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Ding L, Huang J, Huang S. The significance of antibody to hepatitis B surface antigen in infection and clearance of hepatitis B virus. Hum Vaccin Immunother 2025; 21:2445283. [PMID: 39754388 DOI: 10.1080/21645515.2024.2445283] [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: 09/24/2024] [Revised: 11/30/2024] [Accepted: 12/17/2024] [Indexed: 01/06/2025] Open
Abstract
One of the key features of chronic hepatitis B virus (HBV) infection is the inability to mount sufficient and coordinated adaptive immune responses against HBV. Recent studies on HBV-specific B cells and antibody to hepatitis B surface antigen (anti-HBs) have shed light on their role in the pathogenesis of chronic hepatitis B (CHB). Anti-HBs is recognized as a protective immune marker, both for HBV infection clearance and following vaccination, and it is also considered an important indicator of functional cure for CHB. Notably, functional impairment of HBV-specific B cells may be reversible. The restoration of HBV-specific B cell function, along with the induction of an anti-HBs antibody response, is regarded as pivotal for terminating chronic HBV infection and achieving functional cure. This article reviews the significance of anti-HBs in both the infection and clearance of HBV, and discusses the potential of neutralizing antibodies and therapeutic vaccines as promising future strategies.
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Affiliation(s)
- Ling Ding
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuaiwen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Yao Z, Gu Y, Lai X, Yang M, Xu Y, Luo J, Peng S. Trajectories of Serum Hepatitis B Surface antigen (HBsAg) During Treatment and Association With HBsAg Loss in Children With Hepatitis B e Antigen-Positive Chronic Hepatitis B: A Latent Class Trajectory Analysis. J Infect Dis 2025; 231:196-203. [PMID: 38970324 DOI: 10.1093/infdis/jiae349] [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: 10/19/2023] [Revised: 06/21/2024] [Accepted: 07/04/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Changes in serum hepatitis B surface antigen (HBsAg) during treatment are associated with HBsAg loss. However, little is known about the trajectory patterns of HBsAg in early treatment and their relationship to subsequent HBsAg loss. METHODS A retrospective study was conducted on 166 treatment-naive children with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). Latent class trajectory analysis was used to identify trajectory groups of serum HBsAg. Cox proportional hazards models were used to assess the association between HBsAg trajectory groups and HBsAg loss. RESULTS The median follow-up time was 20.70 (interquartile range, 12.54-34.17) months, and HBsAg loss occurred in 70 (42.17%) of all study participants. Using latent class trajectory analysis, HBeAg-positive patients with CHB were classified into 3 trajectory groups: trajectory 1 (sustained stability, 24.70%), trajectory 2 (slow decline, 38.55%), and trajectory 3 (rapid decline, 36.75%), respectively. The risk of achieving HBsAg loss was higher in both trajectory 2 (hazard ratio, 3.65 [95% confidence interval, 1.70-7.83]) and trajectory 3 (7.27 [3.01-17.61]), respectively. CONCLUSIONS Serum HBsAg levels during early treatment can be classified into distinct trajectory groups, which may serve as an additional predictive indicator for HBsAg loss in HBeAg-positive children with CHB.
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Affiliation(s)
- Zhenzhen Yao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yingping Gu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xin Lai
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Meng Yang
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yi Xu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jiayou Luo
- 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
- NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Hunan, China
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Wang JL, Jiang SW, Hu AR, Shi XJ, Zhou AW, Lin K, Fan Y, Jin MH, Zhang HJ. A model based on chitinase 3-like protein for expecting liver severity of hepatitis B virus infections in the immune tolerance phase. Clin Chim Acta 2025; 567:120085. [PMID: 39667422 DOI: 10.1016/j.cca.2024.120085] [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: 08/21/2024] [Revised: 11/27/2024] [Accepted: 12/07/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND The question of whether to treat patients with chronic hepatitis B (CHB) during the immune tolerance (IT) period is a matter of ongoing debate, as it is difficult to discern different levels of liver disease severity. We created and assessed a novel diagnostic model for identifying significant liver tissue damage in individuals with CHB in IT phase. METHODS From November 2018 to December 2022, a cross-sectional study of 311 patients with chronic hepatitis B virus infection (HBV DNA > 30 IU/mL) at Ningbo No. 2 Hospital, Ningbo, China, who underwent liver biopsy, including 44 patients in IT phase. Utilizing univariate regression analyses and logistics analysis, and model was developed and validated to predict the severity of hepatic inflammatory and fibrosis in CHB patients and in IT phase. RESULTS Chitinase 3-like Protein (CHI3L1), albumin (ALB), alanine transaminase (ALT) / aspartate aminotransferase (AST) were identified as independent predictors of liver lesion severity in CHB patients with IT. The three were combined to build the model (named as CAA index), which demonstrated good performance. The CAA index achieved an area under the receiver operating characteristic curve (AUC) of 0.916 (95 % CI, 0.820-1.000) and AUC of validation group was 0.875 (95 % CI, 0.683-1.000). CONCLUSIONS CHI3L1 serves as an independent measure of liver fibrosis and inflammation in CHB. This diagnostic model has some value in assessing the severity of the patient's liver lesion severity and may be a reliable non-invasive diagnostic model helping determine whether treatment is necessary among CHB patients in IT phase.
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Affiliation(s)
- Jia-Lan Wang
- Cixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China; Liver Diseases Center, Ningbo No. 2 Hospital, Ningbo 315020, Zhejiang Province, China
| | - Su-Wen Jiang
- Liver Diseases Center, Ningbo No. 2 Hospital, Ningbo 315020, Zhejiang Province, China
| | - Ai-Rong Hu
- Cixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China; Liver Diseases Center, Ningbo No. 2 Hospital, Ningbo 315020, Zhejiang Province, China.
| | - Xiao-Jun Shi
- Liver Diseases Center, Ningbo No. 2 Hospital, Ningbo 315020, Zhejiang Province, China
| | - Ai-Wu Zhou
- Liver Diseases Center, Ningbo No. 2 Hospital, Ningbo 315020, Zhejiang Province, China
| | - Ken Lin
- Ningbo University Health Science Center, Ningbo 315211, Zhejiang Province, China
| | - Ying Fan
- School of Medicine, Shaoxing University, Shaoxing 31200, Zhejiang Province, China
| | - Meng-Han Jin
- Ningbo University Health Science Center, Ningbo 315211, Zhejiang Province, China
| | - Hao-Jin Zhang
- School of Medicine, Shaoxing University, Shaoxing 31200, Zhejiang Province, China
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Honda T, Ishigami M, Ishizu Y, Imai N, Ito T, Yamamoto K, Yokoyama S, Muto H, Inukai Y, Kato A, Murayama A, Yoshio S, Ishikawa T, Fujishiro M, Kawashima H, Kato T. Gut microbes associated with functional cure of chronic hepatitis B. Hepatol Int 2025:10.1007/s12072-025-10776-9. [PMID: 39869245 DOI: 10.1007/s12072-025-10776-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 01/02/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) is prevalent worldwide and is difficult to eradicate. Current treatment strategies for chronic hepatitis B ultimately seek to achieve functional cure (FC); however, the factors contributing to FC remain unclear. We aimed to investigate the gut microbiota profiles of patients with chronic hepatitis B who achieved FC. METHODS Among 105 HBeAg-negative patients with chronic hepatitis B, 70 were enrolled, after excluding patients with cirrhosis or hepatocellular carcinoma and those receiving nucleoside analogs. The gut microbiota of patients who achieved FC was assessed and compared with that of patients with high-titer of HBV DNA (HBV DNA ≥ 3.3 log IU/mL) or low-titer of HBV DNA (HBV DNA < 3.3 log IU/mL). Furthermore, we used cell culture-generated HBV (HBVcc) as a model for HBV infection to evaluate the effects of short-chain fatty acids (SCFAs) produced by the identified bacteria. RESULTS There was no difference in the alpha or beta diversity of the gut microbiota between the FC group and the other groups. However, compared with the other groups, the FC group presented a greater relative abundance of bacteria that produce SCFAs, especially butyrate. In vitro studies demonstrated that 1.0 mM butyrate reduces HBsAg production in HBVcc-infected cells. Furthermore, butyrate administration was most effective at the post-HBV infection stage. CONCLUSIONS Our findings suggest that butyrate-producing bacteria contribute to FC in HBeAg-negative patients with chronic hepatitis B through butyrate-mediated inhibition of HBV production.
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Affiliation(s)
- Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hisanori Muto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yosuke Inukai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Asuka Kato
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Sachiyo Yoshio
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Kohnodai 1-7-1, Ichikawa, 272-8516, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo, 162-8640, Japan
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Sheng B, Wang D, Wang J. Hepatitis B Virus Reactivation in Patients With HBV-Related Advanced Hepatocellular Carcinoma Undergoing Lenvatinib and Camrelizumab Treatment. Cancer Control 2025; 32:10732748241309046. [PMID: 39754312 DOI: 10.1177/10732748241309046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
OBJECTIVE This study aimed to evaluate hepatitis B virus (HBV) reactivation and its effect on tumor response and survival outcomes in patients with HBV-related advanced hepatocellular carcinoma (HCC) undergoing lenvatinib plus camrelizumab treatment. METHODS 216 patients with HBV-related advanced HCC receiving lenvatinib and camrelizumab were enrolled. Overall survival (OS), progression-free survival, and tumor response were evaluated. Univariate and multivariate analyses were performed to determine risk factors for HBV reactivation. RESULTS HBV reactivation occurred in 24 patients (11.1%). It was associated with poor survival and tumor response in these patients. Undetectable DNA levels, the absence of antiviral therapy, and high ALT levels were identified as vital risk factors for HBV reactivation. After receiving or adjusting the antiviral strategy, tumor response improved in patients with HBV reactivation. CONCLUSIONS HBV reactivation could occur in patients with HBV-related HCC, treated with lenvatinib and camrelizumab, worsening tumor response and patient survival. Regular monitoring of the indicators of HBV infection and effective antiviral treatments are recommended for these patients to prevent severe complications.
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Affiliation(s)
- Bi Sheng
- Department of Pharmacy, Wuhan Third Hospital, Wuhan, China
| | - Dong Wang
- Department of Oncology, Wuhan Union Hospital, Wuhan, China
| | - Jingjing Wang
- Department of Pharmacy, Wuhan Third Hospital, Wuhan, China
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Shao X, Kuang A, Xu G, Yu G, Xu B, Kong X, Meng X, Zeng X. Design, Synthesis, and Biological Evaluation of Novel Trifluoromethylated Dipeptide Mimetics of Matijin-Su as Potent Anti-HBV Agents. Chem Biodivers 2024:e202402061. [PMID: 39714596 DOI: 10.1002/cbdv.202402061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 12/24/2024]
Abstract
A series of Matijin-Su (MTS) derivatives were designed, synthesized and their anti-hepatitis B virus (HBV) activities were evaluated in vitro. Twelve compounds displayed good inhibitory activity against HBV DNA replication with IC50 values at micromolar level (0.14-4.81 µM), and among them, compounds 13d, 13n, and 13o were selected for further study. Compound 13d suppressed the HBeAg secretion with IC50 value of 2.57 µM (SI = 4.31), while had no effect on HBsAg. However, compounds 13n and 13o showed no effect to both HBeAg and HBsAg. The molecular docking studies indicated that compound 13d could form H-bond interaction with protein residues of HBV core protein which deserves further study.
