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van Bömmel F, Degasperi E, van Bömmel A, Facchetti F, Sambarino D, Deichsel D, Brehm J, Kamga Wouambo R, Maier M, Pfefferkorn M, Berg T, Lampertico P. Dynamics of HBV biomarkers during nucleos(t)ide analog treatment: A 14-year study. Hepatol Commun 2025; 9:e0708. [PMID: 40377494 PMCID: PMC12088637 DOI: 10.1097/hc9.0000000000000708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 01/02/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Circulating HBsAg, HBV RNA, and hepatitis B core-related antigen (HBcrAg) are potential biomarkers for the response to nucleos(t)ide analog (NA) treatment discontinuation in patients with chronic hepatitis B (CHB). We retrospectively investigated the long-term kinetics of HBsAg, HBV RNA, and HBcrAg in HBeAg-negative patients treated with NA for up to 14 years in a prospective cohort study. METHODS Ninety-six patients (mean age 65 y, 77% male, 52% with cirrhosis, all HBV genotype D) who were undergoing first (n=33, group A) or second-line (n=63, group B) treatment with tenofovir disoproxil fumarate were included. HBV biomarkers collected during tenofovir disoproxil fumarate treatment were measured in 384 serum samples stored at -20 °C. The combined biomarker endpoints associated with functional cure following NA discontinuation included HBsAg <1000 IU/mL, HBV RNA <54 copies/mL, and HBcrAg <2 log U/mL. RESULTS Before NA treatment, HBV RNA and HBcrAg were detectable in 85% (mean 3.9±2.3 [range, 0-9.2] log10 copies/mL) and 80% (mean 4.3±1.9 [2-8.9] log10 U/mL), respectively, of the patients in group A. In groups A and B, the percentages of patients with detectable HBV RNA levels decreased to 53% and 34%, respectively, during years 8-10 of NA treatment, and to 29% in group B during years 11-14 to 29%. HBcrAg could be quantified in 2% of patients in group B NA treatment years 8-10. Combined biomarker endpoints were met at baseline and at years 1-4, 5-7, 8-10, and 11-14 of treatment by 3.3%, 12% and 14%, 13% and 38%, 26% and 29%, and 41% of patients, respectively. CONCLUSIONS HBV biomarker endpoints are associated with functional cure after the discontinuation of NA increase during long-term NA treatment.
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Affiliation(s)
- Florian van Bömmel
- Department of Medicine II, Division of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Alena van Bömmel
- Computational Biology Group, Leibniz Institute on Aging—Fritz Lipmann Institute, Jena, Germany
| | - Floriana Facchetti
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Dana Sambarino
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Danilo Deichsel
- Department of Medicine II, Division of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Jessica Brehm
- MVZ Medizinische Labore Dessau, Dessau-Roßlau, Germany
| | - Rodrigue Kamga Wouambo
- Department of Medicine II, Division of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Melanie Maier
- Department of Virology, Institute of Medical Microbiology and Virology, Leipzig University Medical Center, Leipzig, Germany
| | - Maria Pfefferkorn
- Department of Medicine II, Division of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Thomas Berg
- Department of Medicine II, Division of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - 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
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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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3
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Yu X, Pfefferkorn M, van Bömmel F, Zhang X, Berg T. Clinical applications of circulating HBV RNA as a potential surrogate biomarker for intrahepatic cccDNA transcriptional activity. Gut 2024; 73:563-566. [PMID: 38123992 DOI: 10.1136/gutjnl-2023-331217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 11/30/2023] [Indexed: 12/23/2023]
Affiliation(s)
- Xiaoqi Yu
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
| | - Maria Pfefferkorn
- Division of Hepatology, Department of Medicine II, University of Leipzig Medical Center, Leipzig, Germany
| | - Florian van Bömmel
- Division of Hepatology, Department of Medicine II, University of Leipzig Medical Center, Leipzig, Germany
| | - Xinxin Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Clinical Research Center, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, University of Leipzig Medical Center, Leipzig, Germany
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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] [Download PDF] [Figures] [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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6
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Li YP, Liu CR, Hao M, Lu R, Dang SS. Clinical cure of hepatitis B: Delight and anticipation. Shijie Huaren Xiaohua Zazhi 2023; 31:837-845. [DOI: 10.11569/wcjd.v31.i20.837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/05/2023] [Accepted: 10/23/2023] [Indexed: 10/27/2023] Open
Affiliation(s)
- Ya-Ping Li
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Chen-Rui Liu
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Miao Hao
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Rui Lu
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
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Sandmann L, Deterding K, Bremer B, Port K, Cornberg M, Wedemeyer H, Maasoumy B. Kinetics and predictive value of HBcrAg, HBV RNA and anti-HBc during bulevirtide treatment of chronic HDV-infected patients. J Viral Hepat 2023; 30:283-286. [PMID: 36648369 DOI: 10.1111/jvh.13804] [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: 10/21/2022] [Revised: 01/02/2023] [Accepted: 01/03/2023] [Indexed: 01/18/2023]
Abstract
The entry inhibitor bulevirtide (BLV) is a new treatment option for patients with chronic hepatitis D virus (HDV) infection and compensated liver disease. The aim of this study was to investigate the kinetic and predictive value of markers reflecting HBV cccDNA transcriptional activity and host immune response activity during BLV treatment in a real-life cohort of HDV infected patients. Levels of HDV RNA, HBV RNA, hepatitis B core related antigen (HBcrAg) and hepatitis B core antibodies (anti-HBc) were measured in 16 patients before (BL), after three (3M) and six (6M) months of treatment with BLV. All patients received nucleos(t)ide analogue treatment. HDV RNA declined in all patients during treatment. 38% (6/16) showed ≥ 2 log HDV RNA decline from BL to 6M and 11 patients (69%) normalized ALT levels. HBV RNA levels were low and only detectable in two to four patients. HBcrAg levels declined in 75% (12/16) of patients. Median HBcrAg levels declined significantly from BL to 6M (3.75 logU/ml (IQR 2.93-4.78) vs. 3.4 logU/ml (IQR 2-4.68), p=0.002). A similar trend was shown for anti-HBc between BL and 6M. Levels of HBcrAg or anti-HBc did not differ significantly between patients with or without ≥ 2 log HDV RNA decline from BL to 6M.After 6 months treatment with BLV, levels of HBcrAg showed a significant decline, while HBV RNA and anti-HBc levels did not change. Reduction of HBV cccDNA transcriptional activity and immunological effects of antiviral treatment might explain these changes.
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Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Braunschweig, Germany.,Center for Individualised Infection Medicine, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Braunschweig, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Braunschweig, Germany
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Zaiets I, Gunewardena S, Menne S, Weinman SA, Gudima SO. Sera of Individuals Chronically Infected with Hepatitis B Virus (HBV) Contain Diverse RNA Types Produced by HBV Replication or Derived from Integrated HBV DNA. J Virol 2023; 97:e0195022. [PMID: 36877036 PMCID: PMC10062156 DOI: 10.1128/jvi.01950-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/11/2023] [Indexed: 03/07/2023] Open
Abstract
This study aimed to better characterize the repertoire of serum hepatitis B virus (HBV) RNAs during chronic HBV infection in humans, which remains understudied. Using reverse transcription-PCR (RT-PCR), real-time quantitative PCR (RT-qPCR), RNA-sequencing, and immunoprecipitation, we found that (i) >50% of serum samples bore different amounts of HBV replication-derived RNAs (rd-RNAs); (ii) a few samples contained RNAs transcribed from integrated HBV DNA, including 5'-HBV-human-3' RNAs (integrant-derived RNAs [id-RNAs]) and 5'-human-HBV-3' transcripts, as a minority of serum HBV RNAs; (iii) spliced HBV RNAs were abundant in <50% of analyzed samples; (iv) most serum rd-RNAs were polyadenylated via conventional HBV polyadenylation signal; (v) pregenomic RNA (pgRNA) was the major component of the pool of serum RNAs; (vi) the area of HBV positions 1531 to 1739 had very high RNA read coverage and thus should be used as a target for detecting serum HBV RNAs; (vii) the vast majority of rd-RNAs and pgRNA were associated with HBV virions but not with unenveloped capsids, exosomes, classic microvesicles, or apoptotic vesicles and bodies; (viii) considerable rd-RNAs presence in the circulating immune complexes was found in a few samples; and (ix) serum relaxed circular DNA (rcDNA) and rd-RNAs should be quantified simultaneously to evaluate HBV replication status and efficacy of anti-HBV therapy with nucleos(t)ide analogs. In summary, sera contain various HBV RNA types of different origin, which are likely secreted via different mechanisms. In addition, since we previously showed that id-RNAs were abundant or predominant HBV RNAs in many of liver and hepatocellular carcinoma tissues as compared to rd-RNAs, there is likely a mechanism favoring the egress of replication-derived RNAs. IMPORTANCE The presence of integrant-derived RNAs (id-RNAs) and 5'-human-HBV-3' transcripts derived from integrated hepatitis B virus (HBV) DNA in sera was demonstrated for the first time. Thus, sera of individuals chronically infected with HBV contained both replication-derived and integrant-transcribed HBV RNAs. The majority of serum HBV RNAs were the transcripts produced by HBV genome replication, which were associated with HBV virions and not with other types of extracellular vesicles. These and other above-mentioned findings advanced our understanding of the HBV life cycle. In addition, the study suggested a promising target area on the HBV genome to increase sensitivity of the detection of serum HBV RNAs and supported the idea that simultaneous detection of replication-derived RNAs (rd-RNAs) and relaxed circular DNA (rcDNA) in serum provides more adequate evaluation of (i) the HBV genome replication status and (ii) the durability and efficiency of the therapy with anti-HBV nucleos(t)ide analogs, which could be useful for improvement of the diagnostics and treatment of HBV-infected individuals.
