considered as a promising predictor in patients who discontinue nucleos(t)ide analogues (NAs). We determined HBV RNA levels in non-cirrhotic HBeAg-negative patients who discontinued NAs and assessed their predictability for 12-month outcomes. Fifty-seven patients of DARING-B study were included. HBV RNA levels were determined in stored monthly serum samples drawn at 0-3 months after end of therapy (EOT). Other markers previously determined in the same cohort including hepatitis B core-related antigen (HBcrAg) were also assessed. HBV RNA at EOT was detectable in 7% of patients, who developed virological/clinical relapse and required retreatment at month 2; in patients with undetectable EOT HBV RNA, 12-month cumulative rates of virological relapse, clinical relapse and retreatment were 68%, 28% and 21%, respectively (p ≤ 0.008). HBV RNA at month-1 after EOT was detectable in 19% of patients being associated with higher probability only of virological relapse (p = 0.001). HBV RNA levels correlated significantly to HBV DNA, HBcrAg, ALT and interferon-induced protein-10, but not HBsAg levels. Combined EOT HBV RNA and HBcrAg detection and/or HBsAg >1000 IU/ml was associated only with higher probability of retreatment having higher sensitivity and lower specificity than HBV RNA alone. In conclusion, serum HBV RNA is detectable in a minority of non-cirrhotic HBeAg-negative patients under effective long-term NAs therapy offering low sensitivity but 100% specificity for early retreatment due to severe clinical relapses after NA discontinuation. The combinations of EOT HBV RNA with HBcrAg and/or high HBsAg levels increase sensitivity but decrease specificity for prediction of retreatment after NAs withdrawal.
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Affiliation(s)
- Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.,Institute of Liver and Digestive Health, University College of London, London, UK
| | - Eleni Papachristou
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Zissis Moschidis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Hippokratio", Athens, Greece
| | - Eirini Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | | | - Gkikas Magiorkinis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Ioannis Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Spilios Manolakopoulos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Fabien Zoulim
- INSERM U1052 - Cancer Research Center of Lyon (CRCL), Lyon, France
| | - Dimitrios Paraskevis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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32
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The Prognostic Value of Serum HBV-RNA during Hepatitis B Virus Infection is Related to Acute-on-Chronic Liver Failure. Can J Gastroenterol Hepatol 2022; 2022:8422242. [PMID: 36148157 PMCID: PMC9489391 DOI: 10.1155/2022/8422242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/11/2022] [Accepted: 08/31/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Serum HBV-RNA levels can predict antiviral response in chronic hepatitis B (CHB) patients; however, its role in HBV-related ACLF (HBV-ACLF) remains unclear. Here, we determined its implications for HBV-ACLF. METHODS Baseline serum HBV-RNA levels were retrospectively detected in HBV-ACLF and CHB patients. The association of serum HBV-RNA level with clinical outcomes was evaluated by performing multiple logistic regression. A nomogram was developed to formulate an algorithm incorporating serum HBV-RNA for predicting the survival of HBV-ACLF patients. After being discharged from the hospital, the HBV-ACLF patients were followed up for 36 weeks. RESULTS In this study, 82 HBV-ACLF patients and 33 CHB patients were included. Serum HBV-RNA levels were significantly higher in CHB patients than in HBV-ACLF patients (4.15 ± 2.63 log10 copies/mL VS 5.37 ± 2.02 log10 copies/mL) (P < 0.05). Among the HBV-ACLF cases, patients with poor outcomes had lower serum HBV-RNA levels, but the difference was not significant. The area under the receiver operating characteristic curve of the serum HBV-RNA inclusive model was 0.745, superior to 0.66 from MELD scores (P < 0.05). During the follow-up for four weeks, the serum HBV-RNA levels, especially in the survival group, were found to be lower than the baseline levels. CONCLUSIONS Serum HBV-RNA levels were associated with disease severity and might predict the long-term clinical outcome of HBV-ACLF patients.
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33
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Zhu M, Wang H, Lou T, Xiong P, Zhang J, Li L, Sun Y, Wu Y. Current treatment of chronic hepatitis B: Clinical aspects and future directions. Front Microbiol 2022; 13:975584. [PMID: 36160238 PMCID: PMC9493448 DOI: 10.3389/fmicb.2022.975584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients’ health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.
