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Hou J, Dong C, Chen J, Chen H, Na R, Zhou B, Hou J, Jiang DK. An intronic genetic variant of ZHX2 predicts response to pegylated interferon α therapy in HBeAg-positive chronic hepatitis B patients. Antiviral Res 2023; 220:105741. [PMID: 39492517 DOI: 10.1016/j.antiviral.2023.105741] [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: 08/19/2023] [Revised: 10/21/2023] [Accepted: 10/27/2023] [Indexed: 11/05/2024]
Abstract
ZHX2 plays a crucial role in host immunity and modulates hepatitis B virus (HBV) replication. However, its correlation with immunomodulator-related treatment, i.g., pegylated interferon α(PegIFNα), for HBV remains uncertain. To explore the link between single nucleotide polymorphisms (SNPs) in ZHX2 and response to PegIFNα therapy for chronic hepatitis B (CHB) patients, we conducted a retrospective study in 945 hepatitis B e antigen (HBeAg)-positive CHB patients with at least 48 weeks of PegIFNα treatment and 24 weeks of follow-up from two phase-IV, multicenter trials (Cohort 1, n = 238; Cohort 2, n = 707). Thirty-eight tag SNPs were selected across the whole ZHX2 gene region. A polygenic score (PGS) was constructed by integrating multiple SNPs. The associations of ZHX2 SNPs and PGS with treatment response were assessed in both cohorts and their combination. Among the 38 tag SNPs, ZHX2_rs17289471 (T>C) was significantly associated with combined response (CR, i.e., HBeAg seroconversion and HBV DNA level <3.3log10IU/mL) at week 72 in both cohorts. The CR rate at week 72 increased steadily from rs17289471 TT to CT and CC genotype carriers in both Cohort 1 (P = 0.002) and Cohort 2 (P = 0.025) as well as Cohort 1 + 2 (P = 3.50 × 10-4). Moreover, a PGS integrating ZHX2_rs17289471 and five other previously identified SNPs was further significantly associated with CR rate at week 72 in Cohort 1 (P = 2.38 × 10-6), Cohort 2 (P = 1.04 × 10-7) and Cohort 1 + 2 (P = 9.37 × 10-13). Overall, ZHX2_rs17289471 and PGS have the potential to predict response to PegIFNα treatment of HBeAg-positive CHB patients.
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Affiliation(s)
- Jia Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533099, China
| | - Chao Dong
- School of Basic Medicine, Inner Mongolia Medical University, Hohhot, 010110, China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 528406, China
| | - Rong Na
- Division of Urology, Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533099, China.
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Chen SL, Xiao H, Li GJ, Shen YJ. Expression Pattern of Cytokines in Patients with Chronic Hepatitis B Receiving PEGinterferon Therapy. Int J Gen Med 2023; 16:1771-1782. [PMID: 37193251 PMCID: PMC10183186 DOI: 10.2147/ijgm.s402524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/27/2023] [Indexed: 05/18/2023] Open
Abstract
Purpose Chronic hepatitis B virus (CHB) infection is a worldwide health problem. Polyethylene glycol (PEG)ylated interferon (PEG-IFN) is an available therapy for CHB that has antiviral and immunomodulatory effects. However, PEG-IFN therapy is limited by the fact that only a subset of patients show a sustained response, its severe side effects, and high cost. The aim of this study was to explore novel biomarkers for the early prediction of PEG-IFN treatment response and to uncover its underlying mechanism. Patients and Methods We enrolled 10 paired patients with Hepatitis B e antigen (HBeAg)-positive CHB who received PEG-IFN-α2a monotherapy. Patient serum samples were collected at 0, 4, 12, 24, and 48 weeks and serum samples were collected from eight healthy people as healthy controls. For confirmation, we enrolled 27 patients with HBeAg-positive CHB receiving PEG-IFN therapy and serum samples at 0 and 12 weeks were obtained. Serum samples were analyzed using Luminex technology. Results Among 27 assessed cytokines, 10 cytokines were identified to have high expression levels. Among them, six cytokines had significant differences in their levels between the patients with HBeAg-positive CHB and the healthy controls (P < 0.05). Potentially, treatment response could be predicted using the early time points of 4, 12, and 24 weeks. Moreover, after 12 weeks of PEG-IFN treatment, increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines were observed. The fold change of IP-10 between 12 weeks and 0 weeks correlated with the decrease in ALT levels from 0 to 12 weeks (r = 0.2675, P = 0.0024). Conclusion In patients with CHB, we observed a certain pattern in the levels of cytokines during treatment with PEG-IFN, and the cytokine IP-10 might be a potential biomarker for treatment response.
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Affiliation(s)
- Shao-Long Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
- Correspondence: Shao-Long Chen, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China, Email
| | - Hong Xiao
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, People’s Republic of China
| | - Guo-Jun Li
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, 315100, People’s Republic of China
| | - Yao-Jie Shen
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China
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Loggi E, Gitto S, Gabrielli F, Franchi E, Seferi H, Cursaro C, Andreone P. Virological Treatment Monitoring for Chronic Hepatitis B. Viruses 2022; 14:1376. [PMID: 35891357 PMCID: PMC9319170 DOI: 10.3390/v14071376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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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Affiliation(s)
- Elisabetta Loggi
- Hepatology Unit, Department of Medical & Surgical Sciences, University of Bologna, 40126 Bologna, Italy;
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
| | - Filippo Gabrielli
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
- Department of Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Elena Franchi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
| | - Hajrie Seferi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
| | - Carmela Cursaro
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy;
| | - Pietro Andreone
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy;
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Medicina Interna Metabolico-Nutrizionale, Ospedale Civile di Baggiovara, Via Pietro Giardini 1355, 41126 Modena, Italy
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Li J, Chen H, Chen J, Zhou B, Hou J, Jiang DK. A Missense Variant in Granulysin is Associated with the Efficacy of Pegylated-Interferon-Alpha Therapy in Chinese Patients with HBeAg-Positive Chronic Hepatitis B. Pharmgenomics Pers Med 2021; 14:1505-1515. [PMID: 34848996 PMCID: PMC8627316 DOI: 10.2147/pgpm.s337962] [Citation(s) in RCA: 2] [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: 09/06/2021] [Accepted: 11/03/2021] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Granulysin (GNLY) is a cytotoxic granule that has been reported to have various antimicrobial activities. We evaluated the association between a missense variant in GNLY (rs11127) and treatment efficacy of pegylated interferon-alpha (PegIFNα) or nucleos(t)ide analogs (NUCs) in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS We included a total of 1823 patients with hepatitis B e antigen (HBeAg)-positive CHB (954 patients treated with PegIFNα and 869 patients treated with NUCs) in four Phase IV multicenter randomized controlled trials. The association of the GNLY rs11127 genotype with the combined response (CR), defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA level <2000 IU/mL was evaluated. A polygenic score (PGS) was constructed to evaluate the cumulative effect of multiple single-nucleotide polymorphisms (SNPs), including rs11127 and several other SNPs, STAT4 rs7574865, CFB rs12614, and CD55 rs28371597, which were reported to be associated with CR. RESULTS GNLY rs11127 was significantly associated with CR in patients treated with PegIFNα. The CR rate in patients with the rs11127 CC genotype was higher than that with the CT or TT genotype (40.98% vs 30.34% or 27.09%, P = 0.003). Furthermore, a PGS integrating GNLY rs11127 and three other SNPs was significantly associated with CR in PegIFNα-treated patients (P < 0.001). However, no significant correlation was found between GNLY rs11127 and CR in NUCs-treated patients. CONCLUSION GNLY rs11127 is an independent biomarker for predicting the response to PegIFNα therapy in HBeAg-positive CHB patients. Furthermore, the PGS, including GNLY rs11127, provides new insights for individualized treatment in clinical practice.
