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Wu D, Kao JH, Piratvisuth T, Wang X, Kennedy PT, Otsuka M, Ahn SH, Tanaka Y, Wang G, Yuan Z, Li W, Lim YS, Niu J, Lu F, Zhang W, Gao Z, Kaewdech A, Han M, Yan W, Ren H, Hu P, Shu S, Kwo PY, Wang FS, Yuen MF, Ning Q. Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0. Clin Mol Hepatol 2025; 31:S134-S164. [PMID: 39838828 PMCID: PMC11925436 DOI: 10.3350/cmh.2024.0780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 01/23/2025] Open
Abstract
As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.
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Affiliation(s)
- Di Wu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Xiaojing Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Patrick T.F. Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Academic Fields of Medicine, Dentistry, and Pharmaceutical Science, Okayama University, Okayama, Japan
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Guiqiang Wang
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wenhui Li
- National Institute of Biological Sciences, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Jilin, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Meifang Han
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Weiming Yan
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Sainan Shu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Paul Yien Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Fu-sheng Wang
- Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine & State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
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Zhang Y, Lin X, Wu H, Chen J, Zheng Q. Systematic review with network meta-analysis: sustained hepatitis B surface antigen clearance after pegylated interferon cessation. Eur J Gastroenterol Hepatol 2024; 36:1159-1170. [PMID: 39083054 DOI: 10.1097/meg.0000000000002823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
The efficacy of different pegylated interferon (PEG-IFN) treatment strategies for achieving sustained hepatitis B surface antigen (HBsAg) clearance in chronic hepatitis B (CHB) remains controversial. This study assesses the efficacy of different PEG-IFN treatment regimens and factors influencing sustained HBsAg clearance after PEG-IFN discontinuation. PubMed , Embase , Web of Science , and the Cochrane Library databases were searched from inception to June 2023, regarding PEG-IFN therapy in CHB. Methodological quality was assessed using the Cochrane risk of bias tool. We explored sources of heterogeneity through univariate meta-regression. Frequentist network meta-analyses were used to compare the efficacy of different PEG-IFN treatment strategies. We analyzed 53 studies (including 9338 CHB patients). After PEG-IFN withdrawal, the annual rates of HBsAg clearance and seroconversion were 6.9% [95% confidence interval (CI), 5.10-9.31] and 4.7% (95% CI, 2.94-7.42). The pooled 1-, 3-, and 5-year sustained HBsAg clearance rates were 7.4%, 9.9%, and 13.0%, and the sustained HBsAg seroconversion rates were 6.6%, 4.7%, and 7.8%, respectively. HBsAg quantification, hepatitis B e antigen status, and PEG-IFN treatment protocols were major sources of heterogeneity. Baseline HBsAg quantification was significantly lower in patients with sustained HBsAg clearance versus those without ( P < 0.046). PEG-IFN combined with tenofovir has the highest probability of achieving HBsAg seroconversion (surface under the cumulative ranking of 81.9%). Sustained HBsAg clearance increased approximately linearly from years 1 to 5 after PEG-IFN discontinuation. Low baseline HBsAg quantification has a significant impact on sustained HBsAg clearance. PEG-IFN combined with tenofovir may be optimal in achieving sustained HBsAg seroconversion.
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Affiliation(s)
- Ying Zhang
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
| | - Xiaoyu Lin
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
| | - Huizhen Wu
- Department of Medical Administration, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jing Chen
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
| | - Qi Zheng
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
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Liu M, Zhao T, Zhang Y, Zhang AM, Geng J, Xia X. The incidence of hepatocellular carcinoma and clearance of hepatitis B surface for CHB patients in the indeterminate phase: a systematic review and meta-analysis. Front Cell Infect Microbiol 2023; 13:1226755. [PMID: 37771696 PMCID: PMC10523783 DOI: 10.3389/fcimb.2023.1226755] [Citation(s) in RCA: 5] [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: 05/28/2023] [Accepted: 08/21/2023] [Indexed: 09/30/2023] Open
Abstract