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Affiliation(s)
- Xiaoshuang Shao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Natural Products Research Center of Guizhou Province/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang, China
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Anxiang Kuang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Natural Products Research Center of Guizhou Province/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang, China
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Guangcan Xu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Natural Products Research Center of Guizhou Province/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang, China
| | - Gang Yu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Natural Products Research Center of Guizhou Province/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang, China
| | - Bixue Xu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Natural Products Research Center of Guizhou Province/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang, China
| | - Xiangkai Kong
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmacy, Guizhou Medical University, Guiyang, China
| | - Xueling Meng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Natural Products Research Center of Guizhou Province/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang, China
| | - Xiaoping Zeng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Natural Products Research Center of Guizhou Province/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang, China
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Zoulim F, Chen PJ, Dandri M, Kennedy PT, Seeger C. Hepatitis B virus DNA integration: Implications for diagnostics, therapy, and outcome. J Hepatol 2024; 81:1087-1099. [PMID: 38971531 DOI: 10.1016/j.jhep.2024.06.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/26/2024] [Accepted: 06/29/2024] [Indexed: 07/08/2024]
Abstract
Hepatitis B virus (HBV) DNA integration - originally recognised as a non-functional byproduct of the HBV life cycle - has now been accepted as a significant contributor to HBV pathogenesis and hepatitis D virus (HDV) persistence. Integrated HBV DNA is derived from linear genomic DNA present in viral particles or produced from aberrantly processed relaxed circular genomic DNA following an infection, and can drive expression of hepatitis B surface antigen (HBsAg) and HBx. DNA integration events accumulate over the course of viral infection, ranging from a few percent during early phases to nearly 100 percent of infected cells after prolonged chronic infections. HBV DNA integration events have primarily been investigated in the context of hepatocellular carcinoma development as they can activate known oncogenes and other growth promoting genes, cause chromosomal instability and, presumably, induce epigenetic alterations, promoting tumour growth. More recent evidence suggests that HBsAg expression from integrated DNA might contribute to HBV pathogenesis by attenuating the immune response. Integrated DNA provides a source for envelope proteins required for HDV replication and hence represents a means for HDV persistence. Because integrated DNA is responsible for persistence of HBsAg in the absence of viral replication it impacts established criteria for the resolution of HBV infection, which rely on HBsAg as a diagnostic marker. Integrated HBV DNA has been useful in assessing the turnover of infected hepatocytes which occurs during all phases of chronic hepatitis B including the initial phase of infection historically termed immune tolerant. HBV DNA integration has also been shown to impact the development of novel therapies targeting viral RNAs.
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Affiliation(s)
- Fabien Zoulim
- Université Claude Bernard Lyon 1, Hospices Civils de Lyon, INSERM, Lyon Hepatology Institute, Lyon, France.
| | - Pei-Jer Chen
- Hepatitis Research Center and Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Partner Site, Germany
| | - Patrick T Kennedy
- Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK
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Yuen MF, Lim YS, Yoon KT, Lim TH, Heo J, Tangkijvanich P, Tak WY, Thanawala V, Cloutier D, Mao S, Arizpe A, Cathcart AL, Gupta SV, Hwang C, Gane E. VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study. Lancet Gastroenterol Hepatol 2024; 9:1121-1132. [PMID: 39389081 DOI: 10.1016/s2468-1253(24)00237-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 07/19/2024] [Accepted: 07/20/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) remains a global concern, with current treatments achieving low rates of HBsAg seroclearance. VIR-2218 (elebsiran), a small interfering RNA agent against HBV transcripts, reduces HBsAg concentrations. We aimed to evaluate the safety and antiviral activity of VIR-2218 with and without pegylated interferon-alpha-2a treatment in participants with chronic HBV. METHODS This open-label, phase 2 study was conducted at 23 sites in six countries (New Zealand, Australia, Hong Kong, Thailand, South Korea, and Malaysia). Adults (aged 18-65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 μg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. This study is registered with ClinicalTrials.gov, NCT03672188, and is ongoing. FINDINGS Between July 2, 2020, and Nov 2, 2021, 124 individuals were screened for eligibility, 84 of whom were enrolled (15 in cohort 1, 15 in cohort 2, 18 in cohort 3, 18 in cohort 4, 13 in cohort 5, and five in cohort 6). Participants were predominantly HBeAg-negative, Asian, and male (66 [79%] participants were male and 18 [21%] were female). Most treatment emergent adverse events were grades 1-2. Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. The mean maximum change from baseline at any timepoint in HBsAg concentration was -2·0 log10 IU/mL (95% CI -2·1 to -1·8) in cohort 1, -2·2 log10 IU/mL (-2·5 to -1·8) in cohort 2, -2·5 log10 IU/mL (-2·8 to -2·1) in cohort 3, -2·4 log10 IU/mL (-3·1 to -1·8) in cohort 4, -3·0 log10 IU/mL (-3·7 to -2·3) in cohort 5, and -1·7 log10 IU/mL (-2·1 to -1·4) in cohort 6. 11 participants (one in cohort 2, one in cohort 3, five in cohort 4, and four in cohort 5) receiving VIR-2218 plus pegylated interferon-alfa-2a had HBsAg seroclearance at any timepoint. Of these, ten (91%; one in cohort 2, five in cohort 4, and four in cohort 5) had anti-HBs seropositivity. Six participants (one in cohort 2, three in cohort 4, and two in cohort 5) had sustained HBsAg seroclearance through to 24 weeks after the end of treatment. No participants receiving VIR-2218 monotherapy (cohort 1) or VIR-2218 plus pegylated interferon-alfa-2a 12-week regimen (cohort 6) had HBsAg seroclearance. 12 (42%) of 26 participants (one of four in cohort 1, two of six in cohort 2, four of seven in cohort 3, four of six in cohort 4, and one of three in cohort 5) who were HBeAg positive at baseline had HBeAg seroclearance or anti-HBe seroconversion. INTERPRETATION The results of this phase 2 study support further development of VIR-2218 as a potential therapy for patients with chronic HBV infection. Additional clinical trials of VIR-2218 with and without pegylated interferon-alfa-2a in combination with an HBsAg-targeting monoclonal antibody are ongoing. FUNDING Vir Biotechnology.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong Special Administrative Region, China.
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ki Tae Yoon
- Liver Center, Pusan National University Yangsan Hospital, Yangsan, South Korea; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, South Korea
| | - Tien-Huey Lim
- Department of Gastroenterology and Hepatology, Middlemore Hospital, Auckland, New Zealand
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Won Young Tak
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine Kyungpook National University, Daegu, South Korea
| | | | | | | | | | | | | | | | - Edward Gane
- Department of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Lim SG, Teo AED, Chan ESY, Phyo WW, Chen DHY, Hargreaves CA. Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression. Clin Gastroenterol Hepatol 2024; 22:2403-2412. [PMID: 38871150 DOI: 10.1016/j.cgh.2024.05.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 04/30/2024] [Accepted: 05/28/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND AND AIMS Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression. METHODS We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up. RESULTS We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse. CONCLUSIONS While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.
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Affiliation(s)
- Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore.
| | - Ada Ee Der Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Edwin Shih-Yen Chan
- Singapore Clinical Research Institute, Consortium for Clinical Research and Innovation Singapore, Singapore; Cochrane Singapore, Singapore; Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Wah Wah Phyo
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - David Hsing Yu Chen
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Carol Anne Hargreaves
- Data Analytics Consulting Centre, Faculty of Science, National University of Singapore, Singapore
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10
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Wang T, Fan Y, Tan S, Wang Z, Li M, Guo X, Yu X, Lin Q, Song X, Xu L, Li L, Li S, Gao L, Liang X, Li C, Ma C. Probiotics and their metabolite spermidine enhance IFN-γ +CD4 + T cell immunity to inhibit hepatitis B virus. Cell Rep Med 2024; 5:101822. [PMID: 39536754 PMCID: PMC11604485 DOI: 10.1016/j.xcrm.2024.101822] [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: 03/17/2024] [Revised: 07/30/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024]
Abstract
The therapeutic potential of commensal microbes and their metabolites is promising in the functional cure of chronic hepatitis B virus (HBV) infection, which is defined as hepatitis B surface antigen (HBsAg) loss. Here, using both specific-pathogen-free and germ-free mice, we report that probiotics significantly promote the decline of HBsAg and inhibit HBV replication by enhancing intestinal homeostasis and provoking intrahepatic interferon (IFN)-γ+CD4+ T cell immune response. Depletion of CD4+ T cells or blockage of IFN-γ abolishes probiotics-mediated HBV inhibition. Specifically, probiotics-derived spermidine accumulates in the gut and transports to the liver, where it exhibits a similar anti-HBV effect. Mechanistically, spermidine enhances IFN-γ+CD4+ T cell immunity by autophagy. Strikingly, administration of probiotics in HBV patients reveals a preliminary trend to accelerate the decline of serum HBsAg. In conclusion, probiotics and their derived spermidine promote HBV clearance via autophagy-enhanced IFN-γ+CD4+ T cell immunity, highlighting the therapeutic potential of probiotics and spermidine for the functional cure of HBV patients.
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Affiliation(s)
- Tixiao Wang
- Department of Endocrinology and Metabolism and Department of Immunology, Qilu Hospital, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yuchen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Siyu Tan
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Zehua Wang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Mengzhen Li
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xiaowei Guo
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xiangguo Yu
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Qinghai Lin
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Leiqi Xu
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Lixiang Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Shiyang Li
- Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Chunyang Li
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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11
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Okada K, Nakayama Y, Xu J, Cheng Y, Tanaka J. A nation-wide medical record database study: Value of hepatitis B surface antigen loss in chronic hepatitis B patients in Japan. Hepatol Res 2024; 54:1004-1015. [PMID: 38748484 DOI: 10.1111/hepr.14056] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 04/16/2024] [Accepted: 04/20/2024] [Indexed: 11/03/2024]
Abstract
AIM Hepatitis B surface antigen (HBsAg) seroclearance is considered to be one of the best surrogate endpoints of functional cure for hepatitis B virus (HBV) infection. However, evidence regarding the relationship between achieving HBsAg seroclearance or a low baseline HBsAg level, and long-term clinical outcomes in Japanese patients with chronic HBV infection remains to be confirmed in a real-world setting. METHODS A retrospective observational cohort study was performed with an electronic medical record database, including data from 230 hospitals across Japan. Chronic HBV infection was defined as two consecutive, positive HBsAg laboratory measurements for HBV infection. The date of the second positive was used as a baseline to identify subsequent HBsAg seroclearance and liver disease progression. RESULTS In the database, 2523 patients with chronic HBV infection were identified as the chronic hepatitis B (CHB) cohort. Among the CHB cohort with an average observational period of 5.19 ± 3.87 years, 202 patients (8%) achieved HBsAg seroclearance after baseline. They had a lower risk of developing hepatocellular carcinoma (HCC) (adjusted hazard ratio [aHR] 0.206, p < 0.01) and cirrhosis (aHR 0.361, p < 0.01). When the CHB cohort was stratified into two groups based on baseline HBsAg levels (<100 IU/mL and ≥100 IU/mL), patients with a lower baseline level of HBsAg (<100 IU/mL) had a lower risk of developing liver disease (HCC aHR 0.600, p < 0.01; cirrhosis aHR 0.618, p < 0.05). CONCLUSIONS These results confirm the clinical significance of HBsAg seroclearance and low HBsAg level at baseline with respect to long-term outcomes of patients with CHB in the Japanese population.
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Affiliation(s)
| | | | - Jennings Xu
- Janssen Research and Development, Titusville, New Jersey, USA
| | - Yang Cheng
- Janssen China Research & Development, Shanghai, China
| | - Junko Tanaka
- Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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12
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Jiang Q, Zhang Y, Duan D, Retout S, Upmanyu R, Glavini K, Triyatni M, Zhu Y, Grippo JF, Jin Y. Using exploratory pharmacokinetic and pharmacodynamic analyses to predict the probability of flu-like symptoms in healthy volunteers and patients with chronic hepatitis B treated with the toll-like receptor 7 agonist ruzotolimod. Clin Transl Sci 2024; 17:e13896. [PMID: 39119977 PMCID: PMC11310849 DOI: 10.1111/cts.13896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 07/03/2024] [Accepted: 07/09/2024] [Indexed: 08/10/2024] Open
Abstract
Ruzotolimod (Toll-like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno-modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug-related adverse events of flu-like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu-like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC-suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu-like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu-like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN-α, neopterin, IP-10, and the transcriptional expression of ISG15, OAS-1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu-like symptoms occurrence increases with PD responses (IFN-α and IP-10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug-related flu-like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu-like symptoms.