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Affiliation(s)
- Igor Zaiets
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University, Washington, DC, USA
| | - Steven A. Weinman
- Department of Internal Medicine, Division of Gastroenterology, Liver Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Severin O. Gudima
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
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9
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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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10
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Wang CR, Liu XQ, Li H, Zhang Q, Zhong GC, Tang Q, Chang Y, Wang JS, Duan YQ, Hu P. PgRNA kinetics predict HBsAg reduction in pregnant chronic hepatitis B carriers after treatment cessation. Front Cell Infect Microbiol 2022; 12:1055774. [PMID: 36579348 PMCID: PMC9791257 DOI: 10.3389/fcimb.2022.1055774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 10/28/2022] [Indexed: 12/14/2022] Open
Abstract
Background Pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) play significant roles in predicting discontinuing treatment outcomes. However, their role in pregnancy has rarely been reported. We aimed to evaluate the performance of pgRNA and HBcrAg kinetics in predicting HBeAg seroconversion and HBsAg reduction postpartum in HBeAg-positive pregnant women. Methods Pregnant HBeAg-positive patients receiving antiviral prophylaxis and ceasing treatment postpartum were included. PgRNA and HBcrAg levels were measured before treatment, at 32 weeks of gestation, and at treatment withdrawal postpartum. Other virological and biochemical parameters were regularly examined until 96 weeks postpartum. Results Of 76 pregnant chronic hepatitis B (CHB) carriers with a median treatment duration of 18.1 weeks, HBeAg seroconversion and HBsAg reduction >0.3 log10 IU/mL at 96 weeks postpartum occurred in 8 (10.5%) and 13 (17.1%) patients, respectively. HBsAg correlated most strongly with pgRNA, while HBeAg correlated most strongly with HBcrAg. Multivariable regression analysis revealed that postpartum pgRNA decline and peak ALT levels were independent predictors of HBsAg reduction. The area under the curve of the regression model was 0.79 and reached as high as 0.76 through bootstrapping validation. The calibration plot showed that the nomogram had a performance similar to that of the ideal model. A decision tree was established to facilitate application of the nomogram. In addition, HBcrAg kinetics, as an independent predictor, performed poorly in predicting HBeAg seroconversion. Conclusions Postpartum pgRNA decline together with peak ALT levels may identify patients with a higher probability of HBsAg reduction after treatment cessation postpartum among pregnant CHB carriers receiving antiviral prophylaxis.
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Affiliation(s)
- Chun-Rui Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-qin Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hu Li
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guo-Chao Zhong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiao Tang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunan Chang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jin-Song Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan-qin Duan
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China,*Correspondence: Peng Hu, ;
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11
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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: 94] [Impact Index Per Article: 31.3] [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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12
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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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13
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Yuen M, Berliba E, Sukeepaisarnjaroen W, Ahn SH, Tanwandee T, Lim Y, Kim YJ, Poovorawan K, Tangkijvanich P, Schwabe C, Eley T, Brown J, Lee ACH, Thi EP, Paratala B, Mani N, Sofia MJ, Picchio G, Sims KD, Gane EJ. Safety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B. Hepatol Commun 2022; 6:3457-3472. [PMID: 36194181 PMCID: PMC9701477 DOI: 10.1002/hep4.2095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 01/21/2023] Open
Abstract
AB-506 is a potent, pan-genotypic small molecule capsid inhibitor that inhibits hepatitis B virus (HBV) pregenomic RNA encapsidation. We assessed the safety, pharmacokinetics, and antiviral activity of AB-506 in two randomized, double-blinded Phase 1 studies in healthy subjects (HS) and subjects with chronic HBV infection (CHB). Single ascending and multiple doses of AB-506 or placebo (30-1000 mg or 400 mg daily for 10 days) were assessed in HS. AB-506 or placebo was assessed at either 160 mg or 400 mg daily for 28 days in subjects with CHB. A second follow-up study examined AB-506 or placebo at 400 mg daily for 28 days in 14 Caucasian and 14 East-Asian HS. Twenty-eight days of AB-506 at 160 mg and 400 mg produced mean HBV-DNA declines from baseline of 2.1 log10 IU/ml and 2.8 log10 IU/ml, respectively. Four subjects with CHB (all Asian) had Grade 4 alanine aminotransferase (ALT) elevations (2 at each dose) as HBV DNA was declining; three events led to treatment discontinuation. In the second follow-up study, 2 Asian HS had serious transaminitis events leading to treatment and study termination. No subjects had bilirubin elevations or signs of hepatic decompensation. Conclusion: AB-506 demonstrated mean HBV-DNA declines of >2 log10 ; however, transient but severe ALT flares were observed in 4 Asian subjects with CHB. In the follow-up study in HS, 2 additional Asian HS had Grade 4 flares, suggesting that AB-506 hepatotoxicity contributed to the ALT elevations. The AB-506 development program was terminated because of these findings.
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Affiliation(s)
- Man‐Fung Yuen
- Department of MedicineUniversity of Hong Kong, Queen Mary HospitalHong KongChina
| | | | | | - Sang Hoon Ahn
- Department of MedicineYonsei University College of Medicine, Severance HospitalSeoulRepublic of Korea
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of MedicineSiriraj Hospital, Mahidol UniversityBangkokThailand
| | - Young‐Suk Lim
- Department of GastroenterologyAsan Medical CenterSeoulRepublic of Korea
| | - Yoon Jun Kim
- Department of Internal MedicineSeoul National University HospitalSeoulRepublic of Korea
| | - Kittiyod Poovorawan
- Faculty of Tropical MedicineHospital for Tropical Diseases, Mahidol UniversityBangkokThailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver CancerChulalongkorn UniversityBangkokThailand
| | | | - Timothy Eley
- Clinical DevelopmentArbutus BiopharmaWarminsterPennsylvaniaUSA
| | - Joanne Brown
- Clinical DevelopmentArbutus BiopharmaWarminsterPennsylvaniaUSA
| | | | - Emily P. Thi
- DiscoveryArbutus BiopharmaWarminsterPennsylvaniaUSA
| | | | - Nagraj Mani
- DiscoveryArbutus BiopharmaWarminsterPennsylvaniaUSA
| | | | - Gaston Picchio
- Clinical DevelopmentArbutus BiopharmaWarminsterPennsylvaniaUSA
| | - Karen D. Sims
- Clinical DevelopmentArbutus BiopharmaWarminsterPennsylvaniaUSA
| | - Edward J. Gane
- Department of MedicineUniversity of AucklandAucklandNew Zealand
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14
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Liu S, Deng R, Zhou B, Liang X, Liu Z, Peng J, Chen J, Zhou Y, Guo Y, Chen Y, Li W, Shen S, Lu X, Zhao S, Liao X, Liang H, Lan Y, Hou J, Fan R, Sun J. Association of Serum Hepatitis B Virus RNA With Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Under Nucleos(t)ide Analogues Therapy. J Infect Dis 2022; 226:881-890. [PMID: 34931674 DOI: 10.1093/infdis/jiab597] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/20/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Whether serum hepatitis B virus (HBV) RNA associates with hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients has not been fully elucidated. METHODS We enrolled 2974 patients receiving nucleos(t)ide analogues (NAs) from a prospective, observational CHB cohort to investigate the effect of serum HBV RNA, measured at study entry (baseline), on HCC development, using Cox regression analyses. RESULTS During median follow-up of 4.4 years, 90 patients developed HCC. Patients with detectable baseline HBV RNA (n = 2072) exhibited significantly higher HCC risk than those with undetectable level (5-year HCC incidence estimated by Kaplan-Meier method: 4.1% versus 1.8%, P = .009; adjusted hazard ratio [aHR] = 2.21, P = .005). HBV RNA levels of 609-99 999 and ≥100 000 copies/mL were associated with incrementally increasing HCC risk (aHR = 2.15 and 3.05, respectively; P for trend = .003), compared to undetectable level (<609 copies/mL). Moreover, patients with single-detectable either HBV DNA or RNA and double-detectable DNA and RNA had 1.57- and 4.02-fold higher HCC risk, respectively, than those with double-undetectable DNA and RNA (P for trend = .001). CONCLUSIONS High-level HBV RNA is associated with increased HCC risk in NAs-treated patients. Achieving undetectable HBV RNA may contribute to better clinical outcomes, indicating it could be a valuable endpoint of anti-HBV treatment.
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Affiliation(s)
- 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
| | - 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
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xieer Liang
- 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
| | - Zhihong 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
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinjun Chen
- 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
| | - Yuanping Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yabing Guo
- 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
| | - Yongpeng Chen
- 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
| | - Wanying Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - 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
| | - Xingyu Lu
- 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
| | - Siru Zhao
- 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
| | - Xingmei Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongyan Liang
- 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
| | - Yu Lan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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15
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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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16
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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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17
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Scholtès C, Hamilton AT, Plissonnier ML, Charre C, Scott B, Wang L, Berby F, French J, Testoni B, Blair A, Subic M, Hoppler M, Lankenau A, Grubenmann A, Levrero M, Heil ML, Zoulim F. Performance of the cobas® HBV RNA Automated Investigational Assay for the Detection and Quantification of Circulating HBV RNA in Chronic HBV Patients. J Clin Virol 2022; 150-151:105150. [DOI: 10.1016/j.jcv.2022.105150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/22/2022] [Accepted: 03/31/2022] [Indexed: 01/02/2023]
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18
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Sandmann L, Yurdaydin C, Deterding K, Heidrich B, Hardtke S, Lehmann P, Bremer B, Manns MP, Cornberg M, Wedemeyer H, Maasoumy B. HBcrAg Levels Are Associated With Virological Response to Treatment With Interferon in Patients With Hepatitis Delta. Hepatol Commun 2022; 6:480-495. [PMID: 34561972 PMCID: PMC8870014 DOI: 10.1002/hep4.1821] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 07/19/2021] [Accepted: 08/01/2021] [Indexed: 01/05/2023] Open
Abstract
Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility.