Background Nearly 30%-40% of patients with chronic hepatitis B do not fall into any of the traditional natural history classification and thus are classified as indeterminate. However, it is unclear whether patients in the indeterminate phase (IP) are at a higher risk for hepatocellular carcinoma (HCC) than those in the defined phases (DP) and would benefit from antiviral therapy. We performed a systematic review and meta-analysis of HCC incidence and HBsAg clearance among patients in the IP versus DP. Methods We defined the clinical phases as per the AASLD 2018 hepatitis B guidance. We searched PubMed, Embase, Medline, and Web of Science for relevant studies that reported HCC incidence or HBsAg clearance in IP versus DP patients published between January 2007 and March 2023. Annual HCC incidence and HBsAg clearance rates were pooled using a random/common-effects model. Results We analyzed data from 14 studies, comprising 7798 IP patients (222 patients developed HCC and 239 achieved HBsAg clearance) and 10,725 DP patients. The pooled annual HCC incidence was 2.54 cases per 1,000 person-years (95% CI, 1.14-4.39) and HBsAg clearance rate was 12.36 cases per 1,000 person-years (95% CI, 10.70-14.13) for the IP patients. IP patients were associated with significantly higher HCC incidence risk (RR = 1.64, 95% CI, 1.34-2.00) and slightly lower annual HBsAg clearance rate (RR = 0.83, 95% CI, 0.70-0.99) than the DP patients. In addition, HBeAg-negative IP patients (2.31%; 95% CI, 0.87-4.45) showed a significantly higher HCC incidence than those who were HBeAg positive (0.00%; 95% CI, 0.00-0.99) (p< 0.001). The Asia-Pacific region IP patients (4.30%; 95% CI, 2.07-7.27) were also associated with a higher HCC incidence versus Europe (0.05%; 95% CI, 0.00-1.39) (p< 0.001). However, there were no significant differences between different strategies (treated vs. untreated: 2.56%; 95% CI, 1.01-4.63 vs. 1.61%; 95% CI, 0.00-5.81, p = 0.09), and heterogeneity was substantial across the studies (I2 = 89%). Conclusion The systematic review and meta-analysis showed a high HCC incidence and low HBsAg clearance among patients in the IP, especially for HBeAg-negative patients and the Asian population. We emphasize that future multicenter prospective cohort studies or randomized trials are needed to verify if expanding antiviral therapy for patients in the IP is associated with reduced HCC risk or good treatment outcomes.
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Affiliation(s)
- Min Liu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
- Department of Infectious Disease and Hepatic Disease, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Taixue Zhao
- Medical School of Kunming University of Science and Technology, Kunming, China
| | - Yuting Zhang
- Department of Infectious Disease and Hepatic Disease, The First People’s Hospital of Yunnan Province, Kunming, China
| | - A-Mei Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Jiawei Geng
- Department of Infectious Disease and Hepatic Disease, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Xueshan Xia
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
- Kunming Medical University, Kunming, China
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Tang Q, Ye J, Zhang Y, Zhang P, Xia G, Zhu J, Wei S, Li X, Zhang Z. Establishment of a multi-parameter prediction model for the functional cure of HBeAg-negative chronic hepatitis B patients treated with pegylated interferonα and decision process based on response-guided therapy strategy. BMC Infect Dis 2023; 23:456. [PMID: 37430256 PMCID: PMC10332036 DOI: 10.1186/s12879-023-08443-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 07/04/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND & AIMS This study aimed to establish multivariate prediction models according to a response-guided therapy (RGT) based strategy at baseline and week 12 and 24 of follow-up to predict the functional cure for HBeAg-negative patients with chronic hepatitis B (CHB) treated with pegylated interferonα (PEG-IFNα). METHODS A total of 242 HBeAg-negative patients with CHB were treated with PEG-IFNα for 52 weeks and followed up for 24 weeks. Responses at the end of follow-up (EOF) were defined as hepatitis B surface antigen (HBsAg) loss, and patients were defined as either responders or non-responders. RESULTS The three most meaningful predictors were an age ≤ 40 years, alanine aminotransferase (ALT) levels ≤ 40 U/L, and HBsAg levels ≤ 100 IU/mL at baseline; ALT levels ≥ 80 U/L, anti-HBc levels ≤ 8.42 S/CO, and HBsAg levels ≤ 50 IU/mL at week 12; and ALT levels ≥ 40 U/L, anti-HBc levels ≤ 8.46 S/CO, and HBsAg levels ≤ 0.2 IU/mL at week 24. The response rates of patients with a score of 0-1 and 4-5 at baseline, week 12, and 24 were 13.5%, 7.8%, and 11.7%; and 63.6%, 68.1%, and 98.1%, respectively. At week 12, the cumulative scores were 0-2, 3-4, 5-7, and 8-10 (response rates 5.0%, 18.9%, 41.3%, and 71.4%, respectively). At week 24, the cumulative scores were 0-3, 4-6, 7-10, and 11-15 (response rates: 1.3%, 12.3%, 37.0%, and 92.5%, respectively). At baseline, patients with scores of 0-1 were slightly recommended; at week 12, patients with 0-1 or 0-2 cumulative scores were recommended to stop treatment. At week 24, patients with a score of 0-1 or a cumulative score of 0-6 were recommended to stop treatment. CONCLUSION We established a multi-parameter prediction model for the functional cure of HBeAg-negative patients with CHB treated with PEG-IFNα.