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Affiliation(s)
| | | | - Dan Duan
- Roche Innovation CenterShanghaiChina
| | | | | | | | | | | | | | - Yuyan Jin
- Roche Innovation CenterShanghaiChina
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13
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Kudaravalli S, Huang DQ, Yeh ML, Trinh L, Tsai PC, Hsu YC, Kam LY, Nguyen VH, Ogawa E, Lee DH, Ito T, Watanabe T, Enomoto M, Preda CM, Ko MKL, Wan-Hin Hui R, Atsukawa M, Suzuki T, Marciano S, Barreira A, Do S, Uojima H, Takahashi H, Quek SXZ, Toe Wai Khine HH, Ishigami M, Itokawa N, Go MS, Kozuka R, Marin RI, Sandra I, Li J, Zhang JQ, Wong C, Yoshimaru Y, Vo DKH, Tseng CH, Lee CJ, Inoue K, Maeda M, Hoang JK, Chau A, Chuang WL, Dai CY, Huang JF, Huang CF, Buti M, Tanaka Y, Gadano AC, Yuen MF, Cheung R, Lim SG, Trinh HN, Toyoda H, Yu ML, Nguyen MH. Sex and ethnic disparities in hepatitis B evaluation and treatment across the world. J Hepatol 2024; 81:33-41. [PMID: 38906621 DOI: 10.1016/j.jhep.2024.02.033] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/21/2024] [Accepted: 02/09/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND & AIMS Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.
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Affiliation(s)
- Sahith Kudaravalli
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States; Trinity College of Arts and Sciences, Duke University, Durham, North Carolina, United States
| | - Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Lindsey Trinh
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States
| | - P C Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Leslie Y Kam
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States
| | - Vy H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Dong Hyun Lee
- Division of Gastroenterology, Department of Internal Medicine, Good Gang-An Hospital, Busan, South Korea
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Japan
| | - Tsunamasa Watanabe
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Carmen Monica Preda
- Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, Romania
| | - Michael K L Ko
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Rex Wan-Hin Hui
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Takanori Suzuki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | | | - Ana Barreira
- Liver Unit, Department of Internal Medicine, Hospital Universitari Valle d'Hebron and Universitat Autònoma de Barcelona, and CIBEREHD del Instituto Carlos III. Barcelona, Spain
| | - Son Do
- Digestive Health Associates of Texas, United States
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | | | - Sabrina X Z Quek
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | | | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Min Seok Go
- Division of Gastroenterology, Department of Internal Medicine, Good Gang-An Hospital, Busan, South Korea
| | - Ritsuzo Kozuka
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Raluca Ioana Marin
- Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, Romania
| | - Irina Sandra
- Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, Romania
| | - Jiayi Li
- Wong Clinics, San Francisco, California, United States
| | - Jian Q Zhang
- Chinese Hospital, San Francisco, California, United States
| | | | - Yoko Yoshimaru
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Dang K H Vo
- Digestive Health Associates of Texas, United States
| | - Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Chul-Jin Lee
- Division of Gastroenterology, Department of Internal Medicine, Good Gang-An Hospital, Busan, South Korea
| | - Kaori Inoue
- Liver Center, Saga University Hospital, Saga, Japan
| | - Mayumi Maeda
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States
| | - Joseph K Hoang
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States
| | - Angela Chau
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; Hepatitis Research Center, College of Medicine 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; Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Valle d'Hebron and Universitat Autònoma de Barcelona, and CIBEREHD del Instituto Carlos III. Barcelona, Spain
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan; Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | | | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States; Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, United States
| | - Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Huy N Trinh
- San Jose Gastroenterology, San Jose, California, United States
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, United States; Department of Epidemiology and Population Health, Stanford University School of Medicine, Palo Alto, California, United States.
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14
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Gopalakrishna H, Ghany MG. Perspective on Emerging Therapies to Achieve Functional Cure of Chronic Hepatitis B. CURRENT HEPATOLOGY REPORTS 2024; 23:241-252. [PMID: 38699562 PMCID: PMC11062629 DOI: 10.1007/s11901-024-00652-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/24/2024] [Indexed: 05/05/2024]
Abstract
Purpose of Review Advancements in our understanding of the hepatitis B viral (HBV) life cycle have paved the way for novel approaches to treat HBV infection. This review summarizes the various strategies being pursued to achieve a functional cure, defined as loss of hepatitis B surface antigen (HBsAg) and absence of viral replication 6 months off-therapy. Recent Findings Direct acting antiviral, host targeting antiviral, and immunological approaches are in various stages of development as treatment for chronic HBV infection. Summary Novel treatments are being developed in pursuit of a cure for HBV. Current evidence suggests a single therapeutic agent alone may be insufficient, necessitating the need for combination therapy targeting HBV and the host immune response. Ongoing research focused on identifying the best therapeutic combination holds promise in achieving functional cure for HBV.
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Affiliation(s)
- Harish Gopalakrishna
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9B-16, Bethesda, MD 20892‐1800, USA
| | - Marc G. Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9B-16, Bethesda, MD 20892‐1800, USA
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15
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Liu X, Xia F, Chen Y, Sun H, Yang Z, Chen B, Zhao M, Bi X, Peng T, Ainiwaer A, Luo Z, Wang F, Lu Y. Chinese expert consensus on refined diagnosis, treatment, and management of advanced primary liver cancer (2023 edition). LIVER RESEARCH 2024; 8:61-71. [DOI: 10.1016/j.livres.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2024]
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16
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Du K, Wang X, Bai Y, Zhang X, Xue J, Li S, Xie Y, Sang Z, Tang Y, Wang X. Development of benzimidazole-based compounds as novel capsid assembly modulators for the treatment of HBV infection. Eur J Med Chem 2024; 271:116402. [PMID: 38636128 DOI: 10.1016/j.ejmech.2024.116402] [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: 03/03/2024] [Revised: 04/06/2024] [Accepted: 04/07/2024] [Indexed: 04/20/2024]
Abstract
Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, the hit compound CDI (IC50 = 2.46 ± 0.33 μM) was identified by screening of an in-house compound library. And then novel potent benzimidazole derivatives were designed and synthesized as core assembly modulators, and their antiviral effects were evaluated in vitro and in vivo biological experiments. The results indicated that compound 26f displayed the most optimized modulator of HBV capsid assembly (IC50 = 0.51 ± 0.20 μM, EC50 = 2.24 ± 0.43 μM, CC50 = 84.29 μM) and high selectivity index. Moreover, treatment with compound 26f for 14 days significantly decreased serum levels of HBV DNA levels in the Hydrodynamic-Injection (HDI) mouse model. Therefore, compound 26f could be considered as a promising candidate drug for further development of novel HBV CAMs with the desired potency and safety.
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Affiliation(s)
- Kaixin Du
- Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Xianyang Wang
- Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yuxin Bai
- Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Xue Zhang
- Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China
| | - Jie Xue
- Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Shanshan Li
- Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Zhipei Sang
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
| | - Yu Tang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Marine Biomedical Research Institute of Qingdao, Qingdao, 266071, China.
| | - Xin Wang
- Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
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17
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Kato D, Choy RWY, Canales E, Dick RA, Lake AD, Shapiro ND, Chin E, Li J, Zhang JR, Wu Q, Saito RD, Metobo S, Aktoudianakis E, Schroeder SD, Yang ZY, Glatt DM, Balsitis S, Gamelin L, Yu M, Cheng G, Delaney WE, Link JO. Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873. ACS Med Chem Lett 2024; 15:546-554. [PMID: 38628802 PMCID: PMC11017420 DOI: 10.1021/acsmedchemlett.4c00037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/18/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024] Open
Abstract
Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.
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Affiliation(s)
- Darryl Kato
- Gilead
Sciences, Foster City, California 94404, United States
| | | | - Eda Canales
- Gilead
Sciences, Foster City, California 94404, United States
| | - Ryan A. Dick
- Maze
Therapeutics, South
San Francisco, California 94080, United States
| | - April D. Lake
- Gilead
Sciences, Foster City, California 94404, United States
| | | | - Elbert Chin
- Gilead
Sciences, Foster City, California 94404, United States
| | - Jiayao Li
- Gilead
Sciences, Foster City, California 94404, United States
| | | | - Qiaoyin Wu
- Gilead
Sciences, Foster City, California 94404, United States
| | - Roland D. Saito
- Gilead
Sciences, Foster City, California 94404, United States
| | - Sammy Metobo
- Circle
Pharma, South San Francisco, California 94080, United States
| | | | | | - Zheng-Yu Yang
- Gilead
Sciences, Foster City, California 94404, United States
| | - Dylan M. Glatt
- 23andMe
Therapeutics, South
San Francisco, California 94080, United States
| | - Scott Balsitis
- Gilead
Sciences, Foster City, California 94404, United States
| | - Lindsay Gamelin
- Gilead
Sciences, Foster City, California 94404, United States
| | - Mei Yu
- Gilead
Sciences, Foster City, California 94404, United States
| | - Guofeng Cheng
- AusperBio
Therapeutics Inc., San Mateo, California 94401, United States
| | | | - John O. Link
- Gilead
Sciences, Foster City, California 94404, United States
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18
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Hou J, Gane E, Balabanska R, Zhang W, Zhang J, Lim TH, Xie Q, Yeh CT, Yang SS, Liang X, Komolmit P, Leerapun A, Xue Z, Chen E, Zhang Y, Xie Q, Chang TT, Hu TH, Lim SG, Chuang WL, Leggett B, Bo Q, Zhou X, Triyatni M, Zhang W, Yuen MF. Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients. Clin Mol Hepatol 2024; 30:191-205. [PMID: 38190830 PMCID: PMC11016473 DOI: 10.3350/cmh.2023.0422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/18/2023] [Accepted: 01/04/2024] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND/AIMS Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. METHODS This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. RESULTS 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported. CONCLUSION 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.
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Affiliation(s)
- Jinlin Hou
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Edward Gane
- New Zealand Liver Transplant Unit, The University of Auckland, Auckland, New Zealand
| | | | | | - Jiming Zhang
- Huashan Hospital, Fudan University, Shanghai, China
| | | | - Qing Xie
- Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chau-Ting Yeh
- Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | | | - Xieer Liang
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | | | | | | | - Yuchen Zhang
- China Innovation Center of Roche, Shanghai, China
| | - Qiaoqiao Xie
- China Innovation Center of Roche, Shanghai, China
| | | | - Tsung-Hui Hu
- Chang Gung Memorial Hospital, Kaohsiung Branch, Kaohsiung, Taiwan
| | | | - Wan-Long Chuang
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Barbara Leggett
- Royal Brisbane & Women’s Hospital, School of Medicine, University of Queensland, Queensland, Australia
| | | | - Xue Zhou
- China Innovation Center of Roche, Shanghai, China
| | | | - Wen Zhang
- China Innovation Center of Roche, Shanghai, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, State Key Laboratory of Liver Research, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
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19
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Farag MS, van Campenhout MJH, Sonneveld MJ, Fung S, van Erpecum KJ, Wong DK, Verhey E, de Man R, De Knegt RJ, Brouwer JT, Baak HC, Feld JJ, Liem KS, Boonstra A, Hansen BE, Janssen HLA. Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B: Multicentre Randomized Trial (PAS Study). J Viral Hepat 2024; 31:197-207. [PMID: 38243144 DOI: 10.1111/jvh.13918] [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: 05/26/2023] [Revised: 12/28/2023] [Accepted: 01/02/2024] [Indexed: 01/21/2024]
Abstract
We studied whether 48 weeks of PEG-IFN alfa-2a add-on increases HBsAg-decline and clearance in HBeAg-negative patients on long-term nucleo(s)tide analogue (NA) therapy. In this investigator-initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg-negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG-IFN alfa-2a add-on (180 μg per week) or continued NA-monotherapy with subsequent follow-up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified-intention-to-treat analysis, 58 patients received PEG-IFN add-on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add-on arm versus none on NA-monotherapy (p < .001), and HBsAg clearance was observed in 6 (10%) PEG-IFN add-on patients versus 0% NA-monotherapy (p = .01). HBVRNA was only detected in 2% after PEG-IFN treatment versus 19% in NA-monotherapy (p = .002) at Week 48. PEG-IFN add-on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG-IFN add-on, whereas an HBsAg level > 200 IU/mL at on-treatment Week 12 was highly predictive of non-response (NPV = 100%). Addition of PEG-IFN to long-term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg-negative patients on long-term NA. On-treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG-IFN add-on and could be used as a potential stopping-rule for PEG-IFN therapy. Our findings support further exploration of immune modulation add-on to antiviral therapy, preferably using response-guided strategies, to increase functional cure rates in patients with CHB.