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Affiliation(s)
- Jing Li
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, People’s Republic of China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
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Lin SR, Yang TY, Peng CY, Lin YY, Dai CY, Wang HY, Su TH, Tseng TC, Liu IJ, Cheng HR, Shen YC, Wu FY, Liu CJ, Chen DS, Chen PJ, Yang HC, Kao JH. Whole genome deep sequencing analysis of viral quasispecies diversity and evolution in HBeAg seroconverters. JHEP Rep 2021; 3:100254. [PMID: 33870157 PMCID: PMC8042178 DOI: 10.1016/j.jhepr.2021.100254] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/26/2021] [Accepted: 01/29/2021] [Indexed: 12/21/2022] Open
Abstract
Background & Aims We aimed to investigate how viral quasispecies of the HBV whole genome evolves and diversifies in response to HBeAg seroconversion and viral control utilising next-generation sequencing (NGS). Methods Fifty HBeAg-positive chronic hepatitis B patients, including 18 treatment-naïve and 32 interferon (IFN)-treated individuals, were recruited. Serial HBV whole genomes in serum were analysed by NGS to determine sequence characteristics and viral quasispecies. Results HBV quasispecies diversity, measured by nucleotide diversity, was negatively correlated with viral load and hepatitis activity. Spontaneous HBeAg seroconverters exhibited significantly greater viral quasispecies diversity than treatment-naïve non-seroconverters from >1 year before seroconversion (0.0112 vs. 0.0060, p <0.01) to >1 year after seroconversion (0.0103 vs. 0.0068, p <0.01). IFN-induced HBeAg seroconverters tended to have higher viral genetic diversity than non-seroconverters along with treatment. Particularly, the IFN responders, defined as IFN-induced HBeAg seroconversion with low viraemia, exhibited significantly greater genetic diversity of whole HBV genome at 6 months post-IFN treatment than IFN non-responders (0.0148 vs. 0.0106, p = 0.048). Moreover, spontaneous HBeAg seroconverters and IFN responders exhibited significantly higher evolutionary rates and more intra-host single-nucleotide variants. Interestingly, in spontaneous HBeAg seroconverters and IFN responders, there were distinct evolutionary patterns in the HBV genome. Conclusions Higher HBV quasispecies diversity is associated with spontaneous HBeAg seroconversion and IFN-induced HBeAg seroconversion with low viraemia, conferring a favourable clinical outcome. Lay summary HBeAg seroconversion is a landmark in the natural history of chronic HBV infection. Using next-generation sequencing, we found that the nucleotide diversity of HBV was negatively correlated with viral load and hepatitis activity. Patients undergoing HBeAg seroconversion had more diverse HBV genomes and a faster viral evolution rate. Our findings suggest HBeAg seroconversion is driven by host selection pressure, likely immune selection pressure.
Deep sequencing of whole HBV genome uncovers the quasispecies changes in chronic hepatitis B patients. The nucleotide diversity of HBV negatively correlates with viraemia during HBeAg loss/seroconversion. Viral quasispecies diversity is greater in spontaneous HBeAg seroconverters before and after seroconversion than in treatment-naïve non-seroconverters. Responders to IFN have greater viral quasispecies diversity than non-responders at 24 weeks after treatment. The genome positions of non-synonymous intra-host single nucleotide variants (iSNVs) of HBV tend to be located at possible T cell epitopes.
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Key Words
- ALT, alanine aminotransferase
- AUC, area under curve
- BCP, basal core promoter
- C, core
- CHB, chronic hepatitis B
- Chronic hepatitis B
- EOT, end of treatment
- HBeAg seroconversion
- IFN, interferon
- IFN-NR, IFN-non-responders
- IFN-No-eSC, IFN-treated HBeAg non-seroconverters
- IFN-RS, IFN-responders
- IFN-eSC, IFN-treated HBeAg seroconverters
- Intra-host single nucleotide variants
- NGS, next-generation sequencing
- ORFs, open reading frames
- P, polymerase
- S, surface
- TN-No-eSC, treatment-naïve non-seroconverters
- TN-eSC, treatment-naïve HBeAg seroconverters
- dN, nonsynonymous substitution rate
- dS, synonymous substitution rate
- iSNVs, intra-host single-nucleotide variants
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Affiliation(s)
- Su-Ru Lin
- Department of Microbiology, National Taiwan University, Taipei, Taiwan
| | - Ta-Yu Yang
- Department of Microbiology, National Taiwan University, Taipei, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan.,Department of Internal Medicine, Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-Yen Dai
- Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Hepato-Biliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hurng-Yi Wang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - I-Jung Liu
- Cardinal Tien Junior College of Healthcare and Management, New Taipei City, Taiwan
| | - Huei-Ru Cheng
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yueh-Chi Shen
- Department of Microbiology, National Taiwan University, Taipei, Taiwan
| | - Fang-Yi Wu
- Department of Microbiology, National Taiwan University, Taipei, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.,Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Department of Microbiology, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Chen H, Sun J, Zhou B, Peng J, Xie Q, Liang X, Fan R, Conran C, Xu J, Ji Y, Zhang X, Sun L, Jia J, Wang G, Hou J, Jiang DK. A missense variant in complement factor B (CFB) is a potential predictor of 24-week off-treatment response to PegIFNα therapy in Chinese HBeAg-positive chronic hepatitis B patients. Aliment Pharmacol Ther 2020; 51:469-478. [PMID: 31943297 DOI: 10.1111/apt.15624] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 09/26/2019] [Accepted: 12/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND To date, 14 single-nucleotide polymorphisms (SNPs) have been identified as susceptibility loci for chronic hepatitis B (CHB). AIM To investigate if these SNPs are associated with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. METHODS We performed a retrospective analysis of 1623 Han Chinese HBeAg-positive CHB patients (782 patients treated with pegylated interferon alpha [PegIFNα] for 48 weeks plus 24 weeks follow-up, and 841 patients treated with nucleos(t)ide analogues [NUCs] for 104 weeks) included in four phase-IV multicentre randomised controlled trials. All 14 SNPs were genotyped for each CHB patient. A polygenic score (PGS) was used to evaluate the cumulative effect of multiple SNPs. The associations of SNPs or PGS with combined response (CR) and hepatitis B s antigen (HBsAg) loss were assessed. RESULTS We found that rs12614, a missense variant of complement factor B (CFB), was significantly associated with CR in PegIFNα-treated patients, and the CR rate in patients with the rs12614 TT/CT genotype was less than one-third of that in patients with the CC genotype (7.4% vs 22.6%, P = 0.009). Moreover, a PGS integrating CFB rs12614 and STAT4 rs7574865 (previously reported to be associated with response to PegIFNα) was significantly associated with both CR (P-trend = 4.000 × 10-4 ) and HBsAg loss (P-trend = 0.010) in PegIFNα-treated patients. However, none of the SNPs were associated with treatment response in NUCs-treated patients. CONCLUSIONS CFB rs12614 is an independent predictor of response to PegIFNα therapy in Chinese HBeAg-positive CHB patients. A PGS integrating CFB rs12614 with STAT4 rs7574865 can effectively discriminate responders to PegIFNα from nonresponders.
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Grants
- 2018M633083 the Postdoctoral Science Foundation of China, China
- 2017GXNSFGA198002 the Innovative Research Team Project of Guangxi Province, China
- 2017ZX10202202 the National Science and Technology Major Project, China
- 2018ZX10301202 the National Science and Technology Major Project, China
- 2017J001 the Grant for Recruited Talents to Start Scientific Research from Nanfang Hospital, China and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University, China
- 2019B020227004 the Key-Areas Research and Development Program of Guangdong Province, China
- 81472618 the General Programs from the National Natural Science Foundation of China, China
- 81670535 the General Programs from the National Natural Science Foundation of China, China
- 2017BT01S131 the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program, China
- 81802833 the National Natural Science Foundation of China, China
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Chen H, Sun J, Zhou B, Xie Q, Liang X, Fan R, Conran C, Xu J, Ji Y, Zhang X, Sun L, Jia J, Wang G, Hou J, Jiang DK. Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha. Clin Gastroenterol Hepatol 2020; 18:196-204.e8. [PMID: 31042581 DOI: 10.1016/j.cgh.2019.04.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/16/2019] [Accepted: 04/19/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Variants in STAT4 (rs7574865) have been associated with seroconversion to hepatitis B e antigen (HBeAg) and reduction in levels of hepatitis B virus (HBV) DNA in patients with chronic infection treated with interferon alpha (IFNA). We evaluated the associations among rs7574865, loss of HB surface antigen (HBsAg, a marker of functional cure of HBV infection), and response to treatment with pegylated IFNA (PegIFN) or nucleos(t)ide analogues (NUCs) in HBeAg-positive patients with chronic HBV infection. METHODS We performed a retrospective analysis of 1823 HBeAg-positive patients with chronic HBV infection (954 patients treated with PegIFN and 869 patients treated with NUCs) included in 4 phase-4 multicenter randomized controlled trials. The Cochran-Armitage trend test was used to evaluate the association of rs7574865 genotype with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <2000 IU/mL) and loss of HBsAg at week 72, for patients given PegIFN, or week 104, for patients given NUCs. RESULTS We found a significant association between rs7574865 genotype and CR (P = .004) and loss of HBsAg (P = .037) in patients treated with PegIFN. In patients with HBV genotype B infection, 43.6% of those with rs7574865 TT achieved a CR, compared to patients with rs7574865 GG (20.5%), and 7.7% had loss of HBsAg, compared to 1.9% of patients with rs7574865 GG. However, in patients treated with NUCs, we found no association of rs7574865 genotype with CR (P = .811) or loss of HBsAg (P=.439). CONCLUSIONS In a retrospective analysis of data from 4 clinical trials, we found rs7574865 in STAT4 to be associated with functional cure of chronic HBV infection by PegIFN treatment, but not NUCs treatment, in HBeAg-positive patients with HBV genotype B infection.