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Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Cihan Yurdaydin
- Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey.,Department of Gastroenterology and HepatologyKoç University Medical SchoolIstanbulTurkey
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Svenja Hardtke
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany.,German Center for Infection Research, HepNet Study-HouseHannoverGermany
| | - Patrick Lehmann
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany.,Center for Individualized Infection MedicineHelmholtz Centre for Infection ResearchHannoverGermany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany.,German Center for Infection Research, HepNet Study-HouseHannoverGermany.,German Center for Infection Research, Partner Site Hannover-BraunschweigHannoverGermany.,Center for Individualized Infection MedicineHelmholtz Centre for Infection ResearchHannoverGermany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany.,German Center for Infection Research, HepNet Study-HouseHannoverGermany.,German Center for Infection Research, Partner Site Hannover-BraunschweigHannoverGermany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany.,German Center for Infection Research, Partner Site Hannover-BraunschweigHannoverGermany.,Center for Individualized Infection MedicineHelmholtz Centre for Infection ResearchHannoverGermany
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19
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Early serum HBV RNA combined with HBsAg response can predict HBeAg seroconversation in patients on Entecavir therapy (ClinicalTrials.gov (NCT03909191)). J Infect 2022; 84:e10-e12. [PMID: 35120973 DOI: 10.1016/j.jinf.2022.01.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 11/23/2022]
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20
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Ye J, Chen J. Interferon and Hepatitis B: Current and Future Perspectives. Front Immunol 2021; 12:733364. [PMID: 34557195 PMCID: PMC8452902 DOI: 10.3389/fimmu.2021.733364] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health burden worldwide for which there is still no effective curative treatment. Interferon (IFN) consists of a group of cytokines with antiviral activity and immunoregulatory and antitumor effects, that play crucial roles in both innate and adaptive immune responses. IFN-α and its pegylated form have been used for over thirty years to treat chronic hepatitis B (CHB) with advantages of finite treatment duration and sustained virologic response, however, the efficacy is limited and side effects are common. Here, we summarize the status and unique advantages of IFN therapy against CHB, review the mechanisms of IFN-α action and factors affecting IFN response, and discuss the possible improvement of IFN-based therapy and the rationale of combinations with other antiviral agents in seeking an HBV cure.
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Affiliation(s)
- Jianyu Ye
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,Research Unit of Cure of Chronic Hepatitis B Virus Infection, Chinese Academy of Medical Sciences, Shanghai, China
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21
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Wu Y, Wen J, Tang G, Zhang J, Xin J. On-treatment HBV RNA dynamic predicts entecavir-induced HBeAg seroconversion in children with chronic hepatitis B. J Infect 2021; 83:594-600. [PMID: 34474058 DOI: 10.1016/j.jinf.2021.08.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/08/2021] [Accepted: 08/28/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B e antigen (HBeAg) seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B patients. This study aimed to explore whether hepatitis B virus (HBV) RNA serum levels can predict HBeAg seroconversion treated with entecavir. METHODS Serum samples from HBeAg-positive children previously treated with entecavir were retrospectively analyzed. HBV RNA levels were measured at baseline, weeks 12, 24, 48, 72 of therapy. Ability of individual biomarkers to predict HBeAg seroconversion was evaluated using receiver operating characteristics (ROC) analyzes. RESULTS Serum HBV RNA was detectable in 51 children with a median of 6.05 (4.04-8.29) log10 IU/mL at baseline. Patients with subsequent HBeAg seroconversion showed a significantly larger decline in median HBV RNA levels during treatment from baseline to week 12 of 1.96 (0.30-3.38) and to week 24 of 2.27 (1.20-3.38) log10 IU/mL, respectively, in comparison to HBeAg-positive patients without HBeAg seroconversion (P < 0.001). Levels of HBV RNA at treatment weeks 12 and 24 showed good ability to predict HBeAg seroconversion (area under ROC scores > 0.85, P < 0.001). CONCLUSION On-treatment HBV RNA dynamic predicts entecavir-induced HBeAg seroconversion in children with chronic hepatitis B living in China.
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Key Words
- ALT,alanine aminotransferase
- AUC, area under the ROC curve
- Abbreviations
- Anti-HBe, hepatitis B e antibody
- BMI, body mass index
- CHB, chronic hepatitis B
- CccDNA, covalently closed circular DNA
- Children
- Chronic hepatitis B
- ETV, entecavir
- GEE, generalized estimating equation
- HBV RNA
- HBV, hepatitis B virus
- HBeAg seroconversion
- HBeAg, hepatitis B e antigen
- HBsAg, hepatitis B surface antigen
- HCC, hepatocellular carcinoma
- LoD, limit of detection
- Marker
- NUC, nucleos/tide
- PEI, Paul-Ehrlich Institute
- PgRNA, pregenomic RNA
- ROC, receiver operating characteristics
- RcDNA, relaxed circular DNA
- ULN, upper limit of normal
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Affiliation(s)
- Yongbin Wu
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China; Institute of Translational Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China.
| | - Jian Wen
- Department of Infectious Diseases, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Guifang Tang
- Department of Infectious Diseases, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Jing Zhang
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Jie Xin
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
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22
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Pisano MB, Giadans CG, Flichman DM, Ré VE, Preciado MV, Valva P. Viral hepatitis update: Progress and perspectives. World J Gastroenterol 2021; 27:4018-4044. [PMID: 34326611 PMCID: PMC8311538 DOI: 10.3748/wjg.v27.i26.4018] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis, secondary to infection with hepatitis A, B, C, D, and E viruses, are a major public health problem and an important cause of morbidity and mortality. Despite the huge medical advances achieved in recent years, there are still points of conflict concerning the pathogenesis, immune response, development of new and more effective vaccines, therapies, and treatment. This review focuses on the most important research topics that deal with issues that are currently being solved, those that remain to be solved, and future research directions. For hepatitis A virus we will address epidemiology, molecular surveillance, new susceptible populations as well as environmental and food detections. In the case of hepatitis B virus, we will discuss host factors related to disease, diagnosis, therapy, and vaccine improvement. On hepatitis C virus, we will focus on pathogenesis, immune response, direct action antivirals treatment in the context of solid organ transplantation, issues related to hepatocellular carcinoma development, direct action antivirals resistance due to selection of resistance-associated variants, and vaccination. Regarding hepatitis D virus, we describe diagnostic methodology, pathogenesis, and therapy. Finally, for hepatitis E virus, we will address epidemiology (including new emerging species), diagnosis, clinical aspects, treatment, the development of a vaccine, and environmental surveillance.
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Affiliation(s)
- María B Pisano
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - Cecilia G Giadans
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Diego M Flichman
- Institute of Biomedical Investigations in Retrovirus and AIDS (INBIRS), School of Medicine, University of Buenos Aires, CONICET, CABA C1121ABG, Buenos Aires, Argentina
| | - Viviana E Ré
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - María V Preciado
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Pamela Valva
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
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23
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Boyd A, Dezanet LNC, Lacombe K. Functional Cure of Hepatitis B Virus Infection in Individuals With HIV-Coinfection: A Literature Review. Viruses 2021; 13:1341. [PMID: 34372547 PMCID: PMC8309973 DOI: 10.3390/v13071341] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022] Open
Abstract
In individuals infected with hepatitis B virus (HBV), the loss of hepatitis B surface antigen (HBsAg) is the ultimate therapeutic goal, which defines "functional cure." For individuals living with human immunodeficiency virus (HIV), functional cure occurs roughly 2 per 100 person-years during potent anti-HBV containing antiretroviral therapy. Although this rate may be higher than expected in treated HBV mono-infected individuals, rates of functional cure widely vary between studies (0.6-10.5 per 100 person-years). Similar to HBV mono-infection, the phase of HBV infection, HBV (sub-)genotypes and hepatitis B "e" Ag-negative variants are associated with functional cure in treated HIV-HBV co-infection. In specifically HIV-HBV co-infected individuals, strong increases in CD4+ T cell counts after treatment initiation have also been linked to functional cure, yet this finding is inconsistent across studies. Several markers directly or indirectly reflecting HBV activity are being developed to predict functional cure, such as quantification of HBsAg, hepatitis B core-related antigen, HBsAg protein composition, anti-hepatitis B core antibodies and interferon-gamma-inducible protein 10. Few have been assessed during treatment in HIV-HBV co-infected individuals and none have been validated to predict functional cure. Novel therapeutics for HBV cure are essential for individuals with HIV-HBV co-infection and need to be separately evaluated in this population.
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Affiliation(s)
- Anders Boyd
- Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, 1018 WT Amsterdam, The Netherlands
- Stichting HIV Monitoring, 1105 BD Amsterdam, The Netherlands
| | - Lorenza N. C. Dezanet
- Institut Pierre Louis d’Épidémiologie et de Santé Publique, INSERM, IPLESP, Sorbonne Université, 75012 Paris, France; (L.N.C.D.); (K.L.)
| | - Karine Lacombe
- Institut Pierre Louis d’Épidémiologie et de Santé Publique, INSERM, IPLESP, Sorbonne Université, 75012 Paris, France; (L.N.C.D.); (K.L.)
- APHP, Hôpital Saint-Antoine, Service de Maladies Infectieuses et Tropicales, 75012 Paris, France
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24
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Zhang X, An X, Shi L, Yang X, Chen Y, Liu X, Li J, Ye F, Lin S. Baseline quantitative HBcAb strongly predicts undetectable HBV DNA and RNA in chronic hepatitis B patients treated with entecavir for 10 years. Sci Rep 2021; 11:13389. [PMID: 34183689 PMCID: PMC8238999 DOI: 10.1038/s41598-021-92757-0] [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: 01/21/2021] [Accepted: 06/09/2021] [Indexed: 12/30/2022] Open
Abstract
The predictive effect of quantitative anti-hepatitis B core on double-negative HBV DNA and RNA remains unstudied. We observed dynamic changes in this measure in chronic hepatitis B patients receiving entecavir for 10 years, evaluating its predictive value for double-negative HBV DNA and RNA. Twenty-seven chronic hepatitis B patients treated with entecavir for 10 years were enrolled in this study. Liver function, quantitative anti-hepatitis B core, hepatitis B surface and e antigens, HBV DNA and RNA were measured at baseline and each follow-up. Virological response was defined as double-negative HBV DNA and RNA; serological response was defined as hepatitis B e antigen seroconversion. After antiviral therapy, quantitative anti-hepatitis B core showed an overall downward trend. Patients with virological response had significantly higher quantitative anti-hepatitis B core levels than those without virological response at baseline. Patients with serological response also had higher quantitative anti-hepatitis B core levels than those without serological response at baseline and week 24. Baseline quantitative anti-hepatitis B core level was the only independent predictor for virological and serological responses. Baseline quantitative anti-hepatitis B core level was powerfully predictive of double-negative HBV DNA and RNA in chronic hepatitis B patients receiving long-term entecavir therapy.