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Affiliation(s)
- Mina S Farag
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - M J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Karel J van Erpecum
- Department of Gastroenterology, University Medical Center, Utrecht, The Netherlands
| | - David K Wong
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Elke Verhey
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert de Man
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert J De Knegt
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Johannes T Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Groep, Delft, The Netherlands
| | - Hubertus C Baak
- Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Kin Seng Liem
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
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20
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Roggendorf H, Shouval D, Roggendorf M, Gerken G. Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrio R) of Chronically HBV Infected Patients. J Pers Med 2024; 14:364. [PMID: 38672991 PMCID: PMC11050803 DOI: 10.3390/jpm14040364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/13/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 μg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent.
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Affiliation(s)
- Hedwig Roggendorf
- Institute of Molecular Immunology, University Hospital TUM, 81675 Munich, Germany
| | - Daniel Shouval
- Liver Unit, Hadassah Medical Center, POB 12000, Jerusalem 91120, Israel;
| | - Michael Roggendorf
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum, 81675 Munich, Germany;
| | - Guido Gerken
- Department of Gastroenterology, Helios Klinikum Niedernberg, 42551 Velbert, Germany;
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21
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Wang Y, Li Q, Li C, Wang C, Wang S, Yuan W, Yu D, Zhang K, Shi B, Chen X, Liu T, Yuan Z, Tong S, Nassal M, Wen YM, Wang YX. Chimeric antigen receptors of HBV envelope proteins inhibit hepatitis B surface antigen secretion. Gut 2024; 73:668-681. [PMID: 37973365 DOI: 10.1136/gutjnl-2023-330537] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVES Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of CHB. HBsAg loss is the key indicator for cure of CHB, but is rarely achieved by current approved anti-HBV drugs. Therefore, novel anti-HBV strategies are urgently needed to achieve sustained HBsAg loss. DESIGN We developed multiple chimeric antigen receptors (CARs) based on single-chain variable fragments (scFvs, namely MA18/7-scFv and G12-scFv), respectively, targeting HBV large and small envelope proteins. Their impacts on HBsAg secretion and HBV infection, and the underlying mechanisms, were extensively investigated using various cell culture models and HBV mouse models. RESULTS After secretory signal peptide mediated translocation into endoplasmic reticulum (ER) and secretory pathway, MA18/7-scFv and CARs blocked HBV infection and virion secretion. G12-scFv preferentially inhibited virion secretion, while both its CAR formats and crystallisable fragment (Fc)-attached versions blocked HBsAg secretion. G12-scFv and G12-CAR arrested HBV envelope proteins mainly in ER and potently inhibited HBV budding. Furthermore, G12-scFv-Fc and G12-CAR-Fc strongly suppressed serum HBsAg up to 130-fold in HBV mouse models. The inhibitory effect lasted for at least 8 weeks when delivered by an adeno-associated virus vector. CONCLUSION CARs possess direct antiviral activity, besides the well-known application in T-cell therapy. Fc attached G12-scFv and G12-CARs could provide a novel approach for reducing circulating HBsAg.
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Affiliation(s)
- Yang Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qiqi Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cong Wang
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shijie Wang
- Deparment of Infectious Diseases, Changzheng Hospital, Navy Medical University, Shanghai, China
| | - Wenjie Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Demin Yu
- Department of Infectious Diseases, Institute of Infectious and Respiratory Diseases, Sino-French Research Center for Life Science and Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ke Zhang
- SCG Cell Therapy Pte Ltd, Singapore
| | - Bisheng Shi
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaomei Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tiantian Liu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuping Tong
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Michael Nassal
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Yu-Mei Wen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yong-Xiang Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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22
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Chen CL, Tseng TC, Liu CJ, Kao JH, Chen PJ, Yang WS. Serum RNase L levels in patients with chronic hepatitis B virus infection. Hepatol Res 2024; 54:244-251. [PMID: 37861347 DOI: 10.1111/hepr.13977] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 09/11/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND/AIMS Chronic hepatitis B virus (HBV) infection still poses a major threat to global health. Oligoadenylate synthetase-ribonuclease L (RNase L) antiviral pathway is one of interferon-induced antiviral effectors. The relationship between RNase L and HBV has never been investigated and we aim to examine the serum RNase L levels in patients with different stages of chronic HBV infection. METHODS The patients were enrolled from 1985 to 2000, who had been HBsAg positive for longer than 6 months, at the National Taiwan University Hospital. In total, 426 patients with chronic HBV infection were included in this study, including 135 inactive carriers, 148 cirrhosis, and 143 hepatocellular carcinoma (HCC) cases. RESULTS The RNase L levels increase as the disease severity increases. Higher RNase L levels were associated with higher HBV viral load, and the HBV-RNase L relationship was replaced by the disease severity status when adding disease status into the model. Compared with inactive carriers, the risk of liver cirrhosis was 60-fold (odds ratio = 60.8, 95% confidence interval = 3.49-1061) with the highest quintile of RNase L levels, after the adjustment of HBV DNA. The dose-response trend was statistically significant with quintiles and one increment of RNase L level in relation to liver cirrhosis. Similar results were found when HCC was compared with inactive carriers, while there was no association when compared between liver cirrhosis and HCC. CONCLUSIONS A positive relationship between serum RNase L and HBV viral titers or advanced disease status is uncovered in this study. Further investigation in this area may provide more details of an innate immune response for HBV and opportunity for novel therapeutic strategy.
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Affiliation(s)
- Chi-Ling Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Shiung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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23
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Mahmood F, Xu R, Awan MUN, Song Y, Han Q, Xia X, Wei J, Xu J, Peng J, Zhang J. HBV Vaccines: Advances and Development. Vaccines (Basel) 2023; 11:1862. [PMID: 38140265 PMCID: PMC10747071 DOI: 10.3390/vaccines11121862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/09/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health problem that is closely related to liver cirrhosis and hepatocellular carcinoma (HCC). The prevalence of acute and chronic HBV infection, liver cirrhosis, and HCC has significantly decreased as a result of the introduction of universal HBV vaccination programs. The first hepatitis B vaccine approved was developed by purifying the hepatitis B surface antigen (HBsAg) from the plasma of asymptomatic HBsAg carriers. Subsequently, recombinant DNA technology led to the development of the recombinant hepatitis B vaccine. Although there are already several licensed vaccines available for HBV infection, continuous research is essential to develop even more effective vaccines. Prophylactic hepatitis B vaccination has been important in the prevention of hepatitis B because it has effectively produced protective immunity against hepatitis B viral infection. Prophylactic vaccines only need to provoke neutralizing antibodies directed against the HBV envelop proteins, whereas therapeutic vaccines are most likely needed to induce a comprehensive T cell response and thus, should include other HBV antigens, such as HBV core and polymerase. The existing vaccines have proven to be highly effective in preventing HBV infection, but ongoing research aims to improve their efficacy, duration of protection, and accessibility. The routine administration of the HBV vaccine is safe and well-tolerated worldwide. The purpose of this type of immunization is to trigger an immunological response in the host, which will halt HBV replication. The clinical efficacy and safety of the HBV vaccine are affected by a number of immunological and clinical factors. However, this success is now in jeopardy due to the breakthrough infections caused by HBV variants with mutations in the S gene, high viral loads, and virus-induced immunosuppression. In this review, we describe various types of available HBV vaccines, along with the recent progress in the ongoing battle to develop new vaccines against HBV.
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Affiliation(s)
- Faisal Mahmood
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (F.M.); (R.X.); (Y.S.); (Q.H.); (X.X.)
- Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming 650021, China;
| | - Ruixian Xu
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (F.M.); (R.X.); (Y.S.); (Q.H.); (X.X.)
| | - Maher Un Nisa Awan
- Department of Neurology, The Affiliated Hospital of Yunnan University, No. 176 Qingnian Road, Kunming 650021, China; (M.U.N.A.); (J.X.)
| | - Yuzhu Song
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (F.M.); (R.X.); (Y.S.); (Q.H.); (X.X.)
| | - Qinqin Han
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (F.M.); (R.X.); (Y.S.); (Q.H.); (X.X.)
| | - Xueshan Xia
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (F.M.); (R.X.); (Y.S.); (Q.H.); (X.X.)
| | - Jia Wei
- Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming 650021, China;
| | - Jun Xu
- Department of Neurology, The Affiliated Hospital of Yunnan University, No. 176 Qingnian Road, Kunming 650021, China; (M.U.N.A.); (J.X.)
| | - Juan Peng
- The Obstetrical Department, The First People’s Hospital of Yunnan Province, Kunming 650032, China;
| | - Jinyang Zhang
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (F.M.); (R.X.); (Y.S.); (Q.H.); (X.X.)
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24
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Mohtashemi N, Dubé K, Thio C, Song S, Patel S, Sugarman J, Bhattacharya D. Patient acceptability of, and attitudes towards, hepatitis B cure research - A scoping review and identification of knowledge gaps. J Virus Erad 2023; 9:100354. [PMID: 38161322 PMCID: PMC10755539 DOI: 10.1016/j.jve.2023.100354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Functional cure, defined as durable loss of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA suppression off therapy, is an increasingly important goal in the treatment of chronic hepatitis B. Although novel treatments aimed at achieving functional cure are being developed and tested in clinical trials, it is important to assess the perspectives of people living with HBV towards these potential treatments and their participation in HBV functional cure research. We have performed a scoping review that revealed that there is limited knowledge regarding patient perspectives of HBV functional cure research and then identified gaps in knowledge for further investigation. Our work highlights the need for further studies in patient perspectives in HBV functional cure research.
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Affiliation(s)
| | - Karine Dubé
- University of California, San Diego, San Diego, CA, USA
| | - Chloe Thio
- Johns Hopkins University, Baltimore, MD, USA
| | - Sihyeong Song
- University of California, Los Angeles, Los Angeles, CA, USA
| | - Shail Patel
- University of California, Los Angeles, Los Angeles, CA, USA
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25
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Cargill T, Cicconi P, Brown A, Holland L, Karanth B, Rutkowski K, Ashwin E, Mehta R, Chinnakannan S, Sebastian S, Bussey L, Sorensen H, Klenerman P, Evans T, Barnes E. HBV001: Phase I study evaluating the safety and immunogenicity of the therapeutic vaccine ChAdOx1-HBV. JHEP Rep 2023; 5:100885. [PMID: 37791379 PMCID: PMC10543776 DOI: 10.1016/j.jhepr.2023.100885] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/23/2023] [Accepted: 07/22/2023] [Indexed: 10/05/2023] Open
Abstract
Background & Aims Millions of people worldwide are infected chronically with HBV, which results in significant morbidity and mortality. Therapeutic vaccination is a strategy that aims to induce functional cure by restoring cellular immunity to HBV. Previously we have shown the candidate HBV immunotherapeutic vaccine ChAdOx1-HBV, encoding all major HBV antigens and a genetic adjuvant (shark invariant chain), is highly immunogenic in mice. Methods Here we report the results of HBV001, a first-in-human, phase I, non-randomised, dose-escalation trial of ChAdOx1-HBV assessed in healthy volunteers and patients with chronic HBV (CHB). Results Vaccination with a single dose of ChAdOx1-HBV was safe and well tolerated in both healthy and CHB cohorts. Vaccination induced high magnitude HBV-specific T cell responses against all major HBV antigens (core, polymerase, and surface) in healthy volunteers. Responses were detected but lower in patients with CHB. T cells generated by vaccination were cross-reactive between HBV C and D genotypes. Conclusions ChAdOx1-HBV is safe and immunogenic in healthy volunteers and patients with CHB. In further studies, ChAdOx1-HBV will be used in combination with other therapeutic strategies with an aim to overcome the attenuated immunogenicity in patients with CHB. Impact and implications Therapeutic vaccine ChAdOx1-HBV, a novel treatment for chronic hepatitis B infection (CHB), has been shown to be immunogenic in preclinical studies. In HBV001, a first-in-human phase I study, we show vaccination with ChAdOx1-HBV is safe and generates high magnitude T cell responses in healthy volunteers and lower levels of responses in patients with CHB. This is an important first step in the development of ChAdOx1-HBV as part of a wider therapeutic strategy to induce hepatitis B functional cure, and is of great interest to patients CHB and clinicians treating the condition. Clinical Trials Registration This study is registered at ClinicalTrials.gov (NCT04297917).