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Affiliation(s)
- Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Qing Xie
- Department of Infectious Diseases, Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xier Liang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Carly Conran
- University of Illinois College of Medicine, Chicago, Illinois
| | - Jianfeng Xu
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - Yuan Ji
- Department of Public Health Sciences, University of Chicago, Chicago, Illinois
| | - Xinxin Zhang
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Sun
- Xiamen Amoytop Biotech Co Ltd, Xiamen, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guiqiang Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China; Peking University International Hospital, Beijing, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China.
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China.
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8
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Limothai U, Chuaypen N, Poovorawan K, Chotiyaputta W, Tanwandee T, Poovorawan Y, Tangkijvanich P. Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon-based therapy in patients with hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2019; 26:1481-1488. [PMID: 31446638 DOI: 10.1111/jvh.13195] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/24/2019] [Accepted: 07/30/2019] [Indexed: 12/18/2022]
Abstract
Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long-term outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG-IFN)-based therapy. Serial serum samples from 91 patients with HBeAg-negative CHB previously treated with PEG-IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post-treatment follow-up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre-treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut-off 2.0 log10 copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut-off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log10 copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG-IFN-based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising "stopping rule" in patients infected with HBV genotypes B or C.
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Affiliation(s)
- Umaporn Limothai
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Watcharasak Chotiyaputta
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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9
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Boyd A, Duchesne L, Lacombe K. Research gaps in viral hepatitis. J Int AIDS Soc 2019; 21 Suppl 2:e25054. [PMID: 29633564 PMCID: PMC5978714 DOI: 10.1002/jia2.25054] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 12/20/2017] [Indexed: 12/21/2022] Open
Abstract
Introduction The World Health Organization has aimed for global elimination of both hepatitis B virus (HBV) and hepatitis C virus (HCV) by 2030. Treatments available to cure HCV and control HBV, as well as vaccination to prevent HBV infection, have certainly allowed for such bold goals, yet the final steps to usher in elimination require further evidence. Discussion We broadly discuss the needs for three major public health approaches. First, an effective vaccine exists for HBV and mass‐vaccination campaigns have resulted in decreases in hepatitis B surface antigen seroprevalence and overall rates of liver‐related morality. Still, HBV vaccination coverage is poor in certain regions of the world, while the reasons for such low coverage require further study. A prophylactic vaccine is probably needed to eliminate HCV, but is not being readily developed. Second, identifying HBV/HCV infected individuals remains a priority to increase awareness of disease status, particularly for key populations. Research evaluating large‐scale implementation of novel, rapid and mobile point‐of‐care tests would be helpful to determine whether increased awareness is achievable in these settings. Third, antiviral therapy allows for strong HBV suppression and HCV cure, while its access depends on financial factors among many others. Although there is strong evidence to treat key populations and specific groups with progressed disease, as stated in current guidelines, the advantages of extending treatment eligibility to decrease onward spread of HBV/HCV infection and prevent further burden of disease are lacking “real world” evidence. Novel anti‐HBV treatments are being developed to target intrahepatocellular HBV replication, but are still in the early phases of clinical development. Each of the strategies mentioned above has specific implications for HIV infection. Conclusions There are certainly effective tools to combat the spread of viral hepatitis and treat infected individuals – yet how they are able to reach key populations, and the infrastructure required to do so, continue to represent the largest research gap when evaluating the progress towards elimination. Continuously adapted and informed research is required to establish the priorities in achieving elimination goals.
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Affiliation(s)
- Anders Boyd
- INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.,Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, Netherlands
| | - Léa Duchesne
- INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Karine Lacombe
- Department of Infectious and Tropical Diseases, Saint-Antoine Hospital, AP-HP, Paris, France.,Sorbonne Universités, INSERM, UPMC Univ Paris 06, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
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10
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Nair S, Li L, Francis S, Turner WW, VanNieuwenhze M, Zlotnick A. Use of a Fluorescent Analogue of a HBV Core Protein-Directed Drug To Interrogate an Antiviral Mechanism. J Am Chem Soc 2018; 140:15261-15269. [PMID: 30375863 DOI: 10.1021/jacs.8b07988] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Heteroaryldihydropyrimidines (HAPs) are antiviral small molecules that enhance assembly of HBV core protein (Cp), lead to assembly of empty and defective particles, and suppress viral replication. These core protein allosteric modulators (CpAMs) bind to the pocket at the interface between two Cp dimers and strengthen interdimer interactions. To investigate the CpAM mechanism, we wanted to examine the cellular distributions of Cp and the CpAM itself. For this reason, we developed a fluorescently labeled CpAM, HAP-ALEX. In vitro, HAP-ALEX modulated assembly of purified Cp and at saturating concentrations induced formation of large structures. HAP-ALEX bound capsids and not dimers, making it a capsid-specific molecular tag. HAP-ALEX labeled HBV in transfected cells, with no detectable background with a HAP-insensitive Cp mutant. HAP-ALEX caused redistribution of Cp in a dose-dependent manner consistent with its 0.7 μM EC50, leading to formation of large puncta and an exclusively cytoplasmic distribution. HAP-ALEX colocalized with the redistributed Cp, but large puncta accumulated long before they appeared saturated with the fluorescent CpAM. CpAMs affect HBV assembly and localization; with a fluorescent CpAM both drug and target can be identified.
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Affiliation(s)
- Smita Nair
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States
| | - Lichun Li
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States.,Assembly BioSciences , Carmel , Indiana 45032 , United States
| | - Samson Francis
- Assembly BioSciences , Carmel , Indiana 45032 , United States
| | - William W Turner
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States.,Assembly BioSciences , Carmel , Indiana 45032 , United States
| | - Michael VanNieuwenhze
- Department of Chemistry , Indiana University , Bloomington , Indiana 47405 , United States
| | - Adam Zlotnick
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States
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11
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Wang ML, Liao J, Wei B, Zhang DM, He M, Tao MC, Chen EQ, Tang H. Comparison of hepatitis B virus core-related antigen and hepatitis B surface antigen for predicting HBeAg seroconversion in chronic hepatitis B patients with pegylated interferon therapy. Infect Dis (Lond) 2018; 50:522-530. [PMID: 29463147 DOI: 10.1080/23744235.2018.1442018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/22/2018] [Accepted: 02/12/2018] [Indexed: 02/05/2023] Open
Abstract
AIM Recent studies revealed that both quantitative hepatitis B surface antigen (qHBsAg) and hepatitis B core-related antigen (qHBcrAg) could serve as a good marker for predicting treatment response and indirectly reflecting intrahepatic cccDNA levels. This study aimed to compare the value of qHBsAg and qHBcrAg in predicting HBeAg seroconversion among patients undergoing PEG-IFN therapy. METHODS A total of 31 HBeAg-positive patients, who underwent PEG-IFN therapy for 12 months and follow-up for six months were retrospectively included in this study. The serum qHBsAg level was measured using Elecsys® HBsAg II Quant Assay and serum qHBcrAg level was measured using chemiluminescence enzyme immunoassay. RESULTS During the 12-month treatment, the absolute levels of serum qHBsAg and qHBcrAg were both lower in patients with HBeAg seroconversion as compared to patients without HBeAg seroconversion, but only the difference in qHBcrAg was significant. During the 6-month follow-up period, both qHBsAg and qHBcrAg levels were rebounded significantly among patients without HBeAg seroconversion. Among patients with HBeAg seroconversion, no sustained significant decline of qHBsAg was observed, but serum qHBcrAg levels continued to decline significantly. The ROC curves analysis showed that both absolute qHBcrAg level and the extent of qHBcrAg decline at month 1 had better performance for the prediction of HBeAg seroconversion at month 6 after treatment, as compared to that of qHBsAg. CONCLUSION Early on-treatment qHBcrAg may be a good biomarker for predicting off-treatment HBeAg seroconversion in patients receiving PEG-IFN therapy.