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Affiliation(s)
- Xi Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China
| | - Xiaocui An
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China.,Department of Infectious Diseases, Hospital of Traditional Chinese Medicine of Yuyang District, Yulin, 719000, China
| | - Lei Shi
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China
| | - Xueliang Yang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China
| | - Yunru Chen
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China
| | - Xiaojing Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China
| | - Jianzhou Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China
| | - Feng Ye
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China.
| | - Shumei Lin
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an City, 710061, Shaanxi Province, China.
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25
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Wu IC, Liu WC, Chiu YC, Chiu HC, Cheng PN, Chang TT. Clinical Implications of Serum Hepatitis B Virus Pregenomic RNA Kinetics in Chronic Hepatitis B Patients Receiving Antiviral Treatment and Those Achieving HBsAg Loss. Microorganisms 2021; 9:1146. [PMID: 34073483 PMCID: PMC8229518 DOI: 10.3390/microorganisms9061146] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is correlated with covalently closed circular DNA. We aimed to investigate the utility of serum HBV pgRNA in chronic hepatitis B patients receiving nucleos(t)ide analogue treatment and those achieving HBsAg loss. One hundred and eighty-five patients were enrolled for studying long-term HBV pgRNA kinetics during treatment. Twenty patients achieving HBsAg loss after treatment were enrolled for examining HBV pgRNA kinetics around HBsAg loss. HBV pgRNA significantly decreased in the high baseline HBV pgRNA (≥6 log copies/mL) group but significantly increased in the low baseline HBV pgRNA (<4 log copies/mL) group after 3-month entecavir treatment. Among the 20 patients achieving HBsAg loss, 13 (65%) patients had serum HBV pgRNA higher than the limit of detection (LOD, 1466 copies/mL) when they achieved HBsAg loss. Finally, all 20 patients had HBV pgRNA going below the LOD within 3 years after achieving HBsAg loss. In conclusion, baseline serum HBV pgRNA alone is insufficient for predicting the trajectory of HBV pgRNA. Most patients still had HBV pgRNA higher than the LOD when they achieved HBsAg loss. Further studies on HBV pgRNA kinetics around HBsAg loss would provide an enhanced basis for further applications of HBV pgRNA.
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Affiliation(s)
| | | | | | | | | | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan; (I.-C.W.); (W.-C.L.); (Y.-C.C.); (H.-C.C.); (P.-N.C.)
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26
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Yeh ML, Huang JF, Yu ML, Chuang WL. Hepatitis b infection: progress in identifying patients most likely to respond to peginterferon alfa. Expert Rev Gastroenterol Hepatol 2021; 15:427-435. [PMID: 33338385 DOI: 10.1080/17474124.2021.1866985] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/17/2020] [Indexed: 02/07/2023]
Abstract
Introduction: Despite the disadvantage of side effects, pegylated interferon alpha (Peg-IFN α) remains an indispensable agent for chronic hepatitis B (CHB) due to its immunomodulatory effect. The selection of a patient most likely to have a favorable response becomes an essential issue for Peg-IFN α therapy.Areas covered: Recent progress in the prediction of the treatment response to Peg-IFN α.Expert opinion: Before Peg-IFN α therapy, baseline host and viral factors, including female sex, younger age, a high alanine aminotransferase level, HBV genotype A or B, and low viral load, predict a favorable response. In addition, on-treatment viral kinetics of hepatitis B surface antigen (HBsAg), e antigen (HBeAg) and HBV DNA help clinicians determine whether to continue or discontinue Peg-IFN α therapy. The novel HBV markers hepatitis B core-related antigen and HBV RNA have recently been investigated as useful predictors. The limited efficacy of Peg-IFN α monotherapy facilitated the development of new strategies of 'add-on' or 'switch to' Peg-IFN α in patients receiving long-term nucleot(s)ide analog treatment, which may lead to an increase in HBeAg and HBsAg loss. In summary, tailored Peg-IFN α therapeutic strategies based on predictors extended the landscape for CHB treatment.
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Affiliation(s)
- Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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27
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Liu S, Wu Y, Deng R, Shen S, Fan R, Peng J, Li W, Liang X, Hou J, Sun J, Zhou B. Methodology-dependent performance of serum HBV RNA in predicting treatment outcomes in chronic hepatitis B patients. Antiviral Res 2021; 189:105037. [PMID: 33711337 DOI: 10.1016/j.antiviral.2021.105037] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/23/2020] [Accepted: 02/06/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Whether different serum HBV RNA detection assays can consistently predict treatment outcomes in patients with chronic hepatitis B remains controversial. METHODS We enrolled 188 patients who had stopped nucleos(t)ide analogues (NAs) (STOP cohort-1, -2) and 78 receiving entecavir (ETV) therapy (ETV cohort) and used double-target (targeting both 5' and 3' ends of the HBV pregenome RNA [DT-RNA]) and three single-target (targeting the S-region [S-RNA], X-region [X-RNA], and poly-A tail of HBV RNA [PolyA-RNA]) assays to predict treatment outcomes. RESULTS In STOP cohorts, DT-RNA, S-RNA and X-RNA at NAs cessation showed higher predictive powers for clinical relapse (time-dependent areas under the curve [AUCs] for years 1, 2, 3, and 4 ranged between 0.724 and 0.772 in cohort-1, and between 0.741 and 0.824 in cohort-2) than the PolyA-RNA (AUCs between 0.604 and 0.611 in cohort-1; and between 0.530 and 0.584 in cohort-2). The predictive power for 2-year HBeAg loss of the four targeted RNAs in the ETV cohort at 6 months were similar (AUCs, 0.848, 0.838, 0.825, and 0.801), and superior to that of the HBV DNA level at 6 months (AUC, 0.721). CONCLUSION The outcome prediction performance of serum HBV RNAs is methodology-dependent. PolyA-RNA detection was not recommended to predict off-treatment relapses.
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Affiliation(s)
- 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
| | - Yaobo Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - 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
| | - 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
| | - Rong Fan
- 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
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wanying Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xieer Liang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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28
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Farag MS, van Campenhout MJH, Pfefferkorn M, Fischer J, Deichsel D, Boonstra A, van Vuuren AJ, Ferenci P, Feld JJ, Berg T, Hansen BE, van Bömmel F, Janssen HLA. Hepatitis B Virus RNA as Early Predictor for Response to Pegylated Interferon Alpha in HBeAg-Negative Chronic Hepatitis B. Clin Infect Dis 2021; 72:202-211. [PMID: 31912157 DOI: 10.1093/cid/ciaa013] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 01/06/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatitis B virus RNA (HBV-RNA) is a novel serum biomarker that correlates with transcription of intrahepatic covalently closed circular (cccDNA), which is an important target for pegylated interferon (PEG-IFN) and novel therapies for functional cure. We studied HBV-RNA kinetics following PEG-IFN treatment and its potential role as a predictor to response in HBeAg-negative chronic hepatitis B (CHB) patients. METHODS HBV-RNA levels were measured in 133 HBeAg-negative CHB patients treated in an international randomized controlled trial (PARC study). Patients received PEG-IFN α-2a for 48 weeks. HBV-RNA was measured from baseline through week 144. Response was defined as HBV-DNA <2000 IU/mL and ALT normalization at week 72. Kinetics of HBV-RNA were compared with HBV-DNA, HBsAg, and HBcrAg. RESULTS Mean HBV-RNA at baseline was 4.4 (standard deviation [SD] 1.2) log10 c/mL. At week 12, HBV-RNA declined by -1.6 (1.1) log10 c/mL. HBV-RNA showed a greater decline in responders compared to nonresponders early at week 12 (-2.0 [1.2] vs -1.5 [1.1] log10 c/mL, P = .04). HBV-RNA level above 1700 c/mL (3.2 log10 c/mL) had a negative predictive value of 91% at week 12 and 93% at week 24 (P = .01) for response. Overall, HBV-RNA showed a stronger correlation with HBV-DNA and HBcrAg (.82 and .80, P < .001) and a weak correlation with HBsAg (.25). At week 12, HBV-RNA was significantly lower among patients with lower HBsAg (<100 IU/mL) or HBsAg loss at week 144. CONCLUSIONS During PEG-IFN treatment for HBeAg-negative CHB, HBV-RNA showed a fast and significant decline that correlates with treatment response and HBsAg loss at long-term follow-up. CLINICAL TRIALS REGISTRATION NCT00114361.
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Affiliation(s)
- Mina S Farag
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Maria Pfefferkorn
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Janett Fischer
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Danilo Deichsel
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Anneke J van Vuuren
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Peter Ferenci
- Department of Internal Medicine 3, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Thomas Berg
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Florian van Bömmel
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
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Kaewdech A, Tangkijvanich P, Sripongpun P, Witeerungrot T, Jandee S, Tanaka Y, Piratvisuth T. Hepatitis B surface antigen, core-related antigen and HBV RNA: Predicting clinical relapse after NA therapy discontinuation. Liver Int 2020; 40:2961-2971. [PMID: 32668074 DOI: 10.1111/liv.14606] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/10/2020] [Accepted: 07/09/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS The safe discontinuation of nucleos(t)ide analogue therapy remains challenging in chronic hepatitis B. We investigated the potential role of quantitative hepatitis B surface antigen, hepatitis B core-related antigen and hepatitis B virus RNA at the end of treatment in predicting off-therapy relapse. METHODS Patients who fulfilled the stopping criteria of the Asian Pacific Association for the Study of the Liver guideline were enrolled. Virological relapse was defined as hepatitis B virus DNA level greater than 2000 IU/mL, and clinical relapse was defined as virological relapse plus alanine aminotransferase level of more than twice the upper limit of normal. RESULTS Ninety-two patients participated. The combination of end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA levels was most predictive of clinical relapse. Multivariate analysis revealed that end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA were independently associated with clinical relapse. During follow-up, no patients with undetectable hepatitis B core-related antigen (<3.0 log10 U/mL) and hepatitis B virusRNA (<2.0 log10 copies/mL) at end of treatment developed clinical relapse, in comparison with 22.9% and 62.5% patients with detectable levels of one or both biomarkers respectively. End-of-treatment quantitative hepatitis B surface antigen was linked to a likelihood of hepatitis B surface antigen clearance. CONCLUSIONS The combined hepatitis B core-related antigen and hepatitis B virus RNA assays at end of treatment were highly predictive of subsequent clinical relapse. These novel biomarkers could potentially be used to identify patients who could safely discontinue nucleos(t)ide analogue therapy.