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Affiliation(s)
- Tamsin Cargill
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Paola Cicconi
- Jenner Vaccine Trials Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Anthony Brown
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Louise Holland
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Jenner Vaccine Trials Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | | | | | - Emily Ashwin
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Jenner Vaccine Trials Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | | | - Senthil Chinnakannan
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | | | | | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, University of Oxford, The Joint Research Office, OUH Cowley, Oxford, UK
| | | | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, University of Oxford, The Joint Research Office, OUH Cowley, Oxford, UK
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26
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Gane EJ, Kim W, Lim TH, Tangkijvanich P, Yoon JH, Sievert W, Sukeepaisarnjaroen W, Thompson AJ, Pavlovic V, Surujbally B, Wat C, Brown BD, Achneck HE, Yuen MF. First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection. J Hepatol 2023; 79:1139-1149. [PMID: 37524230 DOI: 10.1016/j.jhep.2023.07.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 06/12/2023] [Accepted: 07/09/2023] [Indexed: 08/02/2023]
Abstract
BACKGROUND & AIMS RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). METHODS This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). RESULTS RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. CONCLUSIONS These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. CLINICAL TRIAL NUMBER ClinicalTrials.gov NCT03772249. IMPACT AND IMPLICATIONS Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians.
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Affiliation(s)
- Edward J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital and University of Auckland, Auckland, New Zealand
| | - Won Kim
- Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
| | | | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| | | | | | | | | | | | | | - Cynthia Wat
- Roche Products, Welwyn Garden City, United Kingdom
| | - Bob D Brown
- Dicerna Pharmaceuticals Inc., a Novo Nordisk Company, Lexington, Massachusetts, United States
| | - Hardean E Achneck
- Dicerna Pharmaceuticals Inc., a Novo Nordisk Company, Lexington, Massachusetts, United States
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
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27
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Cole AG, Kultgen SG, Mani N, Quintero JG, Yi Fan K, Ardzinski A, Stever K, Dorsey BD, Phelps JR, Lee ACH, Thi EP, Chiu T, Tang S, Horanyi PS, Mayclin SJ, Harasym TO, Sofia MJ. Design, synthesis, and structure-activity relationship of a bicyclic HBV capsid assembly modulator chemotype leading to the identification of clinical candidate AB-506. Bioorg Med Chem Lett 2023; 94:129456. [PMID: 37633618 DOI: 10.1016/j.bmcl.2023.129456] [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: 07/06/2023] [Revised: 08/15/2023] [Accepted: 08/22/2023] [Indexed: 08/28/2023]
Abstract
Disruption of the HBV capsid assembly process through small-molecule interaction with HBV core protein is a validated target for the suppression of hepatitis B viral replication and the development of new antivirals. Through combination of key structural features associated with two distinct series of capsid assembly modulators, a novel aminochroman-based chemotype was identified. Optimization of anti-HBV potency through generation of SAR in addition to further core modifications provided a series of related functionalized aminoindanes. Key compounds demonstrated excellent cellular potency in addition to favorable ADME and pharmacokinetic profiles and were shown to be highly efficacious in a mouse model of HBV replication. Aminoindane derivative AB-506 was subsequently advanced into clinical development.
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Affiliation(s)
- Andrew G Cole
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA.
| | - Steven G Kultgen
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Nagraj Mani
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Jorge G Quintero
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Kristi Yi Fan
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Andrzej Ardzinski
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Kim Stever
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Bruce D Dorsey
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Janet R Phelps
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Amy C H Lee
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Emily P Thi
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Tim Chiu
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Sunny Tang
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Peter S Horanyi
- UCB Pharma, 87 Cambridge Park Drive, Cambridge, MA 02140, USA
| | | | - Troy O Harasym
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
| | - Michael J Sofia
- Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA
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Li H, Wang C, Chai L, Qi X. Combination treatment of pegylated interferon and tenofovir versus tenofovir for people with chronic hepatitis B. Cochrane Database Syst Rev 2023; 2023:CD015730. [PMCID: PMC10401907 DOI: 10.1002/14651858.cd015730] [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: 12/09/2024]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of pegylated interferon combined with tenofovir versus tenofovir monotherapy in adults with chronic hepatitis B.
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29
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Li J, Han KX, Shen JP, Sun WJ, Gao L, Gao YF. Value of XGBoost machine learning model for diagnosis of hepatitis B cirrhosis. Shijie Huaren Xiaohua Zazhi 2023; 31:544-554. [DOI: 10.11569/wcjd.v31.i13.544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/25/2023] [Accepted: 06/21/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND The progression of chronic hepatitis B into cirrhosis is slow and easily ignored, and the construction of a noninvasive diagnostic model for cirrhosis based on routine clinical indicators has become a hot research topic. However, there is still a lack of machine learning models regarding the early diagnosis of cirrhosis.
AIM To investigate the performance of the extreme gradient boosting (XGBoost) machine model in the diagnosis of hepatitis B cirrhosis.
METHODS A retrospective analysis was performed on 1087 patients with chronic hepatitis B virus infection (CHBV) diagnosed for the first time at the Department of Infection, The First/Second Affiliated Hospital of Anhui Medical University from 2010 to 2018. The patients were divided into training and validation sets in a 3:1 ratio according to the randomization principle. Clinical data of all study participants were collected and prediction models were constructed using XGBoost machine learning model. Meanwhile, the aspartate aminotransferase/platelet ratio index (APRI) and fibrosis-4 index (FIB-4) scores were calculated and compared with the XGBoost machine learning model. Area under the curve (AUC) was used to assess the model discrimination, and calibration curve (CA) and decision curve analysis (DCA) were used to assess the model calibration and benefit.
RESULTS A total of 1087 CHBV patients were included, including 817 in the training set and 270 in the validation set. There was no statistical difference between the training and validation sets for all predictor variables (P > 0.05). Cirrhosis occurred in 103 patients in the training set, and APRI and FIB-4 scores were significantly higher in cirrhotic patients than in non-cirrhotic patients (P < 0.05). The relative importance of platelets was the highest among all predictors. The AUCs of the model in the training and validation sets were 0.95 and 0.86 (P < 0.05), respectively, and the Kappa values were 0.78 and 0.74, which suggested that the model was reproducible. CA curve analysis indicated that the model predicted a high degree of agreement with the true situation fit. DCA of the training and validation sets implied that the developed model could result in a high degree of benefit for patients. XGBoost machine learning model was significantly more efficient for the diagnosis of cirrhosis than APRI and FIB-4 scores.
CONCLUSION The XGBoost machine learning model constructed in this study based on common clinical information of CHBV patients has an excellent performance for the diagnosis of cirrhosis and deserves further clinical promotion.
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Affiliation(s)
- Ji Li
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Ke-Xing Han
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Jia-Pei Shen
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Wei-Jie Sun
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Long Gao
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Yu-Feng Gao
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
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30
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Feld JJ, Lok AS, Zoulim F. New Perspectives on Development of Curative Strategies for Chronic Hepatitis B. Clin Gastroenterol Hepatol 2023; 21:2040-2050. [PMID: 37080262 DOI: 10.1016/j.cgh.2023.02.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/24/2023] [Accepted: 02/28/2023] [Indexed: 04/22/2023]
Abstract
A functional cure of chronic hepatitis B defined as sustained hepatitis B surface antigen loss after finite course of therapy is rarely achieved with current therapy but is the goal of novel treatments. Understanding the virological and immunological mechanisms of hepatitis B virus persistence has enabled the identification of novel treatment targets, drug discovery, and the evaluation of novel agents in clinical trials. Lessons were learned from early phase 1 and phase 2 trials regarding the antiviral activity and safety profile of these agents. There is a strong rationale to combine agents to reduce viral replication, reduce viral antigen load, invigorate immune responses, and induce specific adaptive immune responses. Nucleos(t)ide analogs will likely remain an essential backbone of future combinations to control viral replication and prevent resistance to antiviral drugs. In this review, we discuss perspectives on approaches to achieving functional cure, with a review of virological and immunological strategies, highlighting challenges and unresolved questions with the various attempts to achieve cure, as well as exploring alternative endpoints such as partial cure and new noninvasive viral and immunological biomarkers to stratify patients and predict/monitor antiviral response.
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Affiliation(s)
- Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| | - Fabien Zoulim
- INSERM Unit 1052 - Cancer Research Center of Lyon, Lyon Hepatology Institute, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
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31
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Chen W, Gong Y, Long G, Wang X, Yang Y, Liu J, Li H, Tong X, Zhao Q, Yang L, Zuo J, Hu Y. A prodrug of the capsid assembly modulator improved druggability and lowing HBsAg and HBeAg for the treatment of chronic hepatitis B. Eur J Med Chem 2023; 257:115485. [PMID: 37229833 DOI: 10.1016/j.ejmech.2023.115485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/11/2023] [Accepted: 05/12/2023] [Indexed: 05/27/2023]
Abstract
CAMs were disclosed to alter cccDNA levels with sustained hepatitis B surface antigen (HBsAg) loss or seroconversion in preclinical investigation. Here, we report the discovery of a prodrug Yhhu6669 as CAMs based on the intestinal peptide transporter. This compound exhibited the promising anti-HBV activity with sustained suppression of HBV DNA, as well as HBsAg and HBeAg in the AAV HBV mouse model by oral treatment for 7 weeks and maintained for a further 8 weeks following drug withdraw. Our results show an alternative possibility for a functional cure by specific CAMs and provide the basis for the further mechanism study.
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Affiliation(s)
- Wuhong Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China
| | - Ying Gong
- Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Guozhang Long
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xinran Wang
- Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, College of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing, 210023, China
| | - Yurong Yang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, College of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing, 210023, China
| | - Jia Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1st Xiangshan Branch Alley, Hangzhou, 310024, China
| | - Heng Li
- Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xiankun Tong
- Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China
| | - Qiliang Zhao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Li Yang
- Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China.
| | - Jianping Zuo
- Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; School of Chinese Materia Medica, College of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing, 210023, China.
| | - Youhong Hu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1st Xiangshan Branch Alley, Hangzhou, 310024, China.