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Affiliation(s)
- Meng-Lan Wang
- a Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu , People's Republic of China
| | - Juan Liao
- a Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu , People's Republic of China
| | - Bing Wei
- b Department of Laboratory Medicine , West China Hospital, Sichuan University , Chengdu , PR China
| | - Dong-Mei Zhang
- a Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu , People's Republic of China
| | - Ming He
- a Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu , People's Republic of China
| | - Ming-Chuan Tao
- b Department of Laboratory Medicine , West China Hospital, Sichuan University , Chengdu , PR China
| | - En-Qiang Chen
- a Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu , People's Republic of China
| | - Hong Tang
- a Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu , People's Republic of China
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12
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Lin CL, Kao JH. Review article: the prevention of hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2018; 48:5-14. [PMID: 29722445 DOI: 10.1111/apt.14683] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/08/2018] [Accepted: 04/03/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. AIMS To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. METHODS Recent published studies identified from PubMed were comprehensively reviewed. The key words included chronic hepatitis B, HBV, hepatocellular carcinoma, prevention and antiviral therapy. RESULTS The incidence of HCC is extremely high in HBV hyperendemic areas. For HBV patients left untreated, significant risk factors for HCC include male gender, aging, advanced hepatic fibrosis, persistent serum transaminase elevation, specific HBV entry receptor (NTCP) genotype, PM2.5 exposure, HBeAg positivity, HBV genotype C/D/F, high proportion of core promoter mutation, pre-S deletion, high serum levels of HBV DNA and HBsAg as well as co-infection with HCV, HDV and HIV. Primary prevention of HBV-related HCC can be achieved through universal HBV vaccination and anti-viral prophylaxis for high viraemic mothers. The goal of secondary prevention has been reached by effective anti-viral therapy to reduce the risk of HCC development in chronic hepatitis B patients. However, whether HCC is prevented or delayed deserves further examination. Finally, several studies confirmed the tertiary preventive effect of anti-viral therapy in reducing risk of HCC recurrence after curative therapies. CONCLUSIONS Through the strategies of three-level prevention, the global burden of HBV-related HCC should decline over time and even be eliminated in conjunction with HBV cure.
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Affiliation(s)
- C-L Lin
- Department of Gastroenterology, Taipei City Hospital, Taipei, Taiwan.,Department of Psychology, National Chengchi University, Taipei, Taiwan
| | - J-H Kao
- Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
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13
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Jindal A, Vyas AK, Kumar D, Kumar G, Sharma MK, Sarin SK. Higher efficacy of pegylated interferon-α2b add-on therapy in hepatitis B envelope antigen-positive chronic hepatitis B patients on tenofovir monotherapy. Hepatol Res 2018; 48:451-458. [PMID: 29314573 DOI: 10.1111/hepr.13049] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/04/2017] [Accepted: 12/26/2017] [Indexed: 01/08/2023]
Abstract
AIM Monotherapy with pegylated interferon-α (Peg-IFNα) or the nucleos(t)ide analogs (NA) currently approved for treating chronic hepatitis B (CHB) has limited efficacy. Studies on the combination of Peg-IFNα/NA have shown conflicting results. We investigated whether sequentially adding on Peg-IFNα to tenofovir enhances serological response rates. METHODS Treatment-naïve, hepatitis B envelope antigen (HBeAg)-positive CHB patients with moderately elevated alanine aminotransferase (ALT; 48-200 IU/mL) were started on tenofovir (300 mg/day) and enrolled at week 12 in a 1:1 ratio to either receive Peg-IFNα2b add-on (1.5 μg/kg/week) from week 12 to 36 (n = 53) or continue tenofovir monotherapy (n = 53). Both treatment arms received tenofovir consolidation therapy until week 72. The primary end-point was HBeAg loss at week 72. RESULTS At week 72, the rate of HBeAg loss was higher in the Peg-IFNα2b add-on group (35.8%) compared to the tenofovir monotherapy group (17%) (P = 0.028; odds ratio, 2.73, 95% confidence interval, 1.09-6.79), and considerably higher in patients with a baseline hepatitis B virus (HBV)-DNA level >6 log IU/mL (32.6% vs 11.4%; P = 0.021). Rates of HBV-DNA loss (77.4% vs 71.7%; P = 0.51), ALT normalization (62.3% vs 52.8%; P = 0.32), and sustained virologic response (20.8% vs 11.3%; P = 0.18) at week 72 were comparable between the two groups. Significantly more patients in the add-on group had >3 log HBV-DNA reduction at week 36 (92.5% vs 66%; P = 0.001). Four patients treated with Peg-IFNα2b add-on achieved hepatitis B surface antigen (HBsAg) loss compared with one patient receiving tenofovir monotherapy. Decline of HBV-DNA of >2 log at week 4 led to higher HBeAg loss at week 72, independent of treatment arm. No patient had treatment-related adverse effects requiring treatment discontinuation. CONCLUSIONS Twenty-four weeks of Peg-IFNα2b as an add-on sequential regimen to tenofovir is safe and resulted in greater loss of HBeAg and HBsAg compared to tenofovir monotherapy in selected HBeAg-positive patients. Viral load reduction followed by immune modulation is a potentially useful approach.
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashish Kumar Vyas
- Departments of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Devesh Kumar
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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14
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Asymmetric Modification of Hepatitis B Virus (HBV) Genomes by an Endogenous Cytidine Deaminase inside HBV Cores Informs a Model of Reverse Transcription. J Virol 2018; 92:JVI.02190-17. [PMID: 29491156 DOI: 10.1128/jvi.02190-17] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 02/20/2018] [Indexed: 02/07/2023] Open
Abstract
Cytidine deaminases inhibit replication of a broad range of DNA viruses by deaminating cytidines on single-stranded DNA (ssDNA) to generate uracil. While several lines of evidence have revealed hepatitis B virus (HBV) genome editing by deamination, it is still unclear which nucleic acid intermediate of HBV is modified. Hepatitis B virus has a relaxed circular double-stranded DNA (rcDNA) genome that is reverse transcribed within virus cores from a RNA template. The HBV genome also persists as covalently closed circular DNA (cccDNA) in the nucleus of an infected cell. In the present study, we found that in HBV-producing HepAD38 and HepG2.2.15 cell lines, endogenous cytidine deaminases edited 10 to 25% of HBV rcDNA genomes, asymmetrically with almost all mutations on the 5' half of the minus strand. This region corresponds to the last half of the minus strand to be protected by plus-strand synthesis. Within this half of the genome, the number of mutations peaks in the middle. Overexpressed APOBEC3A and APOBEC3G could be packaged in HBV capsids but did not change the amount or distribution of mutations. We found no deamination on pregenomic RNA (pgRNA), indicating that an intact genome is encapsidated and deaminated during or after reverse transcription. The deamination pattern suggests a model of rcDNA synthesis in which pgRNA and then newly synthesized minus-sense single-stranded DNA are protected from deaminase by interaction with the virus capsid; during plus-strand synthesis, when enough dsDNA has been synthesized to displace the remaining minus strand from the capsid surface, the single-stranded DNA becomes deaminase sensitive.IMPORTANCE Host-induced mutation of the HBV genome by APOBEC proteins may be a path to clearing the virus. We examined cytidine-to-thymidine mutations in the genomes of HBV particles grown in the presence or absence of overexpressed APOBEC proteins. We found that genomes were subjected to deamination activity during reverse transcription, which takes place within the virus capsid. These observations provide a direct insight into the mechanics of reverse transcription, suggesting that newly synthesized dsDNA displaces ssDNA from the capsid walls, making the ssDNA accessible to deaminase activity.
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15
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Chuaypen N, Posuwan N, Chittmittraprap S, Hirankarn N, Treeprasertsuk S, Tanaka Y, Shinkai N, Poovorawan Y, Tangkijvanich P. Predictive role of serum HBsAg and HBcrAg kinetics in patients with HBeAg-negative chronic hepatitis B receiving pegylated interferon-based therapy. Clin Microbiol Infect 2018; 24:306.e7-306.e13. [PMID: 28750917 DOI: 10.1016/j.cmi.2017.07.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 07/12/2017] [Accepted: 07/16/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To investigate the role of serum hepatitis B core-related antigen (HBcrAg) kinetics in predicting long-term outcome of pegylated interferon (PEG-IFN)-based therapy in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). METHODS A total of 121 Thai patients with HBeAg-negative CHB recruited from a previous randomized trial of 48-week PEG-IFN alone or combined with entecavir were enrolled. Hepatitis B surface antigen (HBsAg) and HBcrAg levels were serially examined. Paired biopsy samples taken at baseline and after treatment were assessed for intrahepatic covalently closed circular DNA (cccDNA). RESULTS Persistent virologic remission (PVR, defined by persistent hepatitis B virus (HBV) DNA <2000 IU/mL) and HBsAg clearance at 3 years after treatment were 29% (35/121) and 9% (11/121) respectively. Baseline HBcrAg correlated with HBV DNA and cccDNA but not with HBsAg. Baseline HBsAg, as well as HBsAg and HBcrAg, declines were associated with PVR, while HBsAg decline was predictive of HBsAg clearance. High baseline antigen levels (HBsAg ≥3.4 log10 IU/mL plus HBcrAg ≥3.7 log10 U/mL) yielded high negative predictive values of PVR (45/50, 90%) and HBsAg clearance (50/50, 100%). At week 12, declines of HBsAg, HBcrAg and both antigens combined of <0.5 log10 yielded negative predictive values for PVR of 90% (71/79), 82% (61/74) and 96% (48/50) respectively. CONCLUSIONS Quantitative HBcrAg was significantly associated with cccDNA in HBeAg-negative CHB. This novel antigen, together with HBsAg, could identify patients with low probability of PVR and HBsAg clearance in long-term follow-up.