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Affiliation(s)
- Minmin Zhu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Hui Wang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Tao Lou
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Pian Xiong
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Jiebing Zhang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Lele Li
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Yuchao Sun
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
| | - Yingping Wu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
- *Correspondence: Yingping Wu,
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34
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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.
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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
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35
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Surrogate Markers for Hepatitis B Virus Covalently Closed Circular DNA. Semin Liver Dis 2022; 42:327-340. [PMID: 35445388 DOI: 10.1055/a-1830-2741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Chronic infection with the hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of the persistence of the viral template for the viral transcripts, covalently closed circular deoxyribonucleic acid (cccDNA). Detecting changes in cccDNA transcriptional activity is key to understanding fundamental virology, determining the efficacy of new therapies, and deciding the optimal clinical management of HBV patients. In this review, we summarize surrogate circulating biomarkers that have been used to infer cccDNA levels and activity in people with chronic hepatitis B. Moreover, we outline the current shortcomings of the current biomarkers and highlight the clinical importance in improving them and expanding their use.
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36
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Characteristics of HBV Novel Serum Markers across Distinct Phases in Treatment-Naïve Chronic HBV-Infected Patients. DISEASE MARKERS 2022; 2022:4133283. [PMID: 35872701 PMCID: PMC9303147 DOI: 10.1155/2022/4133283] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/16/2022] [Indexed: 11/18/2022]
Abstract
Background and aims. To investigate the clinical implications of serum HBV RNA, serum hepatitis B core-related antigen (HBcrAg), and quantitative anti-HBc in treatment-naïve patients with chronic HBV infection. Methods. A total of 111 patients in total from different disease phases were recruited, including 21 in immune-tolerant (IT) phase, 49 in immune-clearance (IC) phases, 29 in immune-control or low replicative (LR) phase, and 12 in reactivation phases. Serum HBV RNA, anti-HBc, HBcrAg, and intrahepatic covalently closed circular DNA (cccDNA) were quantified and each of these indicator’s correlation with liver inflammation was analyzed. Results. HBeAg-positive individuals had significant higher serum levels of HBV RNA and HBcrAg than those who were HBeAg negative, similar to that of serum HBV DNA. Comparatively, HBV RNA (
=0.79,
) and HBcrAg (
=0.78,
) had almost same higher overall correlation with the cccDNA, as that of HBV DNA (
=0.81,
). Serum anti-HBc level (
= -0.52,
) is negatively correlated with cccDNA level at IT phase rather than the other three phases. When set the cutoff value at 4.00 log10 IU/mL, serum anti-HBc showed potential to indicate liver inflammation, with AUC as 0.79 and the specificities as 78.85% for HBeAg positive, and with AUC as 0.72 and the specificities as 62.16% for HBeAg-negative patients, respectively. Conclusions. In treatment-naïve patients, levels of serological markers HBV RNA and HBcrAg could mirror intrahepatic cccDNA level, but were not superior to HBV DNA level. Serum anti-HBc level had certain potential to be used as a predicting marker for liver inflammation.
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37
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Virological Treatment Monitoring for Chronic Hepatitis B. Viruses 2022; 14:v14071376. [PMID: 35891357 PMCID: PMC9319170 DOI: 10.3390/v14071376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/07/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open
Abstract
More than 250 million people worldwide are currently infected with hepatitis B, despite the effectiveness of vaccination and other preventive measures. In terms of treatment, new therapeutic approaches are rapidly developing, promising to achieve the elimination of infected cells and the complete cure of infection. The on-treatment monitoring of these innovative antiviral treatments will require the implementation of new virological tools. Therefore, new biomarkers are being evaluated besides the traditional virological and serological assays in order to obtain information on different steps of the viral replication cycle and to monitor response to therapy more accurately. The purpose of this work is to describe both standard and innovative tools for chronic hepatitis B treatment monitoring, and to analyse their potential and feasibility.