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32
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Huang Q, Xiao X, Zhuang X, Chen W, Huang Y, Liao J, Wang W, Wang Y, Lu L, Liu Z, Huang J. Peripheral Circulating Exosomal-miRNAs Potentially Mediate the Sensitivity to Interferon Treatment in Chronic Hepatitis B Virus Patients. Viral Immunol 2023; 36:209-221. [PMID: 36944116 DOI: 10.1089/vim.2022.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023] Open
Abstract
Pegylated interferon alfa-2b (Peg-IFN α-2b), a first-line treatment for hepatitis B virus (HBV) infection, can significantly achieve HBsAg clearance in clinic. However, only 30-40% of patients had achieved HBsAg clearance after Peg-IFN α-2b administration. The biological targets and the underline mechanisms that distinguish sensitive and insensitive populations to interferon therapy are still unclear. In the present study, only 33.33% of patients achieved HBsAg loss after 48 weeks of Peg-IFN α-2b therapy. Thirty-six exosomal-microRNAs (miRNAs) in the sensitive group were identified that might induce sensitivity specifically, whereas 32 exosomal-miRNAs in the insensitive group were identified that might induce insensitive specifically. Among these miRNAs, five miRNAs (miR-425-5p, miR-8485, miR-619-5p, miR-181a-5p, and miR-484) might increase the sensitivity to Peg-IFN α-2b therapy by regulating key genes GSK3B, KRAS, FLT1, or GRB2, whereas, 13 miRNAs (miR-195-5p, miR-215-5p, miR-9-5p, miR-130a-3p, miR-214-3p, miR-149-5p, miR-429, miR-200b-3p, miR-200c-3p, miR-16-2-3p, miR-141-3p, miR-200a-3p, and miR-218-5p) might decrease the sensitivity to Peg-IFN α-2b therapy by regulating key genes, FGF2, GSK3B, PDGFRA, FGFR1, KRAS, FLT1, MYC, TGFB2, EFNA1, MAPK9, or GRB2. Furthermore, seven novel miRNAs, namely Novel_352, Novel_459, Novel_527, Novel_677, Novel_717, Novel_749, and Novel_801 were found to be downregulated specifically in the sensitive group, whereas, Novel_142 and Novel_664 were found to be downregulated specifically in the insensitive group. Our data indicate that the serum exosomal-miRNAs could be involved in regulating the sensitivity of chronic HBV (CHB) patients to Peg-IFN α-2b therapy, which might suggest potential novel therapeutic biomarkers and standard options for CHB patients. Clinical Trials.gov ID: NCT04035837.
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Affiliation(s)
- Qiuju Huang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, College of Pharmacy, Guangxi Medical University, Nanning, China
| | - Xin Xiao
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xuerong Zhuang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenli Chen
- Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yanfang Huang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinyao Liao
- Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wensheng Wang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Wang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Linlin Lu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhongqiu Liu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Huang
- Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Pan Y, Xia H, He Y, Zeng S, Shen Z, Huang W. The progress of molecules and strategies for the treatment of HBV infection. Front Cell Infect Microbiol 2023; 13:1128807. [PMID: 37009498 PMCID: PMC10053227 DOI: 10.3389/fcimb.2023.1128807] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/03/2023] [Indexed: 03/17/2023] Open
Abstract
Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis B virus (HBV)-related diseases resulted in approximately 555,000 deaths globally. In view of its high lethality, the treatment of HBV infections has always presented a huge challenge. The World Health Organization (WHO) came up with ambitious targets for the elimination of hepatitis B as a major public health threat by 2030. To accomplish this goal, one of the WHO's strategies is to develop curative treatments for HBV infections. Current treatments in a clinical setting included 1 year of pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both treatments have demonstrated outstanding antiviral effects, it has been difficult to develop a cure for HBV. The reason for this is that covalently closed circular DNA (cccDNA), integrated HBV DNA, the high viral burden, and the impaired host immune responses all hinder the development of a cure for HBV. To overcome these problems, there are clinical trials on a number of antiviral molecules being carried out, all -showing promising results so far. In this review, we summarize the functions and mechanisms of action of various synthetic molecules, natural products, traditional Chinese herbal medicines, as clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), all of which could destroy the stability of the HBV life cycle. In addition, we discuss the functions of immune modulators, which can enhance or activate the host immune system, as well some representative natural products with anti-HBV effects.
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Affiliation(s)
| | | | | | | | | | - Wenhai Huang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
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Wang ZL, Zheng JR, Yang RF, Huang LX, Chen HS, Feng B. An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients: High-sensitivity Quantitative HBsAg Loss. J Clin Transl Hepatol 2023; 11:197-206. [PMID: 36406318 PMCID: PMC9647097 DOI: 10.14218/jcth.2022.00289] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/12/2022] [Accepted: 08/02/2022] [Indexed: 12/04/2022] Open
Abstract
In the era of antiviral therapy, the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus (HBV) replication to the pursuit of serological clearance of HBs surface antigen (HBsAg). Based on the life cycle of HBV, HBsAg originates from covalently closed circular DNA (cccDNA) and integrated HBV DNA, thus reflecting their transcriptional activity. Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA. HBsAg loss improves the recovery of abnormal immune function, which in turn, may further promote the clearance of residual viruses. Combined with functional cure and the great improvement of clinical outcomes, the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B (CHB). For many other risk factors besides HBV itself, patients with HBsAg loss still need regular monitoring. In this review, we summarized the evolution of CHB treatment, the origin of serum HBsAg, the pattern of HBsAg seroclearance, and the effect of HBsAg loss on immune function and disease outcomes. In addition, we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.
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Affiliation(s)
| | | | | | | | | | - Bo Feng
- Correspondence to: Bo Feng, Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, 11 Xizhimen South Street, Xicheng District, Beijing 100044, China. ORCID: https://orcid.org/0000-0001-5084-6715. Tel: +1-381-025-4109, Fax: +86-10-66515490, E-mail:
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35
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Yu HC, Huo WW, Lin KH, Sun WC, Lee CN. Trend patterns of HBsAg kinetics in chronic hepatitis B patients during nucleos(t)ide analogue therapy based on ARMA models. J Formos Med Assoc 2023; 122:458-469. [PMID: 36725372 DOI: 10.1016/j.jfma.2023.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/24/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023]
Abstract
BACKGROUND Trend pattern analysis are lacking for hepatitis B surface antigen (HBsAg) kinetics in chronic hepatitis B (CHB) patients during nucleos(t)ide analogue (Nuc) therapy. We evaluated the trend patterns of HBsAg kinetics by time series analysis and forecasting times to HBsAg seroclearance accordingly. METHODS A total of 116 CHB patients with documented three-month HBsAg levels during the previous more than five years of Nuc therapy were included. The piecewise linear trends of the autoregressive-moving average (ARMA) model were used for time series analysis of HBsAg kinetics trends. Best fitted models were created for each patient using HBsAg datasets with backtracking capability. Predicted time to HBsAg seroclearance was calculated accordingly. RESULTS Four trend patterns of HBsAg kinetics were found: no trend (n = 22, 19.0%), single trend (n = 16, 13.8%), biphasic trend with rapid-slow decline (n = 56, 48.2%) and biphasic trend with rise-decline (n = 22, 19.0%). Except for no-trend patients, the trend became slow reduction as HBsAg declined. Only 6.1% of patients continued rapid decline when the initial HBsAg of the last trend reached <100 IU/mL. Last trend slopes < -10 and rise-decline patterns indicate greater chances of achieving HBsAg seroclearance within two years. CONCLUSIONS Best fitted ARMA models of HBsAg kinetics can be created individually for patients during Nuc therapy. About 67.2% patients have biphasic trend patterns, suggesting the dynamic nature of HBsAg kinetics over time. Trend patterns and last trend slopes predict individual times to HBsAg seroclearance.
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Affiliation(s)
- Hsien-Chung Yu
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Department of Nursing, Meiho Institute of Technology, Ping-Tung 912, Taiwan; Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
| | - Wen-Wei Huo
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Institute of Economics, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Kung-Hung Lin
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Department of Nursing, Meiho Institute of Technology, Ping-Tung 912, Taiwan
| | - Wei-Chih Sun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
| | - Ching-Nun Lee
- Institute of Economics, National Sun Yat-sen University, Kaohsiung 804, Taiwan
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36
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Stephan AS, Kosinska AD, Mück-Häusl M, Muschaweckh A, Jäger C, Röder N, Heikenwälder M, Dembek C, Protzer U. Evaluation of the Effect of CD70 Co-Expression on CD8 T Cell Response in Protein-Prime MVA-Boost Vaccination in Mice. Vaccines (Basel) 2023; 11:vaccines11020245. [PMID: 36851121 PMCID: PMC9966001 DOI: 10.3390/vaccines11020245] [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: 12/04/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Here, we investigate the potential of CD70 co-expression during viral vector boost vaccination to improve an antigen-specific T cell response. To determine the chance of activating antigen-specific T cells by CD70, we used the HBV core antigen as a model antigen in a heterologous protein-prime, Modified Vaccinia virus Ankara (MVA) boost vaccination scheme. Both the HBV core and a CD70 expression cassette were co-expressed upon delivery by an MVA vector under the same promoter linked by a P2A site. To compare immunogenicity with and without CD70 co-expression, HBV-naïve, C57BL/6 (wt) mice and HBV-transgenic mice were prime-vaccinated using recombinant HBV core antigen followed by the MVA vector boost. Co-expression of CD70 increased the number of vaccine-induced HBV core-specific CD8 T cells by >2-fold and improved their effector functions in HBV-naïve mice. In vaccinated HBV1.3tg mice, the number and functionality of HBV core-specific CD8 T cells was slightly increased upon CD70 co-expression in low-viremic, but not in high-viremic animals. CD70 co-expression did not impact liver damage as indicated by ALT levels in the serum, but increased the number of vaccine-induced, proliferative T cell clusters in the liver. Overall, this study indicates that orchestrated co-expression of CD70 and a vaccine antigen may be an interesting and safe means of enhancing antigen-specific CD8 T cell responses using vector-based vaccines, although in our study it was not sufficient to break immune tolerance.
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Affiliation(s)
- Ann-Sophie Stephan
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Anna D. Kosinska
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
| | - Martin Mück-Häusl
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Andreas Muschaweckh
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine, 81675 Munich, Germany
| | - Clemens Jäger
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Natalie Röder
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Mathias Heikenwälder
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany
| | - Claudia Dembek
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
- Correspondence: (C.D.); (U.P.); Tel.: +49-89-4140-6821 (U.P.)
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
- Correspondence: (C.D.); (U.P.); Tel.: +49-89-4140-6821 (U.P.)
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Li X, Xu L, Lu L, Liu X, Yang Y, Wu Y, Han Y, Li X, Li Y, Song X, Cao W, Li T. CD4 + T cell counts and soluble programmed death-1 at baseline correlated with hepatitis B surface antigen decline in HIV/HBV coinfection during combined antiretroviral therapy. Front Cell Infect Microbiol 2023; 13:1178788. [PMID: 37207191 PMCID: PMC10189149 DOI: 10.3389/fcimb.2023.1178788] [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: 03/03/2023] [Accepted: 04/19/2023] [Indexed: 05/21/2023] Open
Abstract
Background Several studies have described the rapid decline and clearance of hepatitis B surface antigen (HBsAg) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection after initiating combined antiretroviral therapy (cART). Early decline of HBsAg levels is associated with HBsAg seroclearance in the treatment of chronic HBV infection. This study aims to evaluate the HBsAg kinetics and the determinants of early HBsAg decline in patients with HIV/HBV coinfection during cART. Methods A total of 51 patients with HIV/HBV coinfection were enrolled from a previously established HIV/AIDS cohort and followed for a median of 59.5 months after cART initiation. Biochemical tests, virology and immunology assessments were measured longitudinally. The kinetics of HBsAg during cART were analyzed. Soluble programmed death-1 (sPD-1) levels and immune activation markers (CD38 and HLA-DR) were measured at baseline, 1-year and 3-year during treatment. HBsAg response was defined as a decline of more than 0.5 log10 IU/ml at 6 months from the baseline after initiation of cART. Results HBsAg declined faster (0.47 log10 IU/mL) in the first six months and attained a decrease of 1.39 log10 IU/mL after 5-year therapy. Seventeen (33.3%) participants achieved a decline of more than 0.5 log10 IU/ml at the first 6 months of cART(HBsAg response) of which five patients achieved HBsAg clearance at a median of 11 months (range: 6-51 months). Multivariate logistic analysis showed the lower baseline CD4+ T cell levels (OR=6.633, P=0.012) and sPD-1 level (OR=5.389, P=0.038) were independently associated with HBsAg response after cART initiation. The alanine aminotransferase abnormality rate and HLA-DR expression were significantly higher in patients who achieved HBsAg response than in those who did not achieve HBsAg response after cART initiation. Conclusion Lower CD4 + T cells, sPD-1, and immune activation were related to a rapid HBsAg decline in patients with HIV/HBV-coinfection after the initiation of cART. These findings imply that immune disorders induced by HIV infection may disrupt immune tolerance to HBV, leading to a faster decline in HBsAg levels during coinfection.