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Affiliation(s)
- N Chuaypen
- Research Unit of Hepatitis and Liver Cancers, Thailand
| | - N Posuwan
- Center of Excellence in Clinical Virology, Thailand
| | | | - N Hirankarn
- Immunology Unit, Department of Microbiology, Thailand
| | - S Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Y Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - N Shinkai
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Y Poovorawan
- Center of Excellence in Clinical Virology, Thailand
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16
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Hepatitis B, C, and Delta—Updates in Screening and Infection Prevention Opportunities for Eradication. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2017. [DOI: 10.1007/s40506-017-0105-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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17
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Ding Y, Lou J, Chen H, Li X, Wu M, Li C, Liu J, Liu C, Li Q, Zhang H, Niu J. Tolerability, pharmacokinetics and antiviral activity of rHSA/IFNα2a for the treatment of chronic hepatitis B infection. Br J Clin Pharmacol 2016; 83:1056-1071. [PMID: 27862178 DOI: 10.1111/bcp.13184] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 10/25/2016] [Accepted: 11/03/2016] [Indexed: 01/05/2023] Open
Abstract
AIMS A recombinant human serum albumin-interferon alpha2a fusion protein (rHSA/IFNα2a) is expected to extend the half-life of IFNα2a. This study aims to evaluate the tolerability, safety and efficacy of rHSA/IFNα2a. METHODS This is an open, randomized, positive control, multiple-dose ascending Phase Ib study. A panel of 32 treatment naïve and non-cirrhotic chronic hepatitis B patients were divided into four cohorts, and each received 600, 750 or 900 μg of rHSA/IFNα2a or 180 μg of PEG-IFNα2a for 3 months. Tolerability, pharmacokinetics and antiviral responses were assessed. RESULTS Thirty-one of 32 enrolled patients completed the treatment study. The rHSA/IFNα2a treatment was better tolerated than the PEG-IFNα2a 180 μg treatment, as evidenced by blood cell counts and higher serum albumin levels. Half-life (t1/2 ) of rHSA/IFNα2a was estimated to be 120-140 h, and is potentially suitable for a dosing interval of 2 weeks or longer. Pharmacokinetics of the last dose between rHSA/IFNα2a 750 μg and PEG-IFNα2a 180 μg, with the exception of t1/2 , was comparable, and a similar kinetics of inhibiting HBV DNA replication was observed in both groups. Mean reductions in serum HBV DNA levels after treatment were -1.32, -2.13, -1.10 and -2.48 log10 IU/ml in the 600, 750 and 900 μg rHSA/IFNα2a groups and PEG-IFNα2a group, respectively. CONCLUSIONS The rHSA/IFNα2a treatment was well tolerated and can be administered biweekly. Similar efficacy in inhibiting HBV replication was observed in both PEG-IFNα2a and rHSA/IFNα2a 750 μg groups.
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Affiliation(s)
- Yanhua Ding
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Jinfeng Lou
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Hong Chen
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Xiaojiao Li
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Min Wu
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Cuiyun Li
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Jingrui Liu
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Chengjiao Liu
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Qingmei Li
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Hong Zhang
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
| | - Junqi Niu
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
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18
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Shen X, Fu B, Liu Y, Guo C, Ye Y, Sun R, Li J, Tian Z, Wei H. NKp30 + NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B. Sci Rep 2016; 6:38778. [PMID: 27941937 PMCID: PMC5150634 DOI: 10.1038/srep38778] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 11/14/2016] [Indexed: 12/23/2022] Open
Abstract
A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-α) achieves sustained off-treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-α is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-γ production, during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-γ+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up-regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-α-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-α-2b therapy.
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Affiliation(s)
- Xiaokun Shen
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Binqing Fu
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yanyan Liu
- Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University and Chaohu Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Chuang Guo
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Ying Ye
- Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University and Chaohu Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Rui Sun
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Jiabin Li
- Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University and Chaohu Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhigang Tian
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
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Boyd A, Piroth L, Maylin S, Maynard-Muet M, Lebossé F, Bouix C, Lascoux-Combe C, Mahjoub N, Girard PM, Delaugerre C, Carrat F, Lacombe K, Miailhes P. Intensification with pegylated interferon during treatment with tenofovir in HIV-hepatitis B virus co-infected patients. J Viral Hepat 2016; 23:1017-1026. [PMID: 27486094 DOI: 10.1111/jvh.12581] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 06/23/2016] [Indexed: 02/06/2023]
Abstract
In hepatitis B "e" antigen (HBeAg) positive patients with hepatitis B virus (HBV) mono-infection, intensification of nucleos(t)ide analogue treatment with pegylated interferon (PegIFN) could help induce higher HBeAg seroclearance rates. Our aim was to determine the long-term effect of adding PegIFN to tenofovir (TDF)-containing antiretroviral therapy on seroclearance in HBeAg-positive patients co-infected with the human immunodeficiency virus (HIV) and HBV. In this prospective matched cohort study, 46 patients with 1-year PegIFN intensification during TDF-containing antiretroviral therapy (TDF+PegIFN) were matched 1:1 to controls undergoing TDF without PegIFN (TDF) using a time-dependent propensity score based on age, CD4+ count and liver cirrhosis status. Kinetics of HBeAg quantification (qHBeAg) and hepatitis B surface antigen quantification (qHBsAg) were estimated using mixed-effect linear regression and time to HBeAg seroclearance or HBsAg seroclearance was modelled using proportional hazards regression. At baseline, previous TDF exposure was a median 39.8 months (IQR=21.4-59.4) and median qHBeAg and qHBsAg levels were 6.9 PEIU/mL and 3.72 log10 IU/mL, respectively (P>.5 between groups). Median follow-up was 33.4 months (IQR=19.0-36.3). During intensification, faster average declines of qHBeAg (-0.066 vs -0.027 PEIU/mL/month, P=.001) and qHBsAg (-0.049 vs -0.026 log10 IU/mL/month, P=.09) were observed in patients undergoing TDF+PegIFN vs TDF, respectively. After intensification, qHBeAg and qHBsAg decline was no different between groups (P=.7 and P=.9, respectively). Overall, no differences were observed in HBeAg seroclearance (TDF+PegIFN=13.2 vs TDF=12.6/100 person·years, P=.5) or HBsAg seroclearance rates (TDF+PegIFN=1.8 vs TDF=1.3/100 person·years, P=.7). In conclusion, PegIFN intensification in HBeAg-positive co-infected patients did not lead to increased rates of HBeAg or HBsAg clearance, despite faster declines of antigen levels while on PegIFN.
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Affiliation(s)
- A Boyd
- INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - L Piroth
- Département d'Infectiologie, CHU and UMR 1347, Université de Bourgogne, Dijon, France
| | - S Maylin
- Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France.,Université Paris-Diderot, Paris, France
| | - M Maynard-Muet
- Service d'Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, INSERM U1052, Lyon, France
| | - F Lebossé
- Service d'Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, INSERM U1052, Lyon, France
| | - C Bouix
- Service d'Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, INSERM U1052, Lyon, France
| | - C Lascoux-Combe
- Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Louis, AP-HP, Paris, France
| | - N Mahjoub
- Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France
| | - P-M Girard
- Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, AP-HP, Paris, France.,Institut Pierre Louis d'Epidémiologie et de Santé Publique, UPMC Univ Paris 06, UMR_S 1136, Sorbonne Universités, Paris, France
| | - C Delaugerre
- Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France.,Université Paris-Diderot, Paris, France.,INSERM U941, Paris, France
| | - F Carrat
- Institut Pierre Louis d'Epidémiologie et de Santé Publique, UPMC Univ Paris 06, UMR_S 1136, Sorbonne Universités, Paris, France.,Département de Santé Publique, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - K Lacombe
- Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, AP-HP, Paris, France.,Institut Pierre Louis d'Epidémiologie et de Santé Publique, UPMC Univ Paris 06, UMR_S 1136, Sorbonne Universités, Paris, France
| | - P Miailhes
- Centre de Recherche sur le Cancer de Lyon, Equipes 15 et 16, INSERM, Unité 1052, UMR 5286, CNRS, Lyon, France.,Service des Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
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20
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Meng ZJ, Yang YD. Potential strategies for "cure" of hepatitis B. Shijie Huaren Xiaohua Zazhi 2016; 24:4438-4449. [DOI: 10.11569/wcjd.v24.i33.4438] [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] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is a worldwide health problem and the main cause of liver cirrhosis, liver failure, and liver cancer. The steady state of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in HBV infected hepatocytes and virus specific immune tolerance contribute to the chronic persistent infection and hard-to-cure of hepatitis B. The presently available therapeutics for hepatitis B can control viral replication, but rarely eliminate HBV surface antigen (HBsAg) or HBV cccDNA. The "cure" of hepatitis B, which is characterized by the HBsAg loss or HBsAg seroconversion, and cccDNA clearance, has been the goal of researchers for years. In recent years, with the robust progress in understanding the HBV pathogenesis and the rapid development of gene editing technology, the "cure" of hepatitis B becomes prospective. This paper aims to summarize the potential strategies for the "cure" of hepatitis B.