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Affiliation(s)
- Qianqian Tang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Jun Ye
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Yafei Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Peixin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Guomei Xia
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Jie Zhu
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Shaofeng Wei
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xu Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China.
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Xie Y, Zhu H, Guo Y, Ma Z, Qi X, Yang F, Mao R, Zhang J. Reduction of Hepatitis B Surface Antigen May Be More Significant in PEGylated Interferon-Alpha Therapy Combined with Nucleotide Analogues than Combined with Nucleoside Analogues in Chronic Hepatitis B Patients: A Propensity Score Matching Study. Can J Gastroenterol Hepatol 2022; 2022:4325352. [PMID: 36531834 PMCID: PMC9750779 DOI: 10.1155/2022/4325352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 11/09/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Background Nucleotide analogues (NTs) monotherapy may have a more significant effect on reducing hepatitis B surface antigen (HBsAg) than nucleoside analogues (NSs) due to their immunomodulatory function. However, this superiority remains unknown when combined with PEGylated interferon α (PegIFNα). Therefore, this study aimed to explore whether NTs have more significant antiviral effects than NSs in combination therapy with PegIFNα. Methods Chronic hepatitis B (CHB) patients treated with PegIFNα plus nucleos(t)ide analogues (NAs) were retrospectively recruited. Efficacy and the predictors of hepatitis B surface antigen (HBsAg) reduction >1 log10 IU/mL after 48 weeks were analyzed. Results A total of 95 patients were included and divided into the PegIFNα + NTs group and the PegIFNα + NSs group. Propensity score matching (PSM) was performed. The PegIFNα + NTs group had a greater reduction of HBsAg (-3.52 vs. -2.33 log10 IU/mL, P=0.032) and a higher proportion of patients with HBsAg reduction >1 log10 IU/mL (100.0% vs. 72.2%, P=0.003) even after PSM. However, HBsAg and hepatitis B e-antigen (HBeAg) loss rates, HBeAg seroconversion rates, degree of HBeAg and hepatitis B virus (HBV) DNA decline, HBV DNA undetectable rates, and alanine aminotransferase (ALT) normalization rates showed no significant differences. Subgroup analyses showed the difference in the reduction of HBsAg was particularly evident in HBeAg-positive and the "add-on" subgroups. PegIFNα plus NTs (OR = 36.667, 95% CI = 3.837-350.384) was an independent predictor for HBsAg reduction >1 log10 IU/mL after 48 weeks. Conclusion This study suggests that PegIFNα plus NTs may lead to more HBsAg reduction, especially in HBeAg-positive and "add-on" patients.
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Affiliation(s)
- Yiran Xie
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yifei Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhenxuan Ma
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xun Qi
- Shanghai Public Health Center of Fudan University, Shanghai, China
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Department of Infectious Diseases, Jing'An Branch of Huashan Hospital, Fudan University, Shanghai, China
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Erken R, Loukachov V, van Dort K, van den Hurk A, Takkenberg RB, de Niet A, Jansen L, Willemse S, Reesink H, Kootstra N. Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B. Hepatology 2022; 76:196-206. [PMID: 35073596 PMCID: PMC9305117 DOI: 10.1002/hep.32352] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/20/2021] [Accepted: 01/07/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here, we quantified the levels of integrated HBV in patients with chronic hepatitis B (CHB) and analyzed the relation between HBV integration, virological activity (plasma HBV DNA and HBsAg levels), and clinical outcomes. APPROACH AND RESULTS We developed and validated a multistep Arthrobacter luteus (Alu)-PCR that specifically amplifies integrated HBV and RT-Alu-PCR detecting mRNA transcripts derived from integrated HBV. Pretreatment liver biopsy samples and baseline characteristics of 124 patients with CHB either treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or receiving no treatment were available for analysis. Integrated HBV sequences containing open reading frame S and X (but not C) and S and X mRNA transcripts derived from integrated HBV could be detected and quantified in liver biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine aminotransferase plasma levels, and the liver histology activity index but not to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic regression analysis showed that lower baseline HBV integration levels were independently associated with HBsAg loss (functional cure) within 5 years follow-up. CONCLUSIONS Integrated HBV levels are strongly correlated with surrogate markers for virological activity but not to cccDNA levels and are predictive for HBsAg loss. Our data suggest that integrated HBV is closely related to HBV replication and may therefore be an important tool in the evaluation and development of treatment modalities aiming to cure CHB.
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Affiliation(s)
- Robin Erken
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands,Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Vladimir Loukachov
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
| | - Karel van Dort
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
| | - Anne van den Hurk
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
| | - R. Bart Takkenberg
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Anniki de Niet
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Louis Jansen
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Sophie Willemse
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Henk Reesink
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeidenthe Netherlands
| | - Neeltje Kootstra
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
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