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Affiliation(s)
- Xiaodi Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ling Xu
- Department of Infectious Diseases and Clinical Microbiology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Lianfeng Lu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaosheng Liu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Yang Yang
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuanni Wu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yang Han
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoxia Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yanling Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaojing Song
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Cao
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Taisheng Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- *Correspondence: Taisheng Li,
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Shi Y, Jin X, Wu S, Liu J, Zhang H, Cai X, Yang Y, Zhang X, Wei J, Luo M, Zhou H, Zhou H, Huang A, Wang D. Release of hepatitis B virions is positively regulated by glucose-regulated protein 78 through direct interaction with preS1. J Med Virol 2023; 95:e28271. [PMID: 36321566 PMCID: PMC10107996 DOI: 10.1002/jmv.28271] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 07/19/2022] [Accepted: 08/27/2022] [Indexed: 12/04/2022]
Abstract
In this study, we investigated the mechanism of hepatitis B virus (HBV)-enveloped particle release. Specifically, we used preS1 as a bait protein to screen host proteins using mass spectroscopy, with the results of immunofluorescence, western blot, co-immunoprecipitation, isothermal titration calorimetry, and pull-down assays identifying glucose-regulated protein (GRP)78 as a specific target for preS1 binding. We employed transcriptome sequencing, enzyme-linked immunosorbent assays, and particle gel assays to investigate the mechanism of GRP78-mediated positive regulation of HBV-enveloped particle release. Additionally, we performed phage-display, surface plasmon resonance, and molecular-docking assays to assess peptides inhibiting enveloped-particle release. We found that HBV upregulated GRP78 expression in liver cell lines and the serum of patients with chronic hepatitis B. Furthermore, GRP78 promoted the release of HBV-enveloped particles in vitro and in vivo within an HBV transgenic mouse model. Moreover, we identified interactions of preS1 peptides with GRP78 via hydrogen bonding and hydrophobic interactions, which effectively inhibited its interaction with HBV-enveloped particles and their subsequent release. These findings provide novel insights regarding HBV virion release, and demonstrated that GRP78 interacted with preS1 to positively regulate the release of HBV-enveloped particles, suggesting GRP78 as a potential therapeutic target for inhibiting HBV infection.
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Affiliation(s)
- Yueyuan Shi
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China.,College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, China.,Department of Clinical Laboratory, The People's Hospital of Yubei District of Chongqing City, Yubei, Chongqing, China
| | - Xin Jin
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, China.,Department of Clinical Laboratory, The Second Hospital of Harbin, Harbin City, Heilongjiang Province, China
| | - Shuang Wu
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China.,Department of Clinical Laboratory, The Affiliated Children Hospital of Xi'an Jiaotong University, Xi'an City, Shanxi Province, China
| | - Junye Liu
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China.,Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an City, Shanxi Province, China
| | - Hongpeng Zhang
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China.,Department of Blood Transfusion, Women and Children's Hospital of Chongqing Medical University, Yubei, Chongqing, China
| | - Xuefei Cai
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China
| | - Yuan Yang
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China
| | - Xiang Zhang
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, China
| | - Jie Wei
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, China
| | - Miao Luo
- Department of Clinical Laboratory, The People's Hospital of Yubei District of Chongqing City, Yubei, Chongqing, China
| | - Hua Zhou
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, China
| | - Huihao Zhou
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China
| | - Deqiang Wang
- Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yuzhong, Chongqing, China.,College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, China
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Yardeni D, Chang KM, Ghany MG. Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure. Gastroenterology 2023; 164:42-60.e6. [PMID: 36243037 PMCID: PMC9772068 DOI: 10.1053/j.gastro.2022.10.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/25/2022] [Accepted: 10/04/2022] [Indexed: 02/03/2023]
Abstract
The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Kyong-Mi Chang
- Medical Research, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
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40
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Cao W, Lu H, Zhang L, Wang S, Deng W, Jiang T, Lin Y, Yang L, Bi X, Lu Y, Zhang L, Shen G, Liu R, Chang M, Wu S, Gao Y, Hao H, Xu M, Chen X, Hu L, Xie Y, Li M. Functional molecular expression of nature killer cells correlated to HBsAg clearance in HBeAg-positive chronic hepatitis B patients during PEG-IFN α-2a therapy. Front Immunol 2022; 13:1067362. [PMID: 36479104 PMCID: PMC9720173 DOI: 10.3389/fimmu.2022.1067362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/02/2022] [Indexed: 11/22/2022] Open
Abstract
Objective To explore whether the frequencies and functional molecules expression of Natural Killer cells (NK cells) are related to hepatitis B surface antigen (HBsAg) disappearance in hepatitis B e envelope antigen (HBeAg)-positive patients with chronic hepatitis B (CHB) throughout peginterferon alpha-2a (PEG-IFN α-2a) treatment. Methods In this prospective research, HBeAg-positive patients with CHB received PEG-IFN α-2a treatment, completing 4-year follow-up. After PEG-IFN α-2a treatment, undetectable HBV DNA, HBsAg loss, and HBeAg disappearance were defined as functional cure. Proportions of NK, CD56dim, CD56bright, NKp46+, NKp46dim, NKp46high, and interferon alpha receptor 2 (IFNAR2)+ NK cells, and the mean fluorescence intensity (MFI) of NK cell surface receptors IFNAR2 and NKp46 were detected. Results 66 patients were enrolled into the study in which 17 patients obtained functional cure. At baseline, hepatitis B virus desoxyribose nucleic acid (HBV DNA) titer in patients with functional cure was remarkably lower than that in Non-functional cure group. Compared with baseline, HBV DNA levels, HBsAg levels, and HBeAg levels significantly declined at week 12 and 24 of therapy in patients with functional cure. At baseline, the negative correlation between CD56bright NK% and HBV DNA and the negative correlation between CD56dim NK% and HBV DNA was showed; CD56bright NK% and IFNAR2 MFI in patients with functional cure were remarkably higher than those in patients without functional cure. After therapy, CD56bright NK% and NKp46high NK% in patients with functional cure were higher than those in patients without functional cure. In Functional cure group, after 24 weeks of treatment NK%, CD56bright NK%, IFNAR2 MFI weakly increased, and NKp46high NK% and NKp46 MFI significantly increased, meanwhile, CD56dim NK% and NKp46dim NK% decreased. Only NKp46 MFI increased after therapy in patients without functional cure. Conclusion The lower HBV DNA load and the higher CD56bright NK% before therapy, and the higher the post-treatment CD56bright NK%, IFNAR2 MFI, NKp46high NK%, the easier to achieve functional cure.
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Affiliation(s)
- Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China,Department of Infectious Diseases, Miyun Teaching Hospital, Capital Medical University, Beijing, China
| | - Huihui Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China,Department of Obstetrics and Gynecology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Luxue Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China,Infectious Disease Department, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoxue Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China,*Correspondence: Minghui Li, ; Yao Xie,
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China,*Correspondence: Minghui Li, ; Yao Xie,
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Kramvis A, Chang KM, Dandri M, Farci P, Glebe D, Hu J, Janssen HLA, Lau DTY, Penicaud C, Pollicino T, Testoni B, Van Bömmel F, Andrisani O, Beumont-Mauviel M, Block TM, Chan HLY, Cloherty GA, Delaney WE, Geretti AM, Gehring A, Jackson K, Lenz O, Maini MK, Miller V, Protzer U, Yang JC, Yuen MF, Zoulim F, Revill PA. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol 2022; 19:727-745. [PMID: 35859026 PMCID: PMC9298709 DOI: 10.1038/s41575-022-00649-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/16/2022] [Indexed: 12/13/2022]
Abstract
Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.
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Affiliation(s)
- Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Hamburg, Germany
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dieter Glebe
- National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Giessen, Germany
| | - Jianming Hu
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Philadelphia, PA, USA
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Daryl T Y Lau
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Capucine Penicaud
- Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Teresa Pollicino
- Laboratory of Molecular Hepatology, Department of Human Pathology, University Hospital "G. Martino" of Messina, Messina, Italy
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Florian Van Bömmel
- Department of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Ourania Andrisani
- Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
| | | | | | - Henry L Y Chan
- Chinese University of Hong Kong, Shatin, Hong Kong
- Union Hospital, Shatin, Hong Kong
| | | | | | - Anna Maria Geretti
- Roche Pharma Research & Early Development, Basel, Switzerland
- Department of Infectious Diseases, Fondazione PTV, Faculty of Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Adam Gehring
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | | | - Mala K Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | | | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Fabien Zoulim
- INSERM Unit 1052 - Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
- Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
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Hu Q, Qi X, Yu Y, Gao Y, Zhang X, Wang Q, Zhang X, Zhuo Y, Li J, Zhang J, Chen L, Huang Y. The efficacy and safety of adding on or switching to peginterferon α-2b in HBeAg-positive chronic hepatitis B patients with long-term entecavir treatment: a multicentre randomised controlled trial. Aliment Pharmacol Ther 2022; 56:1394-1407. [PMID: 36128636 DOI: 10.1111/apt.17222] [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] [Received: 06/04/2022] [Revised: 06/27/2022] [Accepted: 09/04/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND & AIMS The strategies of adding on or switching to peginterferon (PEG-IFN) improved the serological response rates in patients with chronic hepatitis B (CHB) who had previously experienced treatment with nucleos(t)ide analogues. However, robust data on which combination strategy is more effective remain lacking. METHODS In this multicentre, parallel, open-label, randomised, controlled trial, patients with HBeAg-positive CHB who were treated with entecavir ≥2 years, and had hepatitis B surface antigen (HBsAg) <3000 IU/ml, HBeAg <200S/CO and HBV DNA <50 IU/ml were randomly assigned in a 1:1:1 ratio to add on PEG-IFN, switch to PEG-IFN or continue entecavir monotherapy for 48 weeks. The primary endpoint was HBeAg seroconversion at week 48. RESULTS A total of 153 patients were randomised into three treatment arms (50 in add-on, 52 in switch-to and 51 in monotherapy). Compared with continuous entecavir monotherapy, both add-on and switch-to strategies achieved higher rates of HBeAg seroconversion (18.0% vs. 2.0%, p = 0.007; 19.2% vs. 2.0%, p = 0.005, respectively), HBeAg loss (24.0% vs. 5.9%, p = 0.010; 23.1% vs. 5.9%, p = 0.013, respectively), HBsAg < 100 IU/ml (30.0% vs. 0%, p < 0.001; 34.6% vs. 0%, p < 0.001, respectively), and higher HBsAg reduction (-0.90 vs. -0.06 log10 IU/ml, p < 0.001; -0.92 vs. -0.06 log10 IU/ml, p < 0.001, respectively) at week 48. The efficacy was comparable between add-on and switch-to arms (p > 0.05). Adverse events were mainly related to PEG-IFN but generally tolerable. CONCLUSION In patients with CHB who achieved virological response with long-term entecavir, both adding on and switching to PEG-IFN are alternative strategies resulting in higher rates of HBeAg seroconversion and HBsAg reduction than continuous entecavir. CLINICAL TRIALS REGISTRATION Chinese Clinical Trial Registry (www.chictr.org.cn, identifier: ChiCTR-IPR-17012055).