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Wang FD, Zhou J, Li LQ, Wang ML, Tao YC, Wang YH, Zhang DM, Chen EQ. Serum Pregenomic RNA Combined With Hepatitis B Core-Related Antigen Helps Predict the Risk of Virological Relapse After Discontinuation of Nucleos(t)ide Analogs in Patients With Chronic Hepatitis B. Front Microbiol 2022; 13:901233. [PMID: 35814664 PMCID: PMC9257105 DOI: 10.3389/fmicb.2022.901233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/30/2022] [Indexed: 12/01/2022] Open
Abstract
Background and Aim Cessation of nucleos(t)ide analogs (NAs) therapy in patients with chronic hepatitis B (CHB) is uncommon. Although criteria for discontinuation appear in some guidelines, the indicators for assessing discontinuation of NAs are limited, whether NAs can be safely ceased remains a difficult clinical issue. Our study aimed to investigate the role of serum pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) at the end of treatment (EOT) in guiding the safe discontinuation of NAs in CHB patients. Methods This is a retrospective study, clinical data of all CHB patients who discontinued NAs treatment at West China Hospital between June 2020 and January 2021 were collected, including EOT pgRNA, HBcrAg, hepatitis B surface antigen (HBsAg), etc. All patients should meet the Asian-Pacific guideline for discontinuation. Observing virological relapse (VR) rates during 1 year of NAs discontinuation and analyzing the relationship between EOT pgRNA, HBcrAg, and VR. Results A total of 64 patients were enrolled in this study and 33 (51.5%) patients experienced VR in 1 year. EOT pgRNA positivity (OR = 14.59, p = 0.026) and EOT higher HBcrAg levels (OR = 14.14, p = 0.001) were independent risk factors for VR. The area under the receiver-operating characteristic (AUROC) value of EOT HBcrAg for VR was 0.817 (p < 0.001), optimal cut-off value was 3.3 log10 U/mL. Patients with EOT pgRNA positivity and EOT HBcrAg >3.3 log10 U/mL were more likely to experience VR after discontinuation of NAs (88.9 vs. 45.5%, p = 0.027). Conclusion According to current guidelines, a higher VR rate occurs after cessation of NAs. EOT pgRNA positivity and higher HBcrAg level carries a higher risk of VR. Combining these novel markers can better help us assess whether patients can safely cease NAs treatment.
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Affiliation(s)
- Fa-Da Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Department of Infectious Disease, Chengdu Third People’s Hospital, Chengdu, China
| | - Jing Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lan-Qing Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ya-Cao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Dong-Mei Zhang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: En-Qiang Chen,
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Yan HZ, Huang ZH, Guo XG, Peng TT, Yang LL, Liu CW, Ou-Yang S. A Study on Pregenomic RNA and Factors Related to Hepatitis B Virus Infection Based on Real World. Front Public Health 2022; 10:856103. [PMID: 35784246 PMCID: PMC9240609 DOI: 10.3389/fpubh.2022.856103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveThis article aims to study the influencing factors of pgRNA and its change magnitude based on the real world.MethodsA total of 421 patients who were tested for pgRNA were selected. According to the baseline data, the subjects were divided into negative and positive groups. The Chi-square test and logistic regression were used to analyze the influencing factors of pgRNA status. Based on the follow-up data, the rank-sum test and linear regression were used to analyze the influencing factors of pgRNA change magnitude.ResultsA total of 153 (36.3%) of the 421 subjects were pgRNA-negative and 268 (63.7%) were pgRNA-positive. Logistic regression analysis showed that positive HBV DNA (OR: 40.51), positive HBeAg (OR: 66.24), tenofovir treatment (OR: 23.47), and entecavir treatment (OR: 14.90) were the independent risk factors for positive pgRNA. Univariate linear regression showed that the pgRNA change magnitude of patients treated with entecavir was higher than that of patients treated with tenofovir. Multivariate linear regression showed that age was an independent factor influencing pgRNA change magnitude.ConclusionsThe pgRNA of patients who were young, female, HBV DNA-positive, high-HBsAg, HBeAg-positive is higher than the detection line. HBV DNA and HBeAg are the independent risk factors of positive pgRNA. Different antiviral regimens and disease stages have significantly different effects on pgRNA status. There was a significant correlation between pgRNA and FIB-4, suggesting that pgRNA is related to liver fibrosis. The decrease in pgRNA was greater in young patients than in non-young patients. The decrease in pgRNA was greater in patients treated with tenofovir than in patients treated with entecavir.