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21
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Xie DY, Wang SM, Yang JM, Wang LH, Chen HY, Huai C, Shang J, Mao Q, Lei CL, Luo GH, Qian J, Lu DR. IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection. World J Gastroenterol 2016; 22:9813-9821. [PMID: 27956805 PMCID: PMC5124986 DOI: 10.3748/wjg.v22.i44.9813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/19/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) polymorphisms and interferon-α (IFNα) treatment efficiency among Chinese hepatitis B virus (HBV) infection patients.
METHODS Two hundred and twenty five newly diagnosed chronic hepatitis B (CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen (HBeAg) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms (SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes.
RESULTS At the end of the treatment, HBeAg seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218 (A > G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64 (95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response (response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype (response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBeAg seroconversion, combined response or sustained response was observed.
CONCLUSION IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation.
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22
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Man Cho S, Choe BH. Treatment strategies according to genotype for chronic hepatitis B in children. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:336. [PMID: 27761440 PMCID: PMC5066031 DOI: 10.21037/atm.2016.09.06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 08/19/2016] [Indexed: 01/05/2023]
Abstract
This review article was requested by editor-in-chief of this journal as 'pediatric CHB treatment' for the upcoming special issue. The main objective of chronic hepatitis B (CHB) treatment is diminishing the risk of complications related to chronic liver disease. In Asia, there are already some reports about hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infected children. The key points of treatment in children with CHB infections are selection of which patients to treat and conformation of the optimal therapy time that would reduce viral resistance. The choice of therapy is determined by the district (Western/Eastern), HBV genotype, medical accessibility, and economic state of the country. Newly developed nucleos(t)ide analogues (NAs) are potent in children with CHB. However, to improve therapeutic efficacy, physicians are recommended to follow treatment guidelines and determine the specific genotype in the CHB patient. In this article, the treatment of pediatric CHB is reviewed according to differences in genotype.
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Affiliation(s)
- Seung Man Cho
- Department of Pediatrics, Dongguk University School of Medicine, Gyeongju, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
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23
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Zoulim F, Lebossé F, Levrero M. Current treatments for chronic hepatitis B virus infections. Curr Opin Virol 2016; 18:109-16. [PMID: 27318098 DOI: 10.1016/j.coviro.2016.06.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 06/06/2016] [Accepted: 06/06/2016] [Indexed: 12/14/2022]
Abstract
Over 240 million people worldwide are chronically infected with hepatitis B virus (HBV) and although a prophylactic vaccine and effective antiviral therapies are available, no cure exists. Curative regimens are urgently needed because up to one million deaths per year are caused by HBV-related liver cancer and end-stage liver disease. HBV is an hepatotropic virus which belongs to the Hepadnaviridae family and replicates its DNA genome via a reverse transcriptase mechanism. Effective therapies have been developed for chronic hepatitis B (CHB) infection in the last two decades. They rely on the use of interferon alpha and its pegylated formulation, and on nucleos(t)ide analogs that inhibit viral polymerase activity. Their results are discussed in this review as well as future perspectives.
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Affiliation(s)
- Fabien Zoulim
- Cancer Research Center of Lyon (CRCL), Lyon 69008, France; INSERM, U1052, Lyon 69003, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France; Institut Universitaire de France (IUF), 75005 Paris, France.
| | - Fanny Lebossé
- Cancer Research Center of Lyon (CRCL), Lyon 69008, France; INSERM, U1052, Lyon 69003, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), Lyon 69008, France; INSERM, U1052, Lyon 69003, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France; DMISM and CLNS IIT Sapienza, Sapienza University Rome, 00161 Rome, Italy
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24
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Tangkijvanich P, Chittmittraprap S, Poovorawan K, Limothai U, Khlaiphuengsin A, Chuaypen N, Wisedopas N, Poovorawan Y. A randomized clinical trial of peginterferon alpha-2b with or without entecavir in patients with HBeAg-negative chronic hepatitis B: Role of host and viral factors associated with treatment response. J Viral Hepat 2016; 23:427-438. [PMID: 26387494 DOI: 10.1111/jvh.12467] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 08/26/2015] [Indexed: 12/13/2022]
Abstract
Combining peginterferon (PEG-IFN) and a potent nucleoside/nucleotide analogue might improve treatment response in patients with chronic hepatitis B (CHB). The aims of this study were to compare the efficacy of PEG-IFN alpha-2b with or without entecavir in HBeAg-negative CHB and to investigate predictors of response. A total of 126 treatment-naïve patients were randomly assigned to receive monotherapy (n = 63) or combination therapy (n = 63) for 48 weeks. Virological response (VR) was defined as HBV DNA level <2000 IU/mL at week 96. Baseline factors including polymorphisms in the IFNL3 (rs12979860) and HLA-DPA1 (rs3077) genes and on-treatment viral kinetics were determined. At week 48, rates of undetectable HBV DNA were lower in the monotherapy than combination groups, but rates of HBsAg clearance and decline were comparable. At week 96, there was no difference between the corresponding groups regarding virological response (41.3% vs 38.1%, P = 0.856), HBsAg clearance (9.5% vs 4.8%, P = 0.491) and HBsAg decline. Baseline HBsAg level [odds ratio (OR): 3.14 (1.34-7.69), P = 0.012] and rs3077 polymorphism [OR: 2.78 (1.27-6.11), P = 0.011] were independent predictors of response. Patients carried GG genotype of rs3077 with low baseline HBV (<1000 IU/mL) had high probability of achieving VR (76.5%) and HBsAg clearance (29.4%). None of the patients without decrease in HBsAg combined with <2 log10 HBV DNA decline at week 12 achieved a virological response. In conclusion, the combination therapy lead to greater on-treatment HBV DNA suppression but did not improve virological response and HBsAg clearance/decline over monotherapy. Host and viral factors could help optimize decision-making at baseline and during PEG-IFN-based therapy.
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Affiliation(s)
- P Tangkijvanich
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Chulalongkorn University, Bangkok, Thailand
| | | | - K Poovorawan
- Department of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - U Limothai
- Center of Excellence in Clinical Virology, Department of Pediatrics, Chulalongkorn University, Bangkok, Thailand
| | - A Khlaiphuengsin
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Chulalongkorn University, Bangkok, Thailand
| | - N Chuaypen
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Chulalongkorn University, Bangkok, Thailand
| | - N Wisedopas
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Y Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Chulalongkorn University, Bangkok, Thailand
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25
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Liu SHK, Seto WK, Lai CL, Yuen MF. Hepatitis B: treatment choice and monitoring for response and resistance. Expert Rev Gastroenterol Hepatol 2016; 10:697-707. [PMID: 26799653 DOI: 10.1586/17474124.2016.1145547] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite effective preventive primary prevention with vaccination, many people remain infected with hepatitis B virus (HBV) and suffer from its complications. Effective treatments such as interferon-based regimens and oral nucleoside/nucleotides have been developed over the last 30 years, but they are not perfect. Each of the treatments has its own merits, but none can eradicate HBV from the host. As a result, regular monitoring of the response during treatment and after treatment is required. The choice and monitoring of selected treatments, new potential therapeutic agents, and treatment options for drug resistance are discussed in this review.