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Affiliation(s)
- Qiankun Hu
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xun Qi
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yiqi Yu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yueqiu Gao
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinxin Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianqian Wang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xueyun Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yunhui Zhuo
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Li
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Liang Chen
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.,Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
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43
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Hu Y, Sun F, Yuan Q, Du J, Hu L, Gu Z, Zhou Q, Du X, He S, Sun Y, Wang Q, Fan L, Wang L, Qin S, Chen S, Li J, Wu W, Mao J, Zhou Y, Zhou Q, Zhang G, Ding CZ. Discovery and preclinical evaluations of GST-HG131, a novel HBV antigen inhibitor for the treatment of chronic hepatitis B infection. Bioorg Med Chem Lett 2022; 75:128977. [PMID: 36089112 DOI: 10.1016/j.bmcl.2022.128977] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/25/2022] [Accepted: 09/04/2022] [Indexed: 11/09/2022]
Abstract
Chronic hepatitis B (CHB) remains a significant health challenge worldwide. The current treatments for CHB achieve less than 10% cure rates, majority of the patients are on therapy for life. Therefore, cure of CHB is a high unmet medical need. HBV surface antigen (HBsAg) loss and seroconversion are considered as the key for the cure. RG7834 is a novel, orally bioavailable small molecule reported to reduce HBV antigens. Based on RG7834 chemistry, we designed and discovered a series of dihydrobenzopyridooxazepine (DBP) series of HBV antigen inhibitors. Extensive SAR studies led us to GST-HG131 with excellent reduction of HBV antigens (both HBsAg and HBeAg) in vitro and in vivo. GST-HG131 improved safety in rat toxicology studies over RG7834. The promising inhibitory activity, together with animal safety enhancement, merited GST-HG131 progressed into clinical development in 2020 (NCT04499443).
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Affiliation(s)
- Yanbin Hu
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Fei Sun
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Qiang Yuan
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Jinhua Du
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Lihong Hu
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Zhengxian Gu
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Qiong Zhou
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Xiaoting Du
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Shibo He
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Ya Sun
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Qian Wang
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Lirong Fan
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Lina Wang
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Shaohua Qin
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Shuhui Chen
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Jian Li
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Wenqiang Wu
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - John Mao
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - Yixin Zhou
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - Qiaoyun Zhou
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - George Zhang
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - Charles Z Ding
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
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Hoogeveen RC, Dijkstra S, Bartsch LM, Drescher HK, Aneja J, Robidoux MP, Cheney JA, Timm J, Gehring A, de Sousa PSF, Ximenez L, Peliganga LB, Pitts A, Evans FB, Boonstra A, Kim AY, Lewis-Ximenez LL, Lauer GM. Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen + infection. J Hepatol 2022; 77:1276-1286. [PMID: 35716846 DOI: 10.1016/j.jhep.2022.05.041] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/12/2022] [Accepted: 05/25/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. A better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses in patients with different degrees of viral control. METHODS We obtained blood from 124 HBV-infected individuals, including those with acute self-limiting HBV infection, chronic infection, and chronic infection with functional cure. We screened for HBV-specific T cell specificities by ELISpot, assessed the function of HBV-specific T cells using intracellular cytokine staining, and characterized HBV-specific CD4 T cells using human leukocyte antigen (HLA) class II tetramer staining, all directly ex vivo. RESULTS ELISpot screening readily identified HBV-specific CD4 and CD8 T cell responses in acute resolving infection compared with more limited reactivity in chronic infection. Applying more sensitive assays revealed higher frequencies of functional HBV-specific CD4 T cells, but not CD8 T cells, in functional cure compared to chronic infection. Function independent analysis using HLA multimers also identified more HBV-specific CD4 T cell responses in functional cure compared to chronic infection, with the emergence of CD4 T cell memory both after acute and chronic infection. CONCLUSIONS Functional cure is associated with higher frequencies of functional HBV-specific CD4 memory T cell responses. Thus, immunotherapeutic approaches designed to induce HBV functional cure should also aim to improve CD4 T cell responses. LAY SUMMARY Immunotherapy is a form of treatment that relies on harnessing the power of an individual's immune system to target a specific disease or pathogen. Such approaches are being developed for patients with chronic HBV infection, in an attempt to mimic the immune response in patients who control HBV infection spontaneously, achieving a so-called functional cure. However, what exactly defines protective immune responses remains unclear. Herein, we show that functional cure is associated with robust responses by HBV-specific CD4 T cells (a type of immune cell).
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Affiliation(s)
- Ruben C Hoogeveen
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA; Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Suzan Dijkstra
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - Lea M Bartsch
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - Hannah K Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - Jasneet Aneja
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA; Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - Maxwell P Robidoux
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - James A Cheney
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - Joerg Timm
- Institute of Virology, Heinrich Heine University, University Hospital, Düsseldorf, Germany
| | - Adam Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | - Lya Ximenez
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Luis Baiao Peliganga
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Faculdade de Medicina da Universidade Agostinho Neto, Luanda, Angola; Ministério da Saúde de Angola, Luanda, Angola
| | - Anita Pitts
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - Fiona B Evans
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Arthur Y Kim
- Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | | | - Georg M Lauer
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
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Yin GQ, Chen KP, Gu XC. Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment. World J Gastroenterol 2022; 28:5784-5800. [PMID: 36353205 PMCID: PMC9639659 DOI: 10.3748/wjg.v28.i40.5784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/08/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host’s genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.
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Affiliation(s)
- Guo-Qing Yin
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ke-Ping Chen
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Xiao-Chun Gu
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
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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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Dong H, Hong X, He Y, Bao Z, Zhang Y, Shen S, Wang G, Zhang J, Mo R. A carrier-free metal-organic hybrid nanoassembly with combination anti-viral and hepato-protective activity for hepatitis B treatment. Biomater Sci 2022; 10:4356-4366. [PMID: 35786722 DOI: 10.1039/d2bm00407k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal-organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand-GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.
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Affiliation(s)
- He Dong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Xiaodan Hong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Yingjiao He
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Zhengxiang Bao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Ying Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Shiyang Shen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Jingwei Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
| | - Ran Mo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Metabolism and Pharmacokinetics and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
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Hu Q, Wang Q, Xu W, Huang C, Tao S, Qi X, Zhang Y, Li X, Jiang X, Song J, Li Q, Chen L, Huang Y. Development and Validation of a Non-invasive Model to Predict Liver Histological Lesions in Chronic Hepatitis B Patients With Persistently Normal Alanine Aminotransferase and Detectable Viremia. Front Med (Lausanne) 2022; 9:944547. [PMID: 35911415 PMCID: PMC9326251 DOI: 10.3389/fmed.2022.944547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 06/24/2022] [Indexed: 11/13/2022] Open
Abstract
Background A critical and controversial issue is whether antiviral therapy should be recommended in chronic hepatitis B virus (HBV) infection patients with persistently normal alanine aminotransferase (PNALT) and detectable HBV DNA. The study aimed to develop a non-invasive model for predicting significant liver histological changes (SLHC), which is the histological indication for antiviral therapy in chronic hepatitis B (CHB) patients with PNALT and detectable HBV DNA. Methods 398 chronic HBV infection patients with PNALT and detectable HBV DNA who underwent liver biopsy were divided into the estimation set (n = 256) and validation set (n = 142). A multivariate logistic regression model was developed to predict SLHC in the estimation set, and the diagnostic performance was further validated in the validation set. Results 132 patients (33.2%) with PNALT and detectable HBV DNA had SLHC. Aspartate aminotransferase (AST), cholinesterase (ChE), and liver stiffness measurement (LSM) were identified as the independent predictors of SLHC. The AUROC of the SLHC index, which combined AST, ChE, and LSM, was 0.824 and 0.816 in the estimation and validation set, respectively, for the prediction of SLHC. Applying the SLHC index ≤ 0.15, the presence of SLHC could be excluded with high negative predictive value in the estimation set (93.2%) and in the validation set (90.2%). Applying the SLHC index ≥ 0.55, the presence of SLHC could be considered with high positive predictive value in the estimation set (79.2%) and in the validation set (76.5%). Conclusion The SLHC index provides a high accuracy in predicting liver histological indication for antiviral therapy in CHB patients with PNALT and detectable HBV DNA.
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Affiliation(s)
- Qiankun Hu
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qianqian Wang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wei Xu
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Chenlu Huang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Shuai Tao
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xun Qi
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yi Zhang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xinyan Li
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xuhua Jiang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jie Song
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qiang Li
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Qiang Li,
| | - Liang Chen
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Liang Chen,
| | - Yuxian Huang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- *Correspondence: Yuxian Huang,
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Virological Treatment Monitoring for Chronic Hepatitis B. Viruses 2022; 14:v14071376. [PMID: 35891357 PMCID: PMC9319170 DOI: 10.3390/v14071376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/07/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open
Abstract
More than 250 million people worldwide are currently infected with hepatitis B, despite the effectiveness of vaccination and other preventive measures. In terms of treatment, new therapeutic approaches are rapidly developing, promising to achieve the elimination of infected cells and the complete cure of infection. The on-treatment monitoring of these innovative antiviral treatments will require the implementation of new virological tools. Therefore, new biomarkers are being evaluated besides the traditional virological and serological assays in order to obtain information on different steps of the viral replication cycle and to monitor response to therapy more accurately. The purpose of this work is to describe both standard and innovative tools for chronic hepatitis B treatment monitoring, and to analyse their potential and feasibility.
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50
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Cao W, Xie S, Zhang L, Bi X, Lin Y, Yang L, Lu Y, Liu R, Chang M, Wu S, Shen G, Dong J, Xie Y, Li M. Expression of Functional Molecule on Plasmacytoid Dendritic Cells Is Associated With HBsAg Loss in HBeAg-Positive Patients During PEG-IFN α-2a Treatment. Front Immunol 2022; 13:891424. [PMID: 35663955 PMCID: PMC9160736 DOI: 10.3389/fimmu.2022.891424] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/22/2022] [Indexed: 12/18/2022] Open
Abstract
Objective The ideal endpoint of antiviral therapy in chronic hepatitis B (CHB) patients is to clear hepatitis B surface antigen (HBsAg). This study aimed to evaluate whether the expression of functional molecules on plasmacytoid dendritic cells (pDCs) is associated with HBsAg loss in HBeAg-positive patients during peginterferon alpha-2a (PEG IFN α-2a) therapy. Methods A single-center prospective cohort study was performed in HBeAg-positive CHB patients who were treated with PEG-IFN α-2a and followed up for 4 years. HBsAg clearance, HBeAg loss and undetectable HBV DNA achieved by PEG-IFN α-2a therapy was considered as functional cure. The frequencies of pDC and CD86+ pDC in peripheral blood, and the mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDC were measured at starting therapy, after 12 and 24 weeks of therapy. Results Of 63 patients enrolled, 17 patients achieved HBsAg loss. The baseline HBV DNA load in Non-functional-cure group was significantly higher than that in Functional cure group, and the CD86+ pDC% was significantly lower in patients without functional cure. HBV DNA load (OR=0.146, P = 0.002) and CD86+ pDC% (OR=1.183, P = 0.025) were independent factors associated with functional cure confirmed by binary logistic regression analysis. In the Functional cure group, HBsAg, HBeAg, and HBV DNA loads decreased remarkably after 12 weeks and 24 weeks of treatment compared to baseline. In Non-functional-cure group, CD86+ pDC% and CD86MFI increased significantly from baseline after 12 weeks of treatment. In the Functional cure group, compared with baseline, pDC% increased significantly at 24 weeks, while CD86MFI increased significantly after 24 weeks of treatment. Conclusion The lower the baseline HBV DNA load and the more the baseline CD86+ pDC%, the easier it is for patients to obtain functional cure.
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Affiliation(s)
- Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Infectious Diseases, Miyun Teaching Hospital, Capital Medical University, Beijing, China
| | - Si Xie
- Division of Hepatology, Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jianping Dong
- Department of Infectious Diseases, Haidian Hospital, Beijing Haidian Section of Peking University Third Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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