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Affiliation(s)
- Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pimsiri Sripongpun
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Teepawit Witeerungrot
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Songkhla, Thailand
| | - Sawangpong Jandee
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Yasuhito Tanaka
- Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Songkhla, Thailand
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Limothai U, Chuaypen N, Poovorawan K, Chotiyaputta W, Tanwandee T, Poovorawan Y, Tangkijvanich P. Reverse transcriptase droplet digital PCR vs reverse transcriptase quantitative real-time PCR for serum HBV RNA quantification. J Med Virol 2020; 92:3365-3372. [PMID: 32219874 DOI: 10.1002/jmv.25792] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/27/2020] [Accepted: 03/23/2020] [Indexed: 01/02/2023]
Abstract
Serum hepatitis B virus (HBV) RNA is a novel marker reflecting the activity of covalently closed circular DNA. However, the methodology for detecting HBV RNA has been a technical challenge. In this study, the performance of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) for quantifying HBV RNA was compared with that of reverse transcription quantitative real-time PCR (RT-qPCR) in serum samples collected from treatment-naïve patients with different phases of chronic hepatitis B (CHB). A total of 417 serum samples, including 136 HBeAg-positive CHB and 281 HBeAg-negative CHB were examined. HBV RNA levels measured by RT-ddPCR and RT-qPCR showed a high degree of linearity and quantitative correlation. The limit of detections of RT-ddPCR and RT-qPCR assays were 102 and 103 copies/mL, respectively. Our results also demonstrated that RT-ddPCR was superior to RT-qPCR in terms of its consistency for quantifying HBV RNA across all concentrations. In the HBeAg-positive group, serum HBV RNA levels based on RT-ddPCR were moderately correlated with HBV DNA (r = 0.591, P < .001) and HBsAg (r = 0.502, P < .001). Among patients with HBeAg-negative CHB, serum HBV RNA levels were moderately correlated with HBV DNA (r = 0.603, P < .001) but had weak correlation with HBsAg (r = 0.203, P = .001). In summary, RT-ddPCR could enhance the sensitivity of serum HBV RNA detection, particularly among the HBeAg-negative group with low viral loads. Thus, RT-ddPCR could serve as an optimal method for HBV RNA quantification in clinical practice.
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Affiliation(s)
- Umaporn Limothai
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Watcharasak Chotiyaputta
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
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31
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Balagopal A, Grudda T, Ribeiro RM, Saad YS, Hwang HS, Quinn J, Murphy M, Ward K, Sterling RK, Zhang Y, Perelson AS, Sulkowski MS, Osburn WO, Thio CL. Single hepatocytes show persistence and transcriptional inactivity of hepatitis B. JCI Insight 2020; 5:140584. [PMID: 33004689 PMCID: PMC7566712 DOI: 10.1172/jci.insight.140584] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022] Open
Abstract
There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2–4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure. Single-cell laser capture microdissection integrated with droplet digital PCR was used to study hepatocytes from individuals with chronic hepatitis B.
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Affiliation(s)
- Ashwin Balagopal
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tanner Grudda
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ruy M Ribeiro
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.,Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal
| | - Yasmeen S Saad
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hyon S Hwang
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jeffrey Quinn
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michael Murphy
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kathleen Ward
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Richard K Sterling
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Yang Zhang
- Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Alan S Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Mark S Sulkowski
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - William O Osburn
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Chloe L Thio
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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32
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Ding Y, Dou X. Editorial: serum HBV RNA biphasic decline in patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues. Aliment Pharmacol Ther 2020; 52:881-882. [PMID: 32852825 PMCID: PMC7496356 DOI: 10.1111/apt.15975] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
LINKED CONTENT This article is linked to Liu et al papers. To view these articles, visit https://doi.org/10.1111/apt.15890 and https://doi.org/10.1111/apt.15993
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Affiliation(s)
- Yang Ding
- Department of Infectious DiseasesShengjing Hospital of China Medical UniversityShenyangChina
| | - Xiaoguang Dou
- Department of Infectious DiseasesShengjing Hospital of China Medical UniversityShenyangChina
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33
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Liu S, Li W, Sun J. Editorial: serum HBV RNA biphasic decline in patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues-authors' reply. Aliment Pharmacol Ther 2020; 52:883-884. [PMID: 32852824 DOI: 10.1111/apt.15993] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- 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
| | - Wanying Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key, Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - 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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Comparison of Serum Hepatitis B Virus RNA Levels and Quasispecies Evolution Patterns between Entecavir and Pegylated-Interferon Mono-treatment in Chronic Hepatitis B Patients. J Clin Microbiol 2020; 58:JCM.00075-20. [PMID: 32554476 PMCID: PMC7448659 DOI: 10.1128/jcm.00075-20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 05/26/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) RNA may independently predict virological and serological response. This study aimed to compare dynamic changes in serum HBV RNA levels and HBV quasispecies evolution patterns between entecavir and pegylated-interferon mono-treatment in chronic hepatitis B patients and to determine the clinical significance during treatment. TaqMan real-time PCR was used for quantitative analysis. HBV RNA levels were retrospectively determined in serial serum samples from 178 chronic hepatitis B patients who received either entecavir or pegylated-interferon treatment. Hepatitis B virus (HBV) RNA may independently predict virological and serological response. This study aimed to compare dynamic changes in serum HBV RNA levels and HBV quasispecies evolution patterns between entecavir and pegylated-interferon mono-treatment in chronic hepatitis B patients and to determine the clinical significance during treatment. TaqMan real-time PCR was used for quantitative analysis. HBV RNA levels were retrospectively determined in serial serum samples from 178 chronic hepatitis B patients who received either entecavir or pegylated-interferon treatment. Both serum HBV DNA and RNA quasispecies were analyzed via next-generation sequencing. Receiver operating characteristics (ROC) analysis was performed to evaluate the prediction value of individual biomarkers for hepatitis B e antigen (HBeAg) seroconversion. Patients who received pegylated-interferon treatment showed stronger declines in HBV RNA levels than did those who received entecavir treatment. Serum HBV RNA levels were lower in patients with subsequent HBeAg seroconversion. At baseline, the level of HBV RNA was better than other indicators in predicting HBeAg seroconversion. Moreover, the predictive value of serum HBV RNA levels was better in the entecavir group. Baseline HBV RNA exhibited a significantly higher genetic diversity than HBV DNA and had a significant decline after 4 weeks of entecavir treatment. Higher baseline genetic diversity may result in a better outcome in pegylated-interferon-treated patients. Serum HBV RNA levels showed different decline kinetics, and HBV RNA quasispecies showed different evolution patterns in entecavir and pegylated-interferon mono-treatment. Taken together, serum HBV RNA may serve as a promising biomarker of HBeAg seroconversion in patients during antiviral treatment.
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Jiang B, Su R, Ren D, Zheng X, Cao Y, Mi Y, Wang F, Ma P. Evaluation of HBV serological markers in treatment-naïve HBV mono-infected patients and HBV-HIV co-infected patients. Virus Res 2020; 290:198117. [PMID: 32800804 DOI: 10.1016/j.virusres.2020.198117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/28/2020] [Accepted: 08/06/2020] [Indexed: 01/04/2023]
Abstract
OBJECTIVES Many studies have investigated the utility of hepatitis B virus (HBV) serological markers in HBV-infected patients. However, only a few studies have examined HBV serological markers in HBV-human immunodeficiency virus (HIV) co-infected patients. Here, we conducted a cross-sectional study to evaluate correlations of HBV serological markers in treatment-naïve HBV mono-infected patients and HBV-HIV co-infected patients. METHODS HBsAg, HBV DNA, HBV RNA, and HBcrAg were quantified in 51 HBV mono-infected patients and 33 HBV-HIV co-infected patients recruited at Tianjin Second People's Hospital from 2016 to 2019. RESULTS There was no significant difference in serum levels of HBV DNA (P = 0.056), HBV RNA (P = 0.387), HBcrAg (P = 0.714) and HBsAg (P = 0.165) between the patient groups. In HBV mono-infected patients, strong positive correlations were confirmed between HBV RNA and HBV DNA (r=0.620, P < 0.01), HBcrAg and HBV DNA (r=0.802, P < 0.001), and HBcrAg and HBV RNA (r=0.727, P < 0.01). In HBV-HIV co-infected patients, serum HBsAg was very strongly correlated with HBcrAg (r=0.838, P < 0.001). In HBeAg-positive HBV mono-infected patients, all HBV serological markers correlated with each other, whereas only HBV RNA correlated with HBcrAg in HBeAg-negative HBV mono-infected patients (r=0.688, P = 0.007). In HBeAg-positive HBV-HIV co-infected patients, only HBsAg correlated with HBcrAg (r=0.725, P<0.001), whereas HBcrAg and HBV RNA correlated with each other in HBeAg-negative patients (r = 0.683, P=0.010). Moreover, CD4 T-cell counts were not significantly associated with HBsAg, HBV DNA, HBV RNA, and HBcrAg levels. CONCLUSION Compared with HBsAg and HBV DNA, which are widely used in clinical settings, our study confirmed that new HBV serological markers, such as HBV RNA and HBcrAg, have some utility in HBV mono-infected patients and HBV-HIV co-infected patients for monitoring the progression of liver disease.
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Affiliation(s)
- Bei Jiang
- Tianjin Second People's Hospital, Tianjin, 300192, PR China; Tianjin Institute of Hepatology, Tianjin, 300192, PR China
| | - Rui Su
- Tianjin Second People's Hospital, Tianjin, 300192, PR China; Tianjin Institute of Hepatology, Tianjin, 300192, PR China
| | - Doudou Ren
- School of Medicine, Nankai University, Tianjin, 300071, PR China
| | - Xiaoya Zheng
- Tianjin Second People's Hospital, Tianjin, 300192, PR China; Tianjin Institute of Hepatology, Tianjin, 300192, PR China
| | - Yu Cao
- Tianjin Second People's Hospital, Tianjin, 300192, PR China; Tianjin Institute of Hepatology, Tianjin, 300192, PR China
| | - Yuqiang Mi
- Tianjin Second People's Hospital, Tianjin, 300192, PR China; Tianjin Institute of Hepatology, Tianjin, 300192, PR China
| | - Fengmei Wang
- Tianjin Second People's Hospital, Tianjin, 300192, PR China; Tianjin Institute of Hepatology, Tianjin, 300192, PR China.
| | - Ping Ma
- Tianjin Second People's Hospital, Tianjin, 300192, PR China; Tianjin Institute of Hepatology, Tianjin, 300192, PR China.