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Affiliation(s)
- Hao-Zhen Yan
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- School of Public Health, Department of Preventive Medicine, Guangzhou Medical University, Guangzhou, China
| | - Zhi-Hao Huang
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- School of Public Health, Department of Preventive Medicine, Guangzhou Medical University, Guangzhou, China
| | - Xu-Guang Guo
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ting-Ting Peng
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Li-Li Yang
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chong-Wen Liu
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shi Ou-Yang
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Shi Ou-Yang
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Boettler T, Gill US, Allweiss L, Pollicino T, Tavis JE, Zoulim F. Assessing immunological and virological responses in the liver: Implications for the cure of chronic hepatitis B virus infection. JHEP Rep 2022; 4:100480. [PMID: 35493765 PMCID: PMC9039841 DOI: 10.1016/j.jhepr.2022.100480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 11/11/2022] Open
Abstract
Cure from chronic HBV infection is rare with current therapies. Basic research has helped to fundamentally improve our knowledge of the viral life cycle and virus-host interactions, and provided the basis for several novel drug classes that are currently being developed or are being tested in clinical trials. While these novel compounds targeting the viral life cycle or antiviral immune responses hold great promise, we are still lacking a comprehensive understanding of the immunological and virological processes that occur at the site of infection, the liver. At the International Liver Congress 2021 (ILC 2021), a research think tank on chronic HBV infection focused on mechanisms within the liver that facilitate persistent infection and looked at the research questions that need to be addressed to fill knowledge gaps and identify novel therapeutic strategies. Herein, we summarise the discussion by the think tank and identify the key basic research questions that must be addressed in order to develop more effective strategies for the functional cure of HBV infection.
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Affiliation(s)
- 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
- Blizard Institute, Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Lena Allweiss
- I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems sites, Germany
| | - Teresa Pollicino
- Department of Human Pathology, University Hospital "G. Martino" of Messina, Messina, Italy
| | - John E. Tavis
- Department of Molecular Microbiology and Immunology and Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis MO USA
| | - Fabien Zoulim
- INSERM Unit 1052 – Cancer Research Center of Lyon, Department of Hepatology Hospices Civils de Lyon, Lyon University, France
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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.
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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
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Liu R, Li M, Lu Y, Zhang L, Shen G, Wu S, Chang M, Hao H, Hu L, Gao Y, Xu M, Xie Y. Hepatitis B core-related antigen serum levels are associated with significant liver fibrosis in treatment-naive chronic HBV infection patients. J Viral Hepat 2022; 29:438-446. [PMID: 35357759 DOI: 10.1111/jvh.13674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 01/30/2022] [Accepted: 03/11/2022] [Indexed: 12/09/2022]
Abstract
Several hepatitis B virus (HBV) serum markers have been identified as risk factors for liver fibrosis in patients with chronic HBV infection, and several noninvasive fibrosis tests based on serum indexes are now used to identify the severity of liver fibrosis. We aimed to identify the relationship between hepatitis B core-related antigen (HBcrAg) serum levels and liver fibrosis in treatment-naive chronic HBV infection patients. A total of 246 treatment-naive chronic HBV infection patients were enrolled in this study. All of the patients underwent liver biopsies at baseline. Using the METAVIR fibrosis stages, there were 15, 140, 50, 26 and 15 patients in the F0, F1, F2, F3 and F4 stages (METAVIR scoring system), respectively. The biochemical, serological and virological parameters were measured using standard laboratory procedures. The HBcrAg serum levels of the patients were examined via ELISA. HBcrAg serum levels of F2, F3 and F4 stage patients were significantly higher than those of nonsignificant liver fibrosis patients (METAVIR F0-F1), but there were no significant differences among F2, F3 and F4 stage patients. Serum HBcrAg (OR, 2.18; 95% confidence interval [CI], 1.51-3.16), albumin (ALB) (OR, 0.60; 95% CI, 0.41-0.87), prothrombin activity (PTA) (OR, 0.58; 95% CI, 0.40-0.83) and platelet (PLT) counts (OR, 0.38; 95% CI, 0.25-0.57) were associated with significant liver fibrosis (METAVIR F2-F4). The serum HBcrAg value enabled the correct identification of patients with significant fibrosis, with an area under the receiver operating characteristic curve of 0.81 (95% CI, 0.75-0.88). The APRI, FIB-4 index and ALBI score can identify significant liver fibrosis with an area under the ROC curve of 0.74 (95% CI, 0.66-0.81), 0.73 (95% CI, 0.65-0.80) and 0.63 (95% CI, 0.55-0.72), respectively. Compared with these three indexes, the accuracy rate of diagnosis of significant fibrosis based on HBcrAg was higher than that of the FIB-4 index (p = 0.0479) and ALBI score (p = 0.0030). HBcrAg, ALB, PTA serum levels and PLT counts were associated with significant liver fibrosis in treatment-naive chronic HBV infection patients. HBcrAg serum levels enabled the correct identification of patients with significant fibrosis (METAVIR F2-F4), and HBcrAg was more effective than the FIB-4 index and ALBI score.