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Affiliation(s)
- Sze-Hang Kevin Liu
- a Department of Medicine, Queen Mary Hospital , University of Hong Kong , Hong Kong , China
| | - Wai-Kay Seto
- a Department of Medicine, Queen Mary Hospital , University of Hong Kong , Hong Kong , China.,b State Key Laboratory for Liver Research , University of Hong Kong, Queen Mary Hospital , Hong Kong , China
| | - Ching-Lung Lai
- a Department of Medicine, Queen Mary Hospital , University of Hong Kong , Hong Kong , China.,b State Key Laboratory for Liver Research , University of Hong Kong, Queen Mary Hospital , Hong Kong , China
| | - Man-Fung Yuen
- a Department of Medicine, Queen Mary Hospital , University of Hong Kong , Hong Kong , China.,b State Key Laboratory for Liver Research , University of Hong Kong, Queen Mary Hospital , Hong Kong , China
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26
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Chon YE, Kim DJ, Kim SG, Kim IH, Bae SH, Hwang SG, Heo J, Jang JW, Lee BS, Kim HJ, Jun DW, Kim KM, Chung WJ, Choi MS, Jang JY, Yim HJ, Tak WY, Yoon KT, Park JY, Han KH, Suk KT, Lee HW, Jang BK, Ahn SH. An Observational, Multicenter, Cohort Study Evaluating the Antiviral Efficacy and Safety in Korean Patients With Chronic Hepatitis B Receiving Pegylated Interferon-alpha 2a (Pegasys): TRACES Study. Medicine (Baltimore) 2016; 95:e3026. [PMID: 27057828 PMCID: PMC4998744 DOI: 10.1097/md.0000000000003026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 02/10/2016] [Accepted: 02/13/2016] [Indexed: 12/24/2022] Open
Abstract
Currently, limited data are available regarding the efficacy and safety of pegylated interferon alpha-2a (PEG-IFN α-2a) in Korean patients with chronic hepatitis B (CHB), in whom hepatitis B virus (HBV) genotype C is the most common type.We collected data from 439 patients (HBeAg positive, n = 349; HBeAg negative, n = 90) with CHB who were treated with PEG-IFN α-2a as a first-line therapy from 18 institutions. Treatment responses at the end of treatment (ET) and at 6 months posttreatment (PT6) were compared between the patients who were treated for 24 weeks versus 48 weeks, and adverse events (AEs) were evaluated.In HBeAg-positive patients, those who received PEG-IFN α-2a for 48 weeks showed significantly higher HBV DNA suppression (HBV DNA < 2000 IU/mL) than those who were treated for 24 weeks (48 weeks vs 24 weeks; at ET, 44.4% vs 36.7%, P = 0.035; at PT6, 35.9% vs 13.3%, P = 0.035). The HBeAg seroconversion rate at ET was 18.1% in 48-week treatment group, which is significantly higher than the 2.2% (P < 0.001) that was seen in 24-week treatment group. This finding also continued at PT6 (29.0% vs 10.0%, P < 0.001). Following 48 weeks of treatment in HBeAg-negative patients, HBV DNA suppression at ET was higher than in HBeAg-positive patients (87.8% vs 44.4%). AEs were typical of those associated with PEG-IFN α-2a.In naïve Korean HBeAg-positive CHB patients treated with PEG-IFN α-2a, higher rates of HBV DNA suppression and HBeAg seroconversion were achieved in the 48-week treatment group than in the 24-week treatment group without additional risk of AEs.
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Affiliation(s)
- Young Eun Chon
- From the Yonsei University College of Medicine (YEC, JYP, K-HH, SHA), The Catholic University College of Medicine (SHB), Chung-Ang University College of Medicine (HJK, HWL), Hanyang University College of Medicine (DWJ), University of Ulsan College of Medicine (KMK), Sungkyunkwan University College of Medicine (MSC), Soonchunhyang University College of Medicine, Seoul (JYJ), Hallym University College of Medicine, Chuncheon (DJK, KTS), Soonchunhyang University College of Medicine, Bucheon (SGK), Chonbuk National University College of Medicine, Jeonju (IHK), Cha University College of Medicine, Seongnam (SGH), Pusan National University School of Medicine, Busan (JH), The Catholic University College of Medicine, Incheon (JWJ), Chungnam National University College of Medicine, Daejeon (BSL), Keimyung University College of Medicine (WJC, BKJ), Kyungpook National University College of Medicine, Daegu (WYT), Korea University College of Medicine, Ansan (HJY), Pusan National University School of Medicine (KTY), Yangsan, Korea
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Loggi E, Vitale G, Conti F, Bernardi M, Andreone P. Chronic hepatitis B: Are we close to a cure? Dig Liver Dis 2015; 47:836-841. [PMID: 26138799 DOI: 10.1016/j.dld.2015.05.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 05/03/2015] [Accepted: 05/22/2015] [Indexed: 12/11/2022]
Abstract
Approximately 300 million people worldwide are persistently infected with the hepatitis B virus and are at risk of developing hepatocellular carcinoma and liver cirrhosis, which can progress to end-stage liver disease. Despite the effectiveness of the current vaccination policy, the prevalence of the disease remains high, and the burden for health services is considerable. The currently available antiviral strategies are either poorly effective or only effective for non-curative suppression of viral replication. Recent efforts have been focused on improving the cure rate for chronic hepatitis B and developing strategies to eliminate infected cells. Several approaches are under evaluation, and these include targeting the virus at different stages of its life cycle and boosting the antiviral immune response. This article reviews these latest approaches and comments on their feasibility and potential translation into clinical applications.
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Affiliation(s)
- Elisabetta Loggi
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Vitale
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Fabio Conti
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Mauro Bernardi
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Pietro Andreone
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.
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28
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Abstract
INTRODUCTION The hepatitis B virus (HBV) causes chronic hepatitis B (CHB) in ∼350 million people worldwide who have an increased risk of end-stage liver disease and/or hepatocellular carcinoma. SOURCES OF DATA Several peer-reviewed papers featuring new approaches to anti-HBV management. Additionally, we also reviewed recent abstract presentations at international congresses. AREAS OF AGREEMENT There has been great progress in CHB therapy with the development of standard and pegylated interferon (i.e. PEG-IFN) as well as nucleos/tide analogs (NAs). IFN has both antiviral and immunomodulatory effects and through immune-mediated destruction of infected hepatocytes offers the possibility of finite therapy. However, this 'killing for a cure' antiviral strategy may not be tolerated in many, especially in cirrhotic patients. NAs inhibit viral reverse transcriptase, have few side effects and prevent liver disease progression, but cannot offer a cure as they have little effect on the resilient HBV covalently closed circular DNA (cccDNA) intermediate. Moreover, NAs such as tenofovir and entecavir offer a high genetic barrier to resistance, but are expensive and not readily available in many global regions. GROWING POINTS Despite significant treatment advances, there is increased recognition of the need for improved anti-HBV treatments, and new virologic tests for monitoring treatment response. AREAS OF CONTROVERSY The role of quantitative hepatitis B surface antigen, intrahepatic cccDNA levels and viral genotype in selecting treatment candidates and refining NA stopping rules. AREAS TIMELY FOR DEVELOPING NEW RESEARCH Potential new therapies include viral entry inhibitors, RNA interference technologies (i.e. RNAi) and small molecules that modulate cccDNA transcription, as well as novel immunomodulatory therapies to boost HBV-specific T cell responses. The ultimate goal of new tests and anti-HBV therapies is to reduce the burden and expense of life-long CHB treatment, as 'only diamonds are forever'.
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Affiliation(s)
- Carla S Coffin
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
| | - Samuel S Lee
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
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Isorce N, Lucifora J, Zoulim F, Durantel D. Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies. Antiviral Res 2015; 122:69-81. [PMID: 26275801 DOI: 10.1016/j.antiviral.2015.08.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 08/11/2015] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains a major challenge for clinicians, as there are only two types of approved therapies: interferon-alpha (IFN-α) or its pegylated form, Peg-IFN-α and nucleoside analogs (e.g. tenofovir, entecavir...). The first are used as finite-duration treatments of around 48-52 weeks, while the second must be taken life-long to prevent rebound. Other immune-modulators, including other types of recombinant IFNs and cytokines/chemokines, could be developed for treating chronic hepatitis B. Alternatively, strategies aimed either at restoring or favoring the endogenous production of IFNs, cytokines and/or chemokines, or at alleviating HBV-mediated inhibitory processes could also be envisaged. In this article, we review current investigational, preclinical and clinical efforts to implement immune-modulatory components in the therapy of chronic hepatitis B. This review forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B".
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Affiliation(s)
- Nathalie Isorce
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France
| | - Julie Lucifora
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France
| | - Fabien Zoulim
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France; Labex DEVweCAN, Lyon, France; Hospices Civils de Lyon (HCL), Croix-Rousse Hospital, Lyon, France
| | - David Durantel
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France; Labex DEVweCAN, Lyon, France.