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Liu S, Liu Z, Li W, Zhou B, Liang X, Fan R, Deng R, Hou J, Sun J. Factors associated with the biphasic kinetics of serum HBV RNA in patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues. Aliment Pharmacol Ther 2020; 52:692-700. [PMID: 32613672 DOI: 10.1111/apt.15890] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/21/2020] [Accepted: 05/25/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Serum hepatitis B virus (HBV) RNA is a novel biomarker for evaluating treatment response. Detailed information regarding serum HBV RNA kinetics during treatment with nucleos(t)ide analogues (NAs) is limited. AIMS To ascertain serum HBV RNA kinetics during long-term NA treatment and identify associated factors. METHODS We enrolled 76 HBeAg-positive chronic hepatitis B patients receiving NA from randomised controlled trials. Laboratory assays were undertaken every 3 months. Factors associated with serum HBV RNA kinetics were identified by generalised estimating equations. RESULTS Baseline serum HBV RNA was 8.5 ± 1.0 log10 copies/mL. Decline in serum HBV RNA during NA therapy was biphasic: the first phase (HBV DNA detectable) had a fast decrease (median slope, -0.207 log10 copies/mL/month) and was followed by a second phase (HBV DNA undetectable) with slow decrease (median slope, -0.071 log10 copies/mL/month). In the first phase, factors independently associated with lower initial serum HBV RNA were male sex (OR, 0.685, P = 0.044), low baseline HBsAg (OR, 0.525, P = 0.001) and rapid virological response (RVR) (OR, 0.624, P = 0.031). In the second phase, only RVR was independently associated with serum HBV RNA kinetics, including its lower initial level (OR, 0.694, P = 0.043) and greater decline (OR, 0.966, P = 0.002). Based on viral dynamics, time needed to achieve undetectable serum HBV RNA from baseline was 43.56 (IQR: 29.49-66.40) months. CONCLUSION RVR was a significant determinant for biphasic decline in serum HBV RNA during NA treatment, which significantly influenced the treatment duration required to achieve undetectable serum HBV RNA.
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Affiliation(s)
- 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
| | - Zhihong 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
| | - Wanying Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xieer Liang
- 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
| | - Rong Fan
- 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
| | - 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
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Ji X, Xia M, Zhou B, Liu S, Liao G, Cai S, Zhang X, Peng J. Serum Hepatitis B Virus RNA Levels Predict HBeAg Seroconversion and Virological Response in Chronic Hepatitis B Patients with High Viral Load Treated with Nucleos(t)ide Analog. Infect Drug Resist 2020; 13:1881-1888. [PMID: 32606837 PMCID: PMC7319510 DOI: 10.2147/idr.s252994] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 05/28/2020] [Indexed: 01/08/2023] Open
Abstract
Background and Aim Hepatitis B virus (HBV) RNA has attracted increasing attention as a novel serum marker for intrahepatic HBV replication. However, the predictive value of the serum level of HBV RNA for hepatitis B e-antigen (HBeAg) seroconversion and viral response among patients with a high viral load (HVL) is unclear. We evaluated the role of the serum level of HBV RNA as a predictor of treatment response in chronic HBV (CHB) patients with an HVL. Patients and Methods The study cohort was 66 HBeAg-positive CHB patients with an HVL (serum HBV DNA >1.9×106 IU/mL) at baseline from our previous prospective cohort study treated with lamivudine (LAM) and adefovir dipivoxil(ADV) (N=31) or entecavir alone (N=35) for ≤96 weeks. The serum HBV RNA level was quantified by TaqMan® probe-based reverse transcription real-time quantitative polymerase chain reaction at four time points. Results The baseline serum HBV RNA level (in log10 copies/mL) in patients treated with LAM+ADV and ETV monotherapy was 8.97±1.22 and 9.15±0.92, respectively. After nucleos(t)ide analog (NA) therapy, the serum HBV RNA level decreased steadily in all patients (week 0 vs week 12, p<0.001; week 12 vs week 24, p=0.010; week 24 vs week 48, p<0.001). Fifty-three (80.3%) patients achieved a virologic response (VR), and 12 (18.2%) achieved HBeAg seroconversion after 96 weeks. Multivariate analyses revealed that the serum HBV RNA level at week 12 could predict HBeAg seroconversion (OR 3.560, 95% CI: 1.39–9.110, p=0.008) and VR (1.908, 1.115–3.265, 0.018) at 96 weeks. Analyses of receiver operating characteristic curves indicated that the serum HBV RNA level 12 weeks after NA treatment had predictive value for HBeAg seroconversion (AUC=0.847, p<0.001) and VR (AUC=0.736, p=0.011). Conclusion The serum level of HBV RNA at 12 weeks could predict HBeAg seroconversion and a VR during NA treatment in CHB patients with an HVL.
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Affiliation(s)
- Xin Ji
- 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, People's Republic of China
| | - Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of 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, People's Republic of China
| | - GuiChan Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Shaohang Cai
- 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, People's Republic of China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
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van Campenhout MJH, van Bömmel F, Pfefferkorn M, Fischer J, Deichsel D, Boonstra A, van Vuuren AJ, Berg T, Hansen BE, Janssen HLA. Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B. J Viral Hepat 2020; 27:610-619. [PMID: 32052503 PMCID: PMC7383601 DOI: 10.1111/jvh.13272] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/15/2020] [Accepted: 01/24/2020] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG-IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg-positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99-01 study). Patients received 52 weeks PEG-IFN monotherapy (n = 136) or PEG-IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG-IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG-IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow-up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P = .01; week 24:3.7 vs 4.9 log c/mL, P < .001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG-IFN treatment. Early on-treatment HBV RNA level may be used to predict nonresponse.
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Affiliation(s)
- Margo J. H. van Campenhout
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Florian van Bömmel
- Department of Gastroenterology and RheumatologySection of HepatologyUniversity Hospital LeipzigLeipzigGermany
| | - Maria Pfefferkorn
- Department of Gastroenterology and RheumatologySection of HepatologyUniversity Hospital LeipzigLeipzigGermany
| | - Janett Fischer
- Department of Gastroenterology and RheumatologySection of HepatologyUniversity Hospital LeipzigLeipzigGermany
| | - Danilo Deichsel
- Department of Gastroenterology and RheumatologySection of HepatologyUniversity Hospital LeipzigLeipzigGermany
| | - André Boonstra
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Anneke J. van Vuuren
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Thomas Berg
- Department of Gastroenterology and RheumatologySection of HepatologyUniversity Hospital LeipzigLeipzigGermany
| | - Bettina E. Hansen
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands,Institute of Health Policy, Management and EvaluationUniversity of TorontoTorontoCanada,Toronto Center for Liver DiseaseToronto Western and General HospitalUniversity Health NetworkTorontoCanada
| | - Harry L. A. Janssen
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands,Toronto Center for Liver DiseaseToronto Western and General HospitalUniversity Health NetworkTorontoCanada
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39
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Liao H, Liu Y, Li X, Wang J, Chen X, Zou J, Li Q, Liu L, Wang J, Huang B, Lu F, Xu D. Monitoring of serum HBV RNA, HBcrAg, HBsAg and anti-HBc levels in patients during long-term nucleoside/nucleotide analogue therapy. Antivir Ther 2020; 24:105-115. [PMID: 30511941 DOI: 10.3851/imp3280] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND This study was aimed at evaluating the clinical significance of serum HBV RNA, hepatitis B core-related antigen (HBcrAg) and hepatitis B core antibody (anti-HBc) levels in chronic hepatitis B patients with undetectable HBV DNA during nucleoside/nucleotide analogue (NA) treatment. METHODS Fifty-seven patients who received long-term NA treatment of median 5.83 (25%, 75% percentiles 4.67, 7.75) years were enrolled, and 285 serum samples at five time points for each patient were quantitatively analysed for the three serum markers together with serum HBV DNA and hepatitis B surface antigen (HBsAg) levels. RESULTS The HBV RNA level significantly correlated with HBcrAg (r=0.629; P<0.001) but not HBsAg levels (P=0.1460). Nonetheless, the HBcrAg level significantly correlated with the HBsAg level (r=0.469; P<0.001). Hepatitis B e antigen (HBeAg)-positive samples showed higher HBV RNA, HBcrAg and HBsAg levels than HBeAg-negative samples did (all P<0.05). Nine patients with HBeAg loss manifested a significantly greater decline in HBV RNA and HBcrAg levels (median 1.84 [25%, 75% percentiles 1.02, 2.12] log10 copies/ml, 1.14 [0.62, 2.21] log10 U/ml, respectively) compared with those in seven patients without HBeAg loss (0.74 [0.10, 1.08] log10 copies/ml and 0.41 [0.21, 0.69] log10 U/ml, respectively). Overall, serum HBV RNA, HBcrAg, HBsAg and anti-HBc levels gradually decreased with time during NA treatment. At the end of observation, HBV RNA and HBcrAg reached an undetectable level in 26 and 6 (46% and 11%) patients, respectively. CONCLUSIONS Monitoring of HBV RNA and HBcrAg levels is useful for NA-treated patients with undetectable HBV DNA. The attainment of HBV RNA undetectability usually occurs prior to HBcrAg undetectability.