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Affiliation(s)
- Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Brakenhoff SM, de Knegt RJ, Oliveira J, van der Eijk AA, van Vuuren AJ, Hansen BE, Janssen HLA, de Man RA, Boonstra A, Sonneveld MJ. Levels of Antibodies to Hepatitis B Core Antigen Are Associated With Liver Inflammation and Response to Peginterferon in Patients With Chronic Hepatitis B. J Infect Dis 2022; 227:113-122. [PMID: 35599306 PMCID: PMC9796168 DOI: 10.1093/infdis/jiac210] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 03/11/2022] [Accepted: 05/19/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Emerging evidence suggests a pivotal role for B-cell responses in the natural history of chronic hepatitis B. Serum levels of antibodies to hepatitis B core antigen (anti-HBc) vary across infection stages, but their role in predicting response to antiviral therapy is uncertain. METHODS Anti-HBc levels were assessed before peginterferon (PEG-IFN) therapy in patients with chronic hepatitis B who either started de novo PEG-IFN (n = 299; 195 hepatitis B e antigen [HBeAg] positive) or started PEG-IFN as add-on to an existing nucleo(s)tide analogue backbone (n = 91; all HBeAg-positive). Associations were explored between anti-HBc and (1) serum biomarkers, (2) liver histological findings, and (3) treatment response. RESULTS We studied 390 patients. The hepatitis B virus (HBV) genotype were A, B, C, and D in 24%, 9%, 16%, and 49%, respectively; 72% of patients were Caucasian. Among currently untreated HBeAg-positive patients, anti-HBc was correlated with HBV DNA, hepatitis B core-related antigen (HBcrAg), hepatitis B surface antigen (HBsAg), and HBV RNA, but not with alanine aminotransferase (ALT). Higher anti-HBc was associated with more severe histological inflammatory activity (P < .001), irrespective of HBeAg status. After de novo PEG-IFN, higher anti-HBc levels were associated with HBeAg loss, sustained response, HBsAg decline, and HBsAg clearance (P < .050). Among patients treated with add-on PEG-IFN, higher anti-HBc was associated with HBeAg loss (P = .01). CONCLUSIONS Serum anti-HBc levels correlate with histological inflammatory activity. Higher anti-HBc levels were associated with favorable treatment outcomes. These findings suggest that anti-HBc could be used to select patients most likely to respond to immunomodulatory therapy. CLINICAL TRIALS REGISTRATION NCT00114361, NCT00146705, NCT00877760, and NCT01532843.