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Iqbal K, Klevens RM, Kainer MA, Baumgartner J, Gerard K, Poissant T, Sweet K, Vonderwahl C, Knickerbocker T, Khudyakov Y, Xia GL, Roberts H, Teshale E. Epidemiology of Acute Hepatitis B in the United States From Population-Based Surveillance, 2006-2011. Clin Infect Dis 2015; 61:584-92. [PMID: 25904365 DOI: 10.1093/cid/civ332] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 04/15/2015] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND An estimated 20 000 new hepatitis B virus (HBV) infections occur each year in the United States. We describe the results of enhanced surveillance for acute hepatitis B at 7 federally funded sites over a 6-year period. METHODS Health departments in Colorado, Connecticut, Minnesota, Oregon, Tennessee, 34 counties in New York state, and New York City were supported to conduct enhanced, population-based surveillance for acute HBV from 2006 through 2011. Demographic and risk factor data were collected on symptomatic cases using a standardized form. Serum samples from a subset of cases were also obtained for molecular analysis. RESULTS In the 6-year period, 2220 acute hepatitis B cases were reported from the 7 sites. For all sites combined, the incidence rate of HBV infection declined by 19%, but in Tennessee incidence increased by 90%, mainly among persons of white race/ethnicity and those aged 40-49 years. Of all reported cases, 66.1% were male, 57.1% were white, 58.4% were aged 30-49 years, and 60.1% were born in the United States. The most common risk factor identified was any drug use, notably in Tennessee; healthcare exposure was also frequently reported. The most common genotype for all reported cases was HBV genotype A (82%). CONCLUSIONS Despite an overall decline in HBV infection, attributable to successful vaccination programs, a rise in incident HBV infection related to drug use is an increasing concern in some localities.
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Affiliation(s)
- Kashif Iqbal
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - R Monina Klevens
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | | | | | | | | | | | | | | | - Yury Khudyakov
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Guo-Liang Xia
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Henry Roberts
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Eyasu Teshale
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
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Zoulim F, Durantel D. Antiviral therapies and prospects for a cure of chronic hepatitis B. Cold Spring Harb Perspect Med 2015; 5:5/4/a021501. [PMID: 25833942 DOI: 10.1101/cshperspect.a021501] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Current therapies of chronic hepatitis B (CHB) remain limited to either pegylated interferon-α (Peg-IFN-α), or one of the five approved nucleoside analog (NA) treatments. Although viral suppression can be achieved in the majority of patients with high-barrier-to-resistance new-generation NAs (i.e., entecavir and tenofovir), HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5 years. Attempts to improve the response by administering two different NAs or a combination of NA and Peg-IFN-α have been unsuccessful. Therefore, there is a renewed interest to investigate a number of steps in the hepatitis B virus (HBV) replication cycle and specific virus-host cell interactions as potential targets for new antivirals. Novel targets and compounds could readily be evaluated using both relevant in vitro and newly developed in vivo models of HBV infection. The addition of one or several new drugs to current regimens should offer the prospect of markedly improving the response to therapy, thus reducing the burden of drug resistance, as well as the incidence of cirrhosis and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Fabien Zoulim
- INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Hospices Civils de Lyon, Lyon, France
| | - David Durantel
- INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Hospices Civils de Lyon, Lyon, France
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Venegas M, Poniachik J, Fuster F, Hurtado C, Villanueva RA, Brahm J. Genotype F of hepatitis B: response to interferon. Antivir Ther 2014; 20:453-6. [PMID: 25321866 DOI: 10.3851/imp2886] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND The relevance of HBV genotype diversity on interferon (IFN) therapy outcome in chronic hepatitis B patients has recently been highlighted. Data available for genotype F is poor. The aim of this work was to analyse the response of HBV genotype F to treatment with IFN. Additionally, response was analysed according to the role of single nucleotide polymorphisms (SNPs) near to the IL28B gene. METHODS A total of 29 HBeAg-positive patients with chronic infection were included with a median age 47 (18-68) years. Of them, 27 were male. One patient was treated with standard IFN-α for 16 weeks, 6 patients received PEG-IFN-α2a 180 μg weekly for 24 weeks and 22 patients for 48 weeks. Response to treatment was defined as loss of HBeAg, anti-HBe seroconversion and decline of HBV DNA level to below 3 log of baseline (IU/ml) at the 6-month of follow-up. The SNPs rs12979860, rs12980275 and rs8099917 were studied by PCR-RFLP. RESULTS The overall response was obtained in 18 (62%) patients, including one patient who was treated with standard IFN. Additionally, a total of 9 (31%) patients cleared HBsAg, with appearance of anti-HBs. The viral load was undetectable in all of these patients. The same IL28B variants associated with IFN response in HCV infections were also more frequently found in HBV patients compared with non-responders. CONCLUSIONS Our study indicates that treatment with IFN is effective in patients with HBV genotype F.
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Affiliation(s)
- Mauricio Venegas
- Section of Gastroenterology, Department of Medicine, University of Chile Clinical Hospital, Santiago, Chile.
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Yang HC, Kao JH. Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance. Emerg Microbes Infect 2014; 3:e64. [PMID: 26038757 PMCID: PMC4185362 DOI: 10.1038/emi.2014.64] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/17/2014] [Accepted: 07/21/2014] [Indexed: 02/06/2023]
Abstract
Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV). Extensive research over the past decades has unveiled the important role of cccDNA in the natural history and antiviral treatment of chronic HBV infection. cccDNA can persist in patients recovering from acute HBV infection for decades. This explains why HBV reactivation occasionally occurs in patients with resolved hepatitis B receiving intensive immunosuppressive agents. In addition, although advances in antiviral treatment dramatically improve the adverse outcomes of chronic hepatitis B (CHB), accumulating evidence demonstrates that current antiviral treatments alone, be they nucleos(t)ide analogs (NAs) or interferon (IFN), fail to cure most CHB patients because of the persistent cccDNA. NA suppresses HBV replication by directly inhibiting viral polymerase, while IFN enhances host immunity against HBV infection. Viral rebound often occurs after discontinuation of antiviral treatment. The loss of cccDNA can be induced by non-cytolytic destruction of cccDNA or immune-mediated killing of infected hepatocytes. It is known that NA has no direct effect on viral transcription or cccDNA stability. Therefore, the long half-life of hepatocytes leads to a very slow decline in cccDNA in patients under antiviral therapy. Novel antiviral agents targeting cccDNA or cccDNA-containing hepatocytes are thus required for curing chronic HBV infection.
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Affiliation(s)
- Hung-Chih Yang
- Department of Microbiology, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China ; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China ; Department of Internal Medicine, National Taiwan University Hospital , Taipei 10002, Taiwan, China
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China ; Department of Internal Medicine, National Taiwan University Hospital , Taipei 10002, Taiwan, China ; Hepatitis Research Center, National Taiwan University Hospital , Taipei 10002, Taiwan, China ; Department of Medical Research, National Taiwan University Hospital , Taipei 10002, Taiwan, China
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Gill US, Kennedy PTF. Chronic hepatitis B virus in young adults: the need for new approaches to management. Expert Rev Anti Infect Ther 2014; 12:1045-53. [PMID: 25052517 DOI: 10.1586/14787210.2014.940899] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
One in four patients infected with hepatitis B virus (HBV) at birth or in early childhood will develop cirrhosis or hepatocellular carcinoma. Historically, guidelines have overlooked treatment in young people, as the immune tolerant disease phase is considered synonymous with chronic infection in the young. Current treatment aims to suppress HBV replication through long-term nucleos(t)ide therapy with little emphasis on virus eradication. To achieve HBsAg loss, it is accepted that effective immune control of virus is required, mimicking that seen in those who resolve acute HBV infection. We have recently challenged the accuracy of a generic immune tolerant state in young people, thus raising a potential role for earlier treatment. Here we report on our immunological analysis of HBV in young people and the role of a dedicated clinic; we make the case for earlier intervention to achieve effective immune control leading to better outcomes.
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Affiliation(s)
- Upkar S Gill
- Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Abstract
INTRODUCTION Hepatitis B virus (HBV) infection is a global health problem. Peginterferon α (PEG-IFN), which includes PEG-IFN α-2a (Pegasys) and PEG-IFN α-2b (Peg-Intron), can be used to treat patients with chronic hepatitis B (CHB) infection. A finite duration of PEG-IFN therapy may lead to long-term viral suppression. Clinically, it is important to identify super-responders and null-responders to PEG-IFN due to its substantial side effects. AREAS COVERED From the literature review, it is known that PEG-IFN is more effective for hepatitis B e antigen (HBeAg)-positive patients who have high pre-treatment alanine aminotransferase level, lower HBV DNA level and genotype A (vs genotype D), as well as those with more favourable viral predictors, such as precore stop codon or basal core promoter mutants infections in Asian patients and wild-type virus in Caucasian patients. For HBeAg-positive patients and HBeAg-negative patients with genotype D infection, PEG-IFN therapy could be terminated early at week 12 or 24 in primary non-responders defined by the Hepatitis B surface antigen stopping rules. With regard to host factors, single nucleotide polymorphisms of IL28B do not seem to affect the treatment outcomes in Asian patients, but its role in Caucasian patients remains disputed. EXPERT OPINION Most of the known predictors need validation by large prospective trials. In addition, we need to identify more baseline predictors for super-responders in order to achieve personalised PEG-IFN treatment for CHB.
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Affiliation(s)
- Tai-Chung Tseng
- Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Division of Gastroenterology, Department of Internal Medicine , Taipei , Taiwan
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