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Affiliation(s)
- Hao Liao
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yan Liu
- Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - Xiaodong Li
- Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - Jie Wang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiangmei Chen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jun Zou
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qi Li
- Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - Lujie Liu
- Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - Jun Wang
- Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China.,Peking University 302 Clinical Medical School, Beijing, China
| | - Bixia Huang
- Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Dongping Xu
- Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China.,Peking University 302 Clinical Medical School, Beijing, China
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40
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Zhang M, Li G, Shang J, Pan C, Zhang M, Yin Z, Xie Q, Peng Y, Mao Q, Xiao X, Jiang Y, Luo K, Xu Y, Ding H, Fan W, Diego V, Pourkarim MR, De Clercq E, Wang G, Gong G. Rapidly decreased HBV RNA predicts responses of pegylated interferons in HBeAg-positive patients: a longitudinal cohort study. Hepatol Int 2020; 14:212-224. [PMID: 32100261 PMCID: PMC7136184 DOI: 10.1007/s12072-020-10015-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 01/18/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND As an important anti-HBV drug, pegylated interferon α (PegIFNα) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses. METHODS We analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFNα-2a or PegIFNα-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72. RESULTS HBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value < 0.05). HBV RNA ≤ 1000 copies/mL was an optimized cutoff at week 12 that offered better prediction than other HBV biomarkers. This optimized cutoff plus patient age, HBV genotype B, and HBeAg offered a strong estimation of HBeAg seroconversion (accuracy 95.2%, true negative rate 99.8%). CONCLUSION HBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.
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Affiliation(s)
- Min Zhang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Guangdi Li
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, 410078, Hunan, China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
| | - Chen Pan
- Department of Gastroenterology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, Fujian, China
| | - Minxiang Zhang
- Department of Infectious Diseases, The Sixth People's Hospital of Shengyang, Shengyang, 110006, Liaoning, China
| | - Zhibiao Yin
- Department of Infectious Diseases, Guangzhou Eighth People's Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Qing Xie
- Department of Infectious Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yanzhong Peng
- Department of Infectious Diseases, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Qing Mao
- Chongqing Key Laboratory for Research of Infectious Diseases, Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Xinqiang Xiao
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yongfang Jiang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Kaizhong Luo
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yun Xu
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Hai Ding
- Hunan Sansure Biotech Incorporation, Changsha, 410205, Hunan, China
| | - Wenzhou Fan
- Hunan Sansure Biotech Incorporation, Changsha, 410205, Hunan, China
| | - Vidaurre Diego
- Oxford Centre for Human Brain Activity, University of Oxford, Oxford, OX3 7JX, UK
| | - Mahmoud Reza Pourkarim
- Department of Microbiology, Immunology and Transplantation, Division of Clinical and Epidemiological Virology, KU Leuven, 3000, Leuven, Belgium
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Erik De Clercq
- Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, 3000, Leuven, Belgium
| | - Guiqiang Wang
- Department of Infectious Diseases, The Center for Liver Diseases, Peking University First Hospital, Beijing, 100034, China.
| | - Guozhong Gong
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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41
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Fan R, Zhou B, Xu M, Tan D, Niu J, Wang H, Ren H, Chen X, Wang M, Ning Q, Shi G, Sheng J, Tang H, Bai X, Liu S, Lu F, Peng J, Sun J, Xie Q, Hou J. Association Between Negative Results From Tests for HBV DNA and RNA and Durability of Response After Discontinuation of Nucles(t)ide Analogue Therapy. Clin Gastroenterol Hepatol 2020; 18:719-727.e7. [PMID: 31362119 DOI: 10.1016/j.cgh.2019.07.046] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/11/2019] [Accepted: 07/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is no satisfactory way to identify patients who will maintain a response after discontinuation of nuleos(t)ide analogue therapy for chronic hepatitis B virus (HBV) infection. We investigated whether patients with negative results from tests for HBV DNA and HBV RNA (double negative) at the end of treatment maintain a long-term response to treatment. METHODS We performed a post-hoc analysis of data from a 2-year multi-center randomized controlled trial, and its long-term extension trials, on 130 patients with chronic HBV infection who were positive for the HB e antigen (HBeAg-positive; mean age, 30.8 ± 6.9 years; 72.3% male) and received telbivudine with or without adefovir and stopped therapy after they had HBeAg seroconversion and levels of HBV DNA <300 copies/mL for at least 48 weeks (evaluation cohort). Clinical and laboratory assessments were made every 12 or 16 weeks until clinical relapse (defined as HBV DNA > 2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal) or until 4 years off treatment. We validated our findings in a cohort of 40 HBeAg-positive patients (36.5 ± 9.4 years old; 72.5% male) treated with entecavir or tenofovir, and followed after discontinuation for up to 5.5 years. Patients were considered to be negative for HBV DNA if it was not detected in the COBAS Taqman assay. Patients were considered to be negative for HBV RNA if it was not detected by quantitative real-time PCR with 2 different pairs of primers. RESULTS After 4 years off treatment, in the evaluation cohort, 30.8% of patients had a clinical relapse, 54.7% had virologic relapse (HBV DNA >2000 IU/mL in 2 tests), and 16.8% had reappearance of HBeAg in 2 tests (reversion). A significantly lower proportion of double negative patients had a clinical relapse 4 years later (2/35; 8.0%) than of patients who tested positive for either HBV DNA or RNA (32/102; 31.4%; P = .018). In the validation cohort, after 5.5 years of follow up, a lower proportion of double negative patients had clinical relapse (2/13; 15.4%) than of patients who tested positive for either HBV DNA or RNA at the end of treatment (9/27; 33.3%; P = .286) CONCLUSIONS: In an analysis of data from 2 independent cohorts, we associated negative results from tests for HBV DNA and RNA (double negative) at the end of treatment with continued response 4 or more years after discontinuation of therapy in HBeAg-positive patients. These results might be used to identify the best candidates for discontinuation of nuleos(t)ide analogue therapy.
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Affiliation(s)
- Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Min Xu
- 8th People's Hospital, Guangzhou, China
| | - Deming Tan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - Junqi Niu
- Hepatology Unit, No. 1 Hospital affiliated to Jilin University, Changchun, China
| | - Hao Wang
- Hepatology Unit, Peking University People's Hospital, Beijing, China
| | - Hong Ren
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | | | - Maorong Wang
- Department of Infectious Diseases, 81st PLA Hospital, Nanjing, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangfeng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jifang Sheng
- Department of Infectious Diseases, Zhejiang University 1st Affiliated Hospital, Hangzhou, China
| | - Hong Tang
- Department of Infectious Diseases, West China Hospital, Chengdu, China
| | - Xuefan Bai
- Department of Infectious Diseases, Tangdu Hospital, Xi'an, China
| | - Shi Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Ou Q, Guo J, Zeng Y, Chen H. Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection. J Viral Hepat 2020; 27:224-232. [PMID: 31954089 DOI: 10.1111/jvh.13260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 10/19/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023]
Abstract
Covalently closed circular DNA (cccDNA), which is stably present in the nucleus of hepatocytes, is an important indicator for evaluating antiviral efficacy. Since cccDNA quantification requires an invasive procedure, serum biological markers that can effectively reflect the transcriptional activity of intrahepatic virus and the efficacy of treatment are required. Here, from the aspects of virus and host, we outline the focus of clinical research of HBV in recent years, including HBV RNA, empty virus, hepatitis B core-related antigen and changes in the immune response. We briefly discuss their significance in predicting disease activity and monitoring treatment response in chronic hepatitis B. On this basis, some issues worthy of attention in laboratory diagnosis are proposed.
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Affiliation(s)
- Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Jianhui Guo
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Yongbin Zeng
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Huijuan Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
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43
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Xun Z, Liu C, Yu QQ, Lin JP, Huang JL, Yang TW, Wu WN, Wu SH, Ou QS. Albumin-bilirubin score is associated with response to pegylated interferon and nucleos(t)ide analogues in chronic hepatitis B patients. Clin Chim Acta 2019; 502:120-127. [PMID: 31891671 DOI: 10.1016/j.cca.2019.12.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/23/2019] [Accepted: 12/24/2019] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIM Recently, the role of albumin-bilirubin (ALBI) score in chronic hepatitis B (CHB) has not been well-understood. We aimed to investigate the association of ALBI score with natural history of chronic HBV infection and treatment response of CHB patients. METHODS The ALBI score in a cohort of 849 individuals including 721 chronic HBV-infected patients naïve to anti-HBV treatment in different phases and 128 healthy controls were estimated. Additionally, the dynamic changes of ALBI score of 243 hepatitis B e antigen (HBeAg)-positive CHB patients treated with pegylated interferon-alpha (PEG-IFN-α) or nucleos(t)ide analogues (NAs) were tested for 72 weeks. RESULTS ALBI score differed among phases, with the highest score in HBeAg-positive CHB patients, followed by HBeAg-negative CHB patients, HBeAg-positive chronic HBV infection, and HBeAg-negative chronic HBV infection. Besides, CHB patients harbouring high baseline ALBI score exhibited a relatively stronger therapeutic response to PEG-IFN-α or NAs. Moreover, the rate of HBeAg and HBsAg loss in patients with ALBI grade 2 was persistently higher than that in patients with ALBI grade 1 throughout the course of treatment. Furthermore, ALBI score was an independent predictor of sustained response achievement. The combined use of ALBI score, HBeAg and ALT could enhance the predictive value of treatment response. CONCLUSIONS ALBI score differed significantly across the natural course of chronic HBV infection and was correlated with PEG-IFN-α and NAs treatment response in HBeAg-positive CHB patients, which suggested that ALBI score could be useful as an auxiliary clinical factor to determine the initiation of therapy and predict stronger antiviral treatment response.
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Affiliation(s)
- Zhen Xun
- First Clinical College, Fujian Medical University, Fuzhou, China; Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, China
| | - Can Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, China
| | - Qing-Qing Yu
- First Clinical College, Fujian Medical University, Fuzhou, China; Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, China
| | - Jin-Piao Lin
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, China
| | - Jin-Lan Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, China
| | - Ting-Wen Yang
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Wen-Nan Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Song-Hang Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qi-Shui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, China.
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Limothai U, Chuaypen N, Poovorawan K, Chotiyaputta W, Tanwandee T, Poovorawan Y, Tangkijvanich P. Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon-based therapy in patients with hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2019; 26:1481-1488. [PMID: 31446638 DOI: 10.1111/jvh.13195] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/24/2019] [Accepted: 07/30/2019] [Indexed: 12/18/2022]
Abstract
Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long-term outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG-IFN)-based therapy. Serial serum samples from 91 patients with HBeAg-negative CHB previously treated with PEG-IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post-treatment follow-up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre-treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut-off 2.0 log10 copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut-off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log10 copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG-IFN-based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising "stopping rule" in patients infected with HBV genotypes B or C.