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Affiliation(s)
- Sylvia M Brakenhoff
- Correspondence: Sylvia M. Brakenhoff, Erasmus MC, Department of Gastroenterology and Hepatology, internal postal address Na-606, Dr.Molewaterplein 40, 3015 GD Rotterdam, the Netherlands ()
| | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Jeffrey Oliveira
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Annemiek A van der Eijk
- Department of Viroscience, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Anneke J van Vuuren
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Cortese MF, Riveiro-Barciela M, Tabernero D, Rodriguez-Algarra F, Palom A, Sopena S, Rando-Segura A, Roade L, Kuchta A, Ferrer-Costa R, Quer J, Pacin B, Vila M, Casillas R, Garcia-Garcia S, Esteban R, Pumarola T, Buti M, Rodriguez-Frias F. Standardized Hepatitis B Virus RNA Quantification in Untreated and Treated Chronic Patients: a Promising Marker of Infection Follow-Up. Microbiol Spectr 2022; 10:e0214921. [PMID: 35377229 PMCID: PMC9045303 DOI: 10.1128/spectrum.02149-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/11/2022] [Indexed: 02/07/2023] Open
Abstract
The measurement and interpretation of HBV DNA and RNA levels in HBV infected patients treated with antiviral therapy supports the objective of HBV disease management. Here, we quantified circulating HBV RNA through a standardized and sensitive assay in follow-up samples from both naive and treated patients as a marker of infection evolution. HBV DNA (HBV DNA for use in Cobas 6800/8800 Automated Roche Molecular Systems), RNA (Roche HBV RNA Investigational Assay for use in the Cobas 6800/8800; Roche), HBeAg and HBsAg (Elycsys HBsAg chemiluminescence immunoassay by Cobas 8000; Roche), and core-related antigen (Lumipulse G chemiluminescence assay; Fujirebio) levels were measured in cohorts of untreated or nucleos(t)ide treated, HBV-infected subjects in an outpatient hospital setting. HBV DNA levels in untreated people were 3.6 log10 higher than corresponding RNA levels and were stable over 5 years of observation. While only five of 52 treated patients had DNA levels below the lower limit of quantification (10 IU/mL) at the end of follow-up, 13 had HBV RNA levels persistently above this limit, including eight with undetectable DNA. In samples with undetectable core-related antigen we observed a median HBsAg titer 2.7-fold higher than in samples with undetectable RNA (adjusted P = 0.012). Detectable HBV RNA with undetectable HBV DNA was a negative predictor of HBsAg decrease to a level ≤100 IU/mL (P = 0.03). In naive patients the difference between HBV DNA and RNA was higher than previously reported. HBV RNA rapidly decreased during treatment. However, in some cases, it was detectable even after years of effective therapy, being a negative predictor of HBsAg decrease. The investigational RNA assay for use on the Cobas 6800/8800 instruments is a sensitive and standardized method that could be applied in general management of HBV infection. IMPORTANCE This study focused on the quantification of circulating HBV RNA by using a standardized and sensitive assay. Thanks to this system we observed a higher difference between circulating HBV DNA and RNA than previously reported. In treated patients, HBV RNA decreased together with DNA, although some patients presented detectable levels even after years of successful antiviral treatment, suggesting a persistent viral transcription. Of note, the detection of viral RNA when HBV DNA is undetectable was a negative predictor of HBsAg decrease to a level ≤100 IU/mL. This assay could be extremely helpful in HBV patients management to study viral transcription and to identify those treated patients that may achieve sustained viral suppression.
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Affiliation(s)
- Maria Francesca Cortese
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Mar Riveiro-Barciela
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - David Tabernero
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Francisco Rodriguez-Algarra
- The Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Adriana Palom
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Sara Sopena
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ariadna Rando-Segura
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Virology Unit, Microbiology Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Luisa Roade
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alison Kuchta
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Roser Ferrer-Costa
- Department of Biochemistry, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Josep Quer
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Digestive and Liver Disease, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Beatriz Pacin
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Marta Vila
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rosario Casillas
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Selene Garcia-Garcia
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Rafael Esteban
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Tomás Pumarola
- Virology Unit, Microbiology Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Maria Buti
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francisco Rodriguez-Frias
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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Nagra N, Kozarek RA, Burman BE. Therapeutic Advances in Viral Hepatitis A-E. Adv Ther 2022; 39:1524-1552. [PMID: 35220557 DOI: 10.1007/s12325-022-02070-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
Abstract
Viral hepatitis remains a significant global health problem. All forms of viral hepatitis A through E (A-E) can lead to acute symptomatic infection, while hepatitis B and C can lead to chronic infection associated with significant morbidity and mortality related to progression to cirrhosis, end-stage-liver disease, and liver cancer. Viral hepatitis occurs worldwide, though certain regions are disproportionately affected. We now, remarkably, have highly effective curative regimens for hepatitis C, and safe and tolerable medications to suppress hepatitis B activity, and to prevent liver damage and slow disease progression. We have effective vaccines for hepatitis A and B which provide long-lasting immunity, while improved sanitation and awareness can curb outbreaks of hepatitis A and E. However, more effective and available preventive and curative strategies are needed to achieve global eradication of viral hepatitis. This review provides an overview of the epidemiology, transmission, diagnosis, and clinical features of each viral hepatitis with a primary focus on current and future therapeutic and curative options.
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Affiliation(s)
- Navroop Nagra
- Department of Gastroenterology, University of Louisville, Louisville, KY, 40202, USA
| | - Richard A Kozarek
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA
| | - Blaire E Burman
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA.
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Luo M, Zhou B, Hou J, Jiang D. Biomarkers for predicting nucleos(t)ide analogs discontinuation and hepatitis B virus recurrence after drug withdrawal in chronic hepatitis B patients. Hepatol Res 2022; 52:337-351. [PMID: 35089634 DOI: 10.1111/hepr.13749] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/22/2021] [Accepted: 01/20/2022] [Indexed: 12/11/2022]
Abstract
AIM To summarize HBV-related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, providing references for clinical medication, so as to manage CHB patients more scientifically. METHODS Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles. RESULTS We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic-RNA (pgRNA), hepatitis B core-related antigen (HBcrAg), hepatitis B core antibody (anti-HBc), and models containing several indicators for predicting the effectiveness of treatment. CONCLUSIONS HBV DNA, HBV RNA, pgRNA, HBcrAg, anti-HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence.
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Affiliation(s)
- Mengqi Luo
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
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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] [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.
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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
- *Correspondence: Enqiang Chen
| | - 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
- Hong Tang
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Gish RG, Asselah T, Squires K, Mayers D. Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens. Antivir Chem Chemother 2022; 30:20402066221138705. [PMID: 36423233 PMCID: PMC9703507 DOI: 10.1177/20402066221138705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/06/2022] [Indexed: 10/03/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.
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Affiliation(s)
- Robert G Gish
- Hepatitis B Foundation, Doylestown, PA, USA
- Robert G. Gish Consultants, LLC, La Jolla, CA, USA
| | - Tarik Asselah
- Université de Paris, Inserm U1149, Centre de Recherche sur l’inflammation, Paris, France
- Department of Hepatology, AP-HP, Hôpital Beaujon, Clichy, France
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Wang CR, Zhong GC, Chen ZW, Hu P. A Nomogram for Predicting Non-Rebound in HBV-Infected Pregnant Women With Mother-to-Child Transmission Prevention. Front Med (Lausanne) 2021; 8:746759. [PMID: 34805216 PMCID: PMC8596549 DOI: 10.3389/fmed.2021.746759] [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: 07/24/2021] [Accepted: 09/24/2021] [Indexed: 11/15/2022] Open
Abstract
Background: Current guidelines recommend that pregnancies with mother-to-child transmission (MTCT) prevention can cease antiviral treatment after delivery. We aimed to develop a nomogram for predicting non-rebound in HBV-infected pregnant women with MTCT prevention after post-partum nucleos(t)ide analogs (NAs) withdrawal based on parameters before treatment cessation. Methods: Pregnant women receiving antiviral therapy for MTCT prevention and who withdrew from taking NAs after delivery were included in this study. We used the least absolute shrinkage and selection operator (LASSO) logistics and a two-way stepwise regression to select prognostic factors for the risk model, and the concordance index (C-index) was used to assess its discrimination. Internal validation was performed through bootstrapping. Results: Of 92 included patients, 16 and 76 experienced non-rebound and virologic rebound within 48 weeks of post-partum NAs cessation, respectively. Platelet to lymphocyte ratio (PLR) at 34 ± 2 weeks of gestation, a reduction in hepatitis B surface antigen (HBsAg) from baseline to 34 ± 2 weeks of gestation, and hepatitis B virus (HBV) DNA declining from baseline to the end of treatment (EOT) were entered into the final risk model. Its C-index was 0.91 (95% CI, 0.82–0.99), and it reached as high as 0.88 after bootstrapping validation. The decision curve and decision tree were further developed to facilitate the application of this model. Conclusions: We developed a nomogram for predicting non-rebound in pregnant women with MTCT prevention after the withdrawal of antiviral agents, which facilitates physicians in making appropriate treatment recommendations.
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Affiliation(s)
- Chun-Rui Wang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Guo-Chao Zhong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Wei Chen
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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