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Affiliation(s)
- Umaporn Limothai
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Watcharasak Chotiyaputta
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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45
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Gill US, Battisti A, Kennedy PTF. Emerging tools in the changing landscape of chronic hepatitis B management. Expert Rev Anti Infect Ther 2019; 17:943-955. [PMID: 31738607 DOI: 10.1080/14787210.2019.1694906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: The availability of a preventative vaccine, interferon, and nucleos(t)ide analogs have provided progress in the control of chronic hepatitis B (CHB). Despite this, it remains a major contributor to global morbidity and mortality. Developments in our understanding of the pathogenesis of CHB and the emergence of new therapies are paving the way, as we move toward HBV cure.Areas covered: We performed bibliographical searches of online databases to review the literature regarding conventional disease phases of CHB. We provide the latest evidence challenging the perception of the natural history of CHB, noting that previously considered quiescent disease phases may not represent benign disease states devoid of progression. We explore the use of potential novel immunological and viral tools which should enhance disease stratification and management decisions in the coming years. Finally, we discuss the timing of treatment and how this could be initiated earlier to improve treatment outcomes, preventing sequelae of chronic infection.Expert opinion: The treatment paradigm in CHB is set to change with multiple novel agents in early phase clinical trials with the aim of a functional cure. An improved understanding of disease pathogenesis and the timing of treatment will be critical to the success of new therapies.
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Affiliation(s)
- Upkar S Gill
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Arianna Battisti
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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46
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Charre C, Levrero M, Zoulim F, Scholtès C. Non-invasive biomarkers for chronic hepatitis B virus infection management. Antiviral Res 2019; 169:104553. [PMID: 31288041 DOI: 10.1016/j.antiviral.2019.104553] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/05/2019] [Accepted: 07/05/2019] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health burden with over 250 million cases worldwide. This complex infection can lead to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Complete recovery is seldom achieved due to the persistence in infected hepatocytes of covalently closed circular (ccc)DNA, which is not targeted by current antiviral therapies. Routine circulating biomarkers used for clinical monitoring of patients do not accurately reflect the cccDNA pool and transcriptional activity. New biomarkers, such as serum HB core-related Ag and circulating HBV RNAs, are under development. In this review, we discuss surrogate non-invasive biomarkers for evaluating intrahepatic cccDNA abundance and transcriptional activity. We also present their relevance for improving the classification of patients with regards to their natural history and for evaluating novel compounds to assess target engagement and to define new virological endpoints.
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Affiliation(s)
- Caroline Charre
- INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008, Lyon, France; University of Lyon, University Claude Bernard Lyon 1 (UCBL1), Lyon, France; Department of Virology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Massimo Levrero
- INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008, Lyon, France; University of Lyon, University Claude Bernard Lyon 1 (UCBL1), Lyon, France; Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Fabien Zoulim
- INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008, Lyon, France; University of Lyon, University Claude Bernard Lyon 1 (UCBL1), Lyon, France; Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Caroline Scholtès
- INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008, Lyon, France; University of Lyon, University Claude Bernard Lyon 1 (UCBL1), Lyon, France; Department of Virology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France.
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Wu Y, Wen J, Xiao W, Zhang B. Pregenomic RNA: How to assist the management of chronic hepatitis B? Rev Med Virol 2019; 29:e2051. [PMID: 31074177 DOI: 10.1002/rmv.2051] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/31/2019] [Accepted: 04/01/2019] [Indexed: 12/17/2022]
Abstract
Pregenomic RNA (pgRNA) is an emerging serological marker for chronic hepatitis B virus (HBV) infection. While pgRNA is principally the template for viral proteins and viral DNAs, additional novel functions for the serum pgRNA have recently been described. These results extend for pgRNA a regulatory function in the viral life cycle and potentially a role in pathogenesis. Here, we review the diverse roles of pgRNA in HBV replication and pathogenesis, emphasizing how the unique structure of this RNA is key to its various functions. We focus in particular on the role of HBV pgRNA in guiding antiviral therapy including nucleot(s)ide analog interruption and role as a marker of cure with new curative therapies. We also briefly allude to the emerging niche for new direct-acting or indirect-acting antivirals targeting pgRNA.
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Affiliation(s)
- Yongbin Wu
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Jian Wen
- Department of Hematology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Weiwei Xiao
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Bao Zhang
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
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Jia W, Zhu MQ, Qi X, Wang T, Wen X, Chen PD, Fan QQ, Zhang WH, Zhang JM. Serum hepatitis B virus RNA levels as a predictor of HBeAg seroconversion during treatment with peginterferon alfa-2a. Virol J 2019; 16:61. [PMID: 31064399 PMCID: PMC6505123 DOI: 10.1186/s12985-019-1152-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 03/25/2019] [Indexed: 02/08/2023] Open
Abstract
Background Hepatitis B e antigen (HBeAg) seroconversion represents an endpoint of treatment of chronic hepatitis B virus (HBV) infections. Methods We have studied whether levels of serum hepatitis B virus ribonucleic acid (HBV RNA) during pegylated interferon alfa-2a treatment might be helpful for predicting HBeAg seroconversion. 61 HBeAg-positive chronic hepatitis B (CHB) patients treated with pegylated interferon alfa-2a alone or in combination with adefovir (10 mg/day) for 48 weeks were included in this retrospective analysis. Response was defined as HBeAg seroconversion at 24 weeks posttreatment. Receiver operating characteristic analyses were used to identify baseline and on-treatment HBV RNA levels associated with response. Results Twenty-two of 61 (36.1%) patients achieved a response. Baseline HBV RNA levels were lower in responders than in nonresponders (4.55 ± 1.19 and 5.90 ± 1.13 copies/mL, respectively, P = 0.001). Baseline HBV RNA cut off level (200,000 copies/mL) provided a positive predictive value (PPV) of 56.0% and a negative predictive value (NPV) of 77.8%. HBV RNA level (3000 copies/mL) at week 12 provide a PPV of 75.0% and a NPV of 82.8%. Moreover, HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in patients with HBV RNA ≤ 200,000 copies/mL at baseline and HBV RNA ≤ 3000 copies/mL at week 12 (92.9%) versus others (12.5%) (All P < 0.05). Conclusions In Conclusions, serum HBV RNA levels may serve as a novel tool for prediction of HBeAg seroconversion during therapy with pegylated interferon alfa-2a in HBeAg-positive CHB patients. Electronic supplementary material The online version of this article (10.1186/s12985-019-1152-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wen Jia
- Department of Infectious Diseases, Jing'An District Centre Hospital of Shanghai, Fudan University, Shanghai, China.,Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Men Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Xun Qi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Ting Wang
- Department of Infectious Diseases, Jing'An District Centre Hospital of Shanghai, Fudan University, Shanghai, China.,Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Xiao Wen
- Department of Infectious Diseases, Jing'An District Centre Hospital of Shanghai, Fudan University, Shanghai, China.,Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Pei Dong Chen
- Department of Infectious Diseases, Jing'An District Centre Hospital of Shanghai, Fudan University, Shanghai, China.,Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Qing Qi Fan
- Department of Infectious Diseases, Jing'An District Centre Hospital of Shanghai, Fudan University, Shanghai, China.,Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Wen-Hong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Ji Ming Zhang
- Department of Infectious Diseases, Jing'An District Centre Hospital of Shanghai, Fudan University, Shanghai, China. .,Department of Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China.
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Liu S, Zhou B, Valdes JD, Sun J, Guo H. Serum Hepatitis B Virus RNA: A New Potential Biomarker for Chronic Hepatitis B Virus Infection. Hepatology 2019; 69:1816-1827. [PMID: 30362148 PMCID: PMC6438723 DOI: 10.1002/hep.30325] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/16/2018] [Indexed: 12/24/2022]
Abstract
Chronic hepatitis B infection is one of the major etiological causes of liver failure, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. This condition cannot be completely cured by currently available drugs due to the persistent existence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the bona fide transcription template for HBV RNAs, in infected hepatocytes. Because quantifying cccDNA per se requires an invasive procedure, serum biomarkers reflecting intrahepatic cccDNA activity are warranted. Recently, a growing body of research suggests that the circulating HBV RNA may serve as a serum biomarker for HBV infection, treatment, and prognosis. In order to delineate the molecular and clinical characteristics of serum HBV RNA, we systematically reviewed the available literature on serum HBV RNA dating back to the early 1990s. In this review, we summarize the reported serum HBV RNA quantification methods and discuss the potential HBV RNA species in patient serum. We also compare the reported correlations of serum HBV RNA with other serological markers, including HBV DNA, hepatitis B surface antigen, e antigen, and core-related antigen, as well as their correlations with intrahepatic cccDNA, to assess their potential in clinical applications. Future directions for serum HBV RNA research are also discussed.
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Affiliation(s)
- 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
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China,Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Juan D. Valdes
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 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,Corresponding Authors: Haitao Guo, Ph.D: Department of Microbiology & Immunology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202, USA. Phone: 317-274-0530, Fax: 317-278-3331, ; Jian Sun, M.D/Ph.D: Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Phone: 086-20-62787432, Fax: 086-20-62786530,
| | - Haitao Guo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA,Corresponding Authors: Haitao Guo, Ph.D: Department of Microbiology & Immunology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202, USA. Phone: 317-274-0530, Fax: 317-278-3331, ; Jian Sun, M.D/Ph.D: Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Phone: 086-20-62787432, Fax: 086-20-62786530,
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50
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Höner Zu Siederdissen C, Maasoumy B, Cornberg M. New viral biomarkers for Hepatitis B: Are we able to change practice? J Viral Hepat 2018; 25:1226-1235. [PMID: 30187603 DOI: 10.1111/jvh.12993] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Abstract
The management of chronic hepatitis B virus (HBV) infection is challenged by its varying natural course and its stealthy nature. Not all HBV-infected patients will develop complications of infection; however, it is of utmost importance to identify patients who are at risk and require antiviral treatment and/or close surveillance. Hepatic inflammation and quantification of HBV DNA have guided treatment decisions in the last decade, and these guided interventions have been shown to reduce liver-related complications and death. Data on the quantification of additional HBV markers such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here, we review the current evidence of how to use these markers and discuss open issues that require additional research.
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Affiliation(s